ESPE Abstracts (2018) 89 P-P3-400

Clinical and Molecular Characterization of One Nr5a1 Gene Mutation Found in a Patient WITH 46, XY DSD

Amaya Velaa,b, Idoia Martinez De Lapiscinaa, Gustavo Perez De Nanclaresa, Rodriguez Amaiaa,b, Itxaso Ricaa,b, Luis Castañoa & Gema Graua,b


aEndocrinology and Diabetes Research Group, BioCruces Health Research Institute, Cruces University Hospital, UPV/EHU, Ciberer, Ciberderm, Barakaldo, Spain; bPediatric Endocrinology, Cruces University Hospital, Barakaldo, Spain


Introduction: Steroidogenic factor-1 (SF1), encoded by the NR5A1 gene, regulates several genes involved in male sexual determination, such as SOX9 and AMH, cholesterol mobilization and synthesis of a number of steroidogenic enzymes, like 3βHSD, and androgen biosynthesis, like INSL3. Mutations in NR5A1 have been associated to a broad phenotypic spectrum in 46, XY subjects, including pure gonadal dysgenesis, infertility, anorchia or hypospadias, often in conjunction with normal adrenal function. In the present study, we describe a patient with extreme hypospadias, micropenis and bifid scrotum.

Patients and methods: Male patient with 46, XY karyotype presenting at birth scrotal hypospadias, micropenis, undescended testes and bifid scrotum. Biochemical analysis revealed LH: 2.5 mU/ml, FSH: 3.7 mU/ml, Testosterone: 67.5 ng/ml, DHT: 1.7 ng/ml, DHEA-S: 400 ng/ml and Cortisol: 10.4 mcg/dl. Abdominal ultrasound without findings. Good response of the penis to treatment with testosterone. Maternal uncle presented with scrotal hypospadias at birth. Apparently there is no additional family background of interest. Genomic DNA was isolated from peripheral blood leukocytes and genetic characterization was performed using a targeted gene panel by NGS. PCR and Sanger sequencing was used for variant confirmation and to test parents and affected family members to establish the mode of inheritance.

Results: DSD targeted gene panel sequencing identified the heterozygous NR5A1 c.250C>T; p. Arg84Cys mutation. This mutation has been previously reported and associated with gonadal dysgenesis by Reuter Al et al (2007). Functional studies demonstrated that p. Arg84Cys diminishes DNA binding site affinity and transcriptional activity. Mother presenting with precocious puberty, maternal aunt with menstrual disorders and uncle with scrotal hypospadias presented the variation in heterozygosis, as well as the healthy grandfather.

Conclusions: Our results agree with previous studies in which the complex penetrance, expressivity and inheritance of the alterations found in the NR5A1 gene, give rise depending on the mutation to phenotypes in 46 XY patients that encompass from pure gonadal dysgenesis to completely asymptomatic carriers, whereas in 46 XX patients lead to mild forms such as primary ovarian failure.

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