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 EYE 1. Inner epicanthal folds1. Large fontanel 2. Telecanthus2. Flat or low nasal bridge 3. Slanting of palpebral3. Saddle nose, upturned fissures nose 4. Hypertelorism4. Mild micrognathis 5. Brushfield spots5. Cutis aplasia of scalp
EAR SKIN1. Lack of helical fold 1. Dimpling over bones2. Posteriorly rotated pinna3. Preauricular with or without 2. Capillary hemangioma auricular skin tags (face, posterior neck)4. Small pinna 3. Mongolian spots (African5. Auricular (preauricular) pit or Americans, Asians) sinus6. Folding of helix 4. Sacral dimple7. Darwinian tubercle 5. Pigmented nevi8. Crushed (crinkled) ear 6. Redundant skin9. Asymmetric ear sizes10. Low-set ears 7. Cutis marmorata
HAND FOOT1. Simian creases 1. Partial syndactyly of second2. Bridged upper palmar creases3. Clinodactyly of fifth digit and third toes4. Hyperextensibility of thumbs 2. Asymmetric toe length5. Single flexion crease of fifth digit (hypoplasia of middle 3. Clinodactyly of second toe6. phalanx)7. Partial cutaneous syndactyly 4. Overlapping toes8. Polydactyly 5. Nail hypoplasia9. Short, broad thumb10. Narrow, hyperconvex nails 6. Wide gap between hallux and11. Hypoplastic nails second toe12. Camptodactyly13. Shortened fourth digit 7. Deep plantar crease between hallux and second toe
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 ANALYSIS1. 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 Smiths 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