Infertility in couples is a common problem, with both female and male factors contributing to similar extents. Severe, congenital disorders affecting fertility are, however, rare. While folliculogenesis and spermatogenesis are generally orchestrated via different mechanisms, some genetic anomalies can impair both female and male gametogenesis. Minichromosome maintenance complex component 9 (MCM9) is involved in DNA repair and mutations of the MCM9 gene have been previously reported in females with premature ovarian insufficiency (POI). MCM9 is also an emerging cancer risk gene. We performed next-generation and Sanger sequencing of fertility and related genes and hormonal and imaging studies in a kindred whose members had POI and disordered spermatogenesis. We identified a homozygous pathogenic MCM9 variant, c.394C>T (p.Arg132*) in three sisters affected by POI due to ovarian dysgenesis and their brother who had normal pubertal development but suffered from non-obstructive azoospermia. Testicular biopsy revealed Sertoli cell-only testicular histopathology. No evidence of early onset cancer was found in the homozygotic family members, but they were all young (<30 years) at the time of the study. In the male patient the homozygous MCM9 variant led to normal pubertal development and hormonal levels but caused a Sertoli-cell-only syndrome with non-obstructive azoospermia. In the homozygous females studied, the clinical, hormonal, and gonadal phenotypes revealed ovarian dysgenesis consistent with previous reports. Active screening for potential colorectal and other cancer risks in the homozygotic MCM9 subjects has been instigated.

Background: Meningioma is the most frequent primary benign intracranial tumor, with a higher incidence in women. Treatment with progesterone acetates, including cyproterone, nomegestrol, chlormadinone, promegestone, medrogestone, and medroxyprogesterone acetate, has been identified as a risk factor of meningioma, particularly in the anterior and middle cranial fossae. Discontinuation of these treatments often leads to volume stabilization or regression of the tumor. Case Description: A 42-year-old woman undergoing treatment with nomegestrol acetate (NA) presented with headaches and visual loss in her right eye. She was diagnosed with a large spheno-orbital meningioma invading the sphenoid and ethmoid sinuses, associated with hyperostosis of the sphenoid wing. An initial resection was performed using an extended endonasal approach. Immunohistochemistry confirmed a chondroid meningioma, Grade II, with progestin receptor in 100% of the tumor cell nuclei and a Ki-67 proliferation index of 3–5%. NA was immediately stopped on diagnosis. Despite the cessation of the NA, the intraosseous sphenoidal part of the tumor continued to grow, leading to optic nerve compression. A second surgery was performed using a right fronto-temporo-orbito-zygomatic approach. Examination of the dura of the middle fossa showed subtle tumoral infiltration, while the Ki-67% index was estimated at 1%. Examination of the sphenoid bone demonstrated reactive hyperostosis with minimal to no tumor infiltration. Conclusion: This case illustrates that the proliferative activity of the progestin-associated meningioma does not account for intraosseous progression within the sphenoid bone following cessation of progestin therapy. Our observations suggest an upregulation of osteogenesis in infiltrated bone, even as the dural part of the meningioma regresses.