Beyond genital phenotype – Commentary on "Long-term outcomes in 45,X/46,XY mosaicism: a 30-year retrospective study in Hong Kong"

45,X/46,XY mosaicism remains one of the most clinically heterogeneous sex chromosome disorders in pediatric endocrinology.Even the same chromoso mal constitution, affected individuals may present with widely different phenoty pes, ranging from a typical male appearance to genital ambiguity or Turner synd romeassociated features.This variability complicates decisions about sex assignment, gonadal management, growth, and longterm followup.Poon et al. [1] reported longterm outcomes in a large cohort of individuals with 45,X/46,XY mo saicism followed into adulthood, adding valuable data on gonadal tumors, pubertal development, growth, and Turner syndromeassociated comorbidities.A key finding is the association between external genital phenotype and gonadal tumor risk.Patients with lower external genitalia scores were more likely to develop gonadal neoplasia, whereas no gonadal tumors were identified in those with a typical male phenotype.This supports careful phenotypic assessment when counseling families and considering surveillance strategies [2].At the same time, this study shows the limits of phenotypebased prediction.Although genital phenotype was associated with tumor risk, it did not predict long term gonadal function.All males in the cohort spontaneously entered puberty, including those with marked genital ambiguity.Conversely, several individuals with apparently typical male genitalia later developed gonadal insufficiency and required testosterone replacement therapy.Prior longitudinal studies have repor ted similar findings [36].Together, these findings suggest that genital phenotype helps estimate gonadal tumor risk, but offers limited guidance regarding future gonadal function.Growth remains a major clinical concern in this population.Short stature is common and is thought to reflect, at least in part, the contribution of the 45,X cell line and SHOX haploinsufficiency [3,4].Although growth hormone therapy is often considered, evidence for its effect on adult height has remained limited and incon sistent [3,4,7].In the present study, final height did not differ significantly between treated and untreated individuals.This finding should be interpreted cautiously because of the small treated subgroup, late treatment initiation, variable treatment duration, and retrospective design.A recent Korean study in Turner syndrome also found that 3year growth response to growth hormone treatment did not differ significantly according to karyotype, supporting the broader view that chromoso mal category alone may offer limited guidance for predicting growth response [8].Beyond growth and gonadal function, this study reminds us that 45,X/46,XY mosaicism should not be viewed solely through the lens of disorders of sex de velopment.Cardiovascular, renal, thyroid, metabolic, and other Turner syndrome associated comorbidities were observed across the cohort, while screening for these conditions was not consistently performed.This is clinically important