Genetic and Diagnostic Advances in Recurrent Hydatidiform Mole: Implications for Reproductive Counseling

Objective: To provide an updated synthesis of the current knowledge on the epidemiology, pathophysiology, genetic basis, diagnostic strategies, and management of recurrent hydatidiform mole (RHM), incorporating recent molecular and clinical findings. Mechanism: We conducted a narrative review of peer-reviewed literature, focusing on genetic, epigenetic, molecular, and clinical studies addressing the pathogenesis, diagnostic strategies, and clinical management of RHM. Findings in Brief: Mutations in maternal-effect genes, primarily nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 7 (NLRP7) and KH domain-containing 3-like (KHDC3L), account most familial cases, while other subcortical maternal complex (SCMC) genes, including peptidyl arginine deiminase 6 (PADI6), nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 5 (NLRP5), transducin-like enhancer of split 6 (TLE6), zygote arrest 1 (ZAR1), and oocyte-expressed protein (OOEP), have also been implicated. Histological features, such as villous edema, circumferential trophoblastic hyperplasia, and the presence or absence of embryonic or fetal tissue, remain crucial in diagnosis, complemented by p57 immunohistochemistry (IHC) and short tandem repeat (STR) genotyping. Although many cases can be explained by genetic mutations, others may result from epimutations, mosaicism, or polygenic inheritance. Reproductive counseling now incorporates molecular diagnostics. While in vitro fertilization with intracytoplasmic sperm injection (IVF-ICSI) or preimplantation genetic testing (PGT) may reduce recurrence risk, donor oocytes remain the only definitive option for women with confirmed mutations. Conclusions: RHM represents a unique model of imprinting disorders in which defective oocyte biology leads to abnormal conceptions. Integration of molecular diagnostics with clinical management offers a precision medicine approach, while future research may identify new avenues for prevention and targeted interventions.