Background: The investigation of patients with 46,XY DSD is often difficult, with no definitive diagnosis in more than 50% of cases investigated. We describe a new mutation of MAMLD1 in a patient with 46,XY DSD who also showed an alteration in the NR5A1 gene.
Case report: A 5-year-old boy was referred to our clinic for DSD. He was born to non-consanguineous parents and was diagnosed with ambiguous genitalia at birth but had not been previously investigated. Examination showed undescended testes, peno-scrotal hypospadias and microphallus (3 cm). Investigations showed 46,XY karyotype; basal testosterone 0.11 nmol/l with an impaired response to hCG stimulation (peak: 0.5 nmol/l after 1500 UI×6 (every 2 days); basal FSH and LH 1.76 and <0.001 mUI/ml respectively; AMH low at 85.8 pmol/l. No testes could be seen on pelvic ultrasound but genitogram showed the presence of a Mullerian duct remnant connected to the bulbar urethra. At laparoscopic surgery two small testes were found. After three i.m. injections of Testosterone Enanthate 50 mg penile length increased from 3 to 5 cm. Orchidopexy and surgical correction of the hypospadias have been performed.
Molecular studies: Analysis of the NR5A1 (SF1) gene revealed the presence the variant p.Gly146A1a. Mutation analysis of MAMLD1 (CXorf6) showed a heterozygous mutation of MAMLD1 (c.1868G>A//p.Arg623His).
Discussion: Mutations of MAMLD1 have been recently described in patients with complex 46,XY DSD including micropenis, cryptorchidism and peno-scrotal hypospadias. We describe a new heterozygous MAMLD1 (CXorf6) mutation causing 46, XY DSD with partial gonadal dysgenesis. Moreover, our patient presented a variant in the SF1 gene which has been reported more frequently in patients with cryptorchidism and microphallus. It is possible that the two gene alterations have had a digenic effect, with the MAMLD1 having a predominant effect on Leydig cell function while the SF1 variant has contributed to impaired Sertoli cell function.
20 - 22 Sep 2014
European Society for Paediatric Endocrinology