Approach to the Dysmorphic Child

History• Pedigree or family history : to assess the inheritance pattern.• Perinatal history : pregnancy history of the mother , factors that

may relate to deformations or disruptions , maternal exposures to teratogenic drugs or chemicals .

• Natural history of the phenotype : 1. Malformation syndromes caused by chromosomal aneuploidy

or aneusomy and single gene pleiotropic disorders are usually static.

2. Disorders that cause dysmorphic features by the mechanism of metabolic perturbations (Hunter syndrome, Sanfilippo syndrome) are either mild or inapparent at birth and progress relentlessly, causing deterioration of the patient over time.

Physical ExaminationDEFINITIONS OF COMMON CLINICAL SIGNS OF DYSMORPHIC SYNDROMES

MINOR ANOMALIES AND PHENOTYPE VARIANTS*

CRANIOFACIAL

1. Large fontanel2. Flat or low nasal bridge3. Saddle nose, upturned

nose4. Mild micrognathis5. Cutis aplasia of scalp

EYE

1. Inner epicanthal folds2. Telecanthus3. Slanting of palpebral

fissures4. Hypertelorism5. Brushfield spots

EAR

1. Lack of helical fold2. Posteriorly rotated pinna3. Preauricular with or without

auricular skin tags4. Small pinna5. Auricular (preauricular) pit or

sinus6. Folding of helix7. Darwinian tubercle8. Crushed (crinkled) ear9. Asymmetric ear sizes10. Low-set ears

SKIN

1. Dimpling over bones2. Capillary hemangioma

(face, posterior neck)3. Mongolian spots (African

Americans, Asians)4. Sacral dimple5. Pigmented nevi6. Redundant skin7. Cutis marmorata

HAND

1. Simian creases2. Bridged upper palmar creases3. Clinodactyly of fifth digit4. Hyperextensibility of thumbs5. Single flexion crease of fifth digit

(hypoplasia of middle6. phalanx)7. Partial cutaneous syndactyly8. Polydactyly9. Short, broad thumb10. Narrow, hyperconvex nails11. Hypoplastic nails12. Camptodactyly13. Shortened fourth digit

FOOT

1. Partial syndactyly of second and third toes

2. Asymmetric toe length3. Clinodactyly of second toe4. Overlapping toes5. Nail hypoplasia6. Wide gap between hallux

and second toe7. Deep plantar crease between

hallux and second toe

OTHERS

1. Mild calcaneovalgus2. Hydrocele3. Shawl scrotum4. Hypospadias5. Hypoplasia of labia majora

Imaging Studies

• If short stature or disproportionate stature (long trunk and short limbs) is noted, a full skeletal survey should be performed.

• The skeletal survey can yield numerous abnormal features that can be used to narrow the differential diagnosis.

• When there are abnormal neurologic signs or symptoms, central nervous system imaging is indicated.

• Echocardiography and renal ultrasonography, can be useful to identify additional major or minor malformations.

Laboratory Studies

• Cytogenetics with Giemsa-banded peripheral leukocyte karyotype (or chromosome) analysis has been the gold standard and has been performed in most evaluations of the dysmorphic child .

• Array CGH and SNP genotyping with copy number variation (dosage detection) are the most sensitive methods for the detection of genomic alterations associated with multiple congenital anomalies.

• Because many chromosome abnormalities include derangement of the termini (telomeres) of the chromosomes, assays should detect small (submicroscopic) duplications or deletions of the termini of the chromosomes

CLINICAL INDICATIONS FOR KARYOTYPE ANALYSIS

1. At least one major and two minor malformations2. At least two major malformations3. Developmental OR growth retardation with two or

more major or minor anomalies

Diagnosis

• The clinician should organize the findings by their specificity into potential developmental pathophysiologic processes.

• The specificity assessment is the simplest.

• If a child has a patent ductus arteriosus (PDA), mild growth retardation, mild microcephaly, and holoprosencephaly (MRI finding of failure to lateralize the forebrain), micropenis, and ptosis, these findings can be prioritized.

• The PDA, ptosis, mild growth retardation, and mild microcephaly are nonspecific findings (present in many disorders or often present as isolated features not part of a syndrome), whereas holoprosencephaly and micropenis are present in fewer syndromes and are never normal variants

• With this recognition, the clinician can search for disorders that include both holoprosencephaly and micropenis.

• The search can be performed manually using the features index of a textbook such as Smith's Recognizable Patterns of Human Malformation or a computerized database such as the Winter-Baraitser Dysmorphology Database.

• Searching for disorders with both findings leads quickly to a modest list of only 21 disorders.

• One of these is SLOS. The identification of this possible diagnosis prompts the physician to return to the bedside, realize that many of the nonspecific features in the child are common in SLOS, and make a tentative diagnosis of this disorder.

• Although holoprosencephaly is an uncommon manifestation of SLOS, this manifestation makes sense because of the known pathogenetic link between sonic hedgehog and cholesterol biosynthesis.

• Because this disorder is caused by mutations in the sterol delta-7-reductase gene and is associated with elevated 7-dehydrocholesterol, the pediatrician can initiate a consultation with the clinical geneticist for suspected SLOS