PRIMARY OVARIAN INSUFFICIENCY AND DISORDERS OF GONADAL DEVELOPMENT IN THE SAME FAMILY: THINK OF THE NR5A1/ SF-1 SEQUENCE VARIANTS

ABSTRACT Research question: Primary ovarian insufficiency (POI) is defined as the early exhaustion of ovarian function, before the age of 40 years. Its origin is genetic in 20 to 25% of cases. Unusually, sequence variants of the NR5A1/SF-1 gene may result in POI, or various disorders of gonadal development (DGD), or adrenal insufficiency. Design: We describe the cases of two families in which the association of DGD and POI enabled a diagnosis of NR5A1 deleterious variations. Their clinical, hormonal, ultrasound, and genetic characteristics are reported. Results: The mothers of the affected children were 21 and 29 years when POI was diagnosed. Each nonetheless had two spontaneous pregnancies. The children have different phenotypes and different forms of DGD. None of the affected family members had adrenal insufficiency. A new sequence variant of the NR5A1 gene was identified: p.Cys283Phe (c.848G>T) in a family. The NR5A1 sequence variant c.86G>C was found in the other family. Conclusion: Sequence variant of the NR5A1 gene is a possibility that must be considered when a woman with POI or a diminished ovarian reserve has a family member or child with DGD. If a variation is identified genetic counseling is essential for the patient and his/her family.