Endocrine Abstracts

Introduction: Familial hypocalciuric hypercalcaemia (FHH) is commonly caused by mutations in the CASR gene, less commonly in AP2S1 and rarely in GNA11. Only four FHH-associated loss-of-function variants have been reported in GNA11 to date.

Clinical Case: A 30-year-old woman investigated for migraines and paraesthesia in hands and feet was noted to have ionised calcium of 1.38 mmol/l (ref 1.15-1.33 mmol/l), PTH of 5.6 pmol/l (ref 1.6-6.9 pmol/l), and 25-hydroxyvitamin D of 65 nmol/l. Levels of ionised calcium remained between 1.37-1.39 mmol/l, with varying PTH, between 1.9-6.4 pmol/l. Urine calcium/creatinine clearance ratio was 0.0055. Total urinary calcium excretion was 6.0 mmol/day. She had no nephrocalcinosis on ultrasound and normal bone mineral density on DXA. Ultrasound, Sestamibi scintigraphy and CT neck found no parathyroid adenoma or hyperplasia. Genetic sequence analysis was negative for MEN1, MEN4, CDKN1B and RET-mutations. However, she had a heterozygote loss-of-function mutation on GNA11 c.686T>C, p.(Leu229Pro), which was a variant of unknown significance. Investigation of her parents revealed that her father had ionised calcium of 1.42 mmol/l and PTH of 3.3 pmol/l. Later he had ionised calcium of 1.36 mmol/l with PTH of 8.0 pmol/l. Urine calcium/creatinine clearance ratio was 0.0216 and 0.0198. He had osteopenia but no nephrocalcinosis. Genetic testing of the father revealed the same heterozygote mutation. Evaluation of first-degree relatives is ongoing and will further elucidate the role of GNA11 in FHH.

Clinical Lesson: A heterozygote loss-of-function mutation on GNA11 is a novel pathogenic mutation causing FHH and the diagnosis can be difficult to elicit as patients may have normal urinary excretion of calcium. PTH can also vary within the normal range and may be elevated in response to lower levels of hypercalcaemia. Genetic sequence analysis is recommended in these patients.