Phenotype-genotype correlation in nr5a1 gene remains elusive: heterozygosis for p.d293n mutation also leads dsd phenotype

We report on a patient with XY partial gonadal dysgenesis (PGD) with a heterozygous mutation that had already been described in homozygous patients from a family with different phenotypes. Methods: Our patient was referred with 14 days of age due to sex ambiguity. He had a 1.5-cm phallus, penoscrotal hypospadias, and both gonads were in the labioscrotal folds. Horm Res Paediatr 2017;88(suppl 1):1–628 Karyotype was 46,XY. At 6 weeks of age he had normal FSH, DHEA and androstenedione, whereas LH, 17-OHprogesterone and testosterone were elevated, slightly elevated and low, respectively. ACTH test resulted normal but there was no response to hCH test performed at 7 months. Antimullerian hormone was also low. He received a male sex assignment and underwent hypospadias repair. He had a right streak gonad and a left dysgenetic testis, leading to the diagnosis of XY PGD. Spontaneous puberty started at 12 years and progressed normally. At 16 years he had high FSH and LH but normal testosterone. Whole exome sequencing was performed to search for patogenic mutations in genes involved in testis differentiation. Results: Whole exome sequencing revealed heterozygosis of the c.877Ggt;A transition within exon 5 of NR5A1. This change leads to p.D293N mutation that had already been described in four homozygous members of a family: one with XY PGD, one with XX complete gonadal dysgenesis (CGD) and two with XY CGD. Heterozygous members of the family were phenotypically normal. The mother of the present patient was born in the same little town where that family originated. Conclusions: To our knowledge, this is the first p.D293N heterozygous individual to present DSD. The recessive inheritance for this mutation concluded on basis of that family pattern and on the relatively high level of residual activity of the mutated SF-1 is no longer appropriated. SF-1 acts in a dose-dependent manner and regulates many other genes involved in sex differentiation process, which could explain the broad spectrum of phenotypes caused by the same mutation. The present case illustrates the difficulty in establishing an appropriate phenotype-genotype correlation and highlights the importance of genetic knowledge for the correlation of NR5A1 mutations with clinical phenotypes881P1 - 151620220