ESPE Abstracts

Introduction: Mammalian sex development is directly dependent on gonadal determination. Whole exome sequencing in patients with differences of sex development (DSD) allows the discovery of new factors involved in human sex development. One of these factors is NWD1 (NACHT and WD repeat domain containing 1) a cytosolic protein that seems to play a role in modulating androgen receptor signaling. We identified variants in the NWD1 gene in six undervirilized XY patients and in two XX patients. The phenotype of one of the patients with XX karyotype is described here.

Case report: A 15-year-old female adolescent with normal stature presented with delayed puberty (B1), primary amenorrhea and retardation of bone maturation (bone age was 11 years according to Greulich & Pyle). She had normal body proportions. Lab work showed hypergonadotropic hypogonadism (LH 33.6 U/L, reference range: 1.1-3.8 U/L; FSH 106 U/L, reference range: 1.4-4.2 U/L) and unmeasurable estradiol. Testosterone was elevated (1.2 nmol/L, range: 0.2-0.6 nmol/L), ovarian autoantibodies were negative. The external genitalia were female, the uterus was present and the ovaries were very small without follicles at ultrasound. Due to the elevated testosterone value, diagnostic laparoscopy was carried out and ovaries were histologically assessed. The histological workup revealed streak gonads on both sides. The repeated elevated testosterone values are therefore most likely derived from precursors of adrenal origin. The patient was initially put under estrogen replacement therapy leading to normal pubertal development and further growth. Under combined estrogen/progesterone therapy regular menses occurred.

Whole exome sequencing revealed a mutation in NWD1 gene. The patient's variant (c.350delA (Het)) leads to a frameshift and a premature stop codon (p.Asn117ThrTer11). 3D structure analysis shows that over 90% of the protein is lost leading most likely to either degradation or production of a shorter non-functional protein. This mutation is therefore likely to be associated with the clinical presentation of the patient.

Conclusion: The variant in NWD1 gene is likely to be responsible for our patient's phenotype. Accordingly, 3D structure analysis showed that the mutation in this gene most likely leads to either degradation or inactivation of the protein. Another 7 patients with 46, XY and 46, XX DSD carry pathogenic variants in NWD1, suggesting that this gene might be part of the gonadal determination cascade in both sexes.