Familial hypocalciuric hypercalcemia overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ajay Gade MD[2]]
Overview
Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant asymptomatic condition which occurs due to an inactivating missense mutation in the calcium-sensing receptor (CaSR) located on the short arm of the chromosome 3 (FBHH3q). CaSR is a plasma membrane G protein-coupled receptor which is expressed on the parathyroid glands and the renal tubules which 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. FHH can sometimes 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. Very rarely it can present with complications such as pancreatitis, gallstones, chondrocalcinosis. Patients with FHH should be differentiated from the primary hyperparathyroidism to avoid unnecessary parathyroidectomy. Calcium creatinine clearance can be used to differentiate between FHH and primary hypercalcemia. Patients with FHH has a lifespan and quality of living similar to that of the general population.
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 levels of the circulating calcium concentration 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 Familial hypocalciuric hypercalcemia 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, ratios < 0.01 are suggestive of FHH and > 0.01 are 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
There is insufficient evidence about the incidence of familial hypocalciuric hypercalcemia. The prevalence of FHH is estimated to be 0.78 in 100,000 hypercalcemia cases. Patients of all age groups may develop familial hypocalciuric hypercalcemia. There is neither racial or gender predisposition for familial hypocalciuric hypercalcemia.
Risk Factors
There are no established risk factors for familial hypocalciuric hypercalcemia other than the positive family history of benign hypercalcemia.
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. Children with higher serum calcium and magnesium levels with associated learning difficulties may suggest the presence of an 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 and 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, a ratio < 0.01 is suggestive of FHH and > 0.01 is suggestive of primary hyperparathyroidism. Calcium creatinine clearance ratio = [24-hour urine Ca x serum Cr] ÷ [serum Ca x 24-hour urine Cr].
Electrocardiogram
There are no echocardiography/ultrasound findings associated with FHH.
X-ray
There are no x-ray findings associated with familial hypocalciuric hypercalcemia (FHH).
Ultrasound
There are no ultrasound findings associated with familial hypocalciuric hypercalcemia.
CT scan
There are no CT scan findings associated with FHH.
MRI
There are no MRI findings associated with familial hypocalciuric hypercalcemia.
Other Diagnostic Studies
The gene responsible for familial hypocalciuric hypercalcemia maps to chromosome 3q. DNA sequencing test may be helpful in the diagnosis of FHH. The test detects mutations including point mutations, deletions, insertions, and rearrangements in the coding sequences of CaSR.
Treatment
Medical Therapy
There is no treatment for familial hypocalciuric hypercalcemia as it is a benign condition. However, the avoidance of parathyroidectomy should be emphasized to the FHH diagnosed patients.
Surgery
Surgical intervention is not recommended for the management of FHH. Very rarely its done in patients with associated pancreatitis, parathyroid adenoma, hyperparathyroidism, and hypercalciuria.
Primary Prevention
There are no established measures for the primary prevention of familial hypocalciuric hypercalcemia.
Secondary Prevention
Secondary prevention of familial hypocalciuric hypercalcemia includes monitoring for serum calcium annually.