Case report: A Newly Identified G-protein Subunit α-11 Loss-of-Function Variant Causing Familial Hypocalciuric Hypercalcemia Type 2 in an Italian Kindred.

BACKGROUND: FHH2 is the rarest subtype of familial hypocalciuric hypercalcemia disorders affecting the CaSR signaling pathway. It is caused by heterozygous loss-of-function mutations in the GNA11 gene, encoding Gα11 protein. Only seven GNA11 pathogenic variants have been reported so far.

CASE DESCRIPTION: We report the case of a 39-year-old man referred to our outpatient clinic for a non-toxic multinodular goiter. During biochemical examination, mild hypercalcemia with normal PTH levels and low urinary calcium excretion (calcium-creatinine clearance ratio< 0.01) was detected. He had no evidence of kidney stones or nephrocalcinosis and demonstrated normal bone mineral density at dual-energy X-ray absorptiometry. A similar biochemical profile in his mother suggested FHH. Following total thyroidectomy for the goiter, the patient's calcium and PTH levels normalized. Genetic testing identified a novel heterozygous germline frameshift variant in GNA11 (c.980_981del, p.His327LeufsTer150) in the proband, his mother, and his 15-month-old normocalcemic daughter. This frameshift variant, which affects the critical GTPase domain, results in a pathogenic elongated protein with 116 additional amino acids, significantly altering its structure.

CONCLUSIONS: In this report, we describe the eighth FHH2 kindred and highlight the biochemical heterogeneity of this rare condition. Our findings demonstrate that the normalization of serum calcium during follow-up does not necessarily exclude the diagnosis. Furthermore, we underscore the clinical importance of integrating genetic findings with longitudinal biochemical data.