Dysmorphology

Malformations and Dysplasias

Human malformations and dysplasias can be caused by gene mutations, chromosome aberrations and copy number variants, environmental factors, or interactions between genetic and environmental factors ( Table 128.2 ). Some malformations are caused by deleterious sequence variants in single genes, whereas other malformations arise because of deleterious sequence variants in multiple genes acting in combination ( digenic or oligogenic inheritance). In 1996 it was thought that malformations were caused by monogenic defects in 7.5% of patients; chromosomal anomalies in 6%; multigenic defects in 20%; and known environmental factors, such as maternal diseases, infections, and teratogens, in 6–7% ( Table 128.3 ). In the remaining 60–70% of patients, malformations were classified as caused by unknown etiologies. Currently, the percentages have increased for all categories of known causes of malformations, the result of improved cytogenetic and molecular genetic methods for detecting small chromosomal abnormalities and next-generation sequencing studies that can screen multiple genes simultaneously and identify novel genes and deleterious sequence variants.

Many developmental abnormalities that are caused by deleterious sequence variants (mutations)in a single gene display characteristic, mendelian patterns of inheritance (autosomal dominant, autosomal recessive, and X-linked inheritance). Genes that cause birth defects or multiple congenital anomaly syndromes are often transcription factors, part of evolutionarily conserved signal transduction pathways, or regulatory proteins required for key developmental events ( Figs. 128.2 and 128.3 ). Examples include spondylocostal dysostosis syndromes, Smith-Lemli-Opitz syndrome, Rubinstein-Taybi syndrome, and X-linked lissencephaly (“smooth brain”) syndrome (see Table 128.2 ).

Patients with spondylocostal dysostosis (SCD) display a characteristic pattern of vertebral segmentation defects associated with a number of other malformations, such as neural tube defects. The SCD syndromes are etiologically heterogeneous and are 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. Smith-Lemli-Opitz syndrome (SLOS) results from mutations in the sterol delta-7-dehydrocholesterol reductase ( DHCR7 ) gene, an enzyme critical for normal cholesterol biosynthesis. Patients with SLOS (see Fig. 128.2 ) display syndactyly (fusion of the fingers and toes), in particular affecting the 2nd and 3rd toes; postaxial polydactyly (extra digits); anteverted (upturned) nose; ptosis; cryptorchidism; and holoprosencephaly (failure of separation of the 2 cerebral hemispheres). Many of the features in SLOS are shared with those arising from deleterious sequence variants in the SHH genes, and these mutations link cholesterol biosynthesis pathogenically to the sonic hedgehog (SHH) pathway, because SHH is posttranslationally modified by cholesterol (see Chapter 97 ). Rubinstein-Taybi syndrome (see Fig. 128.2 ) typically results from heterozygous, loss-of-function deleterious sequence variants in a gene coding for a broadly acting transcriptional coactivator called CREB-binding protein (CBP) and from deleterious sequence variants in the EP300 gene. The CBP coactivator regulates the transcription of a number of genes, which is why patients with deleterious sequence variants in CBP have a pleiotropic phenotype that includes developmental delays and intellectual disability, broad and angulated thumbs and halluces (1st toes), and congenital heart disease. One of the transcription factors that binds to CBP is GLI3, a member of the SHH pathway (see Fig. 128.2 ). X-linked lissencephaly is a severe neuronal migration defect that causes a smooth brain with reduction or absence of gyri and sulci in males and that gives rise to a variable pattern of intellectual disability and seizures in females. X-linked lissencephaly is caused by deleterious sequence variants in DCX . The DCX protein regulates the activity of dynein motors that contribute to movement of the cell nucleus during neuronal migration.

Malformation syndromes can also be caused by chromosomal aberrations or copy number variants and teratogens (see Tables 128.2 and 128.3 ). Down syndrome typically results from an extra copy of an entire chromosome 21 or, less frequently, an extra copy of the Down syndrome critical region on chromosome 21. Chromosome 21 is a small chromosome that contains an estimated 250 genes, and thus individuals with Down syndrome typically have an increased dosage of the numerous genes encoded by this chromosome that causes their physical differences (see Chapter 98.2 ).

Neural tube defects (NTDs) are an example of a birth defect that displays multifactorial inheritance in most cases. NTDs and a number of other congenital malformations, such as cleft lip and palate, can recur in families, but inheritance for the majority of affected individuals does not occur in a straightforward, mendelian inheritance pattern, and in this situation, multiple genes and environmental factors together likely contribute to the pathogenesis (see Table 128.2 ). Many of the genes involved in NTDs are unknown, so one cannot predict with certainty the mode of inheritance or a precise recurrence risk in the individual case. Empirical recurrence risks can be provided on the basis of population studies and the presence of single or multiple family members with the same malformation. However, one important gene/environment interaction has been identified for NTDs (see Chapter 609.1 ). Folic acid deficiency is associated with NTDs and can result from a combination of dietary factors and increased utilization during pregnancy. A common variant in the gene for an enzyme in the folate recycling pathway, 5,10-methylene-tetrahydrofolate reductase ( MTHFR ), that makes this enzyme less stable, may also be important in folic acid status. Several teratogenic causes of birth defects have been described (see Tables 128.2 and 128.3 ). Ethanol causes a recognizable malformation syndrome that is variably called fetal alcohol syndrome (FAS), fetal alcohol spectrum disorder (FASD), or fetal alcohol effects (FAE) (see Chapter 126.3 ). Children who were exposed to ethanol during the pregnancy can display microcephaly, developmental delays, hyperactivity, and facial dysmorphic features. Ethanol, which is toxic to the developing central nervous system (CNS), causes cell death in developing neurons.

Deformations

Many deformations involve the musculoskeletal system ( Fig. 128.4 ). Fetal movement is required for the proper development of the musculoskeletal system, and restriction of fetal movement can cause musculoskeletal deformations such as clubfoot (talipes). Two major intrinsic causes of deformations are primary neuromuscular disorders and oligohydramnios, or decreased amniotic fluid, which can be caused by fetal renal defects. The major extrinsic causes of deformation are those that result in fetal crowding and restriction of fetal movement. Examples of extrinsic causes include oligohydramnios resulting from chronic leakage of amniotic fluid and abnormal shape of the amniotic cavity. When a fetus is in the breech position ( Fig. 128.5 ), the incidence of deformations is increased 10-fold. The shape of the amniotic cavity also has a profound effect on the shape of the fetus and is influenced by many factors, including uterine shape, volume of amniotic fluid, and the size and shape of the fetus ( Fig. 128.6 ).

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 typically occurs spontaneously. Deformations caused by intrinsic factors, such as multiple joint contractures resulting from CNS or peripheral nervous system defects, have a different prognosis and may be much more significant for the child ( Fig. 128.7 ).

Disruptions

Disruptions are caused by destruction of a previously normally formed organ or body part. At least 2 mechanisms are known to produce disruptions. One involves entanglement, followed by tearing apart or amputation, of a normally developed structure, usually a digit or limb, by strands of amnion floating within amniotic fluid (amniotic bands) ( Fig. 128.8 ). The other mechanism involves interruption to the blood supply to a developing part, which can lead to infarction, necrosis, and resorption of structures distal to the insult. If interruption to the blood supply occurs early in gestation, the disruptive defect typically involves atresia, or absence of a body part. Genetic factors were previously considered to play a minor role in the pathogenesis of disruptions; most occur as sporadic events in otherwise healthy individuals. The prognosis for a disruptive defect is determined entirely by the extent and location of the tissue loss.

Multiple Anomalies: Syndromes and Sequences

The pattern of multiple anomalies that occurs when a single primary defect in early development produces multiple abnormalities because of a cascade of secondary and tertiary developmental anomalies is called a sequence (see Fig. 128.9 ). When evaluating a child with multiple congenital anomalies, the physician must differentiate between multiple anomalies that are caused by a single localized error in morphogenesis (a sequence) from syndromes with multiple malformations. In the former, recurrence risk counseling for the multiple anomalies depends entirely on the risk of recurrence for the single, localized malformation. Pierre-Robin 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), blocking closure of the posterior palatal shelves and causing a U -shaped cleft palate. There are numerous causes of mandibular hypoplasia, all of which can result in characteristic features of Pierre-Robin sequence.