XY disorders of sexual development (DSD) are rare causes of primary amenorrhea and are associated with significant diagnostic and therapeutic implications. We report a novel association of compound heterozygous missense NUP107 variants in a girl with hypergonadotropic hypogonadism and XY karyotype. This 17-year-old girl born of consanguineous marriage presented with absent breast development and primary amenorrhea. Her past medical history included the surgical removal of an abdominal mass which was histologically confirmed to be a germinoma. There were no features of chronic illness, neurological involvement, anosmia, hearing difficulty, or hypothyroidism and no family history of delayed puberty. There were no inguinal swellings, and she was normotensive. There were no phenotypic features suggestive of Turner syndrome and no dysmorphisms. She was tall (164 cm; 1.03 SDS; Corrected height SDS +2.2), with normal weight (53 kg, 0.23 SDS) and BMI (19.7 kg/m2, −0.3SDS) and prepubertal with Tanner staging B1P1. Endocrine investigations revealed hypergonadotropic hypogonadism; LH 44.36 IU/L(RR: 0.541.7 IU/L) and FSH 105.6 IU/L (RR: 1.617 IU/L)] with undetectable estradiol and testosterone levels. Ultrasound of the pelvis showed a small uterus, and right ovary (1×3 cm), with a non-visualized left ovary. Clinical exome sequencing identified compound heterozygous NUP107 gene missense variants in exons 2 and 4. NUP107, a nucleoporin involved in the cytoplasmic-nuclear exchange, is crucial for cell division and meiotic stability, and its defects have been reported in 46XX girls with hypergonadotropic hypogonadism and ovarian dysgenesis. Diseases associated with NUP107 include Ovarian Dysgenesis 6 and Nephrotic Syndrome, Type 11. Functional experiments have shown a gender-selective reproductive phenotype of NUP107 defects without impacting male fertility. Integration of genetic sequencing in cases of 46 XY DSD are warranted to aid diagnosis. Early diagnosis is essential so that HRT treatment begins at the appropriate time as well as counselling about the associated higher risk of malignancy and infertility. A specialist multidisciplinary approach with regular follow-up is required. This is the first report of NUP107 variants in the setting of XY DSD, highlighting the need to elucidate the role of this gene in male reproductive development.
08 Nov 2023 - 10 Nov 2023