DYSMORPHOLOGYis the art of recognizing the pattern of multiple congenital anomalies that occurs with various malformation syndromes

COMMON TYPES

DOWN SYNDROME (DS)❏ most common abnormality

of autosomal chromosomes❏ trisomy 21• 80-90% nondisjunction• 5% translocations• 3% mosaics (may be less

noticeable/less severe) Trisomy 13❏ incidence 1:5,000 live births

Trisomy 18❏ incidence: 1:8,000 live

births, female: male = 3:1

TURNER SYNDROME ❏ genotype: 45X (most

common), mosaic (45X0) ❏ incidence 1:2,500 live

female births NOONAN SYNDROME ❏ genotype: 46XX and 46XY,

autosomal dominant with variable expression

❏ incidence 1:1000 live births KLINEFELTER SYNDROME ❏ genotype: 47 XXY (most

common) ❏ incidence: 1:1,000 live

male births

FRAGILE X ❏ most common

genetic cause of developmental delay in boys

❏ incidence 1:1,250; X-linked recessive

DIGEORGE SYNDROME

❏ 2nd most common genetic diagnosis (next to Down syndrome)

❏ results from microdeletions of 22q11 (unequal crossing of chromosomes in meiosis)

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)

HISTORY

Pregnancy History

birth weight? 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. Infants who are appropriate for gestational age may have a single gene mutation, a multifactorial condition, or, most likely, no genetic disease.

full term, premature, or postmature? When evaluating an older child with developmental disabilities, complications of extreme prematurity may be responsible for the patient's problems. Post-maturity also is associated with some chromosome anomalies (e.g., trisomy 18) and anencephaly.

Was the infant born by vaginal delivery or caesarean section? If the latter, what was the cause? Infants born from breech presentation are more likely to have congenital malformations.

How old were the parents at the time of the child's delivery? 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 AD trait.

Were there complications during the pregnancy? Does the mother have any underlying medical problems? Does she take any medications? Did she smoke cigarettes, drink alcohol, or take any drugs?

When did the mother feel quickening? Were fetal movements active? Neonatal hypotonia may have manifested prenatally; answers to these questions may provide information.

Was there a normal amount of amniotic fluid? An increased amount of fluid may be associated with intestinal obstruction or a CNS 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. Also, a history of pregnancy or neonatal losses should be documented. For a complete discussion of pedigrees,

PHYSICAL EXAMINATION

Growth

The height (length), weight, and head circumference should be measured carefully and plotted on appropriate growth curves.

Growth appropriate for age is consistent with the presence of a single gene disorder, a multifactorially inherited condition, or, most commonly, no genetic disease.

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 check if the child is proportionate. If the limbs are too short for the head and trunk, this implies the presence of a short-limbed bone dysplasia, such as achondroplasia. If the trunk and head are too short for the extremities, it may suggest a disorder affecting the vertebrae, such as spondyloepiphyseal dysplasia.

Craniofacial Head shape should be assessed carefully. 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 either a deformation related to the intrauterine position or a malformation of one side of the face.

The face should be divided into four regions, which should be 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, which extends 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 (interpupillary 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), which suggests Aarskog syndrome (hypertelorism, brachydactyly [short digits], and shawl scrotum). 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.

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 "growth" charts that record length for age), shape (noting thinning of the pinnae, unusual folding), 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.

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 (a shieldlike chest is found 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 the case of 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 AD 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 49. Fluorescent in situ hybridization should be requested when a syndrome with a known chromosomal defect in 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, the latter to look for anomalies in the 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, and an ECG and echocardiogram may be indicated. MRI may be indicated in children with neurologic abnormalities or a spinal defect. The presence of craniosynostosis may indicate a CT scan of the head.

DIAGNOSIS

Although the presence of characteristic findings sometimes may make the definitive diagnosis of a malformation syndrome simple, 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: It offers an explanation to the family why their child was born with congenital anomalies. This may help to allay guilt because parents often believe that they are responsible for their child's problem.

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.

It permits genetic counseling to be done so that the parents can understand the risk to future children. An accurate diagnosis 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 because information on the Internet is not subject to editorial control, and some of the information may be inaccurate. A good site is the National Organization for Rare Disorders (www.rarediseases.org), which acts as 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.

APPROACH TO THE DYSMORPHIC CHILD

History

❏ prenatal/obstetrical history❏ complete 3 generation family pedigree:

consanguinity, stillbirths, neonatal deaths, specific illnesses, mental retardation (MR), multiple miscarriages, ethnicity

Physical Examination

❏ growth parameters: head circumference (HC), height(Ht), and weight (Wt)

❏ skull: contour and symmetry❏ hair: texture and pattern❏ neck: look for redundant

nuchal skin/webbed neck❏ facial gestalt: compare with

siblings and parents❏ ears: structure, size,

placement and rotation❏ eyes and adnexa: distance

apart, orientation, eyebrows and eyelashes, any folds or creases, coloboma, fundus

❏ nose: nasal bridge, nostrils❏ philtrum: length and shape❏ mouth: lips, palate, tongue

and teeth❏ chin: size and position❏ thorax: shape, size, and

nipple spacing❏ hands and feet: creases,

structure (e.g overlapping fingers/toes), and nails

❏ limbs: proportions, reduction defects, and amputations

❏ spine: scoliosis❏ genitalia: ambiguous❏ skin: hair tufts, sacral

dimples/sinus

Investigations

❏ ask for serial photographs if child is older, family pictures

❏ x-rays if bony abnormalities or if suspect a congenital infection

❏ cytogenetic/chromosome studies +/– skin fibroblasts

❏ biochemistry: specific enzyme assays❏ molecular biology for specific testing❏ genetic probes now available e.g. Fragile X,

microdeletion 22❏ counselling and recurrence risk assessment