Hypocalciuric Hypercalcemia, Familial, Type Iii

A number sign (#) is used with this entry because of evidence that familial hypocalciuric hypercalcemia type III (HHC3) is caused by heterozygous mutation in the AP2S1 gene (602242) on chromosome 19q13.

For a general phenotypic description and discussion of genetic heterogeneity of hypocalciuric hypercalcemia, see HCC1 (145980).

Clinical Features

McMurtry et al. (1992) provided clinical and metabolic characterization of familial hypocalciuric hypercalcemia in a kindred from Oklahoma. Nineteen affected members were found. Immunoreactive parathyroid hormone (iPTH) levels, determined in 3 separate immunoassays, became supranormal by about age 30 years in the group of 15 hypercalcemic subjects examined biochemically and appeared to increase further thereafter. Serum alkaline phosphatase activity and creatinine levels were normal in these individuals, but inorganic phosphate levels were lower than in unaffected members of the kindred. Three of 5 affected adults older than age 40 years who were studied radiographically had changes suggestive of osteomalacia. Biopsy of the iliac crest in one of these subjects, a 51-year-old woman, confirmed the presence of defective skeletal mineralization. Differentiation from primary hyperparathyroidism was especially difficult in this kindred because serum iPTH levels may be elevated. Furthermore, the disorder may not be totally benign. Osteomalacia, perhaps due to mild hypophosphatemia, can develop during adulthood in these patients.

Nesbit et al. (2010) studied a kindred from Northern Ireland in which 16 individuals over 3 generations had hypocalciuric hypercalcemia in association with normal or elevated PTH concentrations. In addition, the 16 individuals had significantly higher serum magnesium and PTH levels than their normocalcemic relatives, and hypercalcemic individuals above the age of 30 years had a significantly lower serum phosphate concentration than those below the age of 30 years. Nesbit et al. (2010) noted that these features were all consistent with HHC3, although unlike the Oklahoma family originally described by McMurtry et al. (1992), the Northern Ireland kindred did not exhibit developmental elevations in serum PTH concentration or hypophosphatemic osteomalacia in older affected members.

Clinical Management

Howles et al. (2016) studied 3 unrelated patients with familial hypocalciuric hypercalcemia who each had a different mutation in the AP2S1 gene, R15C (602242.0001), R15L (602242.0002), or R15H (602242.0003). The patients reported headaches, fatigue, and generalized aches and pains, that did not resolve after parathyroidectomy. Treatment with cinacalcet, a calcium-sensing receptor (CASR; 601199) allosteric activator, resulted in more than 20% reductions in serum calcium levels and abatement of symptoms. Howles et al. (2016) concluded that cinacalcet-mediated allosteric modulation of CASR can correct the loss of function due to AP2S1 mutations, and reduce the symptoms of HHC3 associated with all 3 AP2S1 mutations.

Mapping

Trump et al. (1995) studied a 5-generation kindred from Oklahoma, originally reported by McMurtry et al. (1992), in which there were 19 individuals with hypocalciuric hypercalcemia and 2 obligate carriers. Trump et al. (1995) demonstrated lack of linkage to the sites of familial benign hypocalciuric hypercalcemia (HCC1) on 3q21-q24 (145980; see also 601199) and 19p13.3 (HHC2; 145981), as well as lack of linkage to 11q13 and 11p15, where the genes for multiple endocrine neoplasia type I (MEN1; 131100) and PTH (168450) have been mapped, respectively. Thus, this form of FHH, designated the Oklahoma variant, represents a distinct genetic entity.

Lloyd et al. (1999) established linkage between the Oklahoma form of familial benign hypercalcemia and 8 loci in the 19q13 region, with the highest lod score, 6.67 (recombination fraction = 0.00), obtained with D19S606. Recombination events narrowed the critical region to an approximately 12-cM interval flanked by D19S908 and D19S866.

In the Oklahoma kindred with hypocalciuric hypercalcemia that was originally described by McMurtry et al. (1992), Hannan et al. (2010) used 24 polymorphic loci to refine further the HHC3 locus to a 4.1-Mb region flanked by D19S112 and SNP rs245111.

In a 3-generation kindred from Northern Ireland with hypocalciuric hypercalcemia, in which mutation in the CASR gene (601199) and linkage to the CASR locus had been excluded, Nesbit et al. (2010) analyzed 11 polymorphic loci on chromosome 19q13 and established linkage between HHC and 8 of the loci, obtaining the highest peak lod score of 5.98 at D19S412 (theta = 0). Haplotype analysis indicated that the Oklahoma kindred with HHC mapping to chromosome 19q13, originally studied by McMurtry et al. (1992), and the Northern Ireland kindred were not related. Recombination events in the Northern Ireland family narrowed the critical region to a 3.46-Mb interval flanked centromerically by rs1990932 and telomerically by D19S604; combining these data with those of the Oklahoma kindred defined a 2.79-Mb minimum nonrecombinant interval flanked by rs1019212 and D19S879.

Molecular Genetics

Using exome capture and high-throughput sequence analysis of genomic DNA from an affected individual from each of 2 unrelated kindreds with HHC mapping to chromosome 19q13, originally described by McMurtry et al. (1992) and Nesbit et al. (2010), respectively, Nesbit et al. (2013) identified a heterozygous missense mutation in the AP2S1 gene (R15C; 602242.0001). The mutation, which was confirmed by dideoxynucleotide sequencing, segregated completely with disease in each family and was not found in 55 normocalcemic controls. Analysis of the AP2S1 gene in 50 unrelated patients with HHC who were negative for mutation in the CASR gene identified 11 who were heterozygous for AP2S1 missense mutations, all of which involved the R15 residue: R15C in 4 patients, R15L (602242.0002) in 4 patients, and R15H (602242.0003) in 3 patients.

Exclusion Studies

In an affected individual from an Oklahoma kindred with hypocalciuric hypercalcemia mapping to chromosome 19q13, originally reported by McMurtry et al. (1992), Hannan et al. (2010) analyzed 12 candidate genes but found no abnormalities.