A Novel Phenotype Combining Primary Ovarian Insufficiency Growth Retardation and Pilomatricomas With MCM8 Mutation

Context: Primary Ovarian insufficiency (POI) affects 1% of women aged <40 years and leads most often to definitive infertility with adverse health outcomes. Very recently, genes involved in deoxyribonucleic acid (DNA) repair have been shown to cause POI. Objective: To identify the cause of a familial POI in a consanguineous Turkish family. Design: Exome sequencing was performed in the proposita and her mother. Chromosomal breaks were studied in lymphoblastoid cell lines treated with mitomycin (MMC). Setting and patients: The proposita presented intrauterine and postnatal growth retardation, multiple pilomatricomas in childhood, and primary amenorrhea. She was treated with growth hormone (GH) from age 14 to 18 years. Results: We identified a novel nonsense variant in exon 9 of the minichromosome maintenance complex component 8 gene (MCM8) NM_001281522.1: c0.925C >T/p.R309* yielding either a truncated protein or nonsense-mediated messenger ribonucleic acid decay. The variant was homozygous in the daughter and heterozygous in the mother. MMC induced DNA breaks and aberrant metaphases in the patient's lymphoblastoid cells. The mother's cells had intermediate but significantly higher chromosomal breaks compared with a control. Conclusion: We describe a novel phenotype of syndromic POI related to a novel truncating MCM8 variant. We show for the first time that spontaneous tumors (pilomatricomas) are associated with an MCM8 genetic defect, making the screening of this gene necessary before starting GH therapy in patients with POI with short stature, especially in a familial or consanguineous context. Appropriate familial monitoring in the long term is necessary, and fertility preservation should be considered in heterozygous siblings to avoid rapid follicular atresia.