An approach to work-up of dysmorphic patients: clinical, cytogenetic, and molecular aspects

In view of recent advancement in the field of medical genetics, one approach to work-up a dysmorphic patient is to focus on how to study the patient clinically, cytogenetically, and molecularly. A clear understanding about major and minor anomalies, classification and terminologies of errors of morphogenesis, history taking, physical examination, laboratory studies including molecular cytogenetic techniques, genomic imprinting, uniparental disomy, and mosaicism is essential. Several clinical cases from my own experience are provided to illustrate my approach to work-up of dysmorphic patients. Case 1 was a newborn with multiple congenital anomalies (MCA) and a de novo dup (1) (pter-->q25::q12-->qter). Fluorescent in situ hybridization (FISH) unequivocally identified the duplicated region. Case 2 was a stillborn who had frontonasal dysplasia, arrhinencephaly, and other MCA with 46,XX,-7,+der(7), t(2;7) (q31;q36)mat. Her MCA were due to combined effect of trisomy 2q and monosomy 7q. This case helped to define the physical mapping of the critical region for a mild form of holoprosencephaly to 7q36. Case 3 had a classic de Lange phenotype with genital abnormality and sex reversal (46,XX male). Presence of SRY suggests X-Y interchange during paternal meiosis I. Case 4 was a female with primary amenorrhea, short stature, and 45,X/46,X,idic(Y)/47,X,idic(Y),idic(Y). This case demonstrates the need for molecular analyses to confirm the cytogenetic interpretations and allowed the refinement of the breakpoint in the isodicentric Y and karyotype/phenotype correlations. Case 5 & 6 were half sibs with ambiguous genitalia, minor somatic abnormalities, and dup (X) (p21.2-->p22.11)mat. Limited extent of the Xp duplication in these cases allows assignment of the X-linked sex-reversal (SRVX) locus to Xp21.2-->p22.11.