FIHP is a clinically defined entity, based on the absence of expression of the extra-parathyroid manifestations that characterize other familial HPT syndromes. FIHP is genetically heterogeneous, and can be caused by variant expressions of germline mutations in MEN1, HRPT2, CASR, and probably other genes.
One of the puzzling aspects of FIHP is the absence of some of the manifestations of the syndromic forms despite the fact that the same gene is affected. Several possible mechanisms might account for this finding: i) incomplete penetrance of some of the manifestations, as the gnathic and renal features in HPT- JT; ii) difference in the spectrum of mutations: it has been suggested that missense/in-frame deletion mutations may lead to incomplete MEN 1 phenotype, whereas truncating or nonsense mutations are more frequently observed in the full-blown syndrome. However, recent results from our and other groups have ruled out this possibility; iii) different mutations of the same gene may result in various degree of structure change and, accordingly, the capability of the mutated protein of interacting with other proteins may be variously affected. Indeed, either naturally occurring or engineered MEN1 gene mutations have been shown to affect differently binding of menin with JunD; iv) influences from environmental factors and the presence of modifier genes that may contribute to phenotypic variations, as reported in familial adenomatous polyposis.
Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism
FHH is an autosomal dominant syndrome characterized by lifelong moderate hypercalcemia, inappropriate serum PTH levels, and relative hypocalciuria. Parathyroid gland are normal in most patients with FHH. In some families, however, PTH is moderately elevated. The biochemical abnormality of FHH has been attributed to the increased renal retention of calcium that is not quite enough to overcome the decreased parathyroid sensitivity to calcium, so that PTH concentration is inappropriately normal. In rare cases PTH is moderately elevated, suggesting that decreased parathyroid sensitivity to calcium is accompanied by a moderate generalized parathyroid hy- perplasia. This observation suggests that the CASR may be involved in the control of parathyroid proliferation (see below).
FHH mostly maps to CASR gene locus on chromosome 3q21- 24, but genetic heterogeneity has been substantiated with two kindreds that show linkage to either 19p13.3 (FHH i9p) or 19q13 (FHH 19p) also known as Oklahoma variant. Heterozygous and homozygous loss-of-function mutation of CASR gene are responsible for FHH and NSHP, respectively. CASR is ubiquitous but it is most heavily expressed in the parathyroid cells and the thick ascending loop of the kidney. It has three main structural domains: a large extracellular amino-ter- minal domain, a seven transmembrane spanning domain, which characterizes the superfamily of G-protein coupled receptors, and an intracytoplasmic carboxy terminal tail. CASR interacts with extracellular calcium ions, transducing it into an intracellular signal, its protein category products coupling to a cytoplasmic guanyl nucleotide-binding protein. No correlation between the CASR mutation spectrum and the clinical pheno- type has been apparent in FHH families. CASR inactivating mutations may interfere with normal function of the wild-type receptor through the following mechanisms: a) reduced affinity of the receptor for its agonists including calcium; b) inability of the receptor to reach the cell surface; c) failure of the receptor to couple with its appropriate signal transduction pathways; and d) interference of the mutated receptor with the function of the wild type receptor, known as a “dominant negative” effect or production of a truncated, inactive receptor. One large family has been described with a phenotype different from FHH and FIHP. These patients had hypercalcemia, hypercalciuria, and serum PTH levels in the upper part of the normal range. Some family members had parathyroid adenoma or hyperplasia and, unlike FHH, had postoperative reversal of hypercalcemia. Genetic studies identified an atypical inactivating mutation in the intracellular part of the CASR. NSHPT is often diagnosed within a week of birth and may carry a very high mortality rate unless recognized and treated promptly. The severity of the hypercalcemia, bone disease and high PTH levels is mostly explained by the absence of CASR in the homozygous and compound heterozygous forms of NSHPT. The dramatic increase of parathyroid gland volume suggests a negative trophic effect of the normal CASR on cell growth and proliferation.
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Gene knockout model provided the definitive proof for the central role for the normal CASR in calcium metabolism and of inactivating mutations in causing the FHH and NSHPT pheno- types. Heterozygous mice had about a 50% reduction in the expression of the CASR protein both in the parathyroid gland and the kidney compared with the wild type mice. They were similar to wild type mice with normal skeletal films and parathyroid gland histology. They had mild hypercalcemia with normal PTH levels, hypocalciuria and mildly elevated serum magnesium compared with the wild-type mice. In the mutant mice there was a mild elevation of the set point for calcium-regulated PTH release, similar to what has been reported in FHH families. Homozygous mice had a complete absence of CASR protein in the parathyroid and kidney. The phenotypic and biochemical profiles of these mice was comparable to that of NSHPT.