A de novo SOX11 mutation causing hypogonadotropic hypogonadism: a case report and literature review

BACKGROUND: SOX11 variants have been associated with Coffin-Siris syndrome and a broader neurodevelopmental spectrum (IDDMOH), but their role in isolated or syndromic hypogonadotropic hypogonadism (HH) remains under-recognized. CASE PRESENTATION: We report a 13-year-old Chinese girl who presented with delayed puberty (Tanner B1, PH1), infantile uterus and low basal gonadotropins. Trio whole-exome sequencing identified a de-novo heterozygous SOX11 c.346_348del (p.Tyr116del) variant. Olfactory and pituitary MRI revealed bilateral olfactory-bulb/nerve hypoplasia and a pituitary height of 3.4 mm, fulfilling Kallmann-syndrome criteria. GnRH-pump therapy restored gonadotropin output within 72 h. A systematic literature review of 32 additional SOX11-related HH cases (total n = 33) showed that 25/26 phenotyped individuals exhibited Coffin-Siris-compatible features, whereas 13/33 met Kallmann-syndrome criteria. Thirty unique variants were identified, 17/30 clustering within the HMG domain and 15/18 proven de-novo. CONCLUSIONS: SOX11 should be included in Kallmann syndrome gene panels. We propose "SOX11-related disorder" as an overarching diagnostic framework for all individuals with SOX11 likely pathogenic/pathogenic variants, mandating comprehensive baseline evaluation-including endocrine assessment, neurodevelopmental screening, and MRI of olfactory tracts and pituitary-regardless of initial presentation.