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

Abstract

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.