CHAPTER 50 The Approach to the Dysmorphic Child

Dysmorphology is the recognition of the pattern of congenital malformations (often multiple congenital malformations) and dysmorphic features that characterize a particular syndrome. Syndromes are collections of abnormalities, including malformations, deformations, dysmorphic features, and abnormal behaviors that have a unifying, identifiable etiology. This etiology may be the presence of a mutation in a single gene, as is the case in Rett syndrome, a disorder that is caused by a mutation in the MECP2 gene on Xq28; deletion or duplication of chromosomal material, such as is the case in Prader-Willi syndrome, which is caused by the deletion of the paternal copy of the imprinted SNRPN gene; or exposure to a teratogenic substance during embryonic development, as in fetal alcohol syndrome.

DEFINITIONS

Congenital malformations are defined as clinically significant abnormalities in either form or function. They result from localized intrinsic defects in morphogenesis, which were caused by an event that occurred in embryonic or early fetal life. This event may have been a disturbance of development from some unknown cause, but often mutations in developmental genes led to the abnormality. Extrinsic factors may cause disruptions of development by disturbing the development of apparently normal tissues. These disruptions may include amniotic bands, interruption or disruption of blood supply to developing tissues, or exposure to teratogens. A malformation sequence is the end result of a malformation that has secondary effects on later developmental events. An example is the Pierre Robin sequence. The primary malformation, failure of the growth of the mandible during the first weeks of gestation, results in micrognathia, which forces the normal-sized tongue into an unusual position. The abnormally placed tongue blocks the fusion of the palatal shelves, which normally come together in the midline to produce the hard and soft palate; this leads to the presence of a U-shaped cleft palate. After delivery, the normal-sized tongue in the smaller than normal oral cavity leads to airway obstruction, a potentially life-threatening complication.

Deformations arise as a result of environmental forces acting on normal structures. They occur later in pregnancy or after delivery. Oligohydramnios may inhibit lung growth and cause compression of fetal structures, producing clubfoot, dislocated hips, and flattened facies (Potter’s syndrome) (see Chapter 196). Deformations often resolve with minimal intervention, but malformations often require surgical and medical management.

Minor malformations, variants of normal that occur in less than 3% of the population, include findings such as transverse palmar creases, low-set ears, or hypertelorism; when isolated they have no clinical significance. A multiple malformation syndrome is the recognizable pattern of anomalies that results from a single identifiable underlying cause. It may involve a series of malformations, malformation sequences, and deformations. These syndromes often prompt a consultation with a clinical geneticist. Dysmorphology is the specialty focusing on recognition of patterns of malformations that occur in syndromes (Table 50-1).

TABLE 50-1 Glossary of Selected Terms Used in Dysmorphology

TERMS PERTAINING TO THE FACE AND HEAD

Brachycephaly: Condition in which head shape is shortened from front to back along the sagittal plane; the skull is rounder than normal

Canthus: The lateral or medial angle of the eye formed by the junction of the upper and lower lids

Columella: The fleshy tissue of the nose that separates the nostrils

Glabella: Bony midline prominence of the brows

Nasal alae: The lateral flaring of the nostrils

Nasolabial fold: Groove that extends from the margin of the nasal alae to the lateral aspects of the lips

Ocular hypertelorism: Increased distance between the pupils of the two eyes

Palpebral fissure: The shape of the eyes based on the outline of the eyelids

Philtrum: The vertical groove in the midline of the face between the nose and the upper lip

Plagiocephaly: Condition in which head shape is asymmetric in the sagittal or coronal planes; can result from asymmetry in suture closure or from asymmetry of brain growth

Scaphocephaly: Condition in which the head is elongated from front to back in the sagittal plane; most normal skulls are scaphocephalic

Synophrys: Eyebrows that meet in the midline

Telecanthus: A wide space between the medial canthi

TERMS PERTAINING TO THE EXTREMITIES

Brachydactyly: Condition of having short digits

Camptodactyly: Condition in which a digit is bent or fixed in the direction of flexion (a “trigger finger”–type appearance)

Clinodactyly: Condition in which a digit is crooked and curves toward or away from adjacent digits

Hypoplastic nail: An unusually small nail on a digit

Melia: Suffix meaning “limb” (e.g., amelia—missing limb; brachymelia—short limb)

Polydactyly: The condition of having six or more digits on an extremity

Syndactyly: The condition of having two or more digits at least partially fused (can involve any degree of fusion, from webbing of skin to full bony fusion of adjacent digits)

An association differs from a syndrome in that in the former, no single underlying etiology explains the recognizable pattern of anomalies that occur together more than would be expected by chance alone. The VACTERL association (vertebral anomalies, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb anomalies) is an example of a group of malformations that occur more commonly together than might be expected by chance. No single unifying etiology explains this condition, so it is considered an association.

In approximately half of children noted to have one or more congenital malformations, only a single malformation is identifiable; in the other half, multiple malformations are present. About 6% of infants with congenital malformations have chromosomal defects, 7.5% have a single gene disorder, 20% are multifactorial, and approximately 7% are due to exposure to a teratogen. In more than 50% of cases, no cause can be identified.

HISTORY AND PHYSICAL EXAMINATION

Pregnancy History

The history of the pregnancy and birth can reveal multiple risk factors that are associated with dysmorphology. Small for gestational age infants may have a chromosome anomaly or may have been exposed to a teratogen. Large for gestational age infants may be infants of diabetic mothers or have an overgrowth syndrome, such as Beckwith-Wiedemann syndrome. When evaluating an older child with developmental disabilities, complications of extreme prematurity may account for the child’s problems. Postmaturity also is associated with some chromosome anomalies (e.g., trisomy 18) and anencephaly. Infants born from breech presentation are more likely to have congenital malformations.

Advanced maternal age is associated with an increased risk of nondisjunction leading to trisomies. Advanced paternal age may be associated with an increased risk of a new mutation leading to an autosomal dominant trait. Maternal medical problems and exposures (medications, drugs, cigarette smoking, and alcohol use) are associated with malformations (see Chapters 47 and 48).

An increased amount of amniotic fluid may be associated with intestinal obstruction or a central nervous system anomaly that leads to poor swallowing. A decreased amount of fluid may point to a urinary tract abnormality, leading to failure to produce urine or a chronic amniotic fluid leak.

Family History

A pedigree should be constructed, searching for similar or dissimilar abnormalities in first-degree and second-degree relatives. A history of pregnancy or neonatal losses should be documented. For a complete discussion of pedigrees, see Chapter 47.

Page 184

Physical Examination

When examining children with dysmorphic features, the following approach should be used.

Growth

The height (length), weight, and head circumference should be measured carefully and plotted on appropriate growth curves. Small size or growth restriction may be secondary to a chromosomal abnormality, skeletal dysplasia, or exposure to toxic or teratogenic agents. Larger than expected-size suggests an overgrowth syndrome (Sotos or Beckwith-Wiedemann syndrome), or, if in the newborn period, it might suggest a diabetic mother.

The clinician should note if the child is proportionate. Limbs that are too short for the head and trunk imply the presence of a short-limbed bone dysplasia, such as achondroplasia. A trunk and head that are too short for the extremities suggest a disorder affecting the vertebrae, such as spondyloepiphyseal dysplasia.

Craniofacial

Careful examination of the head and face is crucial for the diagnosis of many congenital malformation syndromes. Head shape should be carefully assessed; if the head is not normal in size and shape (normocephalic), it may be long and thin (dolichocephalic), short and wide (brachycephalic), or asymmetric or lopsided (plagiocephalic).

Facial features should be assessed next. Any asymmetry should be noted; asymmetry may be due to a deformation related to intrauterine position or a malformation of one side of the face. The face should be divided into four regions, which are evaluated separately. The forehead may show overt prominence (achondroplasia) or deficiency (often described as a sloping appearance, which occurs in children with primary microcephaly). The midface, extending from the eyebrows to the upper lip and from the outer canthi of the eyes to the commissures of the mouth, is especially important. Careful assessment of the distance between the eyes (inner canthal distance) and the pupils (interpupil distance) may confirm the impression of hypotelorism (eyes that are too close together), which suggests a defect in midline brain formation, or hypertelorism (eyes that are too far apart). The length of the palpebral fissure should be noted and may help define whether the opening for the eye is short, as is found with fetal alcohol syndrome, or excessively long, as in Kabuki makeup syndrome (short stature, mental retardation, long palpebral fissures with eversion of lateral portion of lower lid).

Other features of the eyes should be noted. The obliquity (slant) of the palpebral fissures may be upward (as seen with Down syndrome) or downward (as in Treacher Collins syndrome). The presence of epicanthal folds (Down syndrome and fetal alcohol syndrome) is also important. Features of the nose—especially the nasal bridge, which can be flattened in Down syndrome, fetal alcohol syndrome, and many other syndromes, or prominent as in velocardiofacial syndrome—should be noted.

Page 185

The malar region of the face is examined next. It extends from the ear to the midface. The ears should be checked for size (measured and checked against appropriate growth charts), shape, position (low-set ears are below a line drawn from the outer canthus to the occiput), and orientation (posterior rotation is where the ear appears turned toward the rear of the head). Ears may be low set because they are small (or microtic) or because of a malformation of the mandibular region.

The mandibular region is the area from the lower portion of the ears bounded out to the chin by the mandible. In most newborns, the chin is often slightly retruded (that is slightly behind the vertical line extending from the forehead to the philtrum). If this retrusion is pronounced, the child may have the Pierre Robin malformation sequence. In addition, the mouth should be examined. The number and appearance of the teeth should be noted, the tongue should be observed for abnormalities, and the palate and uvula checked for defects.

Neck

Examination of the neck may reveal webbing, a common feature in Turner syndrome and Noonan syndrome, or shortening, as is seen occasionally in some skeletal dysplasias and in conditions in which anomalies of the cervical spine occur, such as Klippel-Feil syndrome. The position of the posterior hairline also should be evaluated. The size of the thyroid gland should be assessed.

Trunk

The chest may be examined for shape (shieldlike chest in Noonan syndrome and Turner syndrome) and symmetry. The presence of a pectus deformity should be noted and is common in Marfan syndrome. The presence of scoliosis should be assessed; it is common in Marfan syndrome and many other syndromes.

Extremities

Many congenital malformation syndromes have anomalies of the extremities. All joints should be examined for range of motion. The presence of single or multiple joint contractures suggests either intrinsic neuromuscular dysfunction, as in some forms of muscular dystrophy, or external deforming forces that limited motion of the joint in utero. Multiple contractures also are found with arthrogryposis multiplex congenita and are due to a variety of causes. Radioulnar synostosis, an inability to pronate or supinate the elbow, occurs in fetal alcohol syndrome and in some X chromosome aneuploidy syndromes.

Examination of the hands is important. Polydactyly (the presence of extra digits) usually occurs as an isolated autosomal dominant trait but also can be seen in trisomy 13. Oligodactyly (a deficiency in the number of digits) is seen in Fanconi syndrome (anemia, leukopenia, thrombocytopenia, and associated heart, renal, and limb anomalies—usually radial aplasia and thumb malformation or aplasia), in which it is generally part of a more severe limb reduction defect, or secondary to intrauterine amputation, which may occur with amniotic band disruption sequence. Syndactyly (a joining of two or more digits) is common to many syndromes, including Smith-Lemli-Opitz syndrome (see Chapters 199 and 201).

Dermatoglyphics include palmar crease patterns. A transverse palmar crease, indicative of hypotonia during early fetal life, is seen in approximately 50% of children with Down syndrome (and 10% of individuals in the general population). A characteristic palmar crease pattern is seen in fetal alcohol syndrome.

Genitalia

Genitalia should be examined closely for abnormalities in structure. In boys, if the penis appears short, it should be measured and compared with known age-related data. Ambiguous genitalia often are associated with endocrinologic disorders, such as congenital adrenal hyperplasia (girls have masculinized external genitalia, but male genitalia may be unaffected), or chromosomal disorders such as 45,X/46,XY mosaicism or possibly secondary to a multiple congenital anomaly syndrome (see Chapters 174 and 177). Although hypospadias, which occurs in 1 in 300 newborn boys, is a common congenital malformation that often occurs as an isolated defect, if it is associated with other anomalies, especially cryptorchidism, there is a strong possibility of a syndrome.

LABORATORY EVALUATION

Chromosome analysis, either metaphase or prophase, should be ordered for children with multiple congenital anomalies, the involvement of one major organ system and the presence of multiple dysmorphic features, or the presence of mental retardation. For a complete discussion of chromosome analysis, see Chapter 48. Fluorescent in situ hybridization (FISH) should be requested when a syndrome with a known chromosomal defect for which probes are available is suspected. Disorders such as velocardiofacial syndrome, Williams syndrome, and Prader-Willi syndrome are included in this group. Direct DNA analysis can be performed to identify specific mutations. It is necessary to use Web-based resources to keep up-to-date. An extremely helpful website is www.genetests.org, which provides information about the availability of testing for specific conditions and identifies laboratories performing the testing.

Radiologic imaging plays an important role in the evaluation of children with dysmorphic features. Individuals found to have multiple external malformations should have a careful evaluation to search for the presence of internal malformations. Testing might include ultrasound evaluations of the head and abdomen to look for anomalies in the brain, kidney, bladder, liver, and spleen. Skeletal radiographs should be performed if there is concern about a possible skeletal dysplasia. The presence of a heart murmur should trigger a cardiology consultation; an electrocardiogram and echocardiogram may be indicated. Magnetic resonance imaging may be indicated in children with neurologic abnormalities or a spinal defect. The presence of craniosynostosis may indicate a computed tomography scan of the head.

Page 186

DIAGNOSIS

Although the presence of characteristic findings may make the diagnosis of a malformation syndrome straightforward, in most cases no specific diagnosis is immediately evident. Some constellations of findings are rare, and finding a “match” may prove difficult. In many cases, all laboratory tests are normal, and confirmation relies on subjective findings. Clinical geneticists have attempted to resolve this difficulty by developing scoring systems, cross-referenced tables of anomalies that help in the development of a differential diagnosis, and computerized diagnostic programs. An accurate diagnosis is important for the following reasons:

1. It offers an explanation to the family why their child was born with congenital anomalies. This may help allay guilt because parents often believe that they are responsible for their child’s problem.

2. The natural history of many disorders is well described, so a diagnosis allows the physician to anticipate medical problems associated with a particular syndrome and perform appropriate screening. It also provides reassurance that other medical problems are no more likely to occur than they might with other children who do not have the diagnosis.

3. It permits genetic counseling to be done so that the parents can understand the risk to future children and also permits prenatal testing to be done for the disorders for which it is available.

Diagnosis enables the clinician to provide the family with educational materials about the diagnosis and for contact with support groups for particular disorders. The Internet has become an important source for such information, but care should be exercised as information on the Internet is not subject to editorial control. Some of the information may be inaccurate. A good site is the National Organization for Rare Disorders (www.rarediseases.org), a clearinghouse for information about rare diseases and their support groups. Genetic testing information is available at the Genetests website (www.genetests.org). This site provides information on available clinical and research testing for many diseases.