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Autosomal Dominant Hypocalcemia Due to a GNA11 Variant: The First Case in Japan


 Background: Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia and hyperphosphatemia due to hypoparathyroidism. ADH type 1 is caused by gain-of-function variants in CASR gene coding the calcium-sensing receptor. Recently, ADH type 2 caused by gain-of-function variants in GNA11 gene coding G-protein subunit α11 has been recognized.
 Case: A 32-year-old female patient visited our hospital because she suffered from hyperhidrosis, exertional dyspnea, and palpitations. She had a past medical history of paroxysmal kinesigenic dyskinesia confirmed by genetic analysis of PRRT2. Although her sister has unspecified epilepsy, no members of her kindred have episodes of tetany. Her height was 155.7 cm and weight was 64.1 kg. She had goiter with tremor and tachycardia and was diagnosed as Graves’ disease (fT3 >32.55 pg/mL, fT4 >7.77 ng/dL, TSH <0.005 µIU/mL, and TRAb 36.9 IU/L). Thiamazole therapy ameliorated her hyperthyroidism, while serum calcium level was low (7.5 mg/dL) and serum phosphate level was slight high (5.1 mg/dL). Hypoparathyroidism was confirmed because intact-PTH was relatively low (20 pg/mL) under the hypocalcemia. Her episode of tetany that she could not sit on her heels from childhood and her basal ganglia calcification in head CT scan suggest the long disease duration. Germline whole exome sequence detected a rare variant in GNA11 gene; c.1023C>A resulted in p.Phe341Leu. There were no relevant pathogenic variants in other candidate genes such as CASR, PTH, and GCM2. Treatment with 2 µg/day of alfacalcidol and 1200 mg/day of calcium aspartate could not normalize serum calcium level (7.0 mg/dL) and serum phosphate level (5.3 mg/dL) even after 1 year.
 Conclusions: The pathogenicity of the variant, p.Phe341Leu, in GNA11 gene was previously confirmed [1]. ADH type 2 is extremely rare as our literature review found only four previous reports; 17 patients in 5 families [1–4]. Phenotypes of the present case are mild and skeletal growth is normal. Meanwhile, we are having difficulty in management of her hypocalcemia, even though Graves’ disease might affect her bone metabolism. Optimal therapy for ADH type 2 needs further investigation.
 References: [1] Nesbit et al. Mutations Affecting G-protein Subunit α11 in Hypercalcemia and Hypocalcemia. N Engl J Med. 2013; 368: 2476–2486. [2] Li et al. Autosomal Dominant Hypoparathyroidism Caused by Germline Mutation in GNA11: Phenotypic and Molecular Characterization. J Clin Endocrinol Metab. 2014; 99: 1774–83. [3] Piret et al. Identification of a G-Protein Subunit-α11 Gain-of-Function Mutation, Val340Met, in a Family With Autosomal Dominant Hypocalcemia Type 2 (ADH2). J Bone Miner Res. 2016; 31: 1207–14. [4] Tenhola et al. Impaired Growth and Intracranial Calcifications in Autosomal Dominant Hypocalcemia Caused by a GNA11 Mutation. Eur J Endocrinol. 2016; 175: 211–8.