ESPE Abstracts

Introduction: In human, the development of the embryonic gonads represents a complex process involving a large number of genes, some still unknown. Specific pathways have a crucial role for the normal ovarian development, the germ cell genomic stability and hormonal maintenance. These pathways’ dysregulation can lead to POF, clinically manifesting as the absence of pubertal onset and/or amenorrhea.

Objective: To identify candidate genes responsible for POF, in a cohort of adolescent girls.

Methods: A total of 55 adolescent girls were included in this study. All patients made blood tests for the analysis of karyotype, FMR1 gene and array CGH.

Results: Among the 55 patients, 37 girls were diagnosed as POF associated with known disorders: 35 girls with Turner Syndrome (1 mosaicism; 22 miscellaneous karyotypes; 12 monosomies); 1 girl with BPES; 1 girl with APECED. The remaining 18 girls were classified as isolated POF. Among these, the array CGH analysis showed: a frameshift variant on 9q21.13 (gene PCSK5) in 4 patients; a missense variant on 16p13.2 (gene PMM2) in 1 patient; a deletion on 8q23.1 (gene ZFPM2) in 1 patient; a missense variant on 15q26.1 (gene POLG) in 1 patient. PCSK5 encodes for a convertase responsible for the cleavage of different proteins, such as the proAMH. AMH is known to be essential in follicologenesis, so: variants that we revealed can led to PCSK5 dysfunction, responsible for POF? In literature, there are no reports regarding this association, so further studies are needed to examine the cause-effect relation. Regarding the PMM2 gene, our patient was a carrier for the missense variant R141H. In literature is reported one family whose individuals were compound heterozygous for PMM2 mutation but unaffected by the metabolic disease. A female in this family had been diagnosed with POF at 26 years. ZFPM2 is known to be implicated in gonadal development. In literature ZFPM2 mutations were associated with 46, XY sex reversal case reports. In literature, there are no case reports regarding the association between ZFPM2 and POF, but certainly it could be implicated in the pathogenesis of disease. POLG encodes for the polymerase of the mitochondrial genome. Mutations in this gene have been associated with a variety of clinical features, including PEO, ataxia and epilepsy. In literature, are described families affected by PEO, carrying a POLG mutation, presenting also a POF disease.

Conclusion: This study supports the importance of genetic analyses to identify the etiology of POF.