A Novel Hemizygous ANOS1 Variant in a Patient With Kallmann Syndrome and Type 2 Diabetes Mellitus: A Case Report

Kallmann syndrome (KS), a rare genetic disorder, is characterized by congenital hypogonadotropic hypogonadism (CHH) and anosmia or hyposmia.

We report a case of KS with type 2 diabetes mellitus (T2DM) associated with a novel hemizygous missense variant in ANOS1 (NM_000216.4; exon 4; c.505G >C;p.(Gly169Arg)). A 33-year-old male presented with persistent hyperglycemia, delayed pubertal development with absent secondary sexual characteristics, and lifelong anosmia. Olfactory testing, magnetic resonance imaging (MRI) of the pituitary region, and a gonadotropin-releasing hormone (GnRH) stimulation test supported a clinical diagnosis of KS. Trio-based exome sequencing (ES) revealed the aforementioned hemizygous variant in ANOS1. Notably, neither parent harbored this variant, supporting a de novo origin, which is consistent with the variant's potential pathogenicity. Multiple sequence alignment showed that Gly169 is highly conserved across species, suggesting it may be functionally important for the protein. Furthermore, a three-dimensional protein model generated using SWISS-MODEL predicted marked conformational changes in the protein attributable to this amino acid substitution at a highly conserved residue, suggesting a potential functional impact. Notably, emerging evidence has linked ANOS1 variants to dysregulated glucose metabolism, supporting a potential association with T2DM in this case. For treatment, insulin and oral hypoglycemic agents were used for glycemic control, and a GnRH pump was initiated. At the sixth follow-up visit, the patient had achieved satisfactory glycemic control; however, serum testosterone levels remained low despite GnRH pump therapy, so testosterone replacement therapy was subsequently initiated.

ANOS1 variants are genetically diverse and may contribute to both KS pathogenesis and the development of comorbid T2DM, though further studies are needed to confirm this link. For KS patients, close monitoring of fasting glucose, glycated hemoglobin, and oral glucose tolerance test results is advisable to detect diabetes and prediabetes early.