ESPE Abstracts

Background: Disorders of sex development (DSD) due to mutations in the NR5A1 (SF1) gene result in a highly variable phenotype.

Objective: To report the clinical phenotype and the molecular/structural characteristics of the gene-protein product arising from three novel mutations of the NR5A1 (SF1) gene found in patients presenting with 46,XY DSD.

Method: Phenotype determined from interrogation of clinical case notes. Interpretation of DNA-protein molecular interactions were modelled in-silico using PyMOL Molecular Graphic System. Mutation effect and structural analyses verified using PolyPhen2; MutationTaster, SIFT, LRT and SAAP software programmes.

Results: Case 1. Mutation (heterozygous) Q329X. Karyotype 46XY. Female presented age 14yrs with primary amenorrhoea, no breast development, hirsutism, clitoromegaly (6 cm) and narrow blind-ending vagina. Bilateral inguinal gonads and absent uterus detected. Basal serum testosterone (T)=20.6 nmol/l. Mutation results in a truncated SF1 protein at ligand binding domain. Case 2. Mutation (heterozygous) G22D. Karyotype 46XY - confirmed prenatally. Female appearance at birth with normal sized clitoris. Bilateral palpable labial gonads and absent uterus. Post-HCG T=10.1 nmol/l. Mutation alters DNA binding domain site configuration. Case 3. Mutation (heterozygous) A280E. Karyotype 46XY. Female presented age 14yrs with isolated pubic hair development (onset age 8 yrs), clitoromegaly (3 cm) and lack of other pubertal development. Rudimentary uterus detected. Basal T=4.8 nmol/l. Mutation located within central protein core and alters folding. Familial gene screening detected that her father was mosaic for mutations A280E and A280V, whilst her sister (46,XX; currently age 9yrs) was heterozygous for A280E. In all cases, no adrenal dysfunction has been demonstrated to date. All underwent bilateral gonadectomy and female sex assignment. Histology of the gonads showed testicular characteristics in all cases, with no evidence of malignancy. In-silico bioinformatic analyses confirmed all mutations were pathogenic.

Discussion: We report 3 novel NR5A1 mutations presenting with 46XY DSD and variable degrees of virilisation. In-silico molecular and structural analyses confirm the mutations to be highly pathogenic. Case 3 also highlights a sibling with a 46XX karyotype with the same mutation. The clinical significance of this for the sibling is uncertain, and raises specific challenges with respect to provision of counselling, predicting clinical prognosis and future management.