Familial Turner Syndrome With Distinct Karyotypes in Two Cousins: Phenotypic Convergence and Genotypic Heterogeneity

BACKGROUND Familial Turner syndrome (TS) is an uncommon sex chromosome abnormality, typically characterized by the transmission of identical X-chromosomal aberrations (eg, partial or complete deletions) within a lineage. The occurrence of familial TS involving distinct karyotypes within the same generation is exceptionally rare and presents unique challenges for genetic counseling and mechanistic understanding. CASE REPORT Two cousins (aged 20 and 28) from a nonconsanguineous family presented with primary amenorrhea, hypergonadotropic hypogonadism, and short stature. Despite striking phenotypic convergence, karyotyping demonstrated 46,X,i(X)(q10) in the proband (III-17) and 45,X in the cousin (III-13). Pelvic ultrasonography showed absent or underdeveloped internal genital organs and gonadal dysgenesis in both patients. Systematic cardiac and renal screening revealed no structural abnormalities. Whole-exome sequencing and copy number variation analysis performed on 11 relatives (including both patients) ruled out pathogenic variants in known TS-associated loci under American College of Medical Genetics and Genomics 2015/2019 criteria; low-level or tissue-restricted mosaicism could not be definitively excluded. A structured literature review was conducted to compare previously reported familial TS patterns. CONCLUSIONS This report documents a rare instance of intrafamilial phenotypic uniformity despite genotypic heterogeneity. The findings support the hypothesis that functional haploinsufficiency of the X-chromosome short arm (Xp) acts as the convergent pathogenic mechanism for the core TS phenotype, regardless of the specific chromosomal error. Clinicians should recognize that familial clustering can occur via distinct cytogenetic mechanisms, requiring broad prenatal screening rather than targeted testing for recurrence, along with careful counseling regarding the uncertainties of heritability versus coincidental de novo events.