MON-762 - Hypoparathyroidism with A TBX1 Variant of Uncertain Significance: Reconsidering Genetic Etiologies in the Absence of 22Q11 Deletion

Isolated hypoparathyroidism is most commonly autoimmune, post-surgical, or associated with known pathogenic variants. Emerging evidence suggests that select point mutations in T-box transcription factor 1 (TBX1) may cause isolated hypoparathyroidism or partial DiGeorge-like phenotypes even in the absence of 22q11.2 deletions. TBX1 is a dosage-sensitive transcription factor essential for pharyngeal pouch and parathyroid development, and non-classic variants with variable penetrance have important implications for genetic counseling and clinical screening. A 25-year-old man with mild congenital sensorineural hearing loss presented for the management of chronic hypoparathyroidism. He initially presented at age 15 with a hypocalcemic seizure (serum calcium 5.8 mg/dL) and an inappropriately normal parathyroid hormone level. Autoimmune evaluation, microarray analysis, renal imaging, brain MRI, and FISH testing for 22q11.2 deletion were unremarkable, and there was no relevant family history. He was managed with calcium and calcitriol replacement with stable serum calcium but significant hypercalciuria (>479 mg/24 h; ref range < 250 mg/24 h). Multigene hypoparathyroidism testing identified a heterozygous TBX1 c.1009G>C (p.Asp337His) variant of uncertain significance involving the consensus splice site of exon 8. His congenital hearing loss may represent an additional TBX1-related manifestation given TBX1’s role in inner ear development. Genetic evaluation with cascade testing was initiated, and baseline echocardiography and repeat renal imaging are planned to assess for associated anomalies. This case demonstrates that TBX1 variants can impair parathyroid development without the full 22q11.2 deletion phenotype, expanding the phenotypic spectrum of TBX1-associated hypoparathyroidism. Although functional validation is lacking, involvement of the consensus splice region raises concern for aberrant TBX1 splicing. Recognition of such variants should prompt broader clinical screening and family counseling in patients with unexplained hypoparathyroidism.

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