Ovid: Rudolph's Pediatrics

10.3 BIRTH DEFECTS, MALFORMATIONS, AND SYNDROMES

John C. Carey

Michael J. Bamshad

Part of "Chapter 10 - Clinical Genetics and Dysmorphology"

Birth defects are relatively common—about 2% of newborns will have a medically significant malformation recognized during the first day of life. However, approximately one-half of all defects that are present at birth are not diagnosed until later in infancy. Defects that may not be apparent at birth include abnormalities of the central nervous system, cardiovascular system, and sensory systems (eg, hearing, vision) among others. Collectively, it appears that 4% of infants have a medically significant structural anomaly diagnosed by 12 months of age.

Birth defects can be isolated abnormalities or be features of one of the thousands of known genetic syndromes. For example, approximately 75% of children with congenital heart disease have isolated defects, whereas additional birth defects are found in the remaining 25%. The etiology of most birth defects is unknown, although it is estimated that a substantial proportion are caused by mutations in genes that control normal development. Birth defects that arise from an intrinsically abnormal developmental process are called malformations. Birth defects can also result from an alteration of the form, shape, or position of a normally formed body part by mechanical forces and are termed a deformation. For example, oligohydramnios can result in abnormal mechanical constraints on the joint mobility of a fetus leading to the formation of contractures (eg, clubfoot). Birth defects may also be caused by external interference with an originally normal developmental process, known as a disruption. For example, strands of amniotic tissue that become tightly wound around a digit can result in truncation of the digit. An abnormal organization of cells into tissues (eg, a hemangioma) is also sometimes considered a type of birth defect. Of note, malformations and dysplasias are primary disturbances of embryogenesis and histogenesis, respectively. Deformations and disruptions are secondary to a primary extrinsic force.

The presence of a birth defect often evokes an aura of mystery or implies a difference in personhood. Furthermore, terms such as elfin-like face and harelip implicitly reinforce these differences. Yet families who experience the birth of a newborn with a birth defect wrestle with the same questions about cause, responsibility, and outcome as any other family of a child with a serious pediatric disease. Approaching the diagnosis and management of an infant or a child with a birth defect can also be overwhelming in that thousands of different conditions are associated with birth defects, and strategies to diagnose and treat these conditions change rapidly. Despite these challenges, a logical and systematic approach to the evaluation of children with birth defects and the collection of phenotypic data are important for both diagnostic and therapeutic reasons.

The recognition of a well-characterized disorder, even if the etiology is unknown, provides: (1) information on the pattern of inheritance and recurrence risk, (2) the framework and options for the management of future pregnancies, and (3) information that can be used to make general predictions about future manifestations and outcomes, including guidelines for routine care and suggestions for educational interventions, especially when a specific behavioral profile has been associated with a condition (eg, Williams syndrome). A specific diagnosis also eliminates the motivation to perform unnecessary testing and enables the use of appropriate screening tools for anticipated problems. For many families, explaining the diagnosis, natural history, and strategy for health care maintenance and anticipatory guidance helps with coping with the uncertainty that typically surrounds genetic disorders.

CLASSIFICATION OF BIRTH DEFECTS

Because our knowledge of the pathogenetic basis of birth defects is limited, all classification schemes of birth defects and malformations are somewhat arbitrary. Most medical textbooks classify birth defects according to the organ system or body part that is affected (eg, cardiovascular system, limbs). Such classifications can help develop intervention strategies (eg, for surgical palliation) and identification of the general causes of these defects. However, the utility of anatomical classifications becomes limited once specific information on the etiology, natural history, and recurrence is required.

Birth defects can also be classified depending on whether they occur as isolated findings or as a component of multiple congenital anomalies. This particular distinction is probably the most valuable in the evaluation of any infant and child with a birth defect. Compared to children with isolated birth defects, children with multiple birth defects have greater morbidity and mortality and are more likely to have a chromosomal abnormality and/or syndrome diagnosis. Birth defects can also be classified by etiologic categories such as chromosome, single gene, multifactorial, and teratogenic.

Categorization of defects by the developmental process that is perturbed is useful for generating hypotheses about causative pathogenetic mechanisms, although many birth defects can result from the perturbation of more than one pathway, making it difficult to identify the primary disturbance. Although no specific classification is appropriate for all cases, birth defects will be presented according to the developmental process that is disturbed to facilitate understanding of pathogenesis and provide a background for understanding future observations. Accordingly, a brief review of the genetic controls of development, and the cardinal processes that, when disturbed, cause birth defects is provided.

10.3.1 Basic Concepts of Development

Michael J. Bamshad

Development is the process by which a fertilized ovum becomes a mature organism capable of reproduction. Thus, a single fertilized egg divides and grows to form different cell types, tissues, and organs, all of which are arranged in a species-specific body plan (ie, the arrangement and patterning of body segments). Many of the instructions necessary for normal development are encoded by genes that are identical in each cell of an organism. The mechanisms by which identical genetic constitutions create a complex adult organism comprised of many different cells and tissues and the determinants of the fate of each cell, that is, what governs a cell, for example, to become a heart cell or a brain cell, are critical processes. Understanding the pathogenesis of human malformation and genetic syndromes is rooted in developmental biological principles.

Evolution of species requires that development of individual organisms be replicated with high fidelity. Otherwise, it might be difficult to recognize that a group of organisms share similar properties

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that define a species. In sexually reproducing species, the necessary tools and instructions for building an organism that closely resembles its parents are located in the fertilized ovum (zygote). Most of this information is transmitted from parent to offspring via genes that encode signaling molecules and their receptors, DNA transcription factors, components of the extracellular matrix, enzymes, transport systems, and many other proteins. Each of these genetic mediators is expressed in combinations of spatially and temporally overlapping patterns that are used repeatedly to control different developmental processes. Mutations in the genes mediating development are a common cause of human birth defects.

Interactions between neighboring cells are often controlled by proteins that can diffuse across small distances to induce a response and are termed paracrine factors because they are secreted into the space surrounding a cell, unlike hormones that are secreted into the bloodstream. Major paracrine-signaling molecules include the: (1) fibroblast growth factor (FGF) family; (2) hedgehog family; (3) wingless (Wnt) family; and (4) transforming growth factor β (TGF-β) family. Mutations in genes encoding these molecules may lead to abnormal communication between cells.

Many different mechanisms regulate the expression of a gene. (see Sec. 8.1). Genes encoding proteins that function to activate or repress other genes are called transcription factors. Transcription factors commonly do not activate/repress only a single target, but regulate the transcription of many genes that, in turn, regulate other genes in a cascading effect.

Extracellular matrix proteins (EMPs) are secreted macromolecules that serve as scaffolding for all tissues and organs. These molecules include collagens, fibrillins, proteoglycans, and large glycoproteins such as fibronectin, laminin, and tenascin. EMPs are not simply passive structural elements. To facilitate cell migration, EMPs must transiently adhere to a cell's surface, which is accomplished by two families of receptors, integrins and glycosyltransferases. Integrins integrate the extracellular matrix and the cytoskeleton, allowing them to function in tandem.

PATTERN DETERMINATION

The process by which ordered spatial arrangements of differentiated cells create tissues and organs is called pattern formation. The general pattern of the animal body plan is laid down during embryogenesis, which leads to the formation of semiautonomous regions of the embryo in which the process of pattern formation is repeated to form organs and appendages. Such regional specification takes place in several steps: (1) definition of the cells of a region, (2) establishment of signaling centers that provide positional information, and (3) differentiation of cells within a region in response to additional cues.

For pattern formation to occur, cells and tissues communicate with each other through many different signaling pathways. These pathways are used repeatedly and integrated with one another to control specific cell fates. For example, patterning of the vertebrate neural tube, somites, and limbs, as well as the way the left is distinguished from right, employs the secreted protein, sonic hedgehog (Shh). In mouse, lack of Shh activity produces a loss of ventral midline development within the central nervous system. In humans, point mutations in SHH, the human homologue of Shh, cause abnormal midline brain development (eg, holoprosencephaly), severe mental retardation, and early death. However, not all affected individuals have holoprosencephaly; some have only minor birth defects such as a single upper central incisor. Interestingly, attachment of Shh to the lipophilic moiety, cholesterol, appears to be necessary for the proper spatial patterning of hedgehog signaling, which may partly explain how certain human teratogens that inhibit cholesterol biosynthesis as well as disorders of cholesterol metabolism (eg, Smith-Lemli-Opitz syndrome) cause midline brain defects.

Gastrulation

Gastrulation is the process whereby the cells of the blastula are given new positions and neighbors. In the human embryo, gastrulation occurs between days 14 and 28 of gestation. In this process, the embryonic bilaminar disk is transformed into a trilaminar embryo composed of three germ layers: outer ectoderm, inner endoderm, and the interstitial mesoderm. The formation of these layers is a prerequisite for organogenesis. The major structural feature of mammalian gastrulation is the primitive streak, which appears as a thickening of epiblast extending along the anterior to posterior axis.

Neurulation and Ectoderm

Once a trilaminar embryo is formed, the dorsal mesoderm and the overlying ectoderm interact to form the hollow neural tube. This event is called neurulation and is mediated by a process called induction, which occurs when the cells of one embryonic region influence the organization and differentiation of cells in a second embryonic region. Induction of the neural tube and transformation of the flanking mesoderm into an amphibian embryo with clear anterior/posterior and dorsal/ventral axes is controlled by a group of cells known as the Spemann-Mangold organizer.

Neurulation is a critical event in development that initiates organogenesis and divides the ectoderm into three different cell populations: (1) the neural tube, which will eventually form the brain and spinal cord, (2) the epidermis of the skin, and (3) the neural crest cells. In humans, neural tube closure begins at five separate sites that correspond to the locations of common neural tube defects such as anencephaly (absence of the brain), occipital encephalocele, and lumbar myelomeningocele. Neural crest cells migrate from the neuroepithelium along defined routes to tissues where differentiation into a variety of cell types such as sensory neurons, melanocytes, neurons of the small bowel, and smooth muscle occurs.

Mesoderm and Endoderm

The formation of a layer of mesoderm between the endoderm and ectoderm is one of the major events in gastrulation. Mesoderm can be divided into five components: the notochord; dorsal, intermediate, lateral, mesoderms; and head mesenchyme. The notochord is a transient structure that induces the formation of the neural tube and body axis. Dorsal (paraxial) mesoderm is observed on either side of the notochord and differentiates into sclerotomes, myotomes, and dermatomes that form the axial skeleton, appendicular skeleton and skeletal muscles, and connective tissue of the skin, respectively. Intermediate mesoderm forms the kidneys and genitourinary system. Lateral plate mesoderm differentiates into heart, connective tissue of viscera, and the connective tissue elements of the amnion and chorion. Finally, the muscles of the eyes and head arise from head mesenchyme.

The primary function of embryonic endoderm is to form the linings of the digestive tract and the respiratory tree. Outgrowths of the intestinal tract form the pancreas, gallbladder, and liver. A bifurcation of the respiratory tree produces the left and right lungs. The endoderm also produces the pharyngeal pouches that, in conjunction with cells derived from the neural crest, give rise to endodermal-lined

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structures such as the middle ear, thymus, parathyroids, and thyroids.

Axis Specification

Animal body plans have evolved into a wide variety of symmetries. Specification and formation of the axes are critical events in development that determine the orientation of the body plan. The proteins mediating these processes are rapidly being discovered. Many of these mediators have additional roles in patterning of the body plan and tissues.

Formation of the Anterior/Posterior Axis

The anterior/posterior axis of a developing mammalian embryo is defined by the primitive streak. At the anterior end of the primitive streak is a structure called the node, which is homologous to the Hensen node in birds and contains many of the same proteins found in the amphibian organizer. Patterning of the anterior/posterior axis is controlled by the HOX genes that encode transcription factors containing a DNA-binding domain of about 60 amino acids called the homeodomain. In Drosophila these genes compose the homeotic gene complex (HOM-C), which has two classes of genes, Antennapedia and Bithorax.

HOX genes are expressed along the dorsal axis from the anterior boundary of the hindbrain to the tail. Within each cluster, 3′ HOX genes are expressed earlier than 5′ HOX genes, termed temporal collinearity. Furthermore, the boundaries of expression of 3′ HOX genes extend more anteriorly than those of 5′ HOX genes, referred to as spatial collinearity. Thus, Hoxa-1 expression occurs earlier and more anteriorly than the expression of Hoxa-2. These overlapping domains of HOX gene expression produce combinatorial codes that specify the positional commitment of cells and tissues. Collectively these codes identify various regions along the anterior/posterior axis of the trunk and limbs.

Formation of the Dorsal/Ventral Axis

Dorsal/ventral patterning of the vertebrate depends on the interaction between dorsalizing and ventralizing signals, which are mediated, in part, by molecules that act in a concentration-dependent fashion. Molecules that can promote multiple positive responses from a field of undifferentiated cells as a function of concentration are called a morphogens. The function of morphogens can be attenuated or inhibited by antagonists, which bind and inactivate them.

FORMATION OF ORGANS AND APPENDAGES

Subsequent to vertebrate axis determination and gastrulation is the formation of organs and limbs, called organogenesis. Many of the proteins used for patterning and growth of organs and limbs are the same molecules used earlier in blastogenesis. However, additional genes that were transcriptionally silent now become active and encode proteins that may act as switches for organ formation or receptors for recognizing patterning information or participate in the expected function of terminally differentiated cells. To date, most of the developmental genes known to cause human birth defects have prominent roles in this period of development. Mutations in genes that disrupt earlier developmental events may be lethal.

Craniofacial Development

Development of the craniofacial region is directly related to the formation of the underlying central nervous system. In mammalian embryos, neural crest cells from the forebrain and midbrain become the nasal processes, palate, and mesenchyme of the first pharyngeal pouch. This mesenchyme forms the maxilla, mandible, incus, and malleus. The neural crest cells of the anterior hindbrain migrate and differentiate to become the mesenchyme of the second pharyngeal pouch and the stapes and facial cartilage. Cervical neural crest cells produce the mesenchyme of the third, fourth, and sixth pharyngeal arches (in humans the sixth pharyngeal arch degenerates), which become the muscles and bones of the neck. The bones of the skull develop directly from mesenchyme produced by neural crest cells via a process called intramembranous ossification. Complete fusion of these bones usually does not occur until adulthood. Premature fusion (synostosis) of the skull bones (craniosynostosis) causes the head to be misshapen and can impair brain growth (see Sec. 10.3.4).

Development of the Limb

The developing tetrapod limb is one of the best understood classical models of morphogenesis. Many of the signaling pathways and transcriptional control elements that coordinate limb development in model organisms such as Drosophila and chick appear to be conserved in mammals, including humans.

The vertebrate limb is composed of elements derived from lateral plate mesoderm (bone, cartilage, and tendons) and somitic mesoderm (muscle, nerve, and vasculature). The signal that initiates induction of forelimbs and hindlimbs appears to arise in the intermediate mesoderm. Once initiated, proximal/distal growth of the limb bud is dependent on a region of ectoderm called the apical ectodermal ridge (AER), which extends from anterior to posterior along the dorsal/ventral boundary of the limb bud.

Mediation of proximal/distal growth by the AER is controlled, in part, by fibroblast growth factors (FGF2, FGF4, and FGF8) that stimulate proliferation of an underlying population of mesodermal cells in the so-called progress zone (PZ). However, maintenance of the AER depends on a signal from a region in the posterior mesoderm of the limb bud known as the zone of polarizing activity (ZPA). The signaling molecule of the ZPA is sonic hedgehog (Shh), which is also responsible for dorsal/ventral patterning of the central nervous system and establishment of the embryonic left/right axis. The ZPA also specifies positional information along the anterior/posterior of the limb bud.

Defects of the anterior and posterior elements of the upper limb occur in the Holt-Oram syndrome (HOS) and ulnar-mammary syndrome (UMS), respectively. HOS is caused by mutations in the gene TBX5, whereas UMS is caused by mutations in the tightly linked gene TBX3. TBX3 and TBX5 are members of a highly conserved family of DNA transcription factors containing a DNA-binding domain called a T-box.

Organ Formation

Many processes must be coordinated simultaneously to construct a specific arrangement of cells and tissues that manifests the properties of an organ. Similar to limb development, formation of parenchymal organs is notable for the reciprocal induction of the epithelium on the mesenchyme and vice versa. This interaction is mediated by secreted signaling molecules that bind to receptors, transduce the signal through various interconnected pathways, and stimulate or repress DNA transcription. Use of the same elaborate networks to form different organs allows for genomic economy while maintaining developmental flexibility.

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Once a specialized cell within an organ is terminally differentiated, various proteins turn on its molecular machinery so that it may perform its fated function. Often development of the organ and function of the differentiated cell are interrelated. Epithelial-mesenchymal interactions are prominent in the development of cutaneous structures (eg, hair, sweat glands, breasts), parenchymal organs (eg, liver, pancreas), lungs, thyroid, kidneys, and teeth. These interactions are dynamic such that expression patterns in the epithelia and mesenchyme change over time.

One of the largest organs in the body is the skeleton. In contrast to the development of cranial bones by intramembranous ossification, most skeletal bone formation takes place using a cartilaginous template called endochondral ossification. However, both intramembranous and endochondral ossification are regulated by bone-forming cells called osteoblasts. The differentiation of osteoblasts is regulated by an osteoblast-specific transcription factor called Cfba1. Targeted disruption of Cfba1 results in mice with a complete lack of ossification of the skeleton. Heterozygous mice have widened cranial sutures, shortened digits, and abnormalities of the shoulder girdle. Similar defects are found in individuals with cleidocranial dysplasia, which is caused by mutations in CFBA1, the human homologue of Cfba1.

References

Epstein CJ: The new dysmorphology: application of insights from basic developmental biology to the understanding of human birth defects. Proc Natl Acad Sci U S A 92:8566–8573, 1995

Gilbert SF: Developmental Biology. Sunderland, Sinauer Press, 1999

10.3.2 Approach to the Child with Birth Defects

John C. Carey

Michael J. Bamshad

In the mid-1960s, David W. Smith coined the term dysmorphology to describe the field of medicine devoted to the study of abnormal human development. His intent was to propose a term that both replaced teratology (whose literal meaning and reference to monsters was pejorative) and captured the essence of the discipline. The ability to recognize and interpret minor and major anomalies is an important skill that is required for evaluating a child with a birth defect.

A syndrome is a pattern of birth defects that are etiologically related and regularly recur in different individuals (eg, Down syndrome). In other areas of medicine, the word syndrome often refers to a specific set of symptoms that are not necessarily etiologically related (eg, nephrotic syndrome).

A sequence is a primary defect with a secondary cascade of structural changes. Birth defects that represent a sequence are usually localized to a single body area. Whereas a sequence can often be misinterpreted as a group of malformations, more critical inspection reveals a single malformation and a subsequent disruption or deformation. For example, the Pierre Robin sequence is caused by a primary abnormality in mandibular development that produces disruption of palatal closure and secondary obstruction of the airway by the tongue. A sequence can occur in isolation or be a component of an underlying syndrome diagnosis. For example, about 20% of children with Pierre Robin sequence have a disorder of connective tissue called Stickler syndrome (characterized by joint hyperextensibility and myopia).

An association is two or more primary defects that occur in the same individuals more often than is expected by chance: Defining a group of defects as an association suggests that the anomalies are etiologically related to each other, yet the nature and mechanism of that relationship remains unclear. For example, children with defects of the vertebrae, anus, trachea and esophagus, radius, and kidneys (renal) are often labeled with the acronym VATER association. Associations tend to be etiologically heterogenous more often than syndromes, and fewer characteristics of an association are observed in each affected child.

CLINICAL PRACTICE

The approach to a child with birth defects is multifaceted and includes the collection of phenotypic data, determination of the immediate and long-term issues of care, and the provision of the family with psychological support (Fig. 10-14).

FIGURE 10-14 The approach to the management of the child with congenital anomalies. Note the diagnostic pathway and the psychosocial path are in parallel. The step involving the categorization of the problem may lead to one of the other diagnostic algorithms.

Phenotypic data that should be collected include detailed obstetrical, medical, and family histories, a comprehensive physical examination, and ancillary laboratory, physiological, or imaging studies. The gestational and birth history needs to include exposures to over-the-counter and prescription medications as well as illicit drugs, frequency and vigor of fetal movements, intrauterine positioning, quantity and quality of amniotic fluid, maternal medical history, and the results of all prenatal testing. Documentation of at least a three-generation pedigeree is also recommended. The pedigree should include information about the occurrence of sudden deaths, unexpected deaths, or early deaths (ie, deaths at less than 55 years of age); individuals with developmental disabilities, unusual behavioral profiles, and/or mental retardation; individuals with birth defects; degree of relatedness of parents (ie, level of consanguinity); and the ethnic background of the family. Examination of photographs of the parents taken when they were children, of siblings, and of extended family members is especially useful when attempting to determine whether a particular physical characteristic is a diagnostic clue, part of the phenotypic background of the family, or both (ie, when a parent or relative is unknowingly affected as well).

Differentiating between “normal” and “abnormal” physical findings represents the cornerstone of phenotype analysis. Many of the physical findings that are considered abnormal and clues to syndromes are found on the head and/or limbs.

For the cranium and face, the various relationships among the many individual components (hair, ears, forehead, nose, eyes, midface, philtral folds, lips, mouth, jaw, neck, and ears) should form a gestalt (ie, a subjective impression of the overall pattern of relationships). Does a particular feature (eg, a hemangioma or region of marked asymmetric growth) make the face look different from what might be anticipated? Are there several features that when juxtaposed with one another make a face look particularly distinguishable? If a physical feature differs from what one considers “normal,” consider the mechanism that might have produced this impression. For example, if the ear of an infant appears set too low on the side of the head, is it because the ear is small, posteriorly rotated, or that the superior helix is overfolded? Each of these possibilities can produce the illusion that an ear is set too low. Alternatively, an ear with a normal size and structure but placed at the angle of the mandible indicates that the ear is genuinely set too low.

Each physical feature of the face (or hands or chest, etc.) can be classified as to whether the variation is a minor anomaly or mild malformation. Minor anomalies include both qualitative characteristics

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(eg, size of the nasal tip) that can be challenging to judge as normal versus abnormal as well as features that lend themselves to rapid quantitative measurement (eg, distance between the inner canthal folds). Measurement of many of the quantitative features can be compared to normative data collected from selected groups of individuals considered normal. Each physical characteristic must be considered in the context of the general morphology of the family, their ethnic group, and their continent of origin. Many of the physical findings that are used to distinguish among persons of Asian or African descent are quantitative traits that may differ substantially between groups, alone or in combination. For example, short palpebral fissures are a consistent finding in children with fetal alcohol syndrome. However, wide variation exists in the length of the palpebral fissures among individuals of European, Asian, and/or American-Indian ancestry, which makes the interpretation of the importance of short palpebral fissures challenging. Minor malformations are structural changes of a mild degree that have no intrinsic medical significance (unlike major malformations). Examples include auricular tags and posterior polydactyly.

The measurement of a body part or the relationships between parts is an important component of accurate diagnosis. For example, the length of the ear can be a valuable clue when evaluating a child for fragile X syndrome (characterized by a long ear) or trisomy 21 (characterized by a short ear). Apparently wide-spaced eyes can relate to the presence of epicanthal folds, telecanthus (soft-tissue displacement of the inner canthi), short palpebral fissures, or true ocular hypertelorism. Distinction among these possibilities requires astute observation, knowledge of normal facial structure relationships/proportions, and measurements of the inner canthal/interpupillary and outer canthal distances. These distinctions are crucial, because different syndromes are characterized by different abnormalities of eye placement.

Examination of the limbs should be conducted similarly, and the general relationships among the parts of the hand (eg, length of digits, spacing between digits) should be assessed and subsequently each part should be examined individually. The thumb is a particularly complex body part that requires skill in differentiating between normal variations and abnormal findings. Alterations of the thumb include low-set thumbs (usually hypoplastic with an underdeveloped thenar eminence), tapered thumbs, bifid thumbs, and triphalangeal thumbs (three phalanges instead of two). Examination of the flexion creases on the digits including the thumbs is also a valuable observation because these creases develop between 8 and 10 weeks of embryogenesis, and perturbations of the flexion creases (eg, hypoplasia, absence) reflect an abnormality of fetal movement in the first trimester of gestation. For example, children with multiple congenital contractures caused by a reduced quantity of amniotic fluid in the third trimester may have normal flexion creases, whereas an infant with amyoplasia (a form of arthrogryposis) may have complete absence of the flexion creases.

The recognition of minor and major anomalies helps to determine whether a child may have a multiple congenital anomaly syndrome and, if so, how to proceed toward confirmation of a specific diagnosis. Comparing physical findings in members of a child's extended family may indicate that a child who apparently has multiple anomalies simply has an abnormal appearance related to combined

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effects of the parents' unusual but normal physical characteristics. This underscores the point that overinterpretation of multiple minor anomalies in a child is troublesome. Although 10% of newborns have two or more minor anomalies, the overwhelming majority of these otherwise normal appearing infants do not have a specific syndrome and are unlikely to experience further physical and/or developmental problems.

Minor anomalies often provide useful clues as to whether a more severe defect of a body part or organ may be present. Many purported associations have been overstated in the past and probably have little significance (eg, the purported association of accessory nipples and renal defects). However, some minor anomalies are clearly markers for more important underlying defects. For example, the presence of a deep sacral dimple, commonly with an overlying patch of hair or a hemangioma, should prompt further investigation for spinal dysraphism. Pits in the skin or tags of skin near the external ear should bring to mind specific syndrome diagnoses (eg, branchial-otorenal syndrome) and are associated with an increased risk of hearing loss.

The most pivotal step in the diagnostic algorithm of a child with multiple congenital anomalies is categorizing the pattern of findings into a unifying etiologic mechanism (whether or not characteristic of a known syndrome) (Fig. 10-14 and Fig. 10-15). Concluding that a child's phenotypic findings probably fit a recognizable pattern in contrast to representing an isolated defect is critical (Fig. 10-15). A child with an isolated finding (eg, isolated cleft lip) may require no further diagnostic evaluation. In contrast, a child with a pattern of phenotypic findings consistent with a unifying etiologic mechanism may need substantially more testing to reach a diagnosis. For example, a karyotype is virtually always indicated in children with a recognizable but undiagnosed pattern of congenital defects. A skeletal survey may help resolve the diagnosis in a child with a limb abnormality or who is suspected of having a skeletal dysplasia.

FIGURE 10-15 The diagnostic process for evaluating an infant with malformations, single or multiple. A karyotype is indicated in the child with multiple major anomalies or the child with a single major anomaly and multiple minor anomalies.

Most children who are being evaluated for multiple congenital anomalies do not need to be tested for an inborn error of metabolism (see Chap. 8 and Chap. 9). For example, children who have disorders of amino acid metabolism do not present typically with birth defects. However, some conditions with inborn errors of metabolism do present with malformations and/or dysplasias (see Sec. 9.1.7 and Table 9-10). To complicate matters further, some very well-known multiple congenital anomaly syndromes have turned out to be caused by defects of metabolism. For example, Smith-Lemli-Opitz (SLO) syndrome, characterized by multiple malformations and variable cognitive abnormalities, has recently been shown to be a defect of cholesterol biosynthesis caused by mutations in the gene 7-dehydrocholesterol reductase.

If trisomy 21 is excluded, at least 50% of the remaining newborns with multiple congenital anomalies will not have a specific diagnosis. Because of improvements in our understanding of the breadth and evolution of phenotypes as well as advances in diagnostic testing, periodic reevaluation of this group of children will occasionally lead to identification of a diagnosis. Nevertheless, children without a specific diagnosis are frequently labeled with a provisionally unique pattern of anomalies, and their care should be determined via a prudent but flexible strategy of empirical management. Predictions about the outcome of a specific defect should be shared with the family. Genetic counseling about the recurrence risk can be based on empirical estimates. Depending on the organ system involved, an appropriate specialist may facilitate the management of a child with multiple congenital anomalies. Providing adequate psychosocial support for a family is crucial while they are both adapting to the reality that they have child with a birth defect, a child that may have special needs, and realizing that they may be

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at a high risk for having another child with similar problems (Fig. 10-14). Appropriate and effective delivery of this information is important, and long-term relationships with the family are critical (see Table 10-7 and Table 10-8).

References

Hall JG, Froster-Iskenius UG, Allanson JE: Handbook of Normal Physical Measurements. New York, Oxford University Press, 1989

McKusick VM. Mendelian Inheritance In Man, 12th ed., Baltimore, Johns Hopkins University Press, 1998

POSSUM/OSSUM Database c/o Murdoch Institute, Royal Columbian Hospital, Flemington Rd., Parkville, Victoria, Australia 3052

10.3.3 Syndromes of Multiple Congenital Anomalies/Dysplasia

John C. Carey

Rather than memorize the essential findings for all or even most of the multiple congenital anomaly syndromes, it is far more useful to develop a strategy for syndrome recognition that is both logical and practical, yet flexible enough to generalize among genetic conditions. Part of this strategy requires availability of information about genetic disorders that is accurate, succinct, and complete. Many specific textbooks and online databases provide this information (see references for Sec. 10.3.2), and these resources increasingly are becoming available to the families of children with genetic conditions. Consequently, parents are frequently very knowledgeable about a diagnosis before their health care provider has had the opportunity to discuss it with them. Nevertheless, many of the concepts that are required to fully understand the implications of a diagnosis are difficult to grasp. Consequently, primary care physicians must be able to explain the principles of human genetics to the families of children with varied conditions.

It is beyond the scope of this section to provide a comprehensive description of the hundreds of relatively common genetic conditions or thousands of rare genetic disorders. Thus, Table 10-10 summarizes some of the multiple congenital anomaly/dysplasia syndromes.

10.3.4 Craniofacial Disorders

Michael L. Cunningham

Malformations of the face and skull represent a large portion of structural malformations in humans and can have significant morbidity, often requiring surgical management in the first few months of life. Many children with craniofacial disorders are managed in multidisciplinary teams including pediatricians, geneticists, plastic and reconstructive surgeons, maxillofacial surgeons, orthodontists, otolaryngologists, audiologists, speech pathologists, neurosurgeons, social workers, nutritionists, and nurse specialists. This section describes the major types of craniofacial malformations, their classification, and suggested management (Table 10-11).

TABLE 10-11 MALFORMATIONS AND SYNDROMES INVOLVING CRANIOFACIAL STRUCTURES


SYNDROME NAME	CLINICAL PHENOTYPE	INHERITANCE	OMIM#	GENE	LOCUS

Syndromes associated with cleft lip and/or palate
Velocardiofacial syndrome	Pierre Robin sequence, cleft palate, small open mouth, myopathic facies, retrognathia, prominent nose with squared-off nasal tip, hypoplastic nasal alae, learning disability, behavioral/psychiatric disorders, short stature, slender tapering digits (overlapping features with DiGeorge syndrome)	AD	192430	Microdeletion of chromosomal region containing multiple genes	22q11.2
Robin sequence	Micrognathia, cleft palate, glossoptosis, airway obstruction, feeding difficulties	Sporadic, associated with several syndromes with recessive and X-linked forms suggested	261800
Stickler syndrome, type I; type II	Cleft palate, micrognathia, glossoptosis, severe myopia, risk of retinal detachment, midfacial hypoplasia, hearing impairment, arthropathy, pectus, short fourth, fifth metacarpals	AD	180300; 184840	Collagen, type XI, alpha-2 chain (COL11A2)	6p21.3
Van der Woude syndrome	Cleft lip and/or palate, lower lip pits/cysts, ankyloglossia	AD	119300		1q32
Smith-Lemli-Opitz syndrome(see Chap. 9)	Cleft palate, micrognathia, short nose, ptosis, high square forehead, microcephaly, hypospadias, cryptorchidism, VSD, TOF, hypotonia, mental retardation, postaxial polydactyly, 2-3 syndactyly of feet, defect in cholesterol biosynthesis	AR	270400	delta-7-reductase (DHCR7)	11q12-11q13
Ectrodactyly ectodermal dysplasia and clefting syndrome (EEC1; EEC2)	Cleft lip and/or palate, split-hand/split-foot, ectodermal dysplasia (sparse hair, dysplastic nails, hypohydrosis, anodontia), GU anomalies	AD	129900; p63 602077		3q27; 7q11.2-q21.3
Ankyloblepharon ectodermal dysplasia and clefting syndrome (AEC)	Cleft lip and palate, intraoral alveolar bands, maxillary hypoplasia, filiform eyelid fusion (ankyloblepharon), ectodermal dysplasia (sparse hair, dysplastic nails, hypohydrosis, anodontia)	AD	106260	p63	3q27
Kabuki syndrome (Niiakawn-Kuroki)	Cleft palate, arched eyebrow with sparse lateral hair, long palpebral fissures, eversion of lateral third of lower eyelid, brachydactyly, short fifth metacarpal, congenital heart defects, postnatal growth deficiency/dwarfism, mental retardation	Sporadic ?AD	147920
Oral-facial-digital syndrome	Paramedian cleft of upper lip, asymmetric cleft palate, accessory oral frena, lobulate tongue with hamartomas, broad nasal root, small nostrils, syndactyly, brachydactyly, postaxial polydactyly, polycystic renal disease, agenesis of the corpus callosum, X-linked dominant lethal in males	X-linked	311200		Xp22.3-p22.2
Pallister-Hall syndrome	Cleft palate, flat nasal bridge, short nose, multiple buccal frenula, microglossia, micrognathia, malformed ears, hypothalamic hamartoblastoma, hypopituitarism, postaxial polydactyly with short arms, imperforate anus, GU anomalies, IUGR	AD	146510	GLI-Kruppel family member 3 oncogene (GL13)	7p13
Early amnion rupture sequence	Cleft lip and palate, oblique facial clefts, focal areas of scalp aplasia, constriction bands with terminal limb amputations and syndactylies, occasional anencephaly, encephalocele, and ectopia cordis	Sporadic	217100
Syndromes associated with branchial arch derivative anomalies
Hemifacial microsomia (craniofacial microsomia, oculo-auriculo-vertebral spectrum)	Unilateral or bilateral microtia/anotia/atresia, preauricular tags, conductive hearing loss, microphthalmia, mandibular hypoplasia, maxillary hypoplasia, macrostomia, vertebral anomalies (hemivertebra and fusions), structural renal malformations/agenesis	Sporadic	164210
Goldenhar syndrome	Unilateral or bilateral microtia/anotia/atresia, preauricular tags, facial tags, conductive hearing loss, epibulbar lipodermoids, microphthalmia, mandibular hypoplasia, maxillary hypoplasia, macrostomia, cervical vertebral anomalies (hemivertebra and fusions), congenital heart disease	Sporadic, ?AD	164210
Branchiootorenal syndrome (BOR syndrome)	Branchial cleft fistulas, prearuicular pits, cochlear and stapes malformation, mixed sensory and conductive hearing loss, renal dysplasia/aplasia	AD	113650	Eyes absent-1 gene (EYA1)	8q13.3
Treacher Collins mandibulofacial dysostosis	Cleft palate, malar hypoplasia, micrognathia with prominent antigonial notch, down-slanting palpebral fissures, lower eyelid coloboma (missing medial lower lid lashes), microtia/atresia, conductive hearing loss	AD	154500	Treacle (TCOF1)	5q32-q33.1
Nager syndrome (preaxial acrofacial dysostosis)	Cleft palate, malar hypoplasia, down-slanting palpebral fissures, lower eyelid coloboma (missing medial lower lid lashes), mandibular hypoplasia, microtia/atresia, conductive hearing loss, radial ray hypoplasia, hypoplastic/absent thumbs, paternal age effect (dominant and recessive inheritance suggested)	AD/AR	154400		9q32
Miller syndrome (postaxial acrofacial dysostosis)	Cleft palate (occasional cleft lip), malar hypoplasia, down-slanting palpebral fissures, lower eyelid coloboma (missing medial lower lid lashes), mandibular hypoplasia, microtia/atresia, conductive hearing loss, postaxial limb deficiency, absent fifth digital rays, short forearms, gastric and midgut volvulus	AR	263750
Syndromes associated with craniosynostosis
Crouzon syndrome	Craniosynostosis (coronal>lambdoid>sagittal), proptosis, hypertelorism, strabismus, maxillary hypoplasia	AD	123500	Fibroblast growth factor receptor-2 (FGFR2)	10q26
Saethre-Chotzen syndrome	Coronal craniosynostosis (unilateral or bilateral), acrocephaly, brachycephaly, hypertelorism, strabismus, maxillary hypoplasia, ptosis, small ears, cutaneous 2-3 syndactyly of hands (variable)	AD	101400	Twist (TWIST)	7p21
Muenke syndrome	Unilateral coronal>bicoronal craniosynostosis, occasionally with limb anomalies similar to Jackson-Weiss syndrome (OMIM#123150), also known as nonsyndromic craniosynostosis: overlap with the Saethre-Chotzen (OMIM#101400) phenotype has been suggested	AD	602849	Fibroblast growth factor receptor-3 (FGFR3)	4p16.7
Apert syndrome	Craniosynostosis (coronal>lambdoid>sagittal), brachycephaly, acrocephaly, hypertelorism, proptosis, strabismus, maxillary hypoplasia, narrow palate (cathedral ceiling palate), invariable syndactyly (cutaneous and boney), “single nails”	AD	101200	Fibroblast growth factor receptor-2 (FGFR2)	10q26
Pfeiffer syndrome	Craniosynostosis (coronal>sagittal>lambdoid), acrocephaly, hypertelorism, proptosis, maxillary hypoplasia, broad first digits with radial deviation	AD	101600	Fibroblast growth factor receptor-1, 2 (FGFR1, FGFR2)	8p11.2-p11.1; 10q26
Jackson-Weiss syndrome	Craniosynostosis (usually coronal), midfacial hypoplasia, enlarged great toes, 2-3 syndactyly, tarsonavicular and calcaneonavicular fusions in the feet, widely variable expression (eg, foot anomalies without synostosis)	AD	123150	Fibroblast growth factor receptor-2 (FGFR2)	10q26
Crouzon syndrome with acanthosis nigricans	Coronal craniosynostosis with craniofacial appearance of Crouzon syndrome (OMIM#123500) associated with acanthosis nigricans	AD	134934.001	Fibroblast growth factor receptor-3 (FGFR3)	4p16.6
Craniosynostosis, type 2 (Boston-type craniosynostosis)	Coronal craniosynostosis, forehead retrusion, frontal bossing, turribrachycephaly, occasional Kleeblattschaedel deformity (cloverleaf skull), short first metatarsals	AD	123101	Msh homeobox homolog 2 (MSX2)	5q34-q35
Carpenter syndrome (acrocephalopolysyndactyly type II)	Craniosynostosis (coronal>lambdoid>sagittal), hypertelorism, proptosis, acrocephaly, preaxial polysyndactyly, mental retardation, only well described recessive craniosynostosis syndrome	AR	201000
Kleeblattschadel (cloverleaf skull deformity)	Cloverleaf skull (trilobar) coronal, lambdoid, sagittal, and metopic craniosynostosis, proptosis to exophthalmos, hydrocephalus, presumed dominant—all cases to date sporadic, can be seen as part of thanatophoric dysplasia (OMIM#187600) and most forms of syndromic craniosynostosis, a descriptive term for head shape in these cases of severe craniosynostosis	AD	148800
Antley-Bixler syndrome	Coronal and lambdoid craniosynostosis, brachycephaly, proptosis, choanal stenosis/atresia, maxillary hypoplasia, humeroradial synostosis, camptodactyly, multiple contractures	AR	207410
Syndromes associated with calvarial size/shape anomalies
Holoprosencephaly 3 (HPE3)	Microcephaly, ocular hypotelorism to cyclopia, single central incisor, proboscis, midface hypoplasia, brain anomalies range from holoprosencephalon to a structurally normal brain, mental retardation to lethality	AD	142945	Sonic hedgehog	7q36, several other loci identified for this phenotype
Cleidocranial dysostosis	Brachycephaly, frontal and parietal bossing, wormian bones, persistent open anterior fontanelle, maxillary hypoplasia, delayed eruption of deciduous and permanent teeth, supernumerary and fused teeth, hypoplastic to absent clavicles, brachydactyly, joint laxity	AD	119600	Core-binding factor, runt domain, α subunit 1 (CBFA1)	6p21
Neurofibromatosis, type I	Macrocephaly, neurofibroma, plexiform neurofibroma (occasionally intraorbital), dysplasia of the sphenoid bone, hypertelorism, other malignancies, learning disabilities to mental retardation	AD	162200	Neurofibromatosis, type 1 gene (NF1)	17q11.2
Basal cell nevus syndrome (Gorlin syndrome)	Macrocephaly, broad facies, frontal and biparietal bossing, hypertelorism, mandibular prognathism, odontogenic keratocysts of jaws, cleft lip and palate, brachydactyly, rib anomalies, calcification of falx cerebri, mental retardation, paternal age effect	AD	109400	Patched (PTC)	9q22.3-q31
Syndromes associated with hypertelorism or frontonasal malformation
Aarskog syndrome	Hypertelorism, widow's peak, ptosis, down-slanting palpebral fissures, strabismus, maxillary hypoplasia, broad nasal bridge with anteverted nostrils, occasional cleft lip and/or palate, floppy ears, brachydactyly, clinodactyly, joint laxity, shawl scrotum, cryptorchidism, moderate short stature, females mildly affected	X-linked	100050	Faciogenital dysplasia 1 (FGD1)	Xp11
Waardenburg syndrome (type I, type IIA)	Partial albinism, white forelock, premature greying, heterochromia iridis, wide nasal bridge, short philtrum, cleft lip and/or palate, occasional cochlear deafness, spina bifida, lumbosacral myelomenigocele, occasional Hirschsprung disease, dystopia canthorum and absent vagina specific to type 1	AD	193500; 193510	Paired box homeotic gene-3 (PAX3); microphthalmia-associated transcription factor (MITF)	2q35; 3p14.1-p12.3
Craniofrontonasal dysplasia	Coronal synostosis (unilateral>bilateral), frontonasal dysplasia with marked hypertelorism, broad to bifid nose, brachycephaly, broad great toe, syndactyly, hypermobile shoulders with pseudoarthrosis of clavicle, female preponderance (more severe in females), males may have shawl scrotum	X-linked	304110		Xp22
Craniometaphyseal dysplasia	Craniofacial hyperostosis (leonine facies), hypertelorism, wide nasal bridge, cranial nerve compression (facial palsy, deafness, anosmia), characteristic diaphyseal sclerosis and metaphyseal dysplasia of long bone	AD/AR	123000		5p15.2-p14.1
Acrocallosal syndrome	Macrocephaly, prominent forehead and occiput, hypertelorism, absent corpus callosum, hypospadias and cryptorchidism, postaxial polydactyly and hallux duplication, hypotonia and severe mental retardation	AR	200990		12p13.3-p11.2
Greig cephalopolysyndactyly syndrome	Macrocephaly without synostosis, high forehead and bregma, frontal bossing, hypertelorism, bifid great toe and thumb, polysyndactyly, advanced bone age	AD	175700	GLI-Kruppel family member 3 oncogene (GLI3)	7p13
Binder syndrome	Maxillonasal dysplasia, maxiallary hypoplasia, short nose with flat nasal bridge and absent anterior nasal spine, convex upper lip	AD	155050
Reiger syndrome, type 1	Hypertelorism, telecanthus, iris dysplasia, microcornea, corneal opacity, maxillary hypoplasia, broad nasal root, prognathism, protruding lower lip, short philtrum, microdontia, hypodontia, cone-shaped teeth, hypospadias, anal stenosis	AD	180500	RIEG1	4q25-q26
Other craniofacial syndromes
Sturge-Weber syndrome	Hemangiomata in the distribution of the trigeminal nerve can involve the choroid of the eye and the meningies, glaucoma, seizures (those with seizures often have learning disability), no clear evidence for mendelian inheritance	Sporadic	185300
Beckwith-Wiedemann syndrome	Coarse facial features, macroglossia (often with secondary maxillary and mandibular deformity), ear lobe creases, posterior auricular pits, midface hypoplasia, omphalocele, generalized overgrowth or hemihypertrophy, visceromegaly, Wilms tumor (and other malignancies), cryptorchidism, cardiomyopathy	AD, imprinting at 11p15.5	130650	Cyclin-dependent kinase inhibitor IC (CDKN1C)	11p15.5
Cornelia de Lange	Microbrachycephaly, micrognathia, low hairline, synophrys, arched eyebrows, long eyelashes, thin upper lip, low-set ears, spade-like hands, 2-3 syndactyly of toes (more severe limb anomalies common), failure to thrive, prenatal growth deficiency, short stature	Sporadic, dominant forms suggested	122470
Romberg syndrome (progressive hemifacial atrophy, Parry-Romberg syndrome)	Slowly progressive hemifacial atrophy, normal at birth, atrophy of facial soft tissue and bone, always unilateral with well-demarcated median border, malocclusion, hemiatrophy of tongue, enophthalmos on affected side, hyperpigmentation and vitiligo, can be associated with trigeminal neuralgia, migrane-like headaches, and contralateral Jacksonian epilepsy	AD	141300
Freeman-Sheldon syndrome	Whistling facies (with small mouth and vertical skin folds on chin), hypertelorism, “sunken” eyes, small nose, adducted thumbs, ulnar deviation of hands, camptodactyly, clubfoot	AD	193700
Trichorhinophalangeal syndrome (type I)	Micrognathia, “pear-shaped” nose, short stature, brachydactyly with short metacarpals, normal intelligence	AD	190350		8q24.12

Note: Not all phenotypic features listed will necessarily be present in every case. If considering one of these diagnoses, it is suggested to review one or more of the following references: OMIM: Online Mendelian Inheritance of Man: <http://www.ncbi.nlm.nih.gov/omim/ >, 1999; Gorlin RG, Cohen MM, Levin LS: Syndromes of the Head and Neck, 3rd ed. New York, Oxford University Press, 1990; Jones, KL: Smith's Recognizable Forms of Human Malformation, 5th ed. Philadelphia, Saunders, 1996; National Institute of Dental and Craniofacial Research: Listing of craniofacial-oral-dental diseases and disorders: <http://www.nidr.nih.gov/cranio/home.html >, 1998.

All children born with structural malformations of the face and/or skull require a careful physical examination, because many have associated multisystem involvement (20%). The obvious malformations of craniofacial structures can be so dramatic that the examiner overlooks other less obvious associated anomalies that deserve attention and may help to establish a diagnosis. Leaving the examination of the craniofacial anomalies until the remainder of the exam is completed helps to ensure that other anomalies are not overlooked.

There is a national support group for persons with craniofacial abnormalities, Let's Face It (www.faceit.org/letsfaceit).

CLEFT LIP AND PALATE

Isolated Cleft Lip and Palate

Cleft lip and/or palate (CLP) represent one of the most common structural malformations in humans. The incidence of CLP varies depending on race (1/250 births in some native American tribes, 1/350 in Asian-Americans, 1/700 in white Americans, and 1/3000 in black Americans). However, more recent studies indicate that these may be overestimations. Cleft lip and palate in combination is the most common form of orofacial clefting with isolated cleft lip and isolated cleft palate having the following relative frequencies: 1:1.2:2.5 (CL:CP:CLP) (Fig. 10-16).

FIGURE 10-16 Variable expression of cleft lip and palate in two children born to different unaffected fathers. Their mother shows no manifestation of orofacial clefting.

Heredity of Cleft Lip and Palate

Although most cases of CLP represent sporadic (stochastic) events, recurrence in families with isolated CLP is well documented. CLP represents a multifactorial disorder that can have a hereditary component. If the first-born child of a couple has CLP, the risk of the next child having CLP is 3 to 4%. This risk is increased (1) with the birth of additional children with orofacial clefts and (2) if a parent has a cleft and is considered to have a “hereditary predisposition” of CLP (see Sec. 10.1.2). Presently, there is no way to discern sporadic from hereditary forms of isolated CLP, and thus statistically based risk estimates are currently used for genetic counseling. Recently, periconceptual folate supplementation has been suggested to reduce the risk of CLP in these “at risk” families, and some centers have implemented this recommendation.

Although the majority of cases of CLP represent isolated cases, over 290 known syndromes are associated with CLP. Relatively common syndromic forms of orofacial clefting include: Stickler syndrome, 22q11 deletion (velocardiofacial) syndrome, Van der Woude syndrome, and ectodermal dysplasia ectrodactyly and clefting (EEC) syndrome (Table 10-11). Isolated cleft palate, rather than cleft lip and/or palate, is more frequently associated with syndromic forms.

Airway Management

The specifics of management of children with orofacial clefting are center-specific. The first issue to be addressed with any child born with orofacial clefting is airway management. Although children with isolated cleft palate are more prone to airway difficulties, children with CLP can also have airway obstruction, particularly those with Robin sequence: association of micrognathia (small mandible) with isolated clefting of the secondary palate. Although the pathogenesis of Robin sequence has not been proved, it is thought that micrognathia leads to cleft palate in the sixth to seventh weeks of gestation because of superior displacement of the tongue into the nasopharynx preventing fusion of the palatal shelves. The combination of micrognathia and a palatal cleft often results in glossoptosis (pathologic position of the tongue leading to airway obstruction), which requires urgent care ranging from prone positioning to emergent tracheostomy. Some centers use other surgical and nonsurgical means of treatment for more severe obstruction (eg, nasopharyngeal intubation). The American Academy of Pediatrics

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supports prone positioning of infants with orofacial clefting (and other craniofacial malformations) to alleviate minor airway obstruction.

Feeding

Children with cleft palates usually cannot solely breast-feed because an intact palate is necessary to generate the negative pressure required for suckling. For this reason, a number of specialized feeding techniques (eg, squeeze bottles) have been devised. Any child with nonsyndromic cleft palate should be expected to have normal weight gain. A general rule of thumb is that the child should take approximately 2.5 ounces/pound per day to have good growth. Adequate weight gain is imperative in these children, who will require surgical interventions in the first year of life. Infants with cleft palate often have minor swallowing difficulties and/or gastroesophageal reflux (particularly syndromic forms such as 22q11 deletion syndrome).

Surgery

The timing and nature of surgical management for children with orofacial clefting differs from center to center. In general, closure of the lip occurs within the first 5 months of life, and the palate is repaired by age 12 months. The timing of palatal closure by 1 year of age is suggested to optimize speech and language development, but early palate closure (under 6 months) may impede normal midfacial development. Special attention needs to be given to the child with isolated cleft palate associated with respiratory difficulties (particularly in cases of Robin sequence with evidence of glossoptosis) because closure of the palate can exacerbate airway compromise. In addition to the obvious need for surgical management of the orofacial clefting, children with cleft palate (including submucous cleft palate) have an increased risk of persistent middle ear effusions (MEE) and/or chronic recurrent otitis media (OM). In these children, who are predisposed to language difficulties caused by their clefts, hearing must be optimized. The predisposition for MEE and OM is due to abnormal function of the distal eustachian tube. Most children with overt cleft palate require the placement of tympanostomy tubes in the first year of life. Additional surgeries that may be necessary in this population include bone grafting of the alveolar cleft when present, pharyngeal surgeries for improvement of speech, and midfacial advancement in cases of midfacial hypoplasia.

HEMIFACIAL MICROSOMIA (CRANIOFACIAL MICROSOMIA, OCULOAURICULOVERTEBRAL DYSPLASIA)

The association of external ear anomalies (microtia, anotia, canal atresia, and/or preauricular tags) with maxillary and mandibular hypoplasia is the second most common craniofacial malformation in humans. This condition is known as hemifacial microsomia (HFM) (also known as craniofacial microsomia, oculoauriculovertebral dysplasia, lateral face dysplasia, or first and second branchial arch syndrome) and can present with a wide degree of severity. HFM can present as an isolated malformation of craniofacial structures or as a component of a multiple malformation complex (eg, Goldenhar syndrome, VATER). Since approximately 30% of cases of HFM are bilateral, some clinicians prefer the term craniofacial microsomia for this disorder.

ISOLATED HEMIFACIAL MICROSOMIA

At birth, the most critical issues surround airway and feeding difficulties. Severe cases of HFM have airway obstruction caused by the combination of mandibular and maxillary hypoplasia. The management of upper airway obstruction can range from prone or side-lying positioning, to early mandibular surgery, to tracheostomy. Severe mandibular and/or maxillary deficiency can negatively impact oral feeding in the first months of life. Temporary nasogastric and, in some cases, gastrostomy feeding may be necessary.

In the first year of life, children with HFM should have renal ultrasonography to rule out clinically significant renal malformations (10 to 15% estimated to have some renal anomaly). In addition, between 25 to 30% of children with “isolated” HFM have cervical vertebral anomalies. As the structural malformations of the spine rarely have functional significance until later childhood, spine films can be delayed for the first few years to allow more complete ossification and improve the quality of the study. Any child over age 5 years with HFM participating in activities that put the cervical spine in jeopardy should have full c-spine (including flexion/extension views to rule out cervical instability) and thoracic/lumbar radiographs prior to participation. All children with unilateral or bilateral HFM should have formal audiologic evaluation (brainstem auditory evoked response, or other accepted means). Even in apparently unilateral cases, an increased incidence of bilateral hearing loss occurs and is most commonly conductive (owing to the malformation

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of the middle ear ossicles), but a mixed sensory and conductive loss can be present (particularly in syndromic forms, BOR; see Table 10-11).

Beyond the issues present in the first months of life, the major issues for children with HFM are related to (1) hearing, (2) functional reconstruction of the maxilla and mandible, (3) orthodontic issues, and (4) external ear reconstruction.

GOLDENHAR SYNDROME

Goldenhar syndrome is the association of HFM, epibulbar lipodermoids (fibro-fatty masses on the globe of the eye, usually lateral and/or inferior), vertebral defects (fusions and/or hemivertebrae of the cervical-lumbar vertebrae), cardiac malformations (from VSD to outflow tract malformations), and structural kidney malformations. Many experts feel that Goldenhar may represent the more severe end of a clinical spectrum of isolated HFM. In fact, up to 15% of children born with “isolated” HFM can present with cervical vertebral anomalies and/or structural kidney defects.

BOR SYNDROME

Branchio-oto-renal dysplasia (BOR syndrome) is an autosomal-dominant condition that shares many features with HFM. Although patients with BOR syndrome rarely have severe maxillary or mandibular deficiency, the syndrome is characterized by the presence of external ear malformations (“lop” ear), preauricular pits and occasional tags, branchial cleft fistulae of the neck (sometimes extending into the pharynx), mixed sensory and conductive hearing loss associated with cochlear and ossicular chain malformations, renal dysplasia/aplasia, and occasional pulmonary hypoplasia. Recently, a mutation of EYA1 has been identified as the cause of some cases of BOR syndrome (Table 10-11).

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TREACHER COLLINS SYNDROME (MANDIBULOFACIAL DYSOSTOSIS TYPE I)

Treacher Collins syndrome is an autosomal-dominant craniofacial malformation syndrome that shares some phenotypic features with HFM and is caused by a mutation in the TREACLE gene, although significant phenotypic variability between or within affected families occurs. The disorder is characterized by mandibular and maxillary hypoplasia, zygomatic arch clefts, and variable microtia/anotia/atreasia. The hypoplastic mandible usually has a characteristic exaggeration of the antigonial notch. Facial features are notable for downward sloping palpebral fissures (owing to lateral orbital clefts), and colobomata of the lower eyelids (Fig. 10-17). Cleft palate occurs in a minority of patients. Cognition is usually normal; other malformations (eg, cardiac) are rare, although conductive hearing loss is frequently associated. The clinical issues of Treacher Collins syndrome are very similar to those of bilateral HFM (respiratory, feeding, mandibular/maxillary surgery, external ear reconstruction). Two more rare forms of mandibulofacial dysostosis include Nager and Miller syndromes (see Table 10-11).

FIGURE 10-17 Two siblings top panels and lower left panel with variable manifestations of autosomal dominant Treacher Collins Syndrome. Their father, lower right panel was the first individual in his family known to have Treacher Collins Syndrome. Both children were born with cleft palate while their father has an intact palate.

CRANIOSYNOSTOSIS

Craniosynostosis is the pathologic condition of premature fusion of calvarial sutures. The overall incidence of sporadic craniosynostosis is 1 in 1700 to 2500 live births, and the incidence of the hereditary forms is approximately 1 in 25,000. The most common form of single suture fusion is sagittal synostosis (followed by coronal, metopic, and lambdoid, with isolated lambdoid fusion representing only 2 to 3% of all forms of synostosis). Sagittal synostosis is much more common in males (M:F is 5:1). In humans, premature suture fusion results in abnormalities in calvarial shape owing to restriction of growth in the region of a fused suture. In general, the limitation in expansion along the fused suture leads to excessive growth perpendicular to the suture. Thus, a careful examination can usually predict the form of synostosis. In the case of sagittal synostosis, excessive anterior and posterior growth of the skull leads to long narrow head shape with frontal and occipital prominence (scaphocepnaly). The head shape changes in cases of craniosynostosis can be associated with (1) increased intracranial pressure that may result in permanent brain injury and (2) alteration of craniofacial growth leading to midfacial hypoplasia, abnormalities in dental alignment, and orbital deformation. Cases with severe midfacial hypoplasia often have significant airway obstruction and may require tracheostomy. The combination of craniosynostosis and associated facial malformations leads to significant morbidity but rarely mortality.

Patients with craniosynostosis require one or more major reconstructive surgeries to correct the functional deficits associated with their malformations. Syndromic forms often have more midfacial involvement and require additional corrective surgeries. The timing of surgical corrections varies with the treating center and the severity of the malformation. In addition to the craniofacial manifestations of craniosynostosis, some hereditary forms (Apert, Saethre Chotzen, and Pfeiffer) have associated limb anomalies (syndactylies and synostoses) frequently requiring surgical intervention for restoration of function (Table 10-11).

The genetics of craniosynostosis is complex. All the major forms of hereditary craniosynostosis are inherited in an autosomal-dominant pattern. Each form demonstrates a high degree of phenotypic variability and in some instances incomplete penetrance (particularly Muenke and Crouzon syndromes) (Fig. 10-18). Mutations of the fibroblast growth factor receptor (FGFR) family occur in many syndromic forms; however, mutations in the TWIST and MSX2 genes have also been found (Table 10-11). Some clinical molecular laboratories are currently offering mutational testing for these syndromic forms of synostosis. In general, the family of a child who presents with more than one fused suture should be counseled that a hereditary form of synostosis should be considered. Single-suture fusion in the absence of other phenotypic features of syndromic synostosis (eg, ptosis, midfacial hypoplasia, limb anomalies, proptosis) is thought to represent epigenetic events perhaps related to in utero positioning. One must be very careful during assessment of the family history because of numerous examples of “isolated” sagittal and/or coronal synostosis recurring in families.

FIGURE 10-18 Clinical phenotype in a case of bilateral coronal craniosynostosis (top panels) subsequently found to be caused by a FGFR3 mutation Pro(250)Arg. Three dimensional CT scan demonstrating obliteration of the coronal sutures (bottom left panel). Mutational analysis of his parents determined that his father also had the FGFR3 mutation but resulted in minimal phenotypic manifestations (bottom right shown with proband after reconstructive surgery).

The surgical management of craniosynostosis has three main purposes: (1) to increase intracranial volume to reduce the risk of intracranial hypertension, (2) to reduce secondary events related to calvarial suture fusion (facial asymmetry and/or maxillary/mandibular malalignment), and (3) to return the calvarial contour to a more acceptable shape (these conditions lead to progressive deformation of the craniofacial skeleton if left untreated).

POSITIONAL FLATTENING OF CALVARIA (PLAGIOCEPHALY)

Positional plagiocephaly is a postnatal oblique flattening of the skull caused by position preference of the infant. Often associated with torticollis, persistent positioning leads most commonly to flattening of the occipitoparietal area that can be of sufficient severity that secondary changes, including ipsilateral frontal prominence and anterior displacement of the ipsilateral ear, occur. The natural history of positional plagiocephaly is as follows: (1) normal head contour at birth (unless abnormal in utero positioning is present), (2) occipital flattening noted by 1 to 2 months of age (infant usually demonstrating a sleep position preference and/or torticollis at this time), (3) increasing severity until 4 to 5 months, (4) improvement in head contour between 4 to 7 months, and (5) static head deformation after 7 months. The final head shape can be improved by reducing back lying while awake and increasing side-lying position during sleep. Some investigators have suggested that the incidence of this postnatal deformation has increased with the supine sleep position recommended to reduce the incidence of SIDS. The most dramatic aspect of the deformation is the occipital skull flattening often leading to the misdiagnosis of unilateral lambdoid synostosis. Positional plagiocephaly can be distinguished from lambdoid synostosis by physical examination (Table 10-12) and skull radiography (sclerosis of lambdoid suture can be seen on plain films or, preferably, CT scan). Positional plagiocephaly can be left untreated if mild; however, a number of “orthotic” devices (eg, helmets) are available for more severe cases.

TABLE 10-12 CLINICAL DIFFERENTIATION OF POSITIONAL PLAGIOCEPHALY AND LAMBDOID SYNOSTOSIS


PHYSICAL FINDING	POSITIONAL PLAGIOCEPHALY	LAMBDOID SYNOSTOSIS

Ear position (affected side)	Anterior displacement	Posterior and inferior displacement
Ipsilateral frontal prominence	Present (progressive to 7 months)	Absent
Contralateral occipitoparietal prominence	Absent	Present/progressive
Lambdoid ridge and submastoid prominence (affected side)	Absent	Present
Progressive after 7 months	No	Yes

OCULAR HYPERTELORISM AND FRONTONASAL DYSPLASIA

The term frontonasal dysplasia (FND) refers to a constellation of findings ranging from hypertelorism (widely spaced eyes) to complex malformations of nasal, midfacial, and premaxillary structures. The most accurate means of quantitating eye position include measurement of interpupillary distance and/or interorbital distance on skull radiography. Standards for ocular measurements are available (see references for Sec. 10.3.2). Orbital spacing varies between races (eg, blacks have a greater interpupillary distance than whites). In addition, other facial features (lateral displacement of the inner canthi, short palpebral fissures, low nasal bridge, and exotropia) can

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give the false impression of hypertelorism. As with most malformations, hypertelorism and FND can be an isolated finding or a part of a multiple malformation syndrome. Some syndromic examples of frontonasal dysplasia include: Opitz and Aarskog syndromes, the oral-facial-digital syndromes, craniofrontonasal dysplasia, and Waardenburg syndrome, among others (Table 10-11). Overall, 200 syndromes are associated with anomalies of frontonasal development.

The management issues for children with FND vary greatly depending on severity and the presence of associated or syndromic findings. Severe hypertelorism can affect the development of binocularity, and thus all children with FND should be evaluated by a qualified ophthalmologist. FND can be associated with central nervous system anomalies including frontonasal encephaloceles, teratomas/lipomas of the ventral forebrain, agenesis/hypoplasia of the corpus callosum and/or septum pellucidum. Several other less common CNS anomalies can also be seen. In the case of frontonasal encephalocele, the anterior skull base is incompletely formed allowing for ventral displacement of the forebrain into the nasopharynx. Since frontonasal encephalocele occurs in mild cases, nasogastric or nasal suction tubes are not used when FND is present (unless necessary for emergent resuscitation efforts). Even more common than mild FND are congenital nasal dermal sinus tracts that are epithelial-lined and usually extend onto the midline of the nose (from base to tip) or even in the philtral groove. These malformations are thought to represent minor anomalies in embryonic facial growth and are of clinical significance in that they may extend through the cribriform plate (often through the crista galli), representing

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a conduit for CNS infection. Any midline anomaly of nasal development requires high-resolution CT scan to rule out such anomalies.

References

Clarren SK, Anderson B, Wolfe LS: Feeding infants with cleft lip, cleft palate, and cleft lip and palate. Cleft Palate J 24:244, 1987

National Institute of Dental and Craniofacial Research: Listing of craniofacial-oral-dental diseases and disorders: http://www.nidr.nih.gov/cranio/home.html, 1998

Tolarova MM, Cervenka J: Classification and birth prevalence of orofacial clefts. Am J Med Genet 75(2):126–37, 1998

10.3.5 Constitutional Disorders of Bone

John C. Carey

Michael J. Bamshad

Skeletal dysplasias are generalized disorders of bone structure that can produce short stature, osseous deformity, and functional disabilities. More than 230 different skeletal dysplasias have been described by the International Working Group on Constitutional Diseases of Bone; collectively these dysplasias represent approximately half of all constitutional disorders of bone. The overall frequency of the skeletal dysplasias is about 1 in 4000 births, making this class of disorders as common as neurofibromatosis type 1 or Turner syndrome, much better known conditions. In contrast, disorders of bone structure that cause deformities and functional abnormalities of individual bones, either alone or in combination, are called dysostoses. Dysostoses and skeletal dysplasias comprise the constitutional disorders of bone and cause substantial morbidity in children and adults, yet many affected individuals lead relatively “normal” lives, albeit with some special challenges. This section describes the classification, distinguishing characteristics, and management of selected disorders of bone.

Conventionally, the skeletal dysplasias are often grouped according to the anatomic location of the bones that are most severely affected and the histologic abnormalities that are commonly observed. For example, skeletal dysplasias that affect the spine and the epiphyses are called spondyloepiphyseal dysplasias. However, the criteria used to categorize disorders into this classification are inconsistently applied to many skeletal dysplasias (eg, achondroplasia), and this diminishes its heuristic value. The classification schemes used to organize dysostoses are quite varied. No single system has become widely adopted, and, accordingly, the clinical presentation and varied expressions of the dysostoses tend to be difficult to remember accurately. Moreover, some disorders of bone share characteristics of both the skeletal dysplasias and the dysostoses.

The strategy of classifying malformations according to the developmental pathway that is disrupted can be applied to the skeletal dysplasias and dysostoses. The logic of the classification is to separate development of the skeleton into three primary phases: patterning, morphogenesis (ie, condensation, differentiation, and histogenesis), and growth. Dysostoses are typically produced by disturbances of skeletal patterning in a myriad of ways that have historically been categorized by the specific bone (eg, radial defects, fibular-femur complex) or anatomic location affected (eg, truncation defects, posterior polydactyly). Disturbances of bone growth lead to generalized disorders of bone as exemplified by most skeletal dysplasias (eg, achondroplasia). Skeletal disorders characterized by defects of the formation of individual bones have been more difficult to categorize. In these disorders, the patterning of the skeletal elements is normal and the growth of most skeletal elements is unaffected, but the morphogenesis of particular bones is disturbed. Thus, these conditions exhibit features of both skeletal dysplasias and dysostoses. For example, most of the bones in children with campomelic dysplasia exhibit normal patterning and growth. However, the long bones (femur, tibia) of children with campomelic dysplasia are bowed because histogenesis of these bones has been perturbed. Recent studies suggest that expression of the gene encoding type II collagen (COL2A1) is directly regulated by SOX9 protein and that abnormal regulation of COL2A1 during chondrogenesis is a cause of the skeletal abnormalities associated with campomelic dysplasia.

Historically, the term dwarf has been used to refer to persons with bone dysplasias and disproportionate short stature. Because of the pejorative nature of this label and because it evokes thoughts of a different class of personhood, the term has been dropped from usage. The preferred terminology is to refer to a condition by its medical designation (eg, diastrophic dysplasia).

GENERAL APPROACH

The child with a bone dysplasia will present in primarily three ways: (1) as a newborn with short limbs (or trunk) in respiratory distress requiring ventilation, (2) as a newborn or older infant with disproportionate short stature, or (3) as a child with one of the various osseous manifestations associated with the bone dysplasias. An infant in the first group typically has one of the lethal chondrodystrophies (eg, thanatophoric dysplasia) and needs ventilatory support because of pulmonary hypoplasia or another respiratory feature of these conditions. A child with either the second or third presentation likely has one of the various disorders listed in Table 10-13. The systematic approach to the patient with any of the three presentations has been developed by Hall and other authorities in the field (Fig. 10-19).

TABLE 10-13 SKELETAL DYSPLASIAS


CATEGORY OF DISORDER	MAJOR MANIFESTATIONS	LABORATORY/X-RAY	INHERITANCE (OMIM #)	GENE LOCUS/GENE PRODUCT

Disorders of transmembrane receptors
Achondroplasia (see text and Fig. 10-20A)
Thanatophoric dysplasia type I^*	Macrocephaly, rhizomelic shortening	Marked platyspondyly, short ilia, bowed femur with broad metaphyses	AD (187600)	4p16/FGFR3
Thanatophoric dysplasia type II^*	Macrocepaly, cloverleaf skull anomaly	Platyspondyly, straight femur	AD (187610)	4p16/FGFR3
Hypochondroplasia	Mild rhizomelic shortening, macrocephaly	Short pedicles of vertebra; short/broad ilia	AD (146000)	4p16/FGFR3
Disorders of cartilage matrix proteins and collagen
Osteogenesis imperfecta (see text)
Kriest dysphasia	Flat nose, midfacial hypoplasia, short stature, prominent joints	Broad metaphyses of femur; coronal clefts of spine	AD (156556)	12q13/type II collagen
Achondrogenesis type II^*	Flat nose, very short limbs, hydrops	Short tubular bones, deficit/absent ossification of vertebrae	AD (200610)	12q13/type II collagen
Spondyloepiphyseal dysplasia congenita	Myopia, hearing loss, eventually short trunk	Flat vertebrae, odontoid hypoplasia, scoliosis	AD (183900)	12q13/type II collagen
Hypochondrogenesis^*	Flat nose, very short limbs	Relatively normal long bones; vertebral hypoplasia	AD (120140)	12q13/type II collagen
Schmid metaphyseal dysplasia	Mild disproportinate short stature; tibial bowing	Metaphyseal broadening	AD (156500)	6q21/type X collagen
Pseudoachondroplasia	Long trunk, short limbs, leg joints	Platyspondyly, tongue-like projections anteriorly, epiphyseal dysplasia	AD (177170)	19p12/COMP
Multiple epiphyseal dysplasia	Mildly short limbs	Multiple epiphyseal changes, normal spine	AD (600969) (locus heterogeneity)	19p12/COMP
Disorders of transmembrane sulfate transporter
Diastrophic dysplasia	Cleft palate, laryngeal abnormalities, transient swellings of ears	Short long bones, scoliosis, broad metaphyses	AR (222600)	5q32/sulfate transporter
Atelosteogenesis type II^*	Flat nose, very short limbs, +/- cleft palate	Short humeri; fibular hypoplasia	AR (256050)	5q32/sulfate transporter
Achondrogenesis type I^*	Flat nose, very short limbs, hydrops	Short tibular bones, poor ossification of vertebrae	AR (600972)	5q32/sulfate transporter
Disorders of DNA transcription factors
Campomelic dysplasia^*	Macrocephaly, flat nose, cleft palate, clubfeet, dimples over tibia	Short bowed femur and tibia; narrowed ilia; hypoplastic scapulae	AD (114290)	17q24/SOX9
Disorders of bone density
Hypophosphatasia, congenital form^*	Soft skull, short limbs	Very short underossified long bones with spikes; low alkaline phosphatase	AR (241500)	1p36/alkaline phosphatase
Disorders of unknown pathway
Ellis-van Creveld syndrome	Sparse hair, natal teeth, postaxial polydactyly, long/thin chest; genu valgus	Short/broad ilia	AR (225500)	4p/
Jeune dysplasia	Relatively normal face	Short ribs, short/broad ilia	AR (208500)	—
Short rib/polydactyly type I^*	Flat nose, postaxial polydactyly	Metaphyseal spurs; short/horizontal ribs, small ilia	AR (263530)	—
Short rib/polydactyly type II^*	Flat nose; postaxial polydactyly	Short/horizontal ribs; oval-shaped tibiae	AR (263520)	—
Spondylometaphyseal dysplasia	Short trunk, tibial bowing	Platyspondyly, broad metaphyses	AD (120140)	—

* Lethal in neonatal period. OMIM: Online Mendelian Inheritance of Man: <http://www.ncbi.nlm.nih.gov/omim/ >, 1999.

FIGURE 10-19 The diagnostic approach to the child with disproportionate short stature.

The first step is the gathering of the history and physical examination with recognition of the decreased length or height. The pregnancy history may reveal that an abnormality was detected by ultrasonography (eg, short limbs or polyhydramnios), since prenatal diagnosis of a fetus with a presumed skeletal dysplasia is becoming more commonplace. As always, a detailed family history is

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important and may reveal relatives with short stature or consanguinity.

The physical examination should include accurate measurements of length/height, weight, OFC, the arm span, and the upper/lower body ratio. The latter two measurements will define disproportion of the limbs to the trunk. The arm span is usually within 4 cm of the length/height at any age. If arm span is less than 5 cm of length, short limbs are suggested; if more than 5 cm of length, a short trunk is likely. The upper to lower ratio is taken by measuring the distance from the pubis to the heel (lower segment) and substracting this from the length/height to obtain the upper segment. The ratio of the upper to the lower (U/L) is 1.6 to 0.93 from the newborn to the adolescent. Children with an elevated U/L ratio (eg, greater than 1.8 in a newborn) have a short-limbed form of disproportionate short stature while those with a lowered ratio have a short-trunk form. Often the disproportion can be visualized just by simply looking at the infant or child; the upper limbs usually come to about one-third of the length of the thigh when held down by the side. When the fingertips of the hand are at or above the iliac crest, clinical disproportion is present.

The second step in the diagnostic process involves determining which segment of a limb or trunk is the shortest. Usually in any short-limb (or short-trunk) form of short stature there is a decrease in total length. However, one portion is often more shortened than the others, and this can be a clue to a diagnosis. If the upper portion of the limb (ie, the humerus or the femur) is the shorter part (as is the case in achondroplasia), this is referred to as rhizomelic shortening. If the middle segment of the limb (ie, forearm and lower leg) is the relatively shorter part, then this is called mesomelic shortening. Shortening of the distal part of the limb (ie, hands and feet) is called acromelic shortening. If the trunk is the predominant area of shortening (as in Morquio syndrome), then either the neck, thorax, or the entire spine will be short.

The next major step involves documenting all the nonskeletal physical features. Associated clinical findings, either malformations (eg, cleft palate, polydactyly) or important secondary findings (eg, dimples, bowing, contractures), are very helpful in leading to the diagnosis and will facilitate considering specific diagnostic paths. An important associated clinical finding is the presence or absence of serious respiratory difficulties at birth, the hallmark of the so-called lethal chondrodystrophies.

The fourth step in the process is a systematic categorization of the radiographic findings by area of involvement. A complete skeletal survey should include radiographs of the skull, long bones, AP pelvis, and spine and will be necessary in the evaluation of the child with a potential skeletal dysplasia. All the disorders shown in Table 10-13 are characterized by a specific pattern of skeletal abnormalities that are apparent on these radiographs. Most of the bone dysplasias have predictable and nonrandom adverse effects on the epiphyses, metaphyses, and the diaphyses, and spinal involvement varies with each condition. The architecture of the pelvic contour or the vertebral bodies is often distinctive enough to lead to a specific diagnosis (eg, thanatophoric dysplasia). Thus in this way each skeletal dysplasia can be categorized as predominantly involving the epiphyses, metaphyses, or diaphyses and/or the spine (spondylo-). For example, if one utilizes this approach radiologically, the bone findings could be classified as showing a spondyloepiphyseal dysplasia (Kniest dysplasia) or a spondylometaphyseal dysplasia (achondroplasia) and so on.

The final step in the evaluation, if necessary, is to confirm the clinical diagnosis using laboratory tests or histologic findings. For example, assay of skin fibroblasts for defects of type I collagen is sometimes necessary in the diagnosis of osteogenesis imperfecta. Some disorders show abnormalities of calcium and phosphorous (eg, hypophosphatemic rickets) or alkaline phosphatase (eg, hypophosphatasia) (see Sec. 24.11). In a lethal chondrodystrophy (eg, thanatophoric dysplasia type I) biopsy of the growth plate at postmortem examination may be helpful in confirming a clinical diagnosis.

Once a specific diagnosis is made, a plan for health supervision and management can be organized based upon the natural history of the condition. All the skeletal dysplasias, with rare exception (eg, warfarin embryopathy), are single-gene disorders, and with the exception of the few X-linked conditions, are inherited in an autosomal-dominant and/or recessive pattern. The risk of germ-line mosaicism is important for some conditions that are apparently new mutations (eg, osteogenesis imperfecta and campomelic dysplasia). The prenatal diagnosis of chondrodystrophies is also complicated because of changes in the technology and availability of genetic testing.

The psychological aspects of coping with the impact of a bone dysplasia are particularly unique. There are different implications for families in which average-sized parents have a child with a dysplasia or in which parents with achondroplasia (ie, heterozygotes) have a baby homozygous for the mutation causing achondroplasia, which is lethal. There are also different challenges for children with different conditions. In conditions such as achondroplasia or spondyloepiphyseal dysplasia congenita, where short stature is a prominent and consistent feature, a child has to cope with the stigma of

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short stature, a physical appearance of disproportion, the consequences of orthopedic and neurosurgical complications, and day-to-day challenges that medical professionals rarely encounter, such as clothing and bathroom needs and practical changes around the house. The Little People of America is an outstanding resource for families and children (www.lpaonline.org). Most individuals with these conditions deal with them effectively and adapt their lives to these challenges. Sensitivity to the many issues surrounding the emotional and psychological impact is obviously important, and a genuine acceptance of the differences in persons with skeletal dysplasias is also crucial to developing a relationship of caring.

Table 10-13 lists selected skeletal dysplasias, their clinical and radiographic features, and the molecular defect (when known); the conditions are grouped by gene product and function (if known). In addition achondroplasia and osteogenesis imperfecta are discussed in detail. Over 30 different skeletal dysplasias that include significant respiratory insufficiency that usually results in neonatal death have been described. A neonate with disproportionate short stature who has respiratory distress may have a lethal skeletal dysplasia.

SKELETAL DYSPLASIAS CAUSED BY MUTATIONS IN TRANSMEMBRANE RECEPTORS

The prototypic conditions that involve transmembrane receptors are the achondroplasia group and result from mutations in a gene encoding a receptor (fibroblast growth factor receptor 3, FGFR3) that negatively regulates the growth of cartilage. Thus, mutations in FGFR3 activate this receptor, and as a consequence growth is significantly inhibited. The phenotypic overlap between some of the conditions in this group had been observed for decades, and thus investigators were not surprised when different mutations of the same gene were discovered to cause achondroplasia, thanatophoric dysplasia, and hypochondroplasia (Table 10-13).

ACHONDROPLASIA

Achondroplasia is the best-known skeletal dysplasia in humans, occurs in about 1 in 20,000 newborns, and is usually recognized at birth. The syndrome pattern consists of disproportionate short stature with rhizomelic shortening, macrocephaly, and characteristic craniofacial findings including a flat nasal bridge, a prominent forehead, and midfacial hypoplasia (Fig. 10-20A). The hands are short, and the fingers are broad with digits 3 and 4 splayed more distally than proximally, giving the hand a “trident” appearance. The overall length is often in the low-average range at birth but by 2 to 3 months of age, the length is below the fifth percentile. A lumbar gibbus occurs in infancy but usually resolves. Children with achondroplasia usually do not have malformations such as cleft palate or polydactyly that are observed in other newborn skeletal dysplasias.

FIGURE 10-20 A. A child with achondroplasia. Note the rhizomelic shortening. B. Radiograph of the pelvis in a child with achondroplasia. Note the squared-off iliac wings, flat and irregular acetabular roofs, thick femoral necks, and ice-cream-scoop-shaped femoral heads.

The diagnosis of achondroplasia is confirmed by the abnormalities found on the AP pelvis film that includes the upper femurs, which are quite characteristic (Fig 10-20B). The iliac bones are short and round, and the acetabulum is flattened. The shape of the ilia is similar to that found in other conditions, but the head of the femur exhibits a particularly distinctive contour. The other long bones have mildly flared metaphyses; the lumbar vertebrae have short pedicles and posterior scalloping. In general the findings are consistent with a spondylometaphyseal dysplasia.

Individuals with achondroplasia are at risk for a number of problems and complications, including a predisposition to serous otitis media, delay in motor milestones in infancy, bowing of the legs (usually the tibia) presenting after ambulation has started, and orthodontic problems related to the maxillary hypoplasia. Growth curves are available for follow-up of the child with achondroplasia. Length and OFC can be monitored on well-child visits. Average adult height in males with achondroplasia ranges between 118 and 145 cm, and the range in females is between 112 and 136 cm. Limb-lengthening procedures have been performed on some adolescents with achondroplasia and resulted in an increase of several centimeters in height. However, this approach is controversial, and studies of long-term outcome are needed to help determine the risk/benefit ratio of this procedure. The most important manifestation of achondroplasia is related to the stenosis of the foramen magnum and spine. The former presents in infancy, whereas the latter occurs in later years, usually adulthood. Compression of the upper cord at the foramen magnum presents with a myriad of symptoms including apnea (both obstructive and central), quadriparesis, growth delays, and hydrocephalus. Any signs of compression or of hydrocephalus warrant referral to a neurosurgeon and/or neurologist. Some experts have suggested screening for compression using routine sonograms, but the American Academy of Pediatrics guidelines suggest measuring the size and shape of the fontanelle and monthly monitoring of the OFC. Standards of the size of the foramen magnum, as measured by computed tomography or magnetic resonance imaging, in children with achondroplasia are available and can be used to help decide if there is compression at the cervicomedullary junction.

Achondroplasia is an autosomal-dominant disorder with most children having a de novo mutation of FGFR3. Most patients with achondroplasia have an identical missense mutation that results in a substitution of codon 380 of FGFR3; this missense mutation causes a glycine residue to be replaced by an arginine. Patients with hypochondroplasia or thanatophoric dysplasia have different missense mutations in FGFR3.

THANATOPHORIC DYSPLASIAS

Two relatively distinct skeletal dysplasias also involving mutations of FGFR3 are thanatophoric dysplasia I and II, which have similar clinical characteristics but different molecular defects. Both are lethal chondrodystrophies with only a few recorded survivors beyond the neonatal period. Death is usually caused by either compression at the cervicomedullary region by the foramen magnum or pulmonary hypoplasia. The presentation is always in the newborn with many cases now being diagnosed prenatally by ultrasound because of polyhydramnios or the detection of the short limbs.

As in achondroplasia there is true macrocephaly; the limbs are very short with obvious disproportion. There is a notable increase in folds of skin of the limbs and striking shortness and broadness of the digits. The radiographic findings are diagnostic with marked platyspondyly, flared metaphyses of long bones, and short iliac bones. In type I thanatophoric dysplasia the femurs are bowed, but in type II they are straight. Furthermore, the cranium of infants with type II thanatophoric dysplasia often shows the cloverleaf skull malformation.

Type I is caused by mutations in two regions of the extracellular domain of the FGFR3 while type II patients have mutations of codon 650, which is in the intracellular portion of the receptor protein. Both conditions are caused by de novo mutations of FGFR3, and thus parents are at very low recurrence risk. DNA testing for FGFR3 mutations is available both for prenatal diagnosis or confirmatory testing of an infant.

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DISORDERS OF STRUCTURAL PROTEINS OF CARTILAGE

Several different skeletal dysplasias are caused by mutations of genes encoding proteins involved in the extracellular matrix of cartilage (Table 10-13). Functional disturbances of a variety of proteins, including types II, IX, X, and XI collagen and the noncollagenous cartilage oligomeric protein (COMP), have been described.

A principal collagen of bone is type I collagen, a triple helical molecule consisting of two α-1 and one α-2 proteins. Mutations in

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the genes encoding these two proteins (COL1A1 and COL1A2) cause the most common forms of osteogenesis imperfecta (OI), a group of skeletal dysplasias involving abnormalities of bone density.

OSTEOGENESIS IMPERFECTA

Osteogenesis imperfecta represents a heterogeneous group of bone dysplasias that are characterized by osseous fragility, short stature, and a wide range of other skeletal findings that vary with the type of OI. The classification of Sillence is most commonly used and another dozen disorders of bone density and osseous fragility can be placed in this category. However, aside from OI types I to IV, all these entities are very rare.

OI type I is well-known skeletal condition that is sometimes referred to as brittle bone disease, and this autosomal-dominant disorder consists of the variable presence of blue sclerae, delay in fontanelle closure, joint laxity, short stature, and multiple fractures. The prevalence is about 1 in 30,000 births, with the majority of cases being familial and a minority representing de novo mutations. Fractures are uncommon at birth. The sclerae are deep blue, often the hue of a robin's egg, and do not resolve with time as usually occurs in children as a normal variant. Primary or secondary deformities of long bones are uncommon, and the prognosis for normal function is excellent. Fractures from minimal trauma occurring throughout childhood are the rule, but by middle to late adolescence fracture frequency diminishes markedly. Sometimes, child abuse is incorrectly suspected, and can be challenging to resolve because the abnormalities observed in some children with type I OI can be subtle. Radiographs show mild osteopenia of the long bones and wormian bones (bones within sutures). Some families exhibit the dental manifestation of dentinogenesis imperfecta. Scoliosis and hearing impairment from a conductive loss occur in the second or third decade. Biochemical analysis will often show a decrease in the synthesis of type I collagen, and inactivating mutations of either gene can occur.

OI type II is a serious condition usually resulting in newborn death caused by respiratory insuffiency and is the second most common lethal skeletal dysplasia behind the thanatophoric dysplasias. The skull is markedly soft on palpation, and the limbs are short and bowed even beyond the occurrence of fractures. The radiographic contour on the long bones is particularly characteristic with a crumpled appearance, and the ribs are beaded because of callus formation. Studies of COL1A1 demonstrate that point mutations that disrupt helical assembly lead to abnormal collagen formation. Almost all cases are related to de novo mutation of a COL1A1. Because germ-line mosaicism has been documented in a number of families, recurrence risk for parents of a sporadic case is usually given as 6%, which is probably an overestimate of the actual risk because of ascertainment bias.

OI type III usually presents in the newborn infant with multiple fractures. This type of OI was formerly called (along with type II) OI congenita and is sometimes referred to as the progressively deforming type because there is severe osseous fragility leading to bowing and deformity. Indeed, short stature is significant. Many patients with type III OI are not able to ambulate owing to an inability to bear weight. The sclerae are usually blue at birth but lighten with age. Comprehensive rehabilitation emphasizing physical

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supports and bracing is suggested, and referral to a team or an OI clinic (several are located at Shriners' hospitals in North America) is always indicated for children with type III OI. Decisions regarding timing and appropriateness of surgery are complex and require input from experienced orthopedists. Most of the neurologic findings that have been described in patients with OI, including hydrocephalus and basilar skull invagination, occur in this type of OI. Newer therapies that are used in osteoporosis, such as biphosphonates, are being tried in type III OI with some efficacy and improvement. Most cases are caused by point mutations of COL1A1, similar to what is observed in type II and IV OI.

Type IV OI is characterized by marked variability with most cases having a milder phenotype like type I OI. Typically, there are only mild changes of the sclerae, which often become lighter with time. Delay in closure of the fontanelles is common, and fractures are often present at birth. The hallmark of type IV OI is the presence of tibial bowing, which is usually not seen in the other mild type of OI, type I. Dentinogenesis imperfecta is observed in some families. Most patients have point mutations or exon deletions affecting COL1A2.

The Osteogensis Imperfecta Foundation (www.med.virginia.edu/medicine/admin/grants/osteo.html) is an excellent resource for parents of newly diagnosed infants. Their written material helps parents learn how to handle their baby, since it is quite natural for parents to be hesitant to care for their child because of the osseous fragility. A checklist for routine care has been developed for follow-up of children with OI (as well as many other syndromes and skeletal dysplasias) by Wilson and Cooley.

References

Academy of Pediatrics Committee on Genetics: Health supervision for children with achondroplasia. Pediatrics 95:443–451, 1995

Hall BD: Approach to skeletal dysplasias. Pediatr Clin North Am 39:279–305, 1992

International Working Group on Constitutional Diseases of Bone International: Nomenclature of the osteochondrodysplasias. Am J Med Genet 79:376–382, 1997

Taybi H, Lachman RS: Radiology of Syndromes, Metabolic Disorders & Skeletal Dysplasias. Chicago, Year Book, 1996

Wilson GN, Cooley WC: Preventive Management of Children with Congenital Anomalies and Syndromes. Cambridge, Cambridge University Press, 2000

10.3.6 Connective Tissue Dysplasias

Maurice Godfrey

Like the skeletal dysplasias, primary disorders of connective tissue comprise a heterogeneous group of genetic conditions. Because of their importance in pediatric patients, this section focuses on Marfan syndrome and the Ehlers-Danlos syndromes.

MARFAN SYNDROME

Marfan syndrome is a serious heritable disorder of connective tissue with manifestations in many organs, including the eyes, heart, aorta, skeleton, skin, lung, and dura (Table 10-14). The disorder is transmitted in an autosomal-dominant pattern with virtually complete penetrance but variable expression. Without diligent clinical monitoring and treatment, life span may be significantly reduced. The major morbidity and mortality associated with the Marfan syndrome is related to cardiovascular complications. The incidence of the Marfan syndrome has been estimated to be as high as 1 in 5000 individuals and is without gender or ethnic predilection.

TABLE 10-14 CLINICAL MANIFESTATIONS OF THE MARFAN SYNDROME


MAJOR CRITERIA	MINOR CRITERIA

Skeletal system
Pectus carinatum	Moderate pectus excavatum
Pectus excavatum needing surgery	Joint hypermobility
Reduced U/L segment ratio or arm-span-to-height ratio	High arched palate
Wrist and thumb signs
Scoliosis >20%
Reduced extension at elbows (<170%)
Pes planus
Protrusio acetabuli
Ocular system
Ectopia lentis	Abnormally flat cornea Increased axial length of globe Hypoplastic iris or ciliary muscle
Cardiovascular system
Dilation of the ascending aorta	Mitral valve prolapse
Dissection of the ascending aorta	Dilation of main pulmonary artery, without obvious cause, below age 40 years
Pulmonary system
None	Spontaneous pneumothorax Apical blebs
Skin and integument
None	Striae atrophicae Recurrent or incisional hernias
Dura
Lumbosacral dural ectasia	None

Clinical Presentation

Ocular System

The hallmark manifestation of Marfan syndrome is ectopia lentis, or subluxation of the ocular lens, usually bilateral, which is found in 50 to 80% of patients and is often present at or soon after birth. Typically, the lens is displaced upward but the attached zonular fibers remain intact. Some patients can voluntarily replace the lens by head movement, and because the zonular fibers are intact, accommodation may occur. Iridodonesis, or tremor of the iris, indicates the presence of ectopia lentis. Slit-lamp examination as part of a complete ophthalmologic evaluation will directly demonstrate subluxation. Abnormally flat cornea, as measured by keratometry; increased axial length of the globe, as measured by ultrasound; and hypoplastic iris or ciliary muscle are all considered minor criteria for ocular involvement in the Marfan syndrome. Recent studies suggest the possibility of early development of cataracts and open-angle glaucoma.

Cardiovascular System

Progressive dilation of the aortic root and ascending aorta involving at least the sinuses of Valsalva and dissection of the ascending aorta are the major cardiovascular manifestations in the Marfan syndrome

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and may lead to rupture or aortic valvular incompetence with regurgitation. Echocardiography is the diagnostic procedure of choice for monitoring progression of aortic disease in children and adults with the Marfan syndrome. Uncommonly, dilation of the descending or abdominal aorta, or other major arteries, may occur, as well as dilation of the aortic annulus and may result in progressive aortic valvular incompetence with regurgitation manifested as heart failure. Mitral valve prolapse, a minor diagnostic criterion, can be demonstrated by echocardiography in about 80% of patients and may be associated with mitral regurgitation. Aortic regurgitation is both more common and hemodynamically more significant than mitral regurgitation.

Skeletal System

The skeletal manifestations that are characteristic of Marfan syndrome are common in the population, and, consequently, a constellation of several skeletal features must be present to meet diagnostic specificity. Typically, the affected individual is excessively tall for age and has disproportionately long and thin extremities (dolichostenomelia) (Fig. 10-21). Some patients have an apparent muscular hypoplasia, producing a gaunt and emaciated appearance. The palate may be narrow and high-arched, with dental crowding. Abnormality of the anterior chest (both pectus excavatum and carinatum) is common and often asymmetric. Scoliosis or kyphoscoliosis may develop, particularly during the adolescent growth spurt. The hands are narrow and the fingers long and thin (arachnodactyly or “spider fingers”). Joint hypermobility at major and minor joints is manifest by features such as genu recurvatum and flat feet (pes planus). Protrusio acetabuli, determined by radiography, is another skeletal finding useful for clinical diagnosis.

FIGURE 10-21 A young man with Marfan syndrome. Note his tall stature, narrow face, long limbs, and long fingers.

Skeletal disproportion is usually demonstrated in several ways. Arm span exceeds height, and the U/L ratio typically is greater than 2 standard deviations below the mean for race and age. Both these features reflect the relative increase in limb length as compared to trunk length. Metacarpal overgrowth (and joint hypermobility) may be demonstrated by the thumb sign, extension of the thumb past the ulnar border of the hand when apposed to the palm, and by the wrist sign, overlapping of the thumb and fifth finger when these fingers encircle the wrist.

Other Clinical Features

Spontaneous pneumothorax owing to rupture of pulmonary blebs, usually apical, may occur with or without thoracic deformity. Inguinal, femoral, or other hernias may be present and tend to recur following surgical repair. Striae distensae (striae atrophicae) of the skin are often present over buttocks, thighs, and shoulders. Dural ectasia may be an important diagnostic indicator in many patients. In fact, lumbosacral dural ectasia, determined by computed tomography or magnetic resonance imaging, is a major clinical criterion for diagnosis of the Marfan syndrome. Dural ectasia is usually asymptomatic and is thought to be less common in children.

Diagnosis

The clinical variability of Marfan syndrome makes unequivocal diagnosis difficult in mildly affected individuals and necessitates careful physical examination with anthropomorphic measurements, competent ophthalmologic and echocardiographic evaluations, and family studies. The accepted criteria for clinical diagnosis depend upon the presence or absence of an unequivocally affected first-degree relative. If there are no affected first-degree relatives, then diagnosis requires the presence of major criteria in at least two different organ systems and involvement of a third (Table 10-14). In the presence of documented family history of the Marfan syndrome, the presence of one major criterion and involvement of a second organ system are sufficient for diagnosis.

Since the molecular etiology of the Marfan syndrome is known, genetic studies can contribute to clinical diagnosis. For example, the presence of a mutation in the gene encoding fibrillin-1, FBN1, known to cause the Marfan syndrome, or the presence of an FBN1 haplotype, inherited by descent, and associated with unequivocal Marfan syndrome, is major diagnostic criterion. Both have been used for presymptomatic and prenatal diagnosis. In all instances, absence of homocystine in the urine in the absence of pyridoxine supplementation is necessary to rule out homocystinuria, a disorder that may share many features of Marfan syndrome. Other conditions often considered in differential diagnosis include familial or isolated mitral valve prolapse syndrome, familial or isolated annuloaortic

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ectasia (Erdheim disease), and Stickler syndrome (see Table 10-11).

Although definitive diagnosis will be achieved by adherence to specified criteria in most patients, there remains a group of patients with multiple features suggestive but not diagnostic of Marfan syndrome; such patients present a clinical dilemma. On the one hand, overenthusiastic diagnosis may provoke needless psychologic distress and may commit patient and family to extended and possibly lifelong intensive follow-up and drug therapy. On the other hand, nondiagnosis of the Marfan syndrome may place the patient at increased risk for unmanaged and potentially lethal complications. Molecular diagnosis should be strongly considered in such patients. Diagnosis of Marfan syndrome creates the obligation to carefully evaluate the patient's first-degree relatives for this disease.

Pathology and Etiology

The most extensive pathologic studies are those of the cardiovascular system, and the most common histologic manifestation is the so-called cystic medial necrosis, with degeneration of the elastic fibers, irregular hypertrophy of smooth muscle, and focal cystic areas filled with metachromatically staining materials. Valvular changes include thinned and stretched aortic valve cusps, endocarditis of the mitral valve, dilated mitral valve annulus, floppy mitral leaflets, and ruptured and elongated mitral chordae tendineae. Premature dilation of the sinuses of Valsalva is also seen and is a key feature for diagnosis. The glycoprotein fibrillin has been implicated in the etiology of Marfan syndrome. Molecular studies have now documented numerous mutations in the FBN1 gene; most mutations have been unique and thus observed in only one patient or family.

Management

The major goal is the prevention of complications of the disease and anticipation of the need for definitive surgical intervention. Morbidity and mortality are governed primarily by cardiovascular complications, and secondarily by musculoskeletal (eg, kyphoscoliosis, pectus deformities) complications and response to treatment.

Cardiovascular

The most important tool in the management of the cardiovascular complications in the Marfan syndrome is routine, annual or semiannual monitoring by echocardiography. More frequent echocardiographic monitoring may become necessary as aortic dilation or valvular insufficiency progresses. Because progressive aortic dilation typically (but not invariably) precedes dissection, prevention or delay of dilation and surgery prior to dissection or rupture is a central goal. When the aortic diameter reaches 50 to 55 mm (in an adult), surgical intervention must be considered, and a decision for surgery is based on considerations of the rate of aortic dilation, presence of aortic or mitral regurgitation, pulmonary function, age, and, possibly, previous experience with other affected family members. The use of β-adrenergic blockade has become ubiquitous in Marfan patients in an attempt to delay aortic dilation. Some evidence suggests, however, that this treatment is more efficacious in children than adults. Dosage must be tailored for each patient and treatment closely monitored, especially at the beginning. The use of calcium-channel inhibitors is an alternative therapeutic approach. Strenuous physical activity (heavy lifting, isometric exercise) and competitive athletics are contraindicated, but aerobic, noncompetitive exercise is important to overall fitness. Normal play for young children generally needs no restriction. People with the Marfan syndrome are at increased risk for bacterial endocarditis, and prophylactic antibiotics are recommended prior to dental or genitourinary procedures.

Ocular

Annual ophthalmologic evaluations should be obtained beginning in childhood. Patients should be carefully instructed to seek immediate help for onset of visual symptoms, and failure to detect visual problems may result in amblyopia. Dislocated lenses cause few problems in most people, but if the lens interferes with vision, the use of eyeglasses or contact lenses helps to achieve satisfactory vision with correction of refraction. Removal of a subluxated lens is rarely necessary. The eyes need to be protected from injury (sports involving blows to the head, eg, boxing, football), because people with the Marfan syndrome are at increased risk for retinal detachment.

Skeletal

Annual evaluation is critical for the well-being of the patient. Deformity of the spine or anterior chest can be disfiguring and/or may compromise respiratory and/or cardiovascular function. Either reason may require surgery. Bracing may be effective in stabilizing the spine and to avoid surgery. Chest wall deformities, if surgically repaired too early, may recur and intervention in midadolescence or later is recommended unless respiratory or cardiovascular function is reduced. Induction of puberty by exogenous hormonal administration may limit the degree of curvature and deformity caused by scoliosis or kyphoscoliosis and reduce final adult height, which may be advantageous for those individuals, especially girls, whose projected final height exceeds 6 feet. Experience has been favorable and not associated with undue side effects. Joint laxity may delay walking, but stability increases as the child grows and should minimize associated problems. Other orthopedic or surgical complications such as joint instability or various hernias are repaired for the usual indications.

Other

Psychological problems can emerge as a result of a diagnosis of the Marfan syndrome. Although most people cope well, the lifelong stigma and exclusion from sports, especially for boys, may require psychological counseling as part of complete management. Because of the narrow palate, tooth crowding may occur and good dental care, with orthodontic intervention, is required.

Pregnancy imposes increased risk for accelerated aortic dilation in women with Marfan syndrome. Women with moderate to severe cardiovascular involvement are at greatest risk, whereas women with minimal involvement generally tolerate pregnancy well. Genetic counseling regarding recurrence risks should be performed at an appropriate age. Prenatal diagnosis has been done by chorionic villus sampling and genetic linkage analysis.

EHLERS-DANLOS SYNDROMES

The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of connective tissue disorders that share, as fundamental features, alterations of the integrity of the supporting structures of the body. The cardinal manifestations of EDS are hyperextensible (“stretchy”) skin, hypermobile joints, easy bruisability, and dystrophic scarring. Concomitant generalized or localized fragility of various connective tissues leads to a variety of additional features in

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some EDS variants. These manifestations, together with the pattern of inheritance, serve as the basis for the diagnosis and subclassification into several varieties or subtypes. Although the exact prevalence of EDS is unknown, they are believed to be the most common heritable disorders of connective tissue. The spectrum of severity ranges from mild manifestations (thus frequently undiagnosed) to severe debilitation. Certain varieties of EDS are associated with an ominous prognosis.

EDS result from abnormalities of the connective tissues, and the clinical and genetic heterogeneity reflect in part an underlying molecular and biochemical heterogeneity. Recently, a simplified classification of EDS into six major types has been proposed and will be used for describing clinical ascertainment, management, and molecular etiology of each type (Table 10-15).

TABLE 10-15 CHARACTERISTICS OF MAJOR VARIANTS OF EHLERS-DANLOS SYNDROME


NEW DESIGNATION	PREVIOUS DESIGNATION	DIAGNOSTIC CRITERIA—MAJOR	DIAGNOSTIC CRITERIA—MINOR	INHERITANCE	MOLECULAR DEFECTS

Classical type	Type I (gravis) Type II (mitis)	Skin hyperextensibility Tissue fragility Atrophic scars Joint hypermobility	Smooth velvety skin Easy bruising Molluscoid pseudotumors Subcutaneous spheroids Muscle hypotonia Delayed gross motor development	AD	Type V collagen
Hypermobility type	Type III (hypermobile)	Joint hypermobility Skin hyperextensibility and/or smooth velvety skin	Joint dislocations Chronic joint/limb pain	AD	Unknown
Vascular type	Type IV (ecchymotic)	Thin, translucent skin Arterial/intestinal/uterine fragility or rupture Extensive bruising Characteristic facial appearance	Hypermobility of small joints Acrogeria Tendon and muscle rupture Talipes equinovarus Early-onset varicose veins Gingival recession	AD	Type III collagen
Kyphoscoliosis type	Type VI (ocular-scoliotic)	Generalized joint laxity Severe muscle hypotonia at birth Progressive scoliosis from birth Scleral fragility	Tissue fragility Easy bruising Arterial rupture Marfanoid habitus	AR	Lysyl hydroxylase deficiency
Arthrochalasia type	Types VIIA and VIIB (arthrochalasis multiplex congenita)	Severe joint hypermobility; recurrent subluxations Congenital bilateral hip dislocation	Skin hyperextensibility Tissue fragility Easy bruising Muscle hypotonia Kyphoscoliosis	AD	Type I collagen
Dermatosparaxis type	Type VIIC (human dermatosparaxis)	Severe skin fragility Sagging redundant skin	Soft, doughy skin texture Easy bruising Large hernias	AR	Procollagen I N-proteinase deficiency

AD = autosomal dominant; AR = autosomal recessive

All known molecular etiologies involve the biogenesis of the collagens, the major structural fibrous proteins of the body. Many varieties of collagens are known, each of which has a specific and unique distribution in the body, implying a specific functional role. Collagen biogenesis is complex and involves extensive modification of the proteins by different enzymes following synthesis and prior to assembly into biologically useful structural units (eg, fibrils, bundles). Thus, collagen defects might involve either a decrease or absence of a specific variety of collagen or structural abnormalities leading to defective assembly of collagen structural units.

Clinical Features

Skin

The skin in EDS is characteristic in texture and consistency but may vary in apparent thickness: Soft, doughy, and velvety to the touch, like the feel of wet chamois or of a fine sponge. Redundant skin over the hands and feet, is common, sometimes occurring over the stomach as well. When pulled, skin is hyperextensible, or “stretchy” (Fig. 10-22) but returns immediately to a normal configuration when released. Cutaneous hyperextensibility is virtually diagnostic of EDS, but this feature is minimal in several varieties. Hyperextensibility should be tested at a site not subject to mechanical forces or scarring (eg, volar surface of the forearm). Much subcutaneous fat in young children makes skin hyperextensibility difficult to assess.

FIGURE 10-22 Cutaneous hyperelasticity at the elbow in a 6-year-old boy with Ehlers-Danlos type I.

Cutaneous fragility or dermatorrhexis, manifested by splitting of the skin after insignificant trauma, may be a prominent feature. Typically, these wounds occur over the shins, knees, elbows, forehead, and chin, or other areas prone to trauma and tend to bleed little and often present a gaping “fish-mouth” appearance owing to retraction of the adjacent skin. Sutures may pull out of this fragile skin, leading to dehiscence of the wound. The cellular phase of wound healing proceeds normally, but acquisition of tensile strength is delayed. Characteristic so-called cigarette-paper or papyraceous scarring may occur; these scars appear thin, atrophic, shiny, and broad, and are often hyperpigmented and corrugated by fine wrinkles.

Easy bruisability is a major feature, may vary in severity, and may be the initial symptom in young children (child abuse must be considered in the differential diagnosis). Bruising may be generalized or restricted to trauma-prone areas such as the shins. Bleeding from the gums after brushing or dental extractions is also fairly common. Tests for coagulopathy are normal with the exception of a positive test for capillary fragility.

Other skin manifestations of EDS include the so-called molluscoid pseudotumors found typically at pressure points such as the heel, elbows, and knees; irregular firm subcutaneous masses resulting from fibrosis or calcification of hematomas; and small fat-containing cysts called spherules, which resemble phleboliths but may be easily distinguished by their subcutaneous location. Many EDS patients have highly wrinkled palms or soles manifested as adventitious palmar creases.

Joint Manifestations

Joint hypermobility is a cardinal feature of EDS but, as with the cutaneous manifestations, varies with the specific type of syndrome. Typically, joint hypermobility involves both large and small joints; with marked hypermobility, dislocations may be present at birth or occur later. The knees and elbows can be extended past 180° and the fingers extended past 90° from the palmar plane. Often the thumb can be apposed to the radius in flexion, extension, or both (Fig. 10-23). In some patients, feats of remarkable contortion, such as touching the elbows behind the back and placing the head between the knees while bending backward, may be performed easily. Joint mobility decreases with advancing age. Joint effusions may be relatively frequent. Hemarthrosis may occur, especially in vascular EDS. Ligamentous laxity is usually associated with joint hypermobility. Congenital clubfoot, apparently the result of ligamentous laxity and joint hypermobility coupled with intrauterine compression, is not uncommon. On occasions, marked apparent hypotonia with poor motor activity and muscular underdevelopment simulate neuromuscular disease in the newborn infant.

FIGURE 10-23 Joint hypermobility in a 5-year-old boy with Ehlers-Danlos syndrome, type III, benign hypermobile type.

Varieties of Ehlers-Danlos Syndromes

Table 10-15 outlines the six types of EDS, previous designation, diagnostic criteria, mode of inheritance, and molecular defect. Forms of previously classified EDS that do not fit in any of the major types will be noted at the end of this section.

The classical type (previously type I gravis and type II mitis) comprises the bulk of cases of EDS and is characterized by a wide range of severity of skin manifestations including skin hyperextensibility, dystrophic scarring, and marked bruising. The skin may also be smooth and velvety. Other skin lesions include molluscoid pseudotumors, associated with scars at pressure points, and subcutaneous bodies that may be calcified and radiographically detected. Tissue fragility may present surgical difficulties, and hernias may result postoperatively.

Joint hypermobility is also an important diagnostic criterion. Complications of hypermobile joints include sprains and recurrent dislocations often in the shoulder, patella, or temporomandibular joints. Joint hypermobility together with muscle hypotonia may result in delayed gross motor development.

Electron microscopy findings in skin demonstrate large collagen fibrils, many of which are irregular in cross-section. Recently, classical type of EDS was found to be caused by abnormalities of type V collagen. Type V collagen is a heterotrimer composed of the products of two genes, COL5A1 and COL5A2. Mutations have been identified in both genes. Genetic linkage studies can be used for prenatal or postnatal diagnosis in informative families. However, a few families have been excluded using these studies. Thus, the possibility that other genes may also cause EDS remains.

The hypermobility type (previously type III hypermobile) is the only major type of EDS in which the molecular basis remains unknown and is characterized by severe, generalized joint hypermobility with or without dislocations, hemarthroses, and precocious arthritis. Recurrent and frequent dislocations of the shoulders, patella, and temporomandibular joints are common. Skin manifestations

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(hyperextensibility and smooth and velvety) are mild but present, serving to distinguish this disorder from familial articular hypermobility syndrome. Musculoskeletal pain occurs early and becomes chronic. Inheritance is autosomal dominant.

The vascular type (previously type IV arterial/ecchymotic) exhibits considerable clinical heterogeneity, ranging from nearly normal to extensive, wide ecchymoses. The major manifestations of the vascular type of EDS include thin, often semitransparent skin; arterial, intestinal, and/or uterine fragility or rupture; extensive bruising; and a characteristic face. Minor diagnostic features include joint hypermobility limited to digits; acrogeria; talipes equinovarus; early-onset varicose veins; arteriovenous and carotid-cavernous sinus fistula; pneumothorax; gingival recession; and family history that may include sudden death in a close relative.

A prominent venous network over the anterior trunk can be frequently seen through the thin, translucent skin. Bruisability ranges from mild to severe, and some patients may never be free of extensive ecchymoses resulting from inapparent trauma (child abuse must be considered in the differential diagnosis). Large varicose veins may be present. Vasular EDS carry a serious prognosis because of a liability to catastrophic bleeding from defects in major arteries, which may occur without antecedent dilation or dissection and often without apparent trauma. Major bleeding ensues, and operative attempts at vascular repair are almost uniformly unsuccessful because the vessel walls are friable; conservative treatment, whenever possible, is recommended. Aneurysmal dilation and dissection of major vessels may occur. The prognosis for successful repair in patients is at present unclear. Because of the vascular fragility in these patients, angiographic studies are hazardous and should be attempted only for adequate cause and with caution to avoid perforation or dissection of vessels. Arterial rupture generally occurs in the third and fourth decades but may present earlier.

Although less common than arterial rupture, spontaneous rupture of the bowel (primarily large bowel) may recur repeatedly, possibly after intramural bleeding. Transient intestinal obstruction without perforation may also occur. The patient with vascular type EDS who presents with abdominal pain often poses a considerable diagnostic and treatment problem because obstruction, perforation, and arterial bleeding must all be considered, as well as other pathologies. Patients with constipation should be treated with dietary fiber and laxatives, because the use of enemas has caused fatal intestinal perforation in patients, including adolescents. Obstetrical complications have also been reported.

The characteristic facial appearance consisting of thin, pinched nose, thin lips, hollow cheeks, and prominent eyes is due to a decrease in adipose tissue. However, these characteristics are not readily apparent in children, making diagnosis without family history difficult.

The biochemical and molecular basis for this autosomal-dominant form of EDS has been identified as the absence, diminution, or structural abnormality of type III collagen. Numerous mutations

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in the COL3A1 have now been identified. Type III collagen is found principally in tissues of those organs that normally undergo physiological distention, such as blood vessels and hollow viscera. Although prenatal diagnosis is possible in families, there is an inherent risk in obtaining tissue because of its fragility. If vascular EDS are suspected, a skin biopsy should be taken for protein and genetic analysis.

The kyphoscoliosis type (previously type VI ocular-scoliotic) is an autosomal-recessive form of EDS caused by a deficiency of a collagen-modifying enzyme, lysyl hydroxylase. Carriers have about one-half normal levels of enzymatic activity. The major diagnostic criteria consist of joint laxity, severe muscle hypotonia and scoliosis at birth, and scleral fragility. Minor criteria include tissue fragility, easy bruising, arterial rupture, marfanoid habitus, microcornea, and osteopenia (detectable radiographically). Serious ocular problems are not as frequent as previously believed. The severe muscular hypotonia leads to delayed gross motor development, and kyphoscoliosis is progressive. The severity of this phenotype often results in loss of ambulation in the second and third decades of life. Differential diagnosis includes the neonatal form of the Marfan syndrome. A diagnosis of kyphoscoliosis type of EDS should be considered in a “floppy infant.”

Individuals who are either homozygous or compound heterozygotes for mutations in the gene encoding lysyl hydroxylase (PLOD) have been identified. Lysyl hydroxylase normally converts certain lysine residues in collagen to hydroxylysine. Measurement of total urinary hydroxylysyl pyridinoline and lysyl pyridinoline has a high degree of sensitivity and specificity. Dermal lysyl hydroxylase activity and PLOD mutation analysis can also be performed but are not generally available. A rarer and less severe form with normal lysyl hydroxylase activity has also been reported.

The arthrochalasia type (previously types VIIA and VIIB arthrochalasis multiplex congenita) is an autosomal-dominant condition. Typically, infants are born with bilateral hip dislocations and exhibit extreme ligamentous laxity with dramatic hyperextension at the knees and elsewhere. Recurrent joint subluxations are common. Minor diagnostic manifestations are muscular hypotonia, easy bruising, tissue fragility with atrophic scars, kyphoscoliosis, skin hyperextensibility, and mild osteopenia. These factors contribute to breech presentation and delayed gross motor development. The differential diagnosis should include Larsen syndrome.

The defect is caused by the skipping of exon 6 in either the 1 or 2 chains of type I collagen. Type I collagen is the most abundant collagen in skin and bones. Exon 6 encodes the cleavage site for the procollagen I N-terminal peptidase. The absence of the cleavage site causes the persistance of the N-propeptide and the secretion of longer than normal molecules. Biochemical analysis of skin fibroblast collagen may be used for laboratory diagnosis. Electron microscopy has shown irregular and loosely organized collagen fibrils.

The dermatosparaxis type (previously type VIIC human dermatosparaxis) is an autosomal-recessive form of EDS that is caused by a deficiency of the procollagen I N-terminal peptidase. The major diagnostic criteria are severe skin fragility and sagging, redundant skin. Minor manifestations include soft, doughy skin, easy bruising, premature rupture of fetal membranes, and large umbilical or inguinal hernias. Although skin fragility and bruising are prominent, wound healing is normal, and scars are not atrophic. Redundant skin produces a facial appearance similar to children with cutis laxa.

This type of EDS is the recently identified human counterpart of the long-known ovine and bovine disease dermatosparaxis. Electron microscopy of skin has demonstrated ribbon-like collagen fibrils and hieroglyphic shapes such as those seen in dermatosparactic animals. Biochemical confirmation of type I collagen abnormalities is the same as that for the arthrochalasia type. Determination of N-proteinase activity and identification of genetic mutations are not generally available. Individuals either homozygous or compound heterozygotes for mutations have been identified.

Other forms of EDS have appeared in the literature, yet it is unclear whether they are separate entities. Type V, which is X-linked, has only been described in one family. Type VIII is similar to the classical type but presents with periodontal disease, is rare, and may not be a distinct entity. Finally, type X has also been described in one family with many of the cardinal features of EDS, autosomal-recessive inheritance, and abnormal platelet aggregation owing to a fibronectin defect.

Diagnosis of Ehlers-Danlos Syndromes

Most types of EDS are usually readily diagnosed by observation of soft, doughy, hyperelastic skin, joint hypermobility, and easy bruisability. Vascular EDS, by contrast, may be difficult to recognize owing to subtlety of cutaneous features and limited joint findings; easy bruisability, thin skin, and a prominent venous pattern over the anterior trunk may be the major clinical findings. Misdiagnoses typically occur because hyperelasticity of skin is missed and may result in inappropriate investigation (eg, extensive hematologic workup for easy bruising) or inappropriate diagnosis (eg, child abuse). The current revised classification of EDS was designed to refine more specifically the diagnostic criteria for each type of EDS. Because of the prognostic implications, biochemical or molecular confirmation of the vascular and kyphoscoliosis types should be obtained; the latter disease may also be ameliorated by therapy.

Treatment

Complications caused by tissue fragility and biomechanical incompetence may cause considerable morbidity. The major goals are preventive therapy and careful surgical repair of serious complications. Use of shin guards, high-topped boots, and knee pads and limiting physical contact activities have substantially decreased skin splitting, excessive bruising, and dystrophic scarring over the lower extremities. Prolonged wound fixation by stay sutures and taping may prevent dystrophic scarring and dehiscence, and these measures should be continued for about twice as long as usual. Surgical repair of hernias, diverticulae, prolapses, and the like should be accomplished with due consideration of the underlying tissue fragility and delayed recovery of tensile strength; the use of simple precautions to prevent postoperative disruption will almost always be successful.

Scarring and easy bruisability are sometimes a cosmetic problem, and vitamin or other hematinic therapy is of no value. Prolonged bleeding after surgery has been observed in some instances and should be considered prior to intervention. Patients with vascular EDS may be at risk for hemorrhage, and surgery is usually high risk.

The enzyme deficient in kyphoscoliosis type, lysyl hydroxylase, requires ascorbic acid as one cofactor. In selected patients, vitamin C supplementation has increased enzymatic activity. Recurrent dislocations, chronic effusions, and progressive kyphoscoliosis may require surgical repair (usually with limited success).

Recent evidence has begun to suggest that individuals with classical and perhaps hypermobility types of EDS are at risk for progressive aortic root dilation. However, recommendation that patients with these forms of EDS undergo routine echocardiography, similar to that for individuals with the Marfan syndrome, is, for now, premature.

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References

Burrows NP: The molecular genetics of the Ehlers-Danlos syndrome. Clin Exper Dermatol 24:99–106, 1999

Depaepe A, Devereux RB, Dietz HC, et al: Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 62:417–426, 1996

Rossi Foulkes R, Roman MJ, Rosen SE, et al: Phenotypic features and impact of beta blocker or calcium antagonist therapy on aortic lumen size in the Marfan syndrome. Am J Cardiol 83:1364–1368, 1999

10.3.7 Neurocutaneous Disorders

David H. Viskochil

Neurofibromatosis types 1 and 2 (NF1 and NF2), tuberous sclerosis complex (TSC1 and TSC2), and von Hipple Lindau disease (VHL) are neurocutaneous disorders that are loosely classified as phakomatoses (Chap. 25). Additional neurocutaneous conditions are discussed in Sec. 25.18.

The phakomatoses are generally autosomal-dominant conditions that show a consistent pattern of abnormal growth of various tissue, and each affected individual has unique and unpredictable manifestations. The variability of clinical expression of cutaneous manifestations and tumors distinguishes these disorders from other genetic conditions and has multiple causes, including modifier loci, somatic mutation, and simple stoichiometry in cells with haploinsufficiency of the respective neurocutaneous gene. Somatic mutation leading to inactivation of the normal neurocutaneous gene allele, termed second hits, in individuals who have a constitutional mutation is a common theme and suggests that genes causing neurocutaneous disorders fit the paradigm of “tumor suppressors.” Characterization of these genes has led to the identification of biochemical pathways involved in intracellular growth-signaling, information that will lead to the development of novel therapeutic regimens strategically targeted to the regulation of growth of benign tumors associated with these conditions.

NEUROFIBROMATOSIS 1

Clinical Aspects

Neurofibromatosis type 1 is the most common neurocutaneous disorder, affecting about 1 in 3000 people worldwide. The hallmark features of NF1, café-au-lait spots and benign cutaneous neurofibromas, typically arise before the ages 5 and 15, respectively. Approximately two-thirds of individuals with NF1 have only these neurocutaneous manifestations, whereas the remaining one-third display myriad medical complications that are unpredictable, both in timing and severity.

Even though NF1 has been recognized as von Recklinghausen disease by the medical community since the nineteenth century, both its variability and age dependence of clinical manifestations made it essential to establish a well-accepted set of clinical criteria (Table 10-16). The presence of at least two of seven criteria establishes the diagnosis. The typical clinical manifestations allow the diagnosis to be established in children by age 10 years. By virtue of full penetrance in the adult population, NF1 is more straightforward to diagnose in familial cases because it requires only one physical manifestation in addition to an affected first-degree relative. In sporadic cases, NF1-related associations that are not part of the diagnostic criteria sometimes appear prior to the development of a second diagnostic sign.

TABLE 10-16 DIAGNOSTIC CRITERIA FOR NF1 (NEUROFIBROMATOSIS 1)

Six or more cafe-au-lait macules of over 5 mm in greatest diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals
Two or more neurofibromas of any type or one plexiform neurofibroma
Freckling in the axillary or inguinal regions
Optic glioma
Two or more Lisch nodules (iris hamartomas)
A distinctive osseous lesion such as sphenoid dysplasia or thinning of the long bone cortex with or without pseudarthrosis
A first-degree relative (parent, sibling, or offspring) with NF1 by the above criteria

Stumpf DA: Neurofibromatosis: NIH Consensus Statement. 6(12):1-19, 1987; Gutmann DH, et al: The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA, 278:51–57, 1997.

The typical pattern of clinical presentation in NF1 is age-dependent. Usually, multiple café-au-lait spots (CLS) are identified in the first 2 years of life (Fig. 14-13). The observation of greater than five CLS that are greater than 0.5 cm in diameter in toddlers is a classical presentation, but a number of other conditions include multiple CLS (ie, McCune-Albright syndrome), although other signs and symptoms generally enable exclusion of other diagnoses fairly easily.

Intertriginous freckling, which usually involves the axillae and groin areas, occurs in approximately three-quarters of individuals with NF1 who present with multiple CLS and this sign develops by late childhood (Fig 14-13). Lisch nodules can be identified by slit-lamp exam in over 75% of preadolescents.

Neurofibromas are benign peripheral nerve sheath tumors that are a collection of Schwann-like cells, fibroblasts, and extracellular matrix. Cutaneous neurofibromas tend to appear at the time of puberty and progress in number. Dermal neurofibromas can be difficult to detect at their outset and are often most easily palpated along the flanks and lower abdomen as slight depressions rather than bumps. Plexiform neurofibromas, however, are thought to be congenital malformations that tend to present before adolescence. Actively growing plexiform neurofibromas in infancy require a significant amount of medical attention, as these tumors are diffuse, and may extensively entwine internal organs. Only the larger plexiform neurofibromas have a propensity to undergo malignant transformation, and this is rare in the pediatric population.

Optic pathway tumors affect approximately 15% of individuals with NF1, and only half of these are symptomatic. Symptomatic tumors tend to arise in the toddler and early childhood years, and optic pathway tumors rarely develop after puberty.

The skeletal features of NF1 are also age-dependent. Sphenoid wing dysplasia, long-bone bowing with pseudarthrosis, and dysplastic scoliosis all tend to present in infancy or early childhood. The pathophysiology of the various skeletal features is not understood, and it challenges the paradigm of NF1 being a disorder of neural crest origin. Some of the skeletal manifestations are clearly of primary mesodermal origin rather than a secondary reaction to either altered blood supply or the presence of an associated tumor. Both dysplastic scoliosis and pseudarthrosis of long bones are primary defects that require significant orthopedic management and do not usually arise in the context of either plexiform or paraspinal neurofibromas. Like cutaneous neurofibromas, paraspinal neurofibromas tend to arise in later childhood and adolescence. In general,

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these tumors are asymptomatic unless they compress either nerve roots or adjacent spine.

Individuals with NF1 are prone to a number of medical complications that are quite varied, although it is rare that any one individual has more than one major complication. Approximately 40 to 50% have speech impediments and learning problems, which are not specific to NF1. Early recognition and treatment within the educational environment can effectively deal with NF1-related learning problems, which is one reason to provide a provisional diagnosis of NF1 in sporadic cases who only have multiple café-au-lait spots. Short stature, macrocephaly, hypertension, constipation, and chronic headaches are other NF1-related features. Dysplastic scoliosis, deep plexiform neurofibromas, low-grade astrocytomas of the CNS, spinal neurofibromas, malignant peripheral nerve sheath tumors, pheochromocytomas, rhabdomyosarcomas, and myelogenous leukemia are a few of the more serious medical complications associated with NF1.

Molecular Aspects

The NF1 gene spans approximately 335 kb of genomic DNA and is ubiquitously expressed, although the highest level of expression is in the central nervous system. NF1 acts as a tumor suppressor by diminishing signaling through MAPK pathway.

The high sporadic incidence of NF1 suggests that the gene is highly mutable, and it has been calculated that 1 in 10,000 gametes harbor an inactivating NF1 mutation. This propensity for mutation has yet to be adequately explained. The high germ-line mutation rate likely carries over to somatic mutation, which would support the “tumor suppressor” model for NF1 and provide an explanation for the variable and progressive nature of some clinical features. Random acquisition of somatic inactivation of the normal NF1 allele (the second hit) in tissue showing abnormal growth could explain the age-related clinical presentation of many NF1 features, ie, neurofibromas, optic nerve pathways tumors, and dysplastic scoliosis. Leukemia cells, cutaneous neurofibromas, malignant peripheral nerve sheath tumors, and pheochromocytomas have all demonstrated either loss of heterozygosity or homozygous inactivation of NF1.

Management

Approximately half of the individuals with NF1 seen in North America and Europe are sporadic cases. Even though there is a high sporadic incidence, once it is established within a pedigree NF1 behaves like any other autosomal-dominant condition whereby there is a 50% risk for occurrence in each child conceived by an affected parent. However, unlike many other autosomal-dominant conditions, the lack of a genotype-phenotype correlation means that affected family members who have the same NF1 mutation usually have different manifestations. To date, the only evidence for a genotype-phenotype correlation lies with the patients who have large whole-gene deletion and seem to share a phenotype marked by an unusually large number of neurofibromas that present at an earlier age, distinctive facial features differing from family background, and decreased level of intellectual functioning. Most medical complications of NF1 are managed surgically; however, there is clearly a role for “watchful waiting” in this condition.

The clinical recognition of NF1 signifies a need for periodic ophthalmologic evaluations that may not otherwise be performed. Anticipatory guidance counseling encompasses features that are not included in the diagnostic criteria (Table 10-17) but represents age-related concerns of NF1.

TABLE 10-17 ANTICIPATORY GUIDANCE IN NF1

Newborn–2 years
  Café-au-lait spots for diagnosis
  Long bone bowing
  Plexiform neurofibromas
  Optic pathway tumor
  Developmental delay

2–10 years
  Optic pathway tumors
  Plexiform neurofibromas
  Scoliosis
  Hypertension
  Freckling patterns
  Learning problems

10–20 years
  Onset of dermal neurofibromas
  Learning problems
  Self-esteem
  Scoliosis
  Plexiform neurofibromas
  Reproductive decisions
  Hypertension

Adult years
  Offspring
  Progression of dermal and plexiform neurofibromas
  Malignant peripheral nerve sheath tumors
  Hypertension

TUBEROUS SCLEROSIS COMPLEX

Clinical Aspects

Tuberous sclerosis is an autosomal-dominant condition that may affect as many as 1 in 5700 to 1 in 10,000 people, worldwide. Tuberous sclerosis complex (TSC) clinically manifests in many ways as evidenced in the diagnostic criteria outlined in Table 10-18. The hallmark cutaneous features include ash-leaf hypopigmented macules, shagreen patches, facial angiomas and forehead plaques, and ungual and gingival fibromas (Plate 7). The multisystem involvement of TSC is much broader than the other neurocutaneous disorders. Unlike the other common phakomatoses conditions, TSC carries a higher risk for mental retardation, especially when associated with seizures in the first year of life. A difficult diagnostic and counseling issue in TSC is the incomplete penetrance of this condition. Unlike NF1, where affected adults can be readily identified, mild cases of TSC have often been diagnosed only when an affected first-degree relative with TSC has prompted an imaging workup that identifies an asymptomatic manifestation (see Table 10-19). The broad variability of clinical expression within individuals and families with multiple affected members is similar to NF1.

TABLE 10-18 DIAGNOSTIC CRITERIA FOR TUBEROUS SCLEROSIS COMPLEX (TSC)


PRIMARY FEATURES	SECONDARY FEATURES	TERTIARY FEATURES

Facial angiomas Multiple ungual fibromas Cortical tuber (histologically confirmed) Subependymal nodule or giant cell astrocytoma (histologically confirmed) Multiple calcified subependymal nodules protruding into the ventricle (radiographic evidence) Multiple retinal astrocytomas	Affected first-degree relative Cardiac rhabdomyoma (histologic or radiographic confirmation) Retinal hamartoma other than astrocytoma or achromatic patch Cerebral tuber (radiographic confirmation) Noncalcified subependymal nodules (radiographic confirmation) Shagreen patch Forehead plaque Pulmonary lymphangiomyomatosis (histologic confirmation) Renal angiomyolipoma (histologic or radiographic confirmation) Renal cysts (histologic confirmation)	Hypomelanotic macules Confetti skin lesions Renal cysts (radiographic evidence) Randomly distributed enamel pits in deciduous and/or permanent teeth Hamartomatous rectal polyps (histologic confirmation) Bone cysts (radiographic confirmation) Pulmonary lymphangiomyomatosis (radiographic confirmation) Cerebral white-matter migration tracts or gingival fibromas Hamartomas of other organs (histologic confirmation) Infantile spasms

DIAGNOSTIC DEFINITION OF TSC

Presence of either one primary feature and two secondary features or one secondary feature plus two tertiary features—definite TSC Presence of either one secondary plus one tertiary feature or three tertiary features—probable TSC Presence of either one secondary feature or two tertiary features—suspected TSC

SOURCE: Hyman MN, Whitemore VN, NIH Consensus Conference: Tuberous Sclerosis Complex. Arch Neurol 57: 662–665, 2000.

TABLE 10-19 TSC MANAGEMENT


		SURVEILLANCE INITIAL SCREEN OF
	SUSPECTED CASE	KNOWN CASE WITH NO SYMPTOMS	KNOWN CASE WITH SYMPTOMS	FIRST-DEGREE RELATIVE AT TIME OF DIAGNOSIS OF AFFECTED INDIVIDUAL

Funduscopic examination	R	NR	R	R
Brain MR/head CT imaging	R	R^a	R	R^b
Brain EEG	NR^c	NR	R^d	NR
Cardiac ECG and ECHO	R	NR	R^e	NR^f
Renal MR, CT, or ultrasound imaging	R	R^g	R^e	R^h
Dermatologic screening	R	NR	R^d	R
Neurodevelopmental testing	R	Rⁱ	R^d	NR
Pulmonary CT	NR	NR^j	R^d	NR

R = indicates screening recommended; NR = screening not recommended; MR = magnetic resonance, EEG = electroencephalogram; ECG = electrocardiogram; ECHO = echocardiogram; and CT = computed tomography.
^aEvery 1 to 3 years.
^bWith negative physical examination results, CT screen is recommended.
^cUnless seizures are suspected, generally not useful for diagnosis.
^dAs clinically indicated.
^eEvery 6 months to 1 year until involution or size stabilization occurs.
^fProbably less frequently than in children.
^gEvery 3 years until adolescence.
^hUltrasound is generally recommended because of cost, although local imaging expertise may vary.
ⁱRecommended for children at the time of beginning first grade.
^jBaseline screen at age 18.

The typical clinical presentation for TSC is much less predictable than for NF1. Recognition of TSC by physical examination in older children and adults is straightforward. However, the diagnosis is often complicated both by the age dependency of many features and by incomplete cutaneous manifestations of TSC. Identification of hamartomatous involvement of various organs in TSC is necessary for both diagnosis and anticipatory guidance. Prenatal cardiac rhabdomyomas identified by fetal ultrasonography may be the earliest sign of TSC and typically regress over an individual's lifetime. The prevalence of these tumors in TSC in infancy is over 50%, which makes echocardiography one of the more reliable diagnostic screening tests in that age group. Cardiac rhabdomyomas are not

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predictive of other TSC-related features and usually do not cause severe morbidity.

Infantile spasms are considered a tertiary feature of TSC, and approximately 50% of all infants with this type of seizure activity have TSC. The onset of seizures before 1 year of age predicts more significant mental impairment and greater numbers of cortical tubers on brain imaging studies. Regardless of seizure status, both cortical tubers and subependymal nodules become evident by brain imaging in early childhood.

Hypopigmented spots of ash-leaf character can be seen in all ages, even newborns, and, unlike the café-au-lait macules, enhancement with a Wood's lamp may be useful in the diagnostic clinical examination. The hypopigmented skin findings of TSC are not specific; however, the manifestation of clustered spots in a confetti-like

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presentation, in addition to the typical ash-leaf spots, may be the only physical features in the childhood years. Fibrous plaques involving the cranium can also occur in infancy, but other cutaneous features such as adenoma sebaceum and multiple ungual fibromas (primary criteria), and the shagreen patch (secondary criteria), typically present later in life, even after adolescence.

Of the renal manifestations, cysts usually are common in childhood and may be confused with polycystic kidney disease, whereas angiomyolipomas typically arise in middle age and have been found in approximately two-thirds of individuals with TSC who have had an autopsy. Retinal astrocytomas, pitted enamel hypoplasia, and rectal polyps are found in over one-half of TSC patients. All these findings can arise in childhood and should be considered in the diagnostic workup. Finally, pulmonary lymphangioleiomyomatosis, a rare complication of TSC, typically develops in females in the third or fourth decade. The age dependence of the various manifestations of TSC is an important concept that must be considered in the management of pediatric cases of TSC.

Molecular Aspects

Linkage studies have demonstrated that TSC is a genetically heterogeneous condition, mapping to either chromosome 9 (band 9q34.3) or chromosome 16 (band 16p13.3). The TSC1 gene has been isolated, and the gene product, hamartin, is unique with no known function, although it interacts with the ezrin-radixin-moesin family of binding proteins. Complexes between hamartin and ERM-family proteins are proposed to act through a small GTP-binding protein, rho, to mediate a signal transduction pathway, which regulates cell adhesion properties.

The TSC2 gene has also been cloned and partially characterized. TSC2 encompasses approximately 43 kb of genomic DNA, and its 5.5-kb transcript encodes a novel 190- to 200-kDa protein designated tuberin. A small domain at the carboxyl end of tuberin bears homology to the catalytic domain of the GTPase activating protein called rap1GAP, which suggests that tuberin could down-regulate Rap1a-activated mitogenic signaling in specific cell types. Genetic analysis of the TSC1 and TSC2 locus supports a role as a loosely defined tumor suppressor.

Management Issues

TSC is so broad that individuals who may be only mildly affected are at risk of having offspring who may be severely affected. Likewise, the diagnosis of TSC could modify diagnostic evaluations for developmental delay and circumvent unneeded studies.

Like other neurocutaneous disorders, the clinical care of TSC patients is devoted to control of symptoms. Medical management of seizures and cardiac arrhythmias associated with cardiac rhabdomyomas is an important issue to consider. A recommendation of vigabatrin as the drug of first choice to treat TSC infantile spasms has been proposed by an NIH consensus conference. Implementation of surveillance protocols for renal and pulmonary tumors is also important to identify those rare cases early in tumor progression.

NEUROFIBROMATOSIS 2

Clinical Manifestations

Neurofibromatosis 2 (NF2) is an autosomal-dominant condition whose hallmark is the presence of bilateral vestibular schwannomas, previously called acoustic neuromas. The incidence of this condition is estimated at about 1 in 33,000 to 1 in 40,000. Even though NF2 is a neurocutaneous condition with variable clinical expressivity, there is almost complete penetrance by 60 years of age. Diagnostic criteria have been established as shown in Table 10-20. Even though the mean age of onset of symptoms is in the third decade, clinical presentation in childhood is not rare.

TABLE 10-20 DIAGNOSTIC CRITERIA FOR NF2 (NEUROFIBROMATOSIS 2)

Bilateral vestibular schwannomas, either proven histologically or seen by MR imaging with gadolinium enhancement.
A parent, sibling, or child with NF2 and either a unilateral vestibular schwannoma or two or more of the following:
Schwannoma
Posterior subcapsular lenticular opacities
Cerebral calcification
Unilateral vestibular schwannoma and two or more of the following:
Meningioma
Glioma
Schwannoma
Posterior subcapsular lenticular opacities
Cerebral calcification
Multiple meningiomas (two or more) and one or more of the following:
Glioma
Schwannoma
Posterior subcapsular lenticular opacities
Cerebral calcification

SOURCE: Evans DG, Huson SM, Donnai D, Neary W, Blair V, Newton V, Strachan T, Harris R: A genetic study of type 2 neurofibromatosis in the United Kingdom. II. Guidelines for genetic counselling. J Med Genet 29(12):847-852, 1992; adapted from Huson SM, Rosser EM: The phakomatoses. In: Rimon DL, Connor JM, Pyeritz RE, eds: Emery and Rimoin's Principles and Practice of Medical Genetics, 3rd ed. New York, Churchill-Livingstone, 1997, 2269–2302

The presenting symptoms of NF2 are usually related to the vestibular schwannomas: hearing loss, tinnitus, imbalance, and facial weakness. Vestibular schwannomas are found in approximately 95% of individuals with NF2 and are bilateral in 90%. Other CNS tumors occur in approximately one-half of individuals with NF2 and include intracranial meningiomas, spinal schwannomas, cranial nerve schwannomas (the fifth cranial nerve being most common), and ependymomas. Presenile lens opacities or cataracts occur in 50 to 75% of individuals with NF2 and serve as an early clinical sign of the disorder that can be used as a screening modality in the pediatric population. Cutaneous manifestations of NF2 include CLS and skin tumors. Usually there are fewer than 5 CLS. The dermal tumors are either characteristic plaque-like lesions or subcutaneous nodules that are pathologically diagnosed as schwannomas. There are two major clinical forms of NF2. The Gardner subtype is milder with later onset of symptoms and few intracranial or spinal tumors, whereas the Wishart subtype is earlier in onset, more rapid in progression of hearing loss, and has an increased occurrence of intracranial and spinal tumors.

Mapping of NF1 to chromosome 17 and NF2 to chromosome 22 underscores the clinical impression that these two conditions are distinct entities, especially because NF2 does not have neurofibromas.

Molecular Aspects

NF2 genetically maps to the long arm of chromosome 22, and its gene encodes a 595-amino-acid cytoplasmic protein that shares homology with a family of cytoskeletal-associated proteins (ezrin, radixin, and moesin).

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This ERM family of proteins mediates communication between the extracellular milieu and the intracellular cytoskeleton. The NF2 gene product, called either merlin or schwannomin, is unusual because as a structural protein it has tumor suppressor properties. Inactivating mutations correspond to the more severe Gardner phenotype, whereas the milder Wiscott phenotype corresponds to missense and splice-site mutations. Somatic mutation also plays a significant role in the pathology of this condition. Loss of the normal allele in NF2-related tumors has been demonstrated, which supports the hypothesis that NF2 is a bonafide tumor suppressor gene.

Management

Individuals suspected of having NF2 should undergo a comprehensive initial investigation to identify CNS tumors, skin manifestations, and eye findings. Neurosurgical management provides many options, and referral to a center experienced in NF2-related tumors, both adult and pediatric, is warranted. Audiologic evaluations and early facilitation of communication skills in individuals who are at risk for either progressive deafness or acute hearing loss secondary to surgical intervention is important. Genetic linkage studies are warranted in established families. In informative families, linkage analysis could identify those individuals who carry a mutated NF2 gene. Those who have not inherited the chromosome 22 harboring the mutated gene do not need to undergo routine and costly screening tests.

Hearing screens, ophthalmologic evaluations, and radiologic screening in presymptomatic individuals is an important component of NF2 management. Such screening could detect a significant number of presymptomatic adolescents. At-risk screening for vestibular schwannomas is recommended in late childhood with annual sensitive hearing evaluations, including brainstem evoked response testing. MR screening to detect vestibular schwannomas when the tumors are small enough to be surgically removed with preservation of hearing is recommended. A normal MR imaging in late adolescence reduces the likelihood that an at-risk individual has NF2 by 50%, and a normal scan at 30 years of age makes it unlikely that such an at-risk individual has NF2.

VON HIPPEL-LINDAU SYNDROME

Clinical Aspects

Von Hippel-Lindau disease (VHL) is an autosomal-dominant condition characterized by a predisposition to develop tumors in the eyes, central nervous system, kidneys, pancreas, and adrenal gland. Most manifestations of VHL initially present in early adulthood, except for the cardinal features, retinal angioma and cerebellar hemangioblastoma, which can present in the first decade and teenage years, respectively. The well-established diagnostic criteria for the diagnosis of von Hippel-Lindau syndrome are outlined in Table 10-21. The prevalence has been estimated to be about 1 in 40,000 to 50,000 people. Like other neurocutaneous conditions, VHL demonstrates marked variability of clinical expression and relatively high penetrance in the adult population. Imaging studies are helpful to identify asymptomatic individuals who have characteristic malformations and tumors.

TABLE 10-21 DIAGNOSTIC CRITERIA AND SCREENING PROTOCOL FOR VON HIPPEL-LINDAU SYNDROME

Diagnostic criteria:
More than one hemangioblastoma of the central nervous system or retina, or an isolated hemangioblastoma in association with a pheochromocytoma, renal carcinoma, or pancreatic involvement
A first-degree relative with von Hippel-Lindau syndrome and any one manifestation
Screening for affected individuals:
Annual physical examination and urine testing
Annual ophthalmology evaluations
Brain MR scan every 3 years to age 50 and every 5 years thereafter
Annual abdominal MR scan
Annual 24-h urine collection for vanillylmandelic acid
Screening for at-risk relatives:
Annual physical examination and urine testing after age of 5 years
Annual ophthalmology evaluations from age 5 until age 60
Brain MR scan every 3 years from age 15 to 40 years and every 5 years thereafter
Annual abdominal MR from age 20 to age 60
Annual 24-h urine collection for vanillylmandelic acid

SOURCE: Maddock IR, Moran A, Maher ER, Teare MD, Norman A, Payne SJ, Whitehouse R, Dodd C, Lavin M, Hartley N, Super M, Evans DG: A genetic register for von Hippel-Lindau disease. J Med Genet 33(2):120–127, 1996

The cerebellar hamangioblastoma associated with VHL differs from sporadic forms of this tumor, presents earlier in life, and consists of multiple tumors. Symptoms are similar to any posterior fossa tumor, but the majority of VHL-related tumors are cystic rather than solid. Angiomas of the eye occur in approximately half of patients with VHL, and about one-third are bilateral. Without screening, these retinal tumors are usually detected in the second and third decades of life. Hemorrhage, retinal detachment, and visual loss can all occur if not recognized early and treated. At-risk family members are routinely screened for these manifestations as shown in Table 10-21. Other CNS lesions and visceral tumors of VHL present later in life. Renal cell carcinoma usually presents in the fourth decade of life and occurs in approximately 25 to 40% of patients with VHL. A genotype-phenotype correlation with respect to pheochromocytoma in families with VHL occurs, and those families with pheochromocytoma appear less likely to develop renal carcinoma.

Molecular Aspects

VHL genetically maps to chromosome 3p25, and the disease-causing gene is composed of three exons that encode a protein of 213 amino acids. The gene is ubiquitously expressed, and the unique VHL protein (pVHL) is present both in the nucleus and cytoplasm of cells; pVHL plays a role in regulating expression of hypoxia-response genes. The most characterized function of pVHL is its role in transcription elongation. Thus, inactivation of pVHL by mutation of the gene leads to unregulated elongation of transcription of oncogenes and results in tumor growth.

Germ-line mutations can be detected in approximately 75% of families with VHL. The apparent genotype-phenotype correlation with respect to pheochromocytoma may arise as a consequence of missense mutations, whereas “inactivating” mutations are not associated with pheochromocytoma. The identification of second hits in the VHL gene in tumor tissue from individuals with VHL demonstrates that it is a classical tumor suppressor (see Sec. 20.2).

Management

The variability of age of onset of the various tumors makes diagnosis and screening for VHL somewhat ineffective. More than 60% of

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patients do not have the hallmark features of VHL. Thus, more than other neurocutaneous disorders, characterization of the VHL gene allows for effective and appropriate presymptomatic screening by DNA analysis to determine affected status of at-risk family members. The clinical screening protocols for VHL are more extensive than in the other neurocutaneous disorders; therefore clarification of the at-risk status by DNA analysis has a major impact on the diagnostic imaging performed in this condition.

References

Friedman JM, Gutmann DH, MacCollin M, Riccardi VM: Neurofibromatosis: Phenotype, Natural History, and Pathogenesis, 3rd ed. Baltimore, Johns Hopkins, 1999

Hyman MH, Whittemore VH: National Institutes of Health Consensus Conference: Tuberous sclerosis complex. Arch Neurol 57:662–665, 2000

10.3.8 Environmental Causes of Birth Defects

Lynne P. Martinez

Julia Robertson

Marsha Leen-Mitchell

The very definition of a teratogen—any agent, external to the fetal genome, that induces structural or functional alterations during prenatal development—suggests that the clinicians' first encounter may be well after the (prenatal) exposure has occurred. Knowledge of the principles of teratology can direct diagnostic and treatment approaches to a child with dysfunction or dysmorphology of unknown etiology and can be instrumental in guiding initial evaluations well as physician-patient-parent interactions.

TYPES OF PRENATAL EXPOSURES

MEDICATIONS

Few pregnancies progress to term without the use of at least one medication, whether prescription or nonprescription drugs, herbal remedies, or nutritional supplements. If vitamins and minerals are excluded, an average of three to four medications are used during the course of a pregnancy, with analgesics being the most commonly reported. Other common categories include cough and cold products, antacids, antihistamines, antiemetics, barbiturates or sedatives, and antibiotics.

CHEMICALS

Given the growing number of chemical agents being developed or sold for both home and industrial environments, pregnant women are increasingly vulnerable to chemical exposures. Although many such compounds do not appear to be teratogenic to humans, limited human data exist to develop risk assessment. In most cases, however, symptoms of maternal poisoning are present when teratogenic chemical exposure occurs.

INFECTIONS

Infections of primary concern during pregnancy include “childhood” diseases such as varicella and some sexually transmitted diseases such as HIV. When the mother only is exposed to the disease, the fetus is not at risk; fetal effect occurs only when the pregnant woman acquires the active infection.

CHRONIC MATERNAL CONDITIONS

Chronic medical conditions such as insulin-dependent diabetes mellitus or systemic lupus can be teratogenic. In most cases, risk to the fetus increases with the severity of maternal disease and inadequate treatment, emphasizing the necessity of rigorous medical oversight.

OTHER PHYSICAL AGENTS

High doses of ionizing radiation used for therapeutic indications can induce fetal anomalies. Diagnostic radiation (less than 5 rads directly to the uterus) has not been found teratogenic. Chorionic villus sampling is a procedure that carries some risk for the fetus.

FACTORS USED TO DETERMINE TERATOGENIC RISK

In weighing the possibility that a specific teratogen is responsible for a child's disease or defect, one of the most important factors to be considered is background risk. Any pregnancy carries an approximate 4% risk that the fetus will be affected with a major, life-affecting defect. While this level of risk can be increased by maternal teratogenic exposure, it cannot be decreased. A common misconception is that a majority of birth defects are a result of teratogenic exposure. However, teratogens cause only about 5% of the clinically significant congenital structural defects in humans.

Principles of teratology—timing (within the gestational period) of the exposure, dose of the agent, and duration of the exposure—are critical to an accurate determination of teratogen involvement.

TIMING OF EXPOSURE

The time frame at which an exposure occurs during the pregnancy is, arguably, the most important factor to consider when determining teratogenicity. Contemporary understanding of embryology and embryopathy guides this principle. For example, teratogenic exposure between days 15 and 28 after fertilization can be the cause of a neural tube defect, because during this time neural tube closure occurs in the embryo. Parallels can be drawn between teratogenic exposure and development of virtually any other major organ or system. Thus, knowing that the mother was exposed during a critical time for induction of the child's anomaly is vital when evaluating a child for possible teratogenic effects.

DOSE OF THE AGENT

The dosage or measure of exposure to a teratogen appears to have a direct association with effect on the fetus. Fortunately, threshold levels have been estimated for most known human teratogens. For example, the dosages of methotrexate required for therapeutic treatment of rheumatoid arthritis and psoriasis are considerably below those that could induce fetal defects.

DURATION OF EXPOSURE

Since functional as well as structural development of the fetus can be affected by some teratogens, the duration of an exposure can have a significant impact. For example, smoking more than 10 cigarettes each day can affect the growth of the fetus if the smoking continues beyond the twentieth week of gestation. Alcohol can affect functional brain development, and thus heavy consumption of alcohol that continues beyond 24 weeks in the pregnancy is associated with developmental and learning disorders.

EPIDEMIOLOGIC PRINCIPLES

Knowledge of some of the primary tenets of epidemiologic investigation can be instrumental in assessing possible teratogenic etiologies of a patient's condition (see Chap. 8).

CONFOUNDING VARIABLES

Confirmation of a specific drug, chemical, infection, or other exposure as cause for a child's outcome

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can be complicated by the fact that multiple exposures often take place concurrently in the same pregnancy. As an example, early investigations into caffeine led researchers to hypothesize that its consumption during pregnancy resulted in low birth weight infants. Only later was it discovered that heavy coffee drinkers are also more likely to be heavy tobacco users; smoking was thus the confounding variable in lower birth weight.

SPECIES SPECIFICITY

Studies of pregnancy outcomes in animals are not predictive of human outcomes, since teratogenic agents tend to demonstrate species-specific effects. Genetic variability among species produces differences in drug absorption, distribution, and metabolism. Extrapolating from animal data to humans is problematic, because pharmacokinetic profiles vary depending on the drug and species. For example, the limb agenesis observed in children with thalidomide exposure is not seen in the usual animal studies. Other differences may be credited to animals' ability to carry multiple fetuses and variations in placental development and function. Thus, whereas animal models are useful in detecting the mechanisms by which known teratogens exert their influence, such studies are not beneficial in determining which agents are teratogenic in humans.

CLINICAL CONSISTENCY

Most of the identified human teratogens show patterns of abnormalities presenting as syndromes rather than isolated or nonspecific single defects. Although statistically rare, these events have been the hallmark by which teratogens have been “discovered.” Two examples can illustrate this point.

Within three years of release of isotretinoin, a vitamin A congener, three cases of isotretinoin embryopathy characterized by isolated anotia, microtia, and conotruncal heart defects were reported. All three infants had a combination of these anomalies that is rarely seen, heightening the statistical probability that there was a teratogenic agent involved. Based on just three reports, isotretinoin was suspected as a human teratogen, which was established by epidemiologic and clinical investigations.

Case reports of malformations among children exposed to Bendectin (a combination of doxylamine, disydomine, and pyridoxine) in utero were reported, but no pattern of defects could be detected, and epidemiologic analyses found the rate of malformations in patients exposed to the drug was no higher than the background risk of malformations, which demonstrated the lack of teratogenicity of the product. Therefore, the degree of certainty of cause depends on the rarity of the exposure and the distinctiveness of the outcome.

SELECTED ESTABLISHED HUMAN TERATOGENS

The proven human teratogens are relatively few in number, and Table 10-22 outlines a comprehensive list of well-established human teratogens.

TABLE 10-22 KNOWN HUMAN TERATOGENS


TERATOGEN	POTENTIAL DEFECTS	CRITICAL PERIOD	PERCENT AFFECTED

Medications/metals
ACE Inhibitors	Renal dysgenesis Oligohydramnios Skull ossification defects	Second to third trimester	Not established
Alcoholism	Fetal alcohol syndromes: Craniofacial features CNS abnormalities Heart defects Low birth weight Developmental delay	<12 weeks >24 weeks	10–15 Not established
Aminopterin >12mg/week	Spontaneous miscarriage Craniofacial anomalies Limb defects Craniosynostosis Neural tube defects Low birth weight	<14 weeks First trimester >20 weeks	Not established Not established Not established
Androgens/norprogesterones	Masculinization of external female genitalia	>10 weeks	0.3
Carbamazepine	Spina bifida	<30 days pc	1
Carbimazole/methimazole	Hypothyroidism Goiter, scalp defects		Not established
Cigarette smoking >20/day >10/day	Miscarriage Low birth weight	<20 weeks >20 weeks	Not established Not established
Cocaine	Abruptio placentae Intracranial hemorrhage Premature labor/delivery	Second to third trimester Third trimester	Not established Not established
Diethylstilbestrol	Uterine abnormalities Vaginal adenosis Vaginal adenocarcinoma Cervical ridges Male infertility	<12 weeks	Not established
Etretinate	See isotretinoin
Isotretinoin	Fetal death Hydrocephalus CNS defects Microtia/anotia Small or missing thymus Conotruncal heart defects Micrognathia	>15 days pc	45–50
Lithium	Ebstein anomaly	<8 weeks	<1
Methotrexate >10 mg/week	Craniosynostosis Underossified skull Craniofacial anomalies	6 to 9 weeks pc	Not established
	Limb defects
Penicillamine	Cutis laxa		Not established
Phenytoin	Craniofacial anomalies Hypoplastic phalanges/nails Vitamin K deficiency with resultant hemorrhage	First trimester Second to third trimester	10–30 Not established
Solvents, abuse (entire pregnancy)	SGA Developmental delay		Not established
Streptomycin	Hearing loss	Third trimester	Not established
Tetracycline	Stained teeth and bone	≥20 weeks	Not established
Thalidomide	Limb reduction defects Ear anomalies	38 to 50 post-LMP days	15–25
Thiouracil	Spontaneous miscarriage Stillbirth Goiter	First trimester >20 weeks	Not established Not established Not established
Trimethadione	Developmental delay V-shaped eyebrows Low-set ears Irregular teeth	First trimester	Not established
Valproic acid	Spina bifida Craniofacial appearance Preaxial defects	<30 days pc First trimester	1–2 Not established
Warfarin	Nasal hypoplasia Stippled epiphyses CNS defects secondary to cerebral hemorrhage	6 to 9 weeks >12 weeks	Not established Not established
Methylmercury	Cerebral atrophy “Spasticity” seizures Mental retardation	Not established	Not established
Lead	Pregnancy loss	Not established	Not established
Polychlorbiphenyls (PCBs)	Low birth weight
	Skin discoloration	Not established	Not established
Maternal infections
Rubella	Deafness Cataracts Heart defects Mental retardation	Up to 8 weeks 9–12 weeks 12–20 weeks	85 52 16
Cytomegalovirus	Low birth weight Mental retardation Microcephaly Hearing loss	<27 weeks	5
Toxoplasmosis	Hydrocephalus Blindness Mental retardation	10–24 weeks	Not established
Varicella	Skin scarring Limb reduction defects Chorioretinitis Mental retardation	Up to 20 weeks	1
Parvovirus	Miscarriage Fetal hydrops Fetal death	10 to 25 weeks	7–10
Syphilis (untreated)	Abnormal teeth and bones Mental retardation Proteinuria	>5 months	Not established
Venezuelan equine encephalitis	CNS abnormalities Stillbirth	Not established	Not established
Genital herpes type II (primary)	Miscarriage	<20 weeks	Not established
Active genital herpes	Vertical transmission at term delivery	Not established	Not established
Maternal states
Diabetes mellitus	Heart defects Caudal deficiency sequence Femoral hypoplasia	First trimester	6–10
	Renal vein thrombosis	>11 weeks	Not established
Hypo-/hyperthyroidism	Goiter Mental retardation Growth retardation
Phenylketonuria (PKU) (untreated)	Fetal death Microcephaly Mental retardation Craniofacial features Heart defects	Entire pregnancy	Not established
Hypertension	Miscarriage IUGR Placental insufficiency Placental abruptio/previa	<20 weeks >20 weeks	Not established
Seizure disorder (treated)	Oral clefts Heart malformations	First trimester	6–8
Hyperthermia	Neural tube defects	14–30 days pc	1
Systemic lupus erythematosus (SLE)	SAB Stillbirth Prematurity Congenital heart block	<20 weeks >20 weeks	Not established

pc = postconception.

Drugs

Carbamazepine

Carbamazepine (Tegretol) carries a less than 1% risk for a neural tube defect (spina bifida) when exposure occurs between 15 and 29 days after conception. Although other fetal effects (growth retardation and possible developmental delay) have been attributed to carbamazepine, subsequent studies have failed to support an association. The level of risk caused by fetal exposure to carbamazepine is as yet unknown.

Methotrexate/Aminopterin

Methotrexate can have a teratogenic effect when taken between weeks 6 and 9 of gestation at doses higher than 10 mg per week. Craniosynostosis (premature ossification of the skull and sutures), underossified skull, craniofacial abnormalities (wide-spaced eyes, broad nose, small chin, and flattened facies), and limb defects (absent toes, webbed fingers, or shortened limbs) have been reported. The level of fetal risk after exposure to methotrexate is not known.

Based on cases in which aminopterin was used as an abortifacient in high doses (12 mg or more per week), there is an increased risk for spontaneous abortion, low birth weight, craniofacial abnormalities, limb abnormalities, craniosynostosis (premature ossification of the skull and sutures), and possibly neural tube defects (spina bifida or anencephaly). The level of risk for birth defects associated with aminopterin use in the first trimester of pregnancy is unknown.

Thalidomide

Thalidomide was one of the first drugs identified as a human teratogen. When exposure to the drug occurs during days 34 to 50 of gestation, there is a risk of at least 20% for limb reduction defects (missing arms and/or legs) and ear malformations, including deafness. Because of its effectiveness in treating some peripheral neuropathies associated with Hansen disease (leprosy), thalidomide was approved for marketing in the United States in the summer of 1998. The drug's parent company has established an extensive physician and pharmacy registration process along with a detailed patient consent procedure in an effort to avoid additional cases of thalidomide embryopathy in children.

Maternal Disorders

Alcoholism

Heavy consumption of alcohol during pregnancy as a putative cause of poor infant outcome has been considered for more than 100 years. To establish a diagnosis of fetal alcohol syndrome (FAS), findings in at least three categories, in addition to a history of maternal ethanol exposure, must be present: (1) two facial characteristics (Fig. 10-24) including shortened palpebral fissures, epicanthic folds, hypoplastic nasal root, short, upturned nose, hypoplastic or absent philtrum, thin upper lip, and/or hypoplastic mid-face; (2) one abnormality of pre- and/or postnatal growth deficiency such as microcephaly, weight less than tenth percentile, or length/height less than tenth percentile; and (3) one cognitive abnormality including developmental or learning problems. The highest risk of affected infants of chronic alcoholic women who continue drinking throughout pregnancy has been placed at 10 to 15%, although some of the larger studies of pregnant alcoholics place the risk as low as 2%.

FIGURE 10-24 A 1-year-old infant with fetal alcohol syndrome. Note the facial features including a low nasal root, short palpebral fissures, and flat philtral folds.

Unfortunately, the facial characteristics, growth deficiencies, and developmental or learning problems used to diagnose FAS are not specific, making the diagnosis in a particular child problematic. In fact, a FAS diagnosis should not be attempted until the child is at least 1 year of age and, because the face grows and changes, preferably not until the child is 4 to 8 years old. Additionally, prenatal ethanol exposure may manifest as developmental and/or learning difficulties in children of alcoholic mothers who drank heavily during the latter parts of pregnancy, with none of the facial signs of FAS present.

Ethnic variability is another critical consideration when determining whether a child has a “short, upturned nose” or “hypoplastic mid-face.” Norms for length of a nose or palpebral fissures and other features are only now being established for ethnic groups not descended from Northern Europeans. So-called norms, then,

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when applied to native Americans, Latinos, blacks, or those of other ethnicity can lead to erroneous results. Studies have demonstrated that children of economically disadvantaged, nonwhite women are more likely to be evaluated for substance abuse than are their counterparts, leading to the possibility of overdiagnosis of FAS in certain populations.

The benefits and drawbacks of early FAS diagnosis remain controversial. Many argue that early identification of FAS can lead to interventions that will improve the child's life. Others note that the diagnosis of FAS can result in labeling of the child, limiting achievement expectations.

Diabetes Mellitus

Maternal diabetes mellitus is the most common human teratogenic state. Mothers with insulin-dependent diabetes have a 2 to 3 times increased risk for having a child with a congenital defect. The pattern of defects observed in children is not random and includes sacral agenesis, laterality defects (i.e., situs abnormalities), and holoprosencephaly. Improved control of glucose levels prior to conception decreases the risk substantially and underscores the importance of preconceptional counseling.

Human Parvovirus B19/Fifth Disease

Fatal congestive heart failure (hydrops) can occur in 10% of fetuses whose mothers contract this infection during pregnancy. Between 10 and 24 weeks of gestation is the most vulnerable exposure time, with the gestational period after 12 weeks and before 22 weeks comprising the greatest risk. There have been no reported congenital anomalies related to maternal parvovirus infection (see Chap. 13).

Varicella

When a pregnant woman contracts chickenpox during the first trimester, the risk of fetal effects is approximately 1%. If the infection occurs prior to or during limb bud formation, limb reduction defects can result. Other effects of varicella include chorioretinitis, scarring of the skin with muscle atrophy, and a possibility of developmental delay, which is less well established than the eye, skin, and limb effects (see Chap. 13).

Chemicals

Methylmercury

Methylmercury is an organic compound that can accumulate in animals (eg, fish) that are subsequently consumed by humans, and when a pregnant woman develops symptoms of methylmercury poisoning, there is a concern for fetal development at any stage of the pregnancy. The fetal effects of methylmercury poisoning can include cerebral atrophy, seizures, and developmental delay.

Solvents

Studies of solvent exposure in an occupational setting have shown pregnancy loss when mothers experience long-term high doses that create symptoms of toxicity (lightheadedness and headaches). In the absence of these signs of toxicity, no adverse fetal effects have been reported. Some pregnant women abuse solvents, and the fetal effects are discussed in the following section.

Substance Abuse

With the exception of alcohol and possibly cocaine and solvents, no substance of abuse has been conclusively associated with an increased risk of birth defects. However, reversible toxicity and/or withdrawal symptoms may occur in newborns whose mothers abuse certain drugs throughout the pregnancy or in large dosages near the time of delivery. Substance abuse throughout pregnancy has been associated with an increased risk for intrauterine growth retardation, prematurity, and low birth weight regardless of the particular substance abused (see Chap. 2). Also, with needle use, an increased risk for transmission of pathogens such as human immunodeficiency virus (HIV) or hepatitis B can cause adverse health effects for both the mother and infant (see Chap. 13).

Cigarette Smoking

Investigative evidence associates a greater risk of low birth weight commensurate with the number of cigarettes smoked during pregnancy. Also evidence suggests that heavy maternal smoking (more than 10 cigarettes/day) is associated with an increased risk for miscarriage, premature delivery, and stillbirth.

Cocaine

With cocaine use during pregnancy, an increased risk for abruptio placentae, which can result in a miscarriage, stillbirth, or premature delivery, occurs. Used near delivery, cocaine can also be associated with an increased risk for intracranial hemorrhage. Infants whose mothers use cocaine continuously throughout pregnancy or in large amounts near the time of delivery may be at an increased risk for irritability, tremulousness, and muscle rigidity, which usually develop several days after birth, resolve quickly, and seem to have no long-term effects on the infant or child (see Chap. 2).

Solvent Abuse

Case reports suggest an association between maternal solvent abuse and pregnancy loss, intrauterine growth retardation, prematurity, microcephaly, and development delay. However, the magnitude of risk remains unknown.

Most infants exposed to drugs in utero will not have physical signs of problems, but there are concerns that fetal drug exposure can lead to behavioral problems later in childhood. To date, no conclusive studies have been able to confirm this link, but it is presumed that at least a portion of these infants are at risk for learning and behavioral problems. Socioeconomic elements that can accompany maternal substance abuse (ie, inadequate parenting skills, poverty, lack of education) may ultimately prove to have as significant an impact on the long-term outcomes for these children as the physiological consequences (see Chap. 1).

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COUNSELING PATIENTS ABOUT TERATOGENS

Counseling Parents

Most pregnancies in the United States are not planned, and a majority of women will have been exposed to some type of teratogen during their pregnancy. When a child is born with an anomaly, families are therefore likely to focus on a putative teratogen as the cause and frequently turn to their physicians for advice and counsel.

Preconceptional Counseling

Drug exposures early in pregnancy may result in a higher potential for teratogenicity, because this is the critical period of tissue differentiation and organ system development. Because many women are not yet aware that they are pregnant for much of this critical period, preconceptional counseling is critical for women during their reproductive years. Because more than 50% of pregnancies in the United States are not planned, this counseling should not be limited to only those anticipating a pregnancy.

Women who require routine management of medical conditions must be counseled carefully about potential pregnancies. Often, correction or improvement of the condition before conception can improve maternal health during pregnancy and result in a more positive fetal outcome. For example, strict periconceptional control of conditions such as diabetes mellitus and phenylketonuria is known to improve pregnancy outcomes. Ironically, many women are so concerned that their medications may pose a risk to the fetus that they stop taking drugs, which actually has an adverse effect on the fetus.

Counseling women regarding preconceptional use of multivitamins containing folic acid, which may reduce the risk of neural tube defects, is also important. The Centers for Disease Control and Prevention recommend that all women of childbearing years take either a multivitamin with folic acid or a folic acid supplement (0.4 mg) every day.

Counseling Pregnant Patients

The basic approach to counseling a patient about the risk of medication exposure during pregnancy usually includes the 3 to 4% background risk of congenital malformations and the risk-versus-benefit issues of medication use. If medication exposure has already occurred, counselors recommend notification of the pediatrician. One of the most important goals of patient counseling is to avoid unnecessarily alarming the patient. The Organization of Teratology Information Services (OTIS) provides referrals to local Teratology Information Services, which are comprehensive and multidisciplinary resources for medical consultation on prenatal exposures. For a referral to a local service, call 1-888-285-3410. A list of services is available on line at www.ucsd.edu/otis.

PATERNAL EXPOSURES

Although information is available regarding maternal exposures during pregnancy, limited information exists surrounding outcomes from paternal exposures. There is concern that environmental exposures could affect the egg or sperm cells. However, studies of such mutagenic exposures do not reveal an increased risk of birth defects; damage of the germ cells appears only to affect the fertility of those cells. Semen studies of men exposed to known teratogens did not suggested an increased risk of malformations. In addition, concentration of the agent in semen does not appear to have systemic effects in women and therefore does not affect the pregnancy except when an infection is transmitted to the mother through the semen.

References

Briggs GG, Freeman R-K, Sumner J: Yaffe Drugs in Pregnancy and Lactation, 5th ed. Baltimore, Williams & Wilkins, 1998

Institute of Medicine Fetal Alcohol Syndrome: Diagnosis, Epidemiology, Prevention and Treatment. Washington DC, National Academy Press, 1996

Shepard TH: Catalog of Teratogenic Agents, 9th ed. Baltimore, Johns Hopkins, 1998