Hypocalcemia, Autosomal Dominant 2

A number sign (#) is used with this entry because of evidence that autosomal dominant hypocalcemia-2 (HYPOC2) is caused by heterozygous mutation in the GNA11 gene (139313) on chromosome 19p13.

For a discussion of genetic heterogeneity of autosomal dominant hypocalcemia, see HYPOC1 (601198).

Clinical Features

Hunter et al. (1981) reported a large 4-generation family of English Canadian origin segregating what they designated 'autosomal dominant hypoparathyroidism.' There were 8 affected members of the family, 2 of whom were asymptomatic. The proband was evaluated at 6 years old for 'febrile convulsions' and found to have positive Trousseau and Chvostek signs, possible laryngospasm, and low serum calcium (6.3 mg/dl) and phosphorus (7.8 mg/dl) levels, with a parathyroid hormone (PTH) level in the low-normal range (177 pg Eq/ml). The proband's affected father had carpopedal spasm and hypocalcemia with normal phosphorus and PTH levels, and 2 paternal aunts also had symptomatic hypocalcemia, whereas 2 paternal uncles were hypocalcemic but asymptomatic. In addition, 2 male cousins, the sons of an affected aunt, were also hypocalcemic and had stiffness, paresthesias, and carpopedal spasm. Hunter et al. (1981) suggested that the phenotype in this family might be associated with a decrease in overall height: the proband and his 2 affected cousins had short stature (height below the 3rd centile), whereas their unaffected sibs were of normal height, and the affected adults' average heights were shorter than those of their unaffected sibs.

Li et al. (2014) restudied the hypocalcemic kindred originally described by Hunter et al. (1981), including 3 more affected individuals in the next generation who were the children of the 2 male cousins. One cousin had 2 daughters who were diagnosed in infancy, whereas the son of the other cousin was diagnosed at age 20 years after an episode of severe tetany. Li et al. (2014) noted that affected members of the pedigree developed mild postnatal growth failure without evidence of growth hormone (GH; 139250) deficiency and were significantly shorter than their unaffected relatives.

Mannstadt et al. (2013) studied 2 unrelated 4-generation families segregating autosomal dominant hypocalcemia. In the first family, the male proband was diagnosed at 2 years of age with type 1 diabetes mellitus (see 222100), at which time his total calcium level was normal. At 5 years of age, he presented with generalized seizures, some of which were not associated with hypoglycemia; he was treated with carbamazepine for a year and had no recurrences when treatment was discontinued. At 14 years of age, he complained of tremulousness and muscle cramps and was found to be hypocalcemic with inappropriately low PTH levels. Review of the family history at that time revealed autosomal dominant transmission of hypocalcemia on the maternal side. In the second family, the female proband presented with chronic fatigue and occasional muscle cramps at 20 years of age and was found to have mild hypocalcemia and mild hyperphosphatemia with a low PTH level. Family evaluation revealed 9 additional relatives diagnosed with isolated hypoparathyroidism, all of whom had similarly mild symptoms of hypocalcemia. None of the affected members of either family had a history of mucocutaneous candidiasis, hearing loss, or renal abnormalities, and clinical examination was unremarkable; specifically, there was no evidence for skin changes.

Mapping

In a 4-generation family segregating autosomal dominant hypocalcemia in which mutation in the CASR (601199), PTH (168450), and GCM2 (603716) genes had been ruled out, Mannstadt et al. (2013) performed a genomewide scan that revealed linkage to 19p13.3 (lod score, 3.0).

Molecular Genetics

In 8 unrelated patients with hypocalcemia and low or normal serum parathyroid hormone concentrations, who were negative for mutation in the CASR gene (601199), Nesbit et al. (2013) analyzed the candidate gene GNA11 (139313) and identified heterozygosity for missense mutations in 2 patients (R181Q, 139313.0003; and F341L, 139313.0004). Functional analysis in HEK293 cells stably expressing calcium-sensing receptors demonstrated that the mutant GNA11 proteins induce an enhanced sensitivity to changes in extracellular calcium concentrations, similar to the effects of gain-of-function mutations in CASR reported in autosomal dominant hypocalcemia type 1. One of the mutation-positive patients was asymptomatic, whereas the other reported a 10-year history of occasional paresthesias, muscle cramping, and carpopedal spasm. Other family members were unavailable for study.

In a 4-generation family segregating autosomal dominant hypocalcemia mapping to chromosome 19q13.3, Mannstadt et al. (2013) sequenced the candidate gene GNA11 and identified a heterozygous missense mutation (R60C; 139313.0005) that segregated with disease. In an unrelated 4-generation family with hypocalcemia, exome sequencing revealed heterozygosity for a different missense mutation in GNA11 (S211W; 139313.0006) in affected individuals.

In affected members of a large 4-generation family segregating autosomal dominant hypocalcemia and short stature, originally reported by Hunter et al. (1981), Li et al. (2014) performed whole-exome sequencing (WES) followed by filtering that revealed a heterozygous missense mutation in the GNA11 gene (R60L; 139313.0007). Sanger sequencing confirmed that the mutation segregated with disease in the family, and it was not found in 1,200 in-house WES samples. The authors noted that compared to individuals with CASR (601199)-associated hypocalcemia (HYPOC1; 601198), patients with GNA11 mutations lacked hypercalciuria and had normal serum magnesium levels.