Familial hypocalciuric hypercalcemia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ajay Gade MD[2]]

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.

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.

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.

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.

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.

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.

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.

There are no established risk factors for familial hypocalciuric hypercalcemia other than the positive family history of benign hypercalcemia.

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.

Very rarely familial hypocalciuric hypercalcemia can cause complications such as pancreatitis, gallstones, chondrocalcinosis. Prognosis is excellent and patients with FHH have a normal lifespan.

The diagnosis of familial hypocalciuric hypercalcemia is based on the presence of asymptomatic hypercalcemia in the multiple family members, hypercalcemia, and hypocalciuria.

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 of patients with familial hypocalciuric hypercalcemia (FHH) is usually unremarkable. Very rarely patients may have examination findings due to hypercalcemia.

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].

There are no echocardiography/ultrasound findings associated with FHH.

There are no x-ray findings associated with familial hypocalciuric hypercalcemia (FHH).

There are no ultrasound findings associated with familial hypocalciuric hypercalcemia.

There are no CT scan findings associated with FHH.

There are no MRI findings associated with familial hypocalciuric hypercalcemia.

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.

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.

Surgical intervention is not recommended for the management of FHH. Very rarely its done in patients with associated pancreatitis, parathyroid adenoma, hyperparathyroidism, and hypercalciuria.

There are no established measures for the primary prevention of familial hypocalciuric hypercalcemia.

Secondary prevention of familial hypocalciuric hypercalcemia includes monitoring for serum calcium annually.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ajay Gade MD[2]]

Until 1966 many asymptomatic hypercalcemic patients were identified to have familial hypocalciuric hypercalcemia (FHH), then Jackson and Boonstra described their first patient with hypercalcemia presumed to have hyperparathyroidism. He was not cured despite the removal of three and a half hyperplastic parathyroid glands. Subsequently, seventeen family members with hypercalcemia were identified in three generations.

• In the year 1966 FHH was first described by Jackson and Boonstra in a hypercalcemic patient presumed to have hyperparathyroidism. He was not cured despite the removal of three and a half hyperplastic parathyroid glands. Subsequently, seventeen family members with hypercalcemia were identified in three generations.^[1][2]

• A similar family was identified in the year 1972 by Foley Et al. The family members of both the families were asymptomatic and hypercalcemic which is very typical of FHH.^[2]

• In 1990 ten cases of pancreatitis were reported in patients with family members of FHH.^[3]

• In 1990 the National Institutes of Health (NIH) held a conference to establish the principles for diagnosing FHH along with its medical and surgical management guidelines.^[4]
• In 1993 Brown Et al identified a bovine parathyroid cell calcium-sensing receptor cDNA by expression cloning in Xenopus laevis oocytes. The cDNA encodes a predicted 120-kD polypeptide containing a large extracellular domain and 7 membrane-spanning regions characteristic of G protein-coupled cell surface receptors. In addition to parathyroid tissue, it also identified the presence of CaSR in regions of the kidney involved in calcium-regulated calcium and magnesium reabsorption.^[5]

• In 1995 studies were conducted to characterize the mutations of calcium-sensing receptors in FHH and neonatal hyperparathyroidism.^[6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ajay Gade MD[2]]

Familial hypocalciuric hypercalcemia is classified into three types. Type-1 is due to loss-of-function mutations of the calcium-sensing receptor, type-2 is caused by the mutation of GNA 11 gene, type-3 is associated with adaptor-related protein complex 2, sigma 1 subunit (AP2S1) mutations, which alter the endocytosis of calcium-sensing receptor.

FHH is an autosomal dominant benign inherited condition caused by three types of mutations the most common mutation is an inactivating missense mutation of the CaSR located on chromosome 3q. It is very rarely caused by the mutation of GNA11 gene and AP2S1 gene.^[1][2]

There are three types of FHH:

• Type-1: caused by loss-of-function mutations of the calcium-sensing receptor (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.^[3][4]

• Type-2: caused by heterozygous mutation in the GNA11 gene on chromosome 19p13.^[5]
• Type-3: caused by heterozygous mutation in the AP2S1 gene on chromosome 19q13.^[6][7]

Familial Hypocalciuric Hypercalcemia

Type 1 FHH

Type 2 FHH

Type 3 FHH

Mutations of the calcium-sensing receptor

Mutation in the GNA11 gene

Mutation in the AP2S1 gene

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ajay Gade MD[2]]

The pathophysiology of familial hypocalciuric hypercalcemia (FHH) consists of 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 FHH 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 concentration and send this information through the signaling pathway to the parathyroid gland that modifies PTH secretion.

• The pathogenesis of familial hypocalciuric hypercalcemia (FHH) includes the following mechanisms:^{[1][2][3][4][5]}
• The pathophysiology of familial hypocalciuric hypercalcemia (FHH) consists of an inactivating 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 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 and send this information through the signaling pathway to the parathyroid gland that modifies the parathyroid hormone (PTH) secretion.

• The genes involved in the pathogenesis of FHH include mainly CASR, rarely GNA11 and AP2S1.^[6][7]
• The development of FHH is the result of genetic mutations of calcium-sensing receptor (CASR).
• CASR gene located on chromosome 3p13.3-21, inactivating mutation in this gene can cause hypercalcemia whereas the activating mutation causes hypocalcemia.
• If the mutation is heterozygous, then FHH occurs with lifelong asymptomatic hypercalcemia.
• Neonatal severe hyperparathyroidism (NSHPT), a rare disorder characterized by extreme hypercalcemia and bony changes of hyperparathyroidism in infancy occurs due to homozygous mutation.
• The gain of function mutation in the CaSR gene lead to autosomal dominant hypocalcemia.
• 100 different types of CaSR gene alterations have been described in the literature.

FHH sometimes is associated with pancreatitis because the mutation in CaSR can make the pancreas susceptible for inflammation.^[8]

No gross pathology is seen in FHH.

On light microscopy the percentage parenchyma is reduced in parathyroid glands in patients with familial hypocalciuric hypercalcemia, whereas the adipose tissue percentage is increased in the parathyroid glands.^[9][10]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ajay Gade MD[2]]

Familial hypocalciuric hypercalcemia (FHH]) is caused by a mutation in the calcium-sensing receptor (CaSR) gene located on the chromosome 3. The chief cells of the parathyroid gland and the lining the kidney tubule express CaSR, a G protein coupled plasma membrane receptor which has the ability to sense small changes in circulating calcium concentration. This information is sent 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. Inactivating mutation causes hypercalcemia, whereas the activating mutation causes hypocalcemia. Heterozygous loss-of-function mutations give rise to FHH, an asymptomatic hypercalcemia. The homozygous mutation manifests as neonatal severe hyperparathyroidism, a rare disorder characterized by extreme hypercalcemia and the bony changes of hyperparathyroidism. The disorder is known to be autosomal dominant hypocalcemia due to a gain-of-function mutations in the CaSR gene; this may be asymptomatic or may present with seizures. The three types of FHH are known to be caused due to different genetic mutations. Type-1 FHH is caused by a 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 FHH is caused by heterozygous mutation in the GNA11 gene on chromosome 19p13. Type-3 FHH is caused by heterozygous mutation in the AP2S1 gene on chromosome 19q13.

Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant benign inherited condition caused by inactivating missense mutation of the CaSR located on chromosome 3q. There are three types of FHH^{[1][2][3][4][5][6][7]}

• Type-1 FHH: Loss-of-function mutations of the calcium-sensing receptor (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 FHH: heterozygous mutation in the GNA11 gene on chromosome 19p13.
• Type-3 FHH: Heterozygous mutation in the AP2S1 gene on chromosome 19q13.

The genetic causes are as follows^[8][9][10]:

• FHH is caused by a mutation in the CaSR gene located on chromosome 3.
• The chief cells of the parathyroid gland and the lining of the kidney tubule express CaSR a G protein coupled plasma membrane receptor, which has the ability to sense small changes in circulating calcium concentration.
• This information is sent 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.
• Inactivating mutation causes hypercalcemia whereas the activating mutation causes hypocalcemia.
• Heterozygous loss-of-function mutations give rise to FHH, an 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.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ajay Gade MD[2]]

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.

Familial hypocalciuric hypercalcemia should be differentiated from other causes of hypercalcemia. Causes of hypercalcemia include:

Parathyroid-related	Non-parathyroid related	Medication-induced	Other
Primary hyperparathyroidism Secondary hyperparathyroidism Tertiary hyperparathyroidism	Malignancy Humoral hypercalcemia of malignancy Osteolytic tumors Production of calcitriol by tumors Ectopic parathyroid hormone production	Thiazide diuretics Lithium	Nutritional Milk-alkali syndrome Vitamin D toxicity Granulomatous disease Sarcoidosis Surgical Immobilization

Differential diagnosis of Familial Hypocalciuric Hypercalcemia on the basis of hypercalcemia
Disorder		Mechanism of hypercalcemia	Clinical features	Laboratory findings				Imaging & diagnostic modalities
				PTH	Calcium	Phosphate	Other findings
Familial hypocalciuric hypercalcemia		This is a genetic disorder caused by mutation in calcium-sensing receptor gene.	This is a benign condition and does not require treatment.	Normal/↑	Normal/↑		—	Calcium/creatinine clearance ratio
Hyperparathyroidism	Primary hyperparathyroidism	Increase in secretion of parathyroid hormone (PTH) from a primary process in the parathyroid gland. Parathyroid hormone causes an increase in serum calcium.	Usually asymptomatic Hypercalcemia detected on routine biochemical panel	↑	↑	↓/Normal	Normal/↑ calcitriol	Findings of bone resorption: X-ray DEXA Preoperative localization of hyperfunctioning parathyroid gland: Non-Invasive Tc-99m sestamibi scintigraphy Neck ultrasound 4D-CT SPET(P-SPECT) PET MRI Invasive: Super sensitive venous sampling Selective arteriography Angiography Predicting post-operative success: Intraoperative parathyroid hormone monitoring
	Secondary hyperparathyroidism	Increase in secretion of parathyroid hormone (PTH) from a secondary process. Parathyroid hormone causes an increase in serum calcium.	May present with history of: Chronic renal failure Vitamin D deficiency	↑	↓/Normal	↑	—
	Tertiary hyperparathyroidism	Continuous elevation of parathyroid hormone (PTH) even after successful treatment of the secondary cause of elevated parathyroid hormone. Parathyroid hormone causes an increase in serum calcium.	Usually present with a history of: Kidney transplant Usually hyperplasia of all four parathyroid glands	↑	↑	↑	—
Malignancy[1]	Humoral hypercalcemia of malignancy[2][3][4]	Tumor cells secrete parathyroidhormone-related protein (PTHrP) which acts similarly to parathyroid hormone.	Most common cause of malignancy related hypercalcemia. Usually present in solid tumors	—	↑	↓/Normal	↑ PTHrP Normal/↑ calcitriol	Chest X-ray CT scan MRI
	Osteolytic tumors	Multiple myeloma produces osteolysis of bones causing hypercalcemia. Osteolytic metastasis can cause bone resorption causing hypercalcemia.	Most commonly present in multiple myeloma and breast cancer.	↓	↑	—	—	DXA X-ray Mammography Ultrasound ESR Serum protein electrophoresis
	Production of calcitriol	Some tumors have ectopic activity of 1-alpha-hydroxylase leading to increased production of calcitriol. Calcitriol is active form of vitamin D and causes hypercalcemia.	Most commonly present in lymphomas and in some ovarian germ cell tumors.	—	↑	—	↑ Calcitriol	CT scan MRI
	Ectopic parathyroid hormone[5]	Some tumors leads to ectopic production of parathyroid hormone.	In rare instances, small cell carcinoma of lung may produce hypercalcemia by this process.	↑	↑	↓/Normal	Normal/↑ Calcitriol	Chest X-ray CT scan MRI
Medication induced	Lithium[6]	Lithium lowers urinary calcium and causes hypercalcemia. Lithium has been reported to cause an increase in parathyroid hormones and enlargement of parathyroid gland after weeks to months of therapy.	History of mood disorder	↑	↑	—	—	Lithium levels
	Thiazide diuretics	Thiazide diuretics lowers urinary calcium excretion and causes hypercalcemia	History of cardiac disorder Rarely causes hypercalcemia	—	↑	—	—	—
Nutritional	Milk-alkali syndrome	Hypercalcemia caused by high intake of calcium carbonate	History of High milk intake Excess calcium intake for treating: Osteoporosis Dyspepsia May lead to metabolic alkalosis and renal insufficiency.	—	↑	—	—	Renal function test
	Vitamin D toxicity	Excess vitamin D causes increased absorption of calcium from intestine causing hypercalcemia.	History of: Excess intake vitamin D Excess milk fortified with vitamin D[7] Topical application of vitamin D analogue calcipotriol[8]	—	↑	—	↑ Vitamin D (calcidiol and/or calcitriol)	—
Granulomatous disease	Sarcoidosis[9]	Hypercalcemia is caused by endogenous production of calcitriol by disease-activated macrophages.	History of: Cough Dyspnea Chest pain Tiredness or weakness Fever Weight loss	—	↑	—	↑ Calcitriol ↑ ACE levels	Chest X-ray Biopsy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

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.

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^[1].

Patients of all age groups may develop familial hypocalciuric hypercalcemia.

There is incomplete evidence regarding the racial predilection to familial hypocalciuric hypercalcemia.

Familial hypocalciuric hypercalcemia affects men and women equally.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

There are no established risk factors for familial hypocalciuric hypercalcemia other than the positive family history of benign hypercalcemia.

There are no established risk factors for familial hypocalciuric hypercalcemia.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ajay Gade MD[2]]

There is insufficient evidence to recommend routine screening for familial hypocalciuric hypercalcemia (FHH).

• 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 an AP2S1 mutation and may require further genetic evaluation.^[1][2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ajay Gade MD[2]]

Patients with familial hypocalciuric hypercalcemia are asymptomatic but rarely can present with signs and symptoms of hypercalcemia. Very rarely familial hypocalciuric hypercalcemia can cause complications such as pancreatitis, gallstones, chondrocalcinosis. Prognosis is excellent and patients with FHH have a normal lifespan.

Patients with familial hypocalciuric hypercalcemia are asymptomatic but rarely can present with signs and symptoms of hypercalcemia.^[1]

• The complications associated with primary hyperparathyroidism, like osteopenia and nephrolithiasis, is not increased in persons with benign familial hypocalciuric hypercalcemia, and the rates are similar to those in the general population.
• Rarely, a severe form of this disease, neonatal severe primary hyperparathyroidism is seen in infants with homozygous CASR mutations.^[2]
• Very rarely FHH is associated with:^[3][4][5]
  • Pancreatitis
  • Chondrocalcinosis
  • Gallstones

Prognosis is good with a lifespan similar to the general population, in patients with familial hypocalciuric hypercalcemia.^[6]

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