Familial hypocalciuric hypercalcemia overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Overview
Historical Perspective
Until 1966 many asymptomatic hypercalcemic patients were identified to have familial hypocalciuric hypercalcemia, then Jackson and Boonstra described their first patient with hypercalcemia presumed to have hyperparathyroidism. He wasn't cured despite the removal of three and a half hyperplastic parathyroid glands. Subsequently, seventeen family members with hypercalcemia were identified in three generation.
Classification
Three genetically heterogeneous variants are reported so far for familial hypocalciuric hypercalcemia. Type 1 - due to loss-of-functional mutations of the calcium-sensing receptor (encoded by CASR). Type 2 - unknown cause. Type 3 - associated with adaptor-related protein complex 2, sigma 1 subunit (AP2S1) mutations, which alter calcium-sensing receptor endocytosis
Pathophysiology
The pathophysiology of Familial hypocalciuric hypercalcemia is due to an inactivating missense mutation in the calcium-sensing receptor (CaSR) located on the short arm of the chromosome 3 (FBHH3q). The mutation of CaSR is associated with two inherited conditions FBHH and neonatal hyperparathyroidism. CaSR is a plasma membrane G protein-coupled receptor which is expressed on the chief cells of the parathyroid glands and the cells lining the renal tubules. CasR has the ability to sense any changes in the circulating calcium concentrated and send this information through the signaling pathway to the Parathyroid gland that modifies the PTH secretion.
Causes
FHH is caused by a mutation in the CASR gene located on chromosome 3. The calcium-sensing receptor is a plasma membrane G protein-coupled receptor that is expressed on the chief cells of the parathyroid gland and the lining the kidney tubule. CASR has the ability to sense small changes in circulating calcium concentration and send this information to intracellular signaling pathways that modify PTH secretion or renal calcium handling. Inherited abnormalities of the CASR gene located on chromosome 3p13.3-21 can cause either hypercalcemia or hypocalcemia depending upon whether they are inactivating or activating. Heterozygous loss-of-functional mutations give rise to FHH, a lifelong asymptomatic hypercalcemia. The homozygous condition manifests as neonatal severe hyperparathyroidism, a rare disorder characterized by extreme hypercalcemia and the bony changes of hyperparathyroidism. The disorder autosomal dominant hypocalcemia is due to gain-of-function mutations in the CASR gene, this can be asymptomatic or presents with seizures. FHH is classified into three types Type-1: caused by loss-of-function mutations of the CaSR, a G-protein coupled receptor that predominantly signals via G-protein subunit alpha-11 (Gα11) to regulate calcium homeostasis located on chromosome 3q13.3-q21. Type-2: caused by heterozygous mutation in the GNA11 gene on chromosome 19p13. Type-3: caused by heterozygous mutation in the AP2S1 gene on chromosome 19q13.
Differentiating ((Page name)) from Other Diseases
Familial hypocalciuric hypercalcemia must be differentiated from primary hyperparathyroidism to avoid unnecessary parathyroidectomy. Calcium Creatinine Clearance Ratio is used to differentiate FHH from primary hyperparathyroidism, ratio < 0.01 suggestive of FHH and > 0.01 suggestive of primary hyperparathyroidism. This genetic test of the CaSR gene is the gold standard. If negative, Genetic testing for mutation of G alpha 11 and AP2S1 can diagnose FHH2 and FHH3, respectively.
Epidemiology and Demographics
Risk Factors
Screening
Prenatal testing for FHH is not recommended routinely. If both parents have type-1 FHH, their children should be screened for CASR mutation. Genetic screening for the CASR familial mutation is also offered to family members of affected individuals. CaSR and AP2S1 sequencing are done in patients with familial hyperparathyroidism and phenotype suggesting FHH. Learning disabilities in patients, associated with higher serum calcium and magnesium levels may suggest the presence of AP2S1 mutation and may require further genetic evaluation..
Natural History, Complications, and Prognosis
Very rarely familial hypocalciuric hypercalcemia can cause complications such as pancreatitis, gallstones, chondrocalcinosis. Prognosis is excellent and patients with FHH have a normal lifespan.
Diagnosis
Diagnostic Criteria
The diagnosis of familial hypocalciuric hypercalcemia is based on the presence of asymptomatic hypercalcemia in the multiple family members, hypercalcemia, and hypocalciuria.
History and Symptoms
The majority of patients with familial hypocalciuric hypercalcemia (FHH) are asymptomatic. Very rarely can present with signs and symptoms of hypercalcemia such as confusion, fatigue, muscle weakness, constipation, anorexia, anhedonia, headaches, gastroesophageal reflux, polyuria, polydipsia, palpitations, nausea, vomiting thinning of hair.
Physical Examination
Physical examination of patients with familial hypocalciuric hypercalcemia (FHH) is usually unremarkable. Very rarely patients may have examination findings due to hypercalcemia.
Laboratory Findings
Calcium Creatinine Clearance Ratio is used to differentiate FHH from primary hyperparathyroidism, ratio < 0.01 suggestive of FHH and > 0.01 suggestive of primary hyperparathyroidism. Calcium creatinine clearance ratio = [24-hour urine Ca x serum Cr] ÷ [serum Ca x 24-hour urine Cr].