Malformations and/or Dysplasias

Human malformations and dysplasias are caused by the combined effects of genes and environmental factors (Table 102-2). Some malformations are caused by single gene defects or abnormalities of multiple genes acting in concert, and the environment causes others. In 1996, it was thought that malformations were due to monogenic defects in 7.5% of patients; to chromosomal anomalies in 6%; to multigenic defects in 20%; and to known environmental factors, such as maternal diseases, infections, and teratogens, in 6-7% (Table 102-3); in the remaining 60-70% of patients, malformations were classified as due to unknown etiologies. A decade later, the percentages were somewhat higher for all categories of known causes of malformations, a change resulting from improved cytogenetic methods of detecting small chromosomal abnormalities as well as techniques for mapping and cloning disease genes. Since the previous edition of this book, an additional 10-20% of birth defects result from even smaller chromosomal abnormalities detectable by whole genome arrays using comparative genomic hybridization (array CGH) methods. In spite of these advances, we still do not know the causes or even the diagnosis for 40-50% of birth defects.

Many developmental abnormalities are caused by mutations in a single gene and display characteristic mendelian patterns of inheritance. The molecular etiology for more than 250 single gene disorders is known. Affected genes are often part of evolutionarily conserved signal transduction pathways, transcription factors, or regulatory proteins required for key developmental events. Some examples are listed in Table 102-2; they include autosomal recessive spondylocostal dysostosis (SCD) syndrome, the autosomal recessive Smith-Lemli-Opitz syndrome (SLOS), the autosomal dominant Rubinstein-Taybi syndrome, and the X-linked lissencephaly (“smooth brain”) syndrome. The SCD syndrome is etiologically heterogeneous and is often caused by mutations in the gene coding for delta-like 3 (DLL3), a ligand of the Notch receptors. The Notch/delta pathway is conserved throughout evolution and regulates a number of developmental events. Patients with SCD display a characteristic pattern of abnormal vertebral segmentation associated with a number of other malformations, such as neural tube defects. SLOS (Fig. 102-1) results from mutations in the sterol delta-7-reductase gene, an enzyme important in cholesterol biosynthesis. Patients with SLOS display syndactyly (fusion of the fingers and toes) often with polydactyly, upturned nose, ptosis, cryptorchidism, central nervous system hypoplasia, and holoprosencephaly. These mutations link cholesterol biosynthesis pathogenetically to the sonic hedgehog (SHH) pathway, because many of the features of the former disorder are related to defects in SHH, which is post-translationally modified by cholesterol (Chapter 80). Rubinstein-Taybi syndrome (see Fig. 102-1) results from heterozygous loss-of-function mutations in the gene coding for a broadly acting transcriptional coactivator called CBP, or CREB-binding protein. The CBP coactivator regulates the transcription of a number of genes, a fact that helps explain why patients with mutations in CBP have a wide-ranging phenotype that includes mental retardation, broad thumbs and toes, and congenital heart disease. One of the transcription factors that binds to CBP is GLI3, a transcription factor that is part of the SHH pathway (see Fig. 102-1). X-linked lissencephaly—a severe neuronal migration defect that in males causes a smooth brain with reduction or absence of gyri and sulci and in females gives rise to a variable pattern of mental retardation and seizures—is caused by mutations in DCX, a protein that regulates the activity of dynein motors and moves the nucleus during neuronal migration.

Figure 102-1 Mutations in genes that function together in a genetic developmental pathway commonly have overlapping clinical manifestations. Several components of the sonic hedgehog (SHH) pathway have been identified, and their relationships elucidated (see text for further details). Mutations in several members of this pathway result in phenotypes that have facial dysmorphisms, seen in holoprosencephaly, Smith-Lemli-Opitz syndrome, Gorlin syndrome, Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, and Rubinstein-Taybi syndrome.

Other malformation syndromes are caused by chromosomal imbalance, multifactorial inheritance, and teratogens (see Tables 102-2 and 102-3). Down syndrome results from an extra dose of part or all of chromosome 21, a small chromosome that contains ≈ 200 known or predicted genes. It is most commonly caused by trisomy 21, which means that individuals with Down syndrome have an increased dose of as many as 250 genes contained on this chromosome (Chapter 76.1). Neural tube defects (NTDs) are an example of a disorder that displays multifactorial inheritance in the majority of cases. NTDs and a number of other congenital malformations, such as cleft lip and palate, recur in families, but several genes and environmental factors together contribute to the pathogenesis (see Table 102-2). Many of the genes involved in NTDs are unknown, so one cannot predict with certainty a mode of inheritance or a precise recurrence risk. Empiric risks can be provided on the basis of population studies and the presence of single or multiple relatives with the same malformation. However, an important gene/environment interaction has been identified for NTDs (Chapter 585.1). Folic acid status is associated with NTDs and can result from a combination of dietary deficiencies and increased utilization during pregnancy as well as from a common variant in the gene for an enzyme in the folate recycling pathway, 5,10-methylene-tetrahydrofolate reductase, that makes this enzyme less stable. These discoveries led to the recommendation that all women supplement their diets with 400-800 µg of folic acid per day 1 mo before pregnancy and during the 1st 2 mo of pregnancy. This supplementation has resulted in a reduction in the incidence of NTDs by 75%. Several teratogenic causes of birth defects have been described (see Tables 102-2 and 102-3). Ethanol causes a recognizable malformation syndrome called fetal alcohol syndrome (FAS) (Chapter 100.2). Children with FAS display microcephaly, developmental delay, hyperactivity, and facial dysmorphisms. Ethanol, which is toxic to the developing central nervous system, causes cell death of developing neurons.

Deformations

Most deformations involve the musculoskeletal system (Fig. 102-2). Fetal movement is required for the proper development of the normal musculoskeletal system, and anything that restricts fetal movement can cause a musculoskeletal deformation from intrauterine molding. It is important to recognize that deformations can be caused by problems either intrinsic or extrinsic to the developing fetus. Two major intrinsic causes of deformations are primary neuromuscular disorders and oligohydramnios, or decreased amniotic fluid, which is caused by renal defects. The major extrinsic causes of deformation are those that result in fetal crowding to restrict fetal movement. Examples of such extrinsic causes are oligohydramnios from chronic leakage of amniotic fluid, breech presentation (Fig. 102-3), and abnormal shape of the amniotic cavity. When a fetus is in the breech position, the incidence of deformations is increased 10-fold. The shape of the amniotic cavity has a profound effect on the shape of the fetus and is influenced by many factors, including uterine shape; volume of amniotic fluid; size and shape of the fetus; presence of more than one fetus; site of placental implantation; presence of uterine tumors; shape of the abdominal cavity, which is influenced by the pelvis, sacral promontory, and neighboring abdominal organs; and tightness of the abdominal musculature.

Figure 102-2 Deformation abnormalities resulting from uterine compression.

(From Kliegman RM, Jenson HB, Marcdante KJ, et al, editors: Nelson essentials of pediatrics, ed 5, Philadelphia, 2005, Saunders.)

Figure 102-3 Breech deformation sequence.

It is important to determine whether deformations result from intrinsic or extrinsic causes. Most children with deformations from extrinsic causes are otherwise completely normal, and their prognosis is usually excellent. Correction usually occurs spontaneously. Deformations caused by intrinsic factors, such as multiple joint contractures resulting from central nervous system defects, would have a different prognosis and a far greater significance for the child.

Disruption

Disruption defects are caused by destruction of a previously normally formed part. At least two basic mechanisms are known to produce disruption. One involves entanglement followed by tearing apart or amputation of a normally developed structure, usually a digit, arm, or leg, by strands of amnion floating within amniotic fluid (amniotic bands) (Fig. 102-4). The second involves interruption of the blood supply to a developing part, which leads to infarction, necrosis, and/or resorption of structures distal to the insult. If interruption of the blood supply occurs early in gestation, the disruptive defect seen at term usually involves atresia, or absence of a particular part. If the infarction occurs later, necrosis is more likely to be present. Examples of disruptive single primary defects for which infarction has been implicated include nonduodenal intestinal atresia, gastroschisis, porencephaly, and terminal transverse limb reduction defects. Genetic factors usually play a minor role in the pathogenesis of disruptions; most are sporadic events in otherwise normal families. The prognosis for a disruptive defect is determined entirely by the extent and location of the tissue loss.

Figure 102-4 A, Amniotic band disruption sequence. B, Bands constricting the ankle leading to deformational defects and amputations.

(From Jones KJ: Smith’s recognizable patterns of human malformation, ed 6, Philadelphia, 2006, Saunders.)

Multiple Anomalies Syndrome and Sequence

The pattern of multiple anomalies that occurs when a single primary defect in early morphogenesis produces multiple abnormalities through a cascading process of secondary and tertiary errors in morphogenesis is called a sequence. When evaluating a child with multiple anomalies, the physician must differentiate multiple anomalies secondary to a single localized error in morphogenesis (a sequence) from a multiple malformation syndrome. In the former, recurrence risk counseling for the multiple anomalies depends entirely on the risk of recurrence for the single localized malformation. The Robin malformation sequence is a pattern of multiple anomalies produced by mandibular hypoplasia. Because the tongue is relatively large for the oral cavity, it drops back (glossoptosis), blocks closure of the posterior palatal shelves, and causes a U-shaped cleft palate. There are numerous causes of mandibular hypoplasia, all of which result in characteristic features of Robin sequence.

Inborn Errors of Development

The genes mutated in malformation syndromes (as well as genes whose expression is disrupted by environmental agents or teratogens) are part of evolutionarily conserved signal transduction pathways, transcription factors, or regulatory proteins required for key developmental events. We should consider malformations to be inborn errors of development. Consideration of malformations as alterations of important developmental pathways provides a molecular framework for understanding human birth defects.

Chromosomal Imbalances

It has been recognized for more than 50 years that genomic imbalances that result from an additional copy of one whole human chromosome can result in a characteristic and recognizable syndrome. As previously discussed, an additional copy of chromosome 21 results in Down syndrome (Chapter 76); loss of one of the X chromosomes results in Turner syndrome (see Chapter 76 for discussion of syndromes with whole chromosomal imbalances). With the advent of higher-resolution cytogenetics techniques and standardization of chromosome identification using chromosomal preparations, it became possible to identify subchromosomal deletions and duplications. A number of recurrent deletions and duplications were identified that resulted in characteristic and recognizable syndrome (Chapter 76, Table 76-12), such as Williams syndrome (deletion of 7q11.23), Miller-Dieker syndrome (deletion of 17p13.3), Smith-Magenis syndrome (deletion of 17p11.2), and velocardiofacial/DiGeorge syndrome (deletion of 22q11.2). Array CGH (or single-nucleotide polymorphism [SNP]–based genotyping with dosage detection) has made it possible to uncover smaller microdeletions and microduplications associated with various birth defects, mental retardation, and neuropsychiatric disorders. The sensitivity and specificity of array CGH is making it the technique of choice for the initial evaluation of a child with multiple congenital anomalies and/or mental retardation, although it is important to note that all individuals carry dozens of small microdeletions and microduplications as normal variants. Therefore, it is important to examine any of these findings in children with birth defects with databases of normal variants detected in individuals without such birth defects. Array CGH is the preferred method for detecting possible genomic abnormalities associated with multiple congenital anomalies and/or mental retardation.

History

The history for a child with birth defects includes a number of elements that are related to etiologic factors. The first is the pedigree or family history that is necessary to assess the inheritance pattern, or lack thereof, of the disorder. For disorders that have simple mendelian inheritance patterns, the recognition of that pattern can be critical to help narrow the differential diagnosis. A number of common birth defects have complex genetic contributions, such as isolated cleft palate and spina bifida. The recognition of a close relative (or the fetus of a close relative) affected with a birth defect that is similar to that of the proband can be quite useful. A three-generation pedigree is sufficient for this purpose (Chapter 75).

The perinatal history is an essential component of the history (Chapter 88.1). It includes the pregnancy history of the mother (useful for recognition of recurrent miscarriages that may be a sign of a familial chromosomal disorder), factors that may relate to deformations or disruptions (oligohydramnios), and maternal exposures to teratogenic drugs or chemicals (methyl mercury, isotretinoin, and ethanol are potential causes of microcephaly). Although recognition of known teratogens is an important part of the history, it is important to know that many more agents are impugned as teratogenic than are confirmed to be so. Physicians are encouraged to consult experts in teratology and expert information sources such as Teris (http://depts.washington.edu/~terisweb/teris) to analyze specific potential teratogens.

One final component to the history that is often useful is the natural history of the phenotype. Malformation syndromes caused by chromosomal aneuploidy or aneusomy and single gene pleiotropic disorders are usually static. Although the patients can experience new complications over time, the phenotype is not progressive. In contrast, disorders that cause dysmorphic features by the mechanism of metabolic perturbations (Hunter syndrome, Sanfilippo syndrome) are either mild or inapparent at birth and progress relentlessly, causing deterioration of the patient over time.

Physical Examination

The physical examination is essential to the diagnosis of a dysmorphic syndrome. The essential element of the evaluation is objective assessment of the structure of the child. The clinician needs to perform an organized and systematic cataloguing of the size and structure of various body structures. Familiarity with the nomenclature of dysmorphic signs is helpful (Table 102-4). The size and shape of the head is relevant, as many children with Down syndrome have mild microcephaly and brachycephaly (shortened anteroposterior dimension of the skull). Eye position and shape are useful signs for many disorders. There are a number of reference standards with which pediatric physical measurements (interpupillary distance) can be compared. It is also useful to categorize abnormalities as “major” or “minor” birth defects. The former are those that either cause dysfunction (absence of a digit) or require surgical correction (polydactyly), and the latter those that neither cause significant dysfunction nor require surgical correction (mild cutaneous syndactyly) (Table 102-5; Fig. 102-5). By cataloging every available physical parameter, the clinician can recognize the diagnosis or at least have enough information for intelligent discussion of the patient with a consultant.

Figure 102-5 Frequency of major malformations in relation to the number of minor anomalies detected in a given newborn baby.

(From Jones KJ: Smith’s recognizable patterns of human malformation, ed 6, Philadelphia, 2006, Saunders.)

Table 102-4 DEFINITIONS OF COMMON CLINICAL SIGNS OF DYSMORPHIC SYNDROMES

Imaging Studies

Imaging studies can be critical in the diagnosis of a dysmorphic disorder. If short stature or disproportionate stature (long trunk and short limbs) is noted, a full skeletal survey should be performed. The skeletal survey can yield numerous abnormal features that can be used to narrow the differential diagnosis. When there are abnormal neurologic signs or symptoms, central nervous system imaging is indicated. Some children with microcephaly will be recognized to have abnormal cortical migration (lissencephaly), a discovery that markedly narrows the differential diagnosis for microcephaly. Other studies, such as echocardiography and renal ultrasonography, can be useful to identify additional major or minor malformations.

Laboratory Studies

The laboratory evaluation of the dysmorphic child is helpful but complex. Cytogenetics with Giemsa-banded peripheral leukocyte karyotype (or chromosome) analysis has been the gold standard and has been performed in most evaluations of the dysmorphic child (Table 102-6). Array CGH and SNP genotyping with copy number variation (dosage detection) are the most sensitive methods for the detection of genomic alterations associated with multiple congenital anomalies. A practical reason for ordering cytogenetic studies early in the diagnostic process is that it typically takes 7-12 days for results. As long as standard karyotype analysis remains the method used in the initial evaluation of birth defects, one must consider other adjunct cytogenetic tests that can be used to evaluate chromosome defects. Because many chromosome abnormalities include derangement of the termini (telomeres) of the chromosomes, assays should detect small (submicroscopic) duplications or deletions of the termini of the chromosomes. These tests are clinically available and may be considered if results of standard chromosome analysis are negative and until it has been supplanted by the more sensitive method of array CGH or SNP-based typing.

Molecular testing for mutations that cause pleiotropic developmental anomaly syndromes is available for many disorders. In most cases, however, such testing should not be performed as a screening test, but instead should be ordered thoughtfully after the differential diagnosis has been narrowed. It may eventually become feasible to implement high-throughput genomic DNA sequencing as a diagnostic tool, but existing molecular diagnostics are not used for diagnostic screening purposes.

Historically, dysmorphic and metabolic disorders were considered distinct classes of disease. However, as in the case of the Smith-Lemli-Opitz syndrome, metabolic abnormalities of the fetus can cause malformations. A general metabolic screen should be performed unless the differential diagnosis leads the clinician to strongly suspect a nonmetabolic disease.

Diagnosis

The examining physician should gather data on the patient’s pedigree and perinatal and pediatric (for older children) history and should have an appreciation for the natural history of the disorder. At this point, the physician has examined the child, identified abnormal physical features, and obtained appropriate imaging studies and preliminary interpretations.

The clinician should now organize the findings by their specificity into potential developmental pathophysiologic processes. The specificity assessment is the simplest. If a child has a patent ductus arteriosus (PDA), mild growth retardation, mild microcephaly, and holoprosencephaly (MRI finding of failure to lateralize the forebrain), micropenis, and ptosis, these findings can be prioritized. The PDA, ptosis, mild growth retardation, and mild microcephaly are nonspecific findings (present in many disorders or often present as isolated features not part of a syndrome), whereas holoprosencephaly and micropenis are present in fewer syndromes and are never normal variants. With this recognition, the clinician can search for disorders that include both holoprosencephaly and micropenis. The search can be performed manually using the features index of a textbook such as Smith’s Recognizable Patterns of Human Malformation or a computerized database such as the Winter-Baraitser Dysmorphology Database (www.lmdatabases.com/about_lmd.html). Searching for disorders with both findings leads quickly to a modest list of only 21 disorders. One of these is SLOS. The identification of this possible diagnosis prompts the physician to return to the bedside, realize that many of the nonspecific features in the child are common in SLOS, and make a tentative diagnosis of this disorder. Although holoprosencephaly is an uncommon manifestation of SLOS, this manifestation makes sense because of the known pathogenetic link between sonic hedgehog and cholesterol biosynthesis. Because this disorder is caused by mutations in the sterol delta-7-reductase gene and is associated with elevated 7-dehydrocholesterol, the pediatrician can initiate a consultation with the clinical geneticist for suspected SLOS. The consultant can then confirm the diagnosis and begin the process of identifying a laboratory to verify the diagnosis.

Management and Counseling

Management of the affected patient and genetic counseling are essential aspects of the approach to the dysmorphic patient. Children with Down syndrome have a high incidence of hypothyroidism, and children with achondroplasia have a high incidence of cervicomedullary junction constriction. Herein lies one of the many benefits of early and accurate diagnosis, because anticipatory guidance and medical monitoring of patients for syndrome-specific medical risks can prolong and improve their quality of life. When a diagnosis is made, the treating physicians can refer to published information on the natural history and management of particular syndromes through articles, genetics reference texts, and, for more common disorders, general pediatric texts.

The second major benefit of an accurate diagnosis is that it provides data for appropriate recurrence risk estimates. Genetic disorders may have direct effects on only one member of the family, but the diagnosis of the condition has implications for the entire family. One or both parents may be carriers; siblings may be carriers or may wish to know their at-risk status when they reach their reproductive years. Recurrence risk provision is one facet of genetic counseling, which should be a component of all evaluations for families affected with birth defects or other heritable disorders (Chapter 72).

As we understand the underlying pathophysiology of genetic disorders, particularly with respect to the developmental pathways that are disrupted by mutant genes, it will likely be possible to identify potential therapeutic targets amenable to pharmacologic intervention. Once such potential therapies are devised, the precise delineation of the syndrome responsible for the multiple congenital anomalies displayed by an individual will lead to institution of the appropriate intervention for modulating symptoms or even to ameliorate aspects of the phenotype.