Familial Hypocalciuric
Hypercalcemia (CASR)
For information on ordering genetic testing for familial hypercalciuric hypercalcemia, click here. Frequently Used Abbreviations: CASR:calcium-sensing receptor; FHH: familial hypocalciuric hypercalcemia; HPT: hyperparathyroidism; PTH: parathyroid hormone; Introduction Familial Hypocalciuric Hypercalcemia (FHH) is also known as Familial Benign Hypercalcemia because it is generally asymptomatic and does not require treatment. However, FHH is easily confused with milder cases of the more common primary hyperparathyroidism (HPT), which is generally treated by parathyroidectomy. In the case of FHH, parathyroidectomy is not only unnecessary but also inappropriate, since it does not cure FHH-associated hypercalcemia (1). It is therefore important to identify patients with FHH to prevent unnecessary parathyroidectomy. Unfortunately, current diagnostic methods do not always allow reliable differentiation between FHH and milder cases of primary HPT (2). Since most cases of FHH are associated with loss-of-function mutations in a single gene (CASR), genetic testing can assist in the diagnosis of FHH (3). Genetic testing for FHH-associated mutations in CASR can help to prevent unnecessary and inappropriate parathyroidectomy in patients with FHH. Types and Causes of FHH The vast majority of FHH is caused by autosomal dominant loss-of-function mutations in the gene CASR, which codes for the calcium-sensing receptor (CASR). CASR is a G-protein coupled membrane receptor expressed in the parathyroid glands and the kidneys, among other tissues (4). In the parathyroid glands, CASR mediates the feedback inhibition of parathyroid hormone release in response to a rise in the blood calcium concentration. Loss-of-function mutations in CASR impair the feedback inhibition of parathyroid hormone secretion in response to a rise in the blood calcium concentration. Thus, higher than normal blood calcium levels are necessary to inhibit release of parathyroid hormone, resulting in hypercalcemia associated with inappropriately normal or mildly elevated levels of parathyroid hormone. The degree of hypercalcemia depends on how severely the mutation affects the function of the CASR molecule. In the kidneys, CASR is involved in the feedback inhibition of parathyroid hormone-independent calcium reabsorption. Loss-of-function mutations in CASR prevent feedback inhibition of calcium reabsorption in response to a rise in the blood calcium concentration. Since calcium continues to be efficiently reabsorbed despite hypercalcemia, the calcium concentration in the urine is unexpectedly low relative to the calcium concentration in the blood (relative hypocalciuria). If you want to learn more about Function of CASR please click here.
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Clinical Presentation of FHH FHH is characterized by hypercalcemia, relative hypocalciuria, slight hypermagnesemia, and inappropriately normal to high levels of parathyroid hormone (PTH) (5, 6). In rare cases, loss-of-function mutations in CASR can also be associated with hypercalciuria (7, 8). Although hypercalcemia is present from birth, it is often noticed later in life during a routine serum chemistry screen.
In the majority of cases, FHH is asymptomatic and does not lead to the complications associated with primary HPT, such as generalized bone demineralization and kidney stones. In a few FHH patients, pancreatitis, gallstones, chondrocalcinosis, or kidney stones have been reported (5, 8, 9).
Diagnosis of FHH Hypercalcemia - Calcium/creatinine clearance ratio <0.01
- Hypercalcemic infant/child in family
- Genetic testing for mutations in CASR
FHH is considered in individuals with asymptomatic persistent hypercalcemia accompanied by inappropriately normal or mildly elevated blood levels of parathyroid hormone. Differentiation from primary HPT can often be achieved by measuring the renal calcium/creatinine clearance ratio, which generally is less than 0.01 in patients with FHH and higher in patients with primary HPT (6).
However, reliable distinction between FHH and primary HPT is not always possible based on blood or urine measurements alone. Blood parathyroid hormone levels may be elevated in both situations, and urine calcium concentrations may not always be strikingly different between FHH and primary HPT. Occasionally, loss-offunction mutations in CASR can even be associated with hypercalciuria, similar to primary HPT (7, 8).
Genetic testing for FHH-associated mutations in CASR can allow a diagnosis of FHH in cases where biochemical tests remain inconclusive. In addition, the detection of mutations in CASR can confirm a diagnosis of FHH reached on the basis of biochemical tests. Treatment of FHH
In contrast to most cases of primary HPT, FHH does not require any treatment. Parathyroidectomy is not only unnecessary, but also ineffective in the case of FHH.
Genetics of FHH
Monogenic Autosomal dominant Close to 100%
Clinical Presentation of FHH - Hypercalcemia
- Hypocalciuria
- Normal to high levels of PTH
- Hypermagnesemia
FHH is characterized by hypercalcemia, relative hypocalciuria, slight hypermagnesemia, and inappropriately normal to high levels of parathyroid hormone (PTH) (5, 6). In rare cases, loss-of-function mutations in CASR can also be associated with hypercalciuria (7, 8). Although hypercalcemia is present from birth, it is often noticed later in life during a routine serum chemistry screen. In the majority of cases, FHH is asymptomatic and does not lead to the complications associated with primary HPT, such as generalized bone demineralization and kidney stones. In a few FHH patients, pancreatitis, gallstones, chondrocalcinosis, or kidney stones have been reported (5, 8, 9). Diagnosis of FHH
Hypercalcemia Calcium/creatinine clearance ratio <0.01 Hypercalcemic infant/child in family Genetic testing for mutations in CASR FHH is considered in individuals with asymptomatic persistent hypercalcemia accompanied by inappropriately normal or mildly elevated blood levels of parathyroid hormone. Differentiation from primary HPT can often be achieved by measuring the renal calcium/creatinine clearance ratio, which generally is less than 0.01 in patients with FHH and higher in patients with primary HPT (6). However, reliable distinction between FHH and primary HPT is not always possible based on blood or urine measurements alone. Blood parathyroid hormone levels may be elevated in both situations, and urine calcium concentrations may not always be strikingly different between FHH and primary HPT. Occasionally, loss-offunction mutations in CASR can even be associated with hypercalciuria, similar to primary HPT (7, 8). Genetic testing for FHH-associated mutations in CASR can allow a diagnosis of FHH in cases where biochemical tests remain inconclusive. In addition, the detection of mutations in CASR can confirm a diagnosis of FHH reached on the basis of biochemical tests. Treatment of FHH
In contrast to most cases of primary HPT, FHH does not require any treatment. Parathyroidectomy is not only unnecessary, but also ineffective in the case of FHH.
Genetics of FHH
- Monogenic
- Autosomal dominant
- Close to 100%
The vast majority of FHH is caused by autosomal dominant loss-of-function mutations in CASR. In only two families, FHH was shown to be associated with a gene other than CASR (10).
While heterozygosity for a loss-of-function mutation in CASR usually causes FHH, homozygosity typically leads to neonatal severe hyperparathyroidism (3). Very rarely, the effect of a loss-of-function mutation in CASR is so mild that homozygosity for this mutation leads to FHH instead of neonatal severe hyperparathyroidism, while heterozygous individuals are normocalcemic (11, 12).
Of note, gain-of-function mutations in CASR do not lead to FHH, but to the “complementary” condition, hypercalciuric hypocalcemia, also known as autosomal dominant hypocalcemia (13). Genetic Testing for FHH
The Familial Hypocalciuric Hypercalcemia Evaluation detects mutations in CASR and can help establish or confirm a diagnosis of FHH in hypercalcemic individuals. In particular, genetic testing for FHH allows distinction between FHH and mild primary HPT, which cannot always be differentiated on the basis of blood or urine tests. Identification of FHH is important in order to prevent unnecessary and inappropriate parathyroidectomy in patients with FHH.
How Is Genetic Testing for FHH Performed? DNA for sequencing is obtained from leukocytes present in a small blood sample. The coding sequences of CASR are amplified in a highly specific manner through a polymerase chain reaction (PCR), and all PCR products are fully sequenced. Sequencing results are interpreted, and a detailed result report is sent to the patient’s physician. Ordering testing for familial hypocalciuric hypercalcemia, click here. Download a printable pdf of this review. 
1. Law WM Jr, Heath H 3rd (1985) Familial benign hypercalcemia (hypocalciuric hypercalcemia). Clinical and pathogenetic studies in 21 families. Ann Intern Med 102:511-9.
Link to PubMed
2. Pearce SH, Trump D, Wooding C, Besser GM, Chew SL, Grant DB, Heath DA, Hughes IA, Paterson CR, Whyte MP, et al (1995) Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism. J Clin Invest 966:2683-92.
Link to PubMed
3. Pollak MR, Brown EM, Chou YH, Hebert SC, Marx SJ, Steinmann B, Levi T, Seidman CE, Seidman JG (1993) Mutations in the human Ca2+-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 75:1297-303.
Link to PubMed
4. Brown EM, MacLeod RJ (2001) Extracellular Calcium Sensing and Extracellular Calcium Signaling. Physiological Reviews 81:239-97.
Link to PubMed
5. Heath H 3rd (1989) Familial benign (hypocalciuric) hypercalcemia. A troublesome mimic of mild primary hyperparathyroidism. Endocrinol Metab Clin North Am 18:723-40.
Link to PubMed
6. Hendy GN, D'Souza-Li L, Yang B, Canaff L, Cole DE (2000) Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. Hum Mutat 16:281-96.
Link to PubMed
7. Pasieka JL, Andersen MA, Hanley DA 1990 Familial benign hypercalcaemia: hypercalciuria and hypocalciuria in affected members of a small kindred. Clin Endocrinol (Oxf) 33:429-33.
Link to PubMed
8. Carling T, Szabo E, Bai M, Ridefelt P, Westin G, Gustavsson P, Trivedi S, Hellman P, Brown EM, Dahl N, Rastad J. (2000) Familial hypercalcemia and hypercalciuria caused by a novel mutation in the cytoplasmic tail of the calcium receptor. J Clin Endocrinol Metab 85:2042-47.
Link to PubMed
9. Pearce SH, Wooding C, Davies M, Tollefsen SE, Whyte MP, Thakker RV (1996) Calcium-sensing receptor mutations in familial hypocalciuric hypercalcaemia with recurrent pancreatitis. Clin Endocrinol (Oxf) 45:675-80.
Link to PubMed
10. Thakker RV (2004) Diseases associated with the extracellular calcium-sensing receptor. Cell Calcium 35(3):275-82.
Link to PubMed
11. Aida K, Koishi S, Inoue M, Nakazato M, Tawata M, Onaya T (1995) Familial hypocalciuric hypercalcemia associated with mutation in the human Ca2+-sensing receptor gene. J Clin Endocrinol Metab 80:2594-8.
Link to PubMed
12. Chikatsu N, Fukumoto S, Suzawa M, Tanaka Y, Takeuchi Y, Takeda S, Tamura Y, Matsumoto T, Fujita T (1999) An adult patient with severe hypercalcaemia and hypocalciuria due to a novel homozygous inactivating mutation of calcium-sensing receptor. Clinical Endocrinology 50:537-43.
Link to PubMed
13. Finegold DN, Armitage MM, Galiani M, Matise TC, Pandian MR, Perry YM, Deka R, Ferrell RE (1994) Preliminary localization of a gene for autosomal dominant hypoparathyroidism to chromosome 3q13. Pediatr Res 36:414-7.
Link to PubMed
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