The Dysmorphic Infant

When and Why to Consider a Genetic Evaluation

A genetic evaluation can provide many benefits besides providing an underlying diagnosis. Management changes may occur in over half of patients. Management changes may include screening for additional congenital anomalies, screening for hypertrophic cardiomyopathy or cancer, or changes to an inhibitor (in vascular anomalies). Importantly, genetic diagnosis can also give families a recurrence risk and give them the option for preimplantation genetic testing or other prenatal diagnostic options.

When should a genetics evaluation be considered? The following clinical situations prompt a further genetic evaluation and counseling by a specialist:

• Multiple anatomic anomalies

• History of maternal exposure to teratogens

• Familial disorders

• Increased carrier frequency or ethnic risk

• Consanguinity

• Multiple pregnancy losses

If a congenital anomaly is identified in the presenting patient or proband, especially if the defect is associated with other anatomic anomalies, short stature, or developmental delays, the features of a specific genetic syndrome may be present. A known history of maternal exposure to a potential teratogen would also be an indication for consultation. Conditions appearing to be familial, a family history of hereditary disorders involving malformation of a major organ, or major physical differences such as unusual body proportions, short stature, or irregular skin pigmentation would warrant genetic investigation. Intellectual disability, blindness, hearing loss, or neurologic deterioration in multiple family members suggests a genetic etiology. Likewise, a genetics evaluation is indicated for strong family history of cancer or a defined ethnic risk for specific disorders, such as the higher carrier frequency for Tay–Sachs disease in individuals with Ashkenazi Jewish heritage. The occurrence of multiple pregnancy losses would also raise the suspicion of a genetically influenced cause and indicate the need for further investigation and counseling.

Patterns of Anomalies

When performing the evaluation, it is important for the physician to consider if the anomaly is primary or secondary and how the multiple congenital anomalies may be associated with each other. The occurrence of malformations can fit into one of several categories ( Box 27.1 ). A syndrome is a “collection of anomalies involving more than one developmental region or organ system.” The word itself means a “running together” or “pattern of multiple anomalies thought to be pathogenically related.” Therefore, a given congenital anomaly may be an isolated defect in an otherwise normal individual or part of a multiple malformation syndrome. In some individuals, a sequence may occur when the primary malformation itself can determine additional defects through an interrelated cascade of physical and functional processes. A classic example is the Pierre Robin sequence (PRS), consisting of a small, recessed jaw, midline U-shaped cleft palate, and relatively large and protruding tongue. The primary anomaly is the small jaw, which does not allow adequate room for the tongue and displaces it superiorly. The displaced tongue prevents closure of the palatine shelves, causing the cleft palate.

In addition, a cluster of several malformations that are not developmentally related can occur in a nonrandom fashion called an association that may appear without characteristic dysmorphic features. One such statistically nonrandom association of defects consists of v ertebral defects, a nal atresia, c ardiac defects, t racheoesophageal fistula, e sophageal atresia, r enal dysplasia, and l imb anomalies (VACTERL). It should be noted that not all features need to be present and that the extent of involvement of each system is widely variable. Although there have been various candidate genes and chromosomal regions described in some patients with VACTERL association, there is no common genetic etiology known at this time, likely due to the heterogenous presentation of these patients. However, there are many overlapping genetic syndromes that need to be excluded before concluding that a patient has VACTERL association. Associations often manifest as sporadic rather than familial occurrences. Because they are not clearly related by a common etiology or pathogenesis, associations are not considered syndromes and do not technically constitute a diagnosis. Instead, they are a recognition of a statistically significant association of features. It is important to remember that many of these same anomalies can occur as features of chromosomal aneuploidy or other syndromes. Chromosomal aneuploidy refers to the presence of an abnormal number of chromosomes in a cell.

Syndromic malformations tend to occur in more than one developmental field. A field defect or complex is a set of primary malformations in a developmental field that originates from a single or primary abnormality in embryonic development (see Box 27.1 ).

When generating a differential diagnosis of malformations that might occur together, the evaluator must also consider structures that may appear abnormally formed but in fact are structures that underwent normal development and then received some insult that distorted their true form ( Box 27.2 ). For example, a deformation describes the abnormal form, shape, or position of a part of the body that was caused by mechanical forces. Examples are clubfoot, hip dislocation, and craniofacial asymmetry; they can result from intrinsic (embryonic) or extrinsic (intrauterine) mechanical forces that alter the shape or position of an organ or part that had already undergone normal differentiation. Deformations are estimated to occur in 2% of births, and such factors as fetal crowding from the presence of multiple fetuses and uterine malformations, as well as oligohydramnios, and a face presentation during delivery can cause them.

Along similar lines, a disruption describes a “morphologic defect of an organ, part of an organ, or larger region of the body resulting from the extrinsic breakdown of, or an interference with, an originally normal developmental process.” The classic example of a disruption is entanglement of the fetus in amniotic bands. Amniotic bands are ribbons of amnion that have ruptured in utero and cause disruptions of normal developmental processes in the fetus, either through physical blockage or interruption of the blood supply or by entangling and tearing of developing structures. This effect is seen most often with digits and limbs, and remnants of the bands, or constriction marks, can frequently be seen at birth. If the fetus should swallow a band, a cleft palate might result; this etiology is a very different etiology from that of cleft palate occurring as a primary malformation. Recurrence risk counseling of the parent would be very different in these two scenarios.

Dysplasias occur when there is “an abnormal organization of cells into tissue(s) and its morphologic results.” Dysplasia tends to be tissue-specific rather than organ-specific (e.g., skeletal dysplasia) and can be localized or generalized.

In summary, structural or morphologic changes identified at birth can occur during intrauterine development as a result of malformations, deformations, disruptions, or dysplasias. However, approximately 90% of deformations undergo spontaneous correction. Malformations and disruptions often require surgical intervention when possible. Dysplasias are typically not correctable, and the affected individual experiences the clinical effects of the underlying cell or tissue abnormality for life ( Table 27.2 ).

Genetics Evaluation

The clinical geneticist incorporates the following five essential tools in the evaluation of a child suspected of having a primary genetic disorder:

• History: prenatal, birth, and medical

• Pedigree analysis and family history

• Specialized clinical evaluations: Physical examination and adjunct studies

• Literature review

• Specialized laboratory tests (e.g., karyotype, chromosomal microarray, sequencing)