CHAPTER 84

Approach to the Child With Dysmorphism

Henry J. Lin, MD, and Moin Vera, MD, PhD

Evaluation for structural anomalies is an essential part of all pediatric examinations. Visible errors in morphogenesis are a source of potentially useful information in the evaluation of a patient with abnormal symptoms, such as seizures. Additionally, major malformations frequently require treatment, and the presence of 1 anomaly suggests that others may also exist.

The study of congenital defects was termed dysmorphology by David Smith, MD, in 1966. The anomalies fall into 2 categories: minor and major. Minor malformations are those of “no medical or cosmetic consequence to the patient.” An example is a supernumerary nipple that appears as a hyperpigmented papule along the nipple line. Identification of minor malformations is important, because they may indicate the presence of a more generalized pattern of malformation. Major malformations are those that have “an adverse effect on either the function or social acceptability of the individual.” Cleft lip and palate are major malformations that have functional as well as cosmetic relevance to the patient’s health. Severe congenital malformations as defined by the Centers for Disease Control and Prevention are “defects that cause death, hospitalization or intellectual disability; necessitate significant surgical procedures; are disfiguring; or interfere with physical performance.”

Epidemiology

Structural anomalies are common in the general population. Most are minor. In the first comprehensive analysis of minor structural anomalies, Marden in 1964 reported that 7% to 14% of newborns have at least 1 minor anomaly on surface examination. Other studies indicate that up to 40% of newborns have 1 anomaly. The presence of 3 or more minor malformations has predictive value in identifying a major malformation. Among newborns, 0.8% have 2 minor malformations, and 11% of these patients have a major malformation. Three or more minor malformations occur in 0.5% of newborns, and 90% of these patients have a major malformation. Data from the National Collaborative Perinatal Project revealed that 44.8% of these anomalies were craniofacial manifestations and 45.3% were skin abnormalities. Autopsies of expired fetuses show an increased incidence of minor and major malformations. Males are affected with minor malformations more often than females. Frequencies of minor and major malformations vary along racial lines, depending on the specific malformations. For example, postaxial polydactyly occurs in 16 of 10,000 births among whites and in 140 of 10,000 births among blacks. Hemangiomas occur in 350 of 10,000 births among whites, whereas the frequency among blacks is 100 in 10,000 births.

Three percent of all pregnancies produce a child with a significant genetic disease or birth defect. These malformations account for a great proportion of morbidity and mortality in the pediatric population. Of all pediatric hospital admissions, 33% to 50% involve a child with a disease with a genetic component.

Clinical Presentation

With the advent of various prenatal tests and diagnostic modalities, detection of anomalies may occur during pregnancy. Abnormalities on routine prenatal screening raise the possibility of finding an anomaly in the newborn. For example, an elevated maternal α-fetoprotein may be indicative of a neural tube defect. Amniocentesis or chorionic villus biopsy may reveal abnormal chromosomes associated with malformations. Standard prenatal ultrasonography examinations can demonstrate structural defects in utero, which can be further delineated on specific fetal ultrasonography examinations. More recently, maternal plasma cell-free DNA has been used for noninvasive prenatal testing for trisomy syndromes.

Most structural anomalies develop during the first trimester of gestation and, if not detected prenatally, are noted in the delivery room or newborn nursery (see Chapter 25). Many major congenital defects are obvious on a thorough physical examination. Other major defects, such as a tracheoesophageal fistula, are not evident on clinical examination but become readily apparent as the neonate adapts to extrauterine life and experiences difficulties with feeding. Minor anomalies may be overlooked on initial newborn examination. If developmental disability manifests by age 6 months in an infant who exhibited minor anomalies as a newborn, however, the physician should thoroughly evaluate the infant for minor anomalies that may aid in identifying the cause of the condition.

Sometimes dysmorphic features are not present at birth but become apparent as the child grows and develops. Such features may be associated with dysplasias, that is, defects in cellular metabolism that manifest after birth (eg, skeletal dysplasia that becomes more apparent as the bones grow).

Pathophysiology

In terms of pathophysiology, structural defects can be separated into 4 different types of errors in morphogenesis: malformation, deformation, disruption, and dysplasia (Box 84.1). All these types of errors can result in a sequence of abnormalities.

Previously, the term “malformation” was used descriptively to denote an anomaly; however, it is also used to denote a specific pathogenic mechanism. A malformation is a permanent defect in a structure caused by an intrinsic abnormality in the development of that structure. An example of a malformation is an endocardial cushion defect in a patient with Down syndrome. Malformation syndromes frequently are caused by chromosomal abnormalities, single-gene disorders involving genes that program for structure, or environmental teratogens. Teratogens interfere with organ development during a critical period in embryogenesis, resulting in organ dysgenesis. Alcohol, certain drugs, x-ray irradiation, viral infections, and other environmental exposures can all be teratogens. More than 30 drugs have been proven to be teratogenic.

Deformation results from exertion of mechanical pressure by external forces on the developing fetus. This mechanism involves no intrinsic defect of the fetus. Deformation associated with intrauterine forces can be caused by uterine constraint, an abnormally shaped uterus, or multiparous pregnancy. For example, flexible talipes equinovarus (ie, clubfoot) is a deformation caused by uterine constraint. Postnatal deformations can also occur, such as plagiocephaly caused by an infant sleeping on his or her back.

With disruption, an agent outside the fetus causes cell death, resulting in a permanent defect in fetal development. Disruptive events result in tissue destruction. Examples of disruptive events are tissue ischemia secondary to vascular compromise, viral infection at a critical gestational age (eg, Zika virus infection), and mechanical interference with normal development. An amniotic band is an example of a mechanical disruptive agent; an amniotic band can cause amputation of a developing limb by restricting blood flow to it.

Dysplasias, which often are caused by a single-gene defect, are structural abnormalities that occur as the result of abnormal cellular metabolism and/or organization. Dysplasia can be apparent in utero (and therefore at birth [eg, skeletal dysplasia]) or later. Mucopolysaccharidosis type I causes dysplasias that manifest postnatally secondary to absence of the lysosomal hydrolase, α-L-iduronidase. Glycosaminoglycans accumulate in parenchymal and mesenchymal tissues after birth. Affected children develop coarse facies, an enlarged tongue, misshapen bones, and hepatosplenomegaly, among other features.

Differential Diagnosis

In generating an appropriate differential diagnosis for a child with dysmorphism, it is essential to identify all minor and major malformations. The differential diagnosis varies depending on the specific findings. A thorough patient history and physical examination are necessary to aid in establishing the list of conditions to consider. For the patient with multiple anomalies, identifying the most specific and rarest anomaly can direct the health professional to a narrower list of possible diagnoses. For example, nail hypoplasia, which occurs in fetal hydantoin syndrome, is much rarer than congenital cardiac disease, which occurs in multiple syndromes. The health professional should be familiar with the prominent features of the more common syndromes. Reference texts, such as Smith’s Recognizable Patterns of Human Malformation, are helpful in establishing differential diagnosis lists and in finalizing diagnoses. In addition, several helpful websites are available, such as OMIM (Online Mendelian Inheritance in Man), PubMed, Google and Google Scholar, and others that were specifically developed for the delineation of syndromes and genetic disorders.

In evaluating a neonate or an infant with congenital anomalies, the physician should attempt to separate the findings into 1 of 5 categories: an isolated defect, a developmental field defect, a birth defect association, a sequence pattern, or a dysmorphic syndrome. The first step is to determine whether the anomaly is isolated. If so, does it represent a failure in development in 1 location, such as a cleft lip? Most isolated anomalies are believed to have a multifactorial inheritance, representing the interaction between multiple genes and unknown external influences. Typically, the risk of recurrence for isolated anomalies in future pregnancies is 2% to 5%.

A developmental field defect is a pattern of anomalies that occurs in structures that are in close physical proximity during embryologic development. The defects may involve a limited region and may be the result of a single disruptive event (eg, vascular compromise); thus, the risk for recurrence in subsequent pregnancies is low. One example of such a defect is hemifacial microsomia (ie, oculoauriculovertebral defect), which is believed to be caused by disruption of vascular flow to the first and second branchial arches. The disruption results in hypoplasia of the malar, maxillary, and mandibular region on 1 side with associated microtia and vertebral defects.

Birth defect associations are those in which a combination of anomalies occurs together frequently but the pattern does not fit a known field defect or syndrome. Etiologies of association defects may be unknown, and risk for recurrence in subsequent pregnancies may be low. One of the more common associations is the VACTERL association (vertebral anomalies, anal atresia, cardiac defects, tracheoesophageal fistula, renal defects, and limb defects).

A sequence pattern of anomalies occurs when 1 malformation results in multiple dysmorphic features. For example, oligohydramnios sequence with Potter facies results from renal agenesis. The renal malformation causes oligohydramnios, which in turn causes fetal joint contractures, pulmonary hypoplasia, and a flattened face.

A syndrome is a constellation of anomalies that are pathogenetically related. Chromosomal abnormalities (eg, trisomy 21), single-gene disorders, and teratogens can produce syndromes. Alcohol is the most common teratogen to which fetuses may be exposed. Alcohol exposure in utero causes growth failure, intellectual disability, microcephaly, a short nose, and small distal phalanges (see Chapter 147). Children with intellectual disability and structural anomalies are at increased risk for having a syndrome and should undergo genetic or genomic testing.

Evaluation

History

A complete history is essential (Box 84.2). The history begins prenatally with information from the mother on duration of pregnancy, possible teratogen exposure, fetal activity, diagnostic test results, and any complications of pregnancy. The delivery history should include information on the type of delivery, newborn presentation, and size at birth, including growth percentiles. Neonatal adaptation and feeding patterns are important parameters to assess. The subsequent medical history also should be obtained. The identification of associated intellectual disability is an essential part of the history.

A thorough family history is equally important, including a ped-igree. Specifically, the family should be questioned about parental ages, information pertaining to possible consanguinity, and any history of fetal loss or early infant deaths. Family histories of birth defects or disabilities should be documented.

Physical Examination

The physical examination should be extremely thorough, and all morphologic findings should be noted. As previously mentioned, the craniofacial area and skin are common sites for anomalies, but all organ systems should be extensively evaluated. Even minor anomalies, such as a supernumerary nipple or clinodactyly, may have significance. Objective measurements should be obtained when possible. Normal growth curves are available for evaluating measurements of the face (and other body parts), such as inner canthal distances, palpebral fissure lengths, and ear lengths. Unusual hair whorl patterns and dermatoglyphics (eg, appearance of the palmar creases) should be noted. Physical data, including height, weight, and head circumference, should be plotted and the growth percentiles checked. A complete ophthalmologic evaluation may be indicated to detect abnormalities such as cataracts or cherry-red spots.

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