gms | German Medical Science

Background: Disorders of Sex Development affect the development of chromosomal, gonadal and/or anatomic sex. We analyzed a patient with ambiguous genitalia aiming to correlate the genetic findings with the phenotype.

Materials and methods: Blood and tissue samples from a male patient with penoscrotal hypospadia were analyzed by immunohistochemistry karyotyping and FISH. DNA was sequenced for the AR, SRY and DHH genes and further 26 loci in different sex-development chromosomes were analyzed by MLPA. The gonosomal origin was evaluated through STR analysis and SNP-Array.

Results: Histopathology revealed a streak-gonad, a fallopian tube and a rudimentary uterus, positive for PLAP, cytokeratin-7 and c-kit and negative for oestrogen-, androgen- and progesterone-receptors, alpha-inhibin, alpha-1-fetoprotein, beta-HCG and oct-4. Karyotyping showed a 45,X/46,XY mosaic, yet FISH showed both 46,XX/46,XY mosaic (gonad and urethral platte), 46,XX (uterus and tube) and 46,XY karyotypes (rudimentary testicular tissue). The DNA sequencing revealed intact sequences in SOX9, WNT4, NR0B1, NR5A1, CYP21A2, SRY, AR and DHH. UPD was confirmed by STR-Analysis, which showed only one maternal allele for all X-chromosome markers (uniparental isodisomy), with weaker SRY signal and 4:1 ratio in the X:Y signal.

Conclusion: Our findings suggest that the observed complex DSD phenotype is the result of somatic gonosomal mosaicism and UPD despite a normal blood karyotype. The presence of UPD warrants an adequate genetic counselling for the family and frequent, life-long, preventive follow-up controls in the patient.