ESPE Abstracts (2015) 84 P-2-321

Familial Mutation of NR5A1/SF-1 Gene Associated with DSD and Spleen Agenesis: A New Syndrome?

Pascal Philiberta,b, Francis Poulatb, Françoise Audranc, Maryse Cartignyd, Françoise Parisa, Charles Sultana & Sylvie Manouvrier-Hanud


aCHRU and Université de Montpellier, Montpellier, France; bInstitut de Génétique Humaine – CNRS UPR1142, Montpellier, France; cCHRU de Montpellier, Montpellier, France; dCHRU and Université de Lille, Lille, France


Background: A recent report (JCI, 2014) described a new homozygous NR5A1/SF-1 mutation in a patient with XY DSD and spleen agenesis. To date, no other data have confirmed this association, raising the hypothesis of fortuity.

Case presentation and method: We had the opportunity to study an adolescent girl referred for virilisation during puberty. She presented voice deepening and clitoral hypertrophy. Biological investigations showed high plasma testosterone (2 ng/ml) and gonadotropin levels and undetectable levels of AMH and inhibin B. The family history revealed that her father had had surgery for hypospadias in infancy. At 45 years, he was hospitalized for purpura fulminans, at which time asplenia was diagnosed.

Results: Sonography and MRI showed three small residues which were evocated for spleen. Genetic investigation identified a new heterozygous NR5A1 gene mutation (c.1227C>A) within exon 7. This mutation creates a premature stop codon (p.Tyr409X) and results in a truncated protein. The father’s genetic analysis revealed the same mutation. However, this mutation was absent from both paternal grandparents. In vitro assays of this mutation are in progress to investigate the mutant transactivation capabilities.

Conclusion: As reported in mice, SF-1 gene invalidation leads to XY complete gonadal dysgenesis, adrenal agenesis and abnormal spleen development. In human, an SF-1 mutation may lead to both gonadal dysgenesis and spleen hypotrophy, raising the suggestion of a new syndrome. These data underline the usefulness of spleen function investigation in all patients with SF-1 gene mutation.

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