This study covers the 5-year interval prior to COVID-19 admission for an otherwise healthy 46,XX adolescent expanding the developmental characterization of an unusual convergence of amenorrhea and genetic mutations. The patient experienced rapid collapse of endogenous estradiol output followed by secondary amenorrhea at 13 years of age. Euploid, diffusely hypocellular bone marrow was present on biopsy, although anemia or reduced total immunoglobulin production was not identified. Bone density was 1.5 years below mean; multiple dental anomalies were also documented. While alterations in “master regulator” genes RUNX2, SALL1, and SAMD9 are usually diagnosed in early childhood when missed milestones, dysmorphic features, or chronic infection/immune impairment warrant cross-disciplinary evaluation, this study is the first known report to associate ovarian failure with adolescence with such variants. Immunoglobulin patterns, osseous histomorphology, dentition, hematology/renal screening, pelvic anatomy, ovarian reserve data, and thyroid findings are also correlated. Although severe pathology is typically encountered when any of these genes are disrupted alone, this longitudinal survey reveals that a mild phenotype can prevail if these 3 variants occur simultaneously. Periodic monitoring is planned given the unclassified status of this unique mutation set.