Familial hypocalciuric hypercalcemia (patient information): Difference between revisions
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==Overview== | ==Overview== | ||
Familial hypocalciuric hypercalcemia is | Familial hypocalciuric hypercalcemia is an autosomal dominant inherited disorder characterized by asymptomatic hypercalcemia and low urinary calcium. | ||
==What are the Symptoms of Familial hypocalciuric hypercalcemia?== | ==What are the Symptoms of Familial hypocalciuric hypercalcemia?== | ||
The majority of patients with FHH are asymptomatic.However, FHH can present with signs and symptoms of hypercalcemia such as: | The majority of patients with FHH are asymptomatic.However, FHH can present with signs and symptoms of hypercalcemia such as: | ||
* [[Constipation]] | * [[Constipation]] | ||
* [[ | * [[Polyuria]] | ||
* [[ | * [[Polydipsia]] | ||
* [[ | * [[Anorexia]] | ||
* [[ | * [[Anhedonia]] | ||
* Abdominal pain | * Abdominal pain | ||
* [[Muscle weakness]] | * [[Muscle weakness]] | ||
* [[Confusion]] | * [[Confusion]] | ||
* [[Fatigue]] | * [[Fatigue]] | ||
* Neuropsychiatric symptoms. | * Neuropsychiatric symptoms<ref name="pmid20059346">{{cite journal |vauthors=Whitcomb DC |title=Genetic aspects of pancreatitis |journal=Annu. Rev. Med. |volume=61 |issue= |pages=413–24 |year=2010 |pmid=20059346 |doi=10.1146/annurev.med.041608.121416 |url=}}</ref>. | ||
==What Causes Familial hypocalciuric hypercalcemia?== | ==What Causes Familial hypocalciuric hypercalcemia?== | ||
FHH is an autosomal dominant benign inherited condition caused by inactivating missense mutation of the CASR located on chromosome 3q<ref name="pmid25104082">{{cite journal |vauthors=Stratta P, Merlotti G, Musetti C, Quaglia M, Pagani A, Izzo C, Radin E, Airoldi A, Baorda F, Palladino T, Leone MP, Guarnieri V |title=Calcium-sensing-related gene mutations in hypercalcaemic hypocalciuric patients as differential diagnosis from primary hyperparathyroidism: detection of two novel inactivating mutations in an Italian population |journal=Nephrol. Dial. Transplant. |volume=29 |issue=10 |pages=1902–9 |year=2014 |pmid=25104082 |doi=10.1093/ndt/gfu065 |url=}}</ref><ref name="pmid26963950">{{cite journal |vauthors=Vargas-Poussou R, Mansour-Hendili L, Baron S, Bertocchio JP, Travers C, Simian C, Treard C, Baudouin V, Beltran S, Broux F, Camard O, Cloarec S, Cormier C, Debussche X, Dubosclard E, Eid C, Haymann JP, Kiando SR, Kuhn JM, Lefort G, Linglart A, Lucas-Pouliquen B, Macher MA, Maruani G, Ouzounian S, Polak M, Requeda E, Robier D, Silve C, Souberbielle JC, Tack I, Vezzosi D, Jeunemaitre X, Houillier P |title=Familial Hypocalciuric Hypercalcemia Types 1 and 3 and Primary Hyperparathyroidism: Similarities and Differences |journal=J. Clin. Endocrinol. Metab. |volume=101 |issue=5 |pages=2185–95 |year=2016 |pmid=26963950 |doi=10.1210/jc.2015-3442 |url=}}</ref>. | |||
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<ref name="pmid26729423">{{cite journal |vauthors=Gorvin CM, Cranston T, Hannan FM, Rust N, Qureshi A, Nesbit MA, Thakker RV |title=A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2) |journal=J. Bone Miner. Res. |volume=31 |issue=6 |pages=1200–6 |year=2016 |pmid=26729423 |pmc=4949650 |doi=10.1002/jbmr.2778 |url=}}</ref><ref name="pmid23802516">{{cite journal |vauthors=Nesbit MA, Hannan FM, Howles SA, Babinsky VN, Head RA, Cranston T, Rust N, Hobbs MR, Heath H, Thakker RV |title=Mutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia |journal=N. Engl. J. Med. |volume=368 |issue=26 |pages=2476–2486 |year=2013 |pmid=23802516 |pmc=3773604 |doi=10.1056/NEJMoa1300253 |url=}}</ref>. | |||
* Type-2: caused by heterozygous mutation in the GNA11 gene on chromosome 19p13<ref name="pmid28176280">{{cite journal |vauthors=Szalat A, Shpitzen S, Tsur A, Zalmon Koren I, Shilo S, Tripto-Shkolnik L, Durst R, Leitersdorf E, Meiner V |title=Stepwise CaSR, AP2S1, and GNA11 sequencing in patients with suspected familial hypocalciuric hypercalcemia |journal=Endocrine |volume=55 |issue=3 |pages=741–747 |year=2017 |pmid=28176280 |doi=10.1007/s12020-017-1241-5 |url=}}</ref>. | |||
* Type-3: caused by heterozygous mutation in the AP2S1 gene on chromosome 19q13<ref name="pmid24731014">{{cite journal |vauthors=Hendy GN, Canaff L, Newfield RS, Tripto-Shkolnik L, Wong BY, Lee BS, Cole DE |title=Codon Arg15 mutations of the AP2S1 gene: common occurrence in familial hypocalciuric hypercalcemia cases negative for calcium-sensing receptor (CASR) mutations |journal=J. Clin. Endocrinol. Metab. |volume=99 |issue=7 |pages=E1311–5 |year=2014 |pmid=24731014 |doi=10.1210/jc.2014-1120 |url=}}</ref><ref name="pmid26646938">{{cite journal |vauthors=Mayr B, Schnabel D, Dörr HG, Schöfl C |title=GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts |journal=Eur. J. Endocrinol. |volume=174 |issue=5 |pages=R189–208 |year=2016 |pmid=26646938 |doi=10.1530/EJE-15-1028 |url=}}</ref>. | |||
* The calcium-sensing receptor is | ===Genetic Causes=== | ||
* CASR has the ability to sense small changes in circulating calcium concentration and send this information that | *FHH is caused by a mutation in the CASR gene located on chromosome 3<ref name="pmid11013439">{{cite journal |vauthors=Hendy GN, D'Souza-Li L, Yang B, Canaff L, Cole DE |title=Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia |journal=Hum. Mutat. |volume=16 |issue=4 |pages=281–96 |year=2000 |pmid=11013439 |doi=10.1002/1098-1004(200010)16:4<281::AID-HUMU1>3.0.CO;2-A |url=}}</ref>. | ||
* Inherited abnormalities of the CASR gene | * 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. | |||
* A common polymorphism in the intracellular tail of the CASR, Ala to Ser at position 986, has a modest effect on the serum calcium concentration in healthy individuals<ref name="pmid11013439">{{cite journal |vauthors=Hendy GN, D'Souza-Li L, Yang B, Canaff L, Cole DE |title=Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia |journal=Hum. Mutat. |volume=16 |issue=4 |pages=281–96 |year=2000 |pmid=11013439 |doi=10.1002/1098-1004(200010)16:4<281::AID-HUMU1>3.0.CO;2-A |url=}}</ref><ref name="pmid15241791">{{cite journal |vauthors=Pidasheva S, D'Souza-Li L, Canaff L, Cole DE, Hendy GN |title=CASRdb: calcium-sensing receptor locus-specific database for mutations causing familial (benign) hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia |journal=Hum. Mutat. |volume=24 |issue=2 |pages=107–11 |year=2004 |pmid=15241791 |doi=10.1002/humu.20067 |url=}}</ref><ref name="pmid15662592">{{cite journal |vauthors=Felderbauer P, Hoffmann P, Klein W, Bulut K, Ansorge N, Epplen JT, Schmitz F, Schmidt WE |title=Identification of a novel calcium-sensing receptor gene mutation causing familial hypocalciuric hypercalcemia by single-strand conformation polymorphism analysis |journal=Exp. Clin. Endocrinol. Diabetes |volume=113 |issue=1 |pages=31–4 |year=2005 |pmid=15662592 |doi=10.1055/s-2004-830523 |url=}}</ref>. | |||
==Who is at Highest Risk?== | ==Who is at Highest Risk?== | ||
==Diagnosis== | ==Diagnosis== | ||
==When to Seek Urgent Medical Care?== | ==When to Seek Urgent Medical Care?== | ||
==Treatment Options== | ==Treatment Options== | ||
==Medical Therapy== | ==Medical Therapy== | ||
There is no treatment for FHH as it is a benign condition. However, the avoidance of parathyroidectomy should be emphasized to the FHH diagnosed patients. | There is no treatment for FHH as it is a benign condition. However, the avoidance of parathyroidectomy should be emphasized to the FHH diagnosed patients<ref name="pmid3977197">{{cite journal |vauthors=Law WM, Heath H |title=Familial benign hypercalcemia (hypocalciuric hypercalcemia). Clinical and pathogenetic studies in 21 families |journal=Ann. Intern. Med. |volume=102 |issue=4 |pages=511–9 |year=1985 |pmid=3977197 |doi= |url=}}</ref><ref name="pmid2673770">{{cite journal |vauthors=Heath H |title=Familial benign (hypocalciuric) hypercalcemia. A troublesome mimic of mild primary hyperparathyroidism |journal=Endocrinol. Metab. Clin. North Am. |volume=18 |issue=3 |pages=723–40 |year=1989 |pmid=2673770 |doi= |url=}}</ref>. | ||
==Surgery== | ==Surgery== | ||
| Line 50: | Line 54: | ||
===Indications=== | ===Indications=== | ||
Parathyroidectomy in FHH is rarely done in patients if associated conditions are present along with the FHH such as | Parathyroidectomy in FHH is rarely done in patients if associated conditions are present along with the FHH such as<ref name="pmid19423559">{{cite journal |vauthors=Brachet C, Boros E, Tenoutasse S, Lissens W, Andry G, Martin P, Bergmann P, Heinrichs C |title=Association of parathyroid adenoma and familial hypocalciuric hypercalcaemia in a teenager |journal=Eur. J. Endocrinol. |volume=161 |issue=1 |pages=207–10 |year=2009 |pmid=19423559 |doi=10.1530/EJE-09-0257 |url=}}</ref><ref name="pmid10843194">{{cite journal |vauthors=Carling T, Szabo E, Bai M, Ridefelt P, Westin G, Gustavsson P, Trivedi S, Hellman P, Brown EM, Dahl N, Rastad J |title=Familial hypercalcemia and hypercalciuria caused by a novel mutation in the cytoplasmic tail of the calcium receptor |journal=J. Clin. Endocrinol. Metab. |volume=85 |issue=5 |pages=2042–7 |year=2000 |pmid=10843194 |doi=10.1210/jcem.85.5.6477 |url=}}</ref> | ||
* [[Parathyroid adenoma]] | * [[Parathyroid adenoma]] | ||
* [[Pancreatitis]] | * [[Pancreatitis]] | ||
| Line 57: | Line 61: | ||
==Where to find Medical Care for Familial hypocalciuric hypercalcemia?== | ==Where to find Medical Care for Familial hypocalciuric hypercalcemia?== | ||
Call for an appointment with your healthcare provider if you have symptoms of hypercalcemia. | |||
==Prevention== | ==Prevention== | ||
| Line 63: | Line 67: | ||
==What to Expect (Outlook/Prognosis)?== | ==What to Expect (Outlook/Prognosis)?== | ||
==Possible Complications== | ==Possible Complications== | ||
| Line 81: | Line 84: | ||
{{WH}} | {{WH}} | ||
{{WS}} | {{WS}} | ||
Revision as of 03:30, 22 September 2017
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Familial hypocalciuric hypercalcemia |
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Where to find medical care for Familial hypocalciuric hypercalcemia? |
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For the WikiDoc page for this topic, click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Overview
Familial hypocalciuric hypercalcemia is an autosomal dominant inherited disorder characterized by asymptomatic hypercalcemia and low urinary calcium.
What are the Symptoms of Familial hypocalciuric hypercalcemia?
The majority of patients with FHH are asymptomatic.However, FHH can present with signs and symptoms of hypercalcemia such as:
- Constipation
- Polyuria
- Polydipsia
- Anorexia
- Anhedonia
- Abdominal pain
- Muscle weakness
- Confusion
- Fatigue
- Neuropsychiatric symptoms[1].
What Causes Familial hypocalciuric hypercalcemia?
FHH is an autosomal dominant benign inherited condition caused by inactivating missense mutation of the CASR located on chromosome 3q[2][3]. 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[4][5].
- Type-2: caused by heterozygous mutation in the GNA11 gene on chromosome 19p13[6].
- Type-3: caused by heterozygous mutation in the AP2S1 gene on chromosome 19q13[7][8].
Genetic Causes
- FHH is caused by a mutation in the CASR gene located on chromosome 3[9].
- 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.
- A common polymorphism in the intracellular tail of the CASR, Ala to Ser at position 986, has a modest effect on the serum calcium concentration in healthy individuals[9][10][11].
Who is at Highest Risk?
Diagnosis
When to Seek Urgent Medical Care?
Treatment Options
Medical Therapy
There is no treatment for FHH as it is a benign condition. However, the avoidance of parathyroidectomy should be emphasized to the FHH diagnosed patients[12][13].
Surgery
Surgical intervention is not recommended for the management of FHH.
Indications
Parathyroidectomy in FHH is rarely done in patients if associated conditions are present along with the FHH such as[14][15]
- Parathyroid adenoma
- Pancreatitis
- Hyperparathyroidism
- Hypercalciuria
Where to find Medical Care for Familial hypocalciuric hypercalcemia?
Call for an appointment with your healthcare provider if you have symptoms of hypercalcemia.
Prevention
There are no established measures for the primary or secondary prevention of familial hypocalciuric hypercalcemia.
What to Expect (Outlook/Prognosis)?
Possible Complications
Very rarely FHH can cause complications secondary to hypercalcemia, which includes:
- Urinary tract infection due to kidney stones and blockage
- Peptic ulcer disease
- Pancreatitis
- Pseudogout
Sources
http://www.nlm.nih.gov/medlineplus/ency/article/000434.htm
- ↑ Whitcomb DC (2010). "Genetic aspects of pancreatitis". Annu. Rev. Med. 61: 413–24. doi:10.1146/annurev.med.041608.121416. PMID 20059346.
- ↑ Stratta P, Merlotti G, Musetti C, Quaglia M, Pagani A, Izzo C, Radin E, Airoldi A, Baorda F, Palladino T, Leone MP, Guarnieri V (2014). "Calcium-sensing-related gene mutations in hypercalcaemic hypocalciuric patients as differential diagnosis from primary hyperparathyroidism: detection of two novel inactivating mutations in an Italian population". Nephrol. Dial. Transplant. 29 (10): 1902–9. doi:10.1093/ndt/gfu065. PMID 25104082.
- ↑ Vargas-Poussou R, Mansour-Hendili L, Baron S, Bertocchio JP, Travers C, Simian C, Treard C, Baudouin V, Beltran S, Broux F, Camard O, Cloarec S, Cormier C, Debussche X, Dubosclard E, Eid C, Haymann JP, Kiando SR, Kuhn JM, Lefort G, Linglart A, Lucas-Pouliquen B, Macher MA, Maruani G, Ouzounian S, Polak M, Requeda E, Robier D, Silve C, Souberbielle JC, Tack I, Vezzosi D, Jeunemaitre X, Houillier P (2016). "Familial Hypocalciuric Hypercalcemia Types 1 and 3 and Primary Hyperparathyroidism: Similarities and Differences". J. Clin. Endocrinol. Metab. 101 (5): 2185–95. doi:10.1210/jc.2015-3442. PMID 26963950.
- ↑ Gorvin CM, Cranston T, Hannan FM, Rust N, Qureshi A, Nesbit MA, Thakker RV (2016). "A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2)". J. Bone Miner. Res. 31 (6): 1200–6. doi:10.1002/jbmr.2778. PMC 4949650. PMID 26729423.
- ↑ Nesbit MA, Hannan FM, Howles SA, Babinsky VN, Head RA, Cranston T, Rust N, Hobbs MR, Heath H, Thakker RV (2013). "Mutations affecting G-protein subunit α11 in hypercalcemia and hypocalcemia". N. Engl. J. Med. 368 (26): 2476–2486. doi:10.1056/NEJMoa1300253. PMC 3773604. PMID 23802516.
- ↑ Szalat A, Shpitzen S, Tsur A, Zalmon Koren I, Shilo S, Tripto-Shkolnik L, Durst R, Leitersdorf E, Meiner V (2017). "Stepwise CaSR, AP2S1, and GNA11 sequencing in patients with suspected familial hypocalciuric hypercalcemia". Endocrine. 55 (3): 741–747. doi:10.1007/s12020-017-1241-5. PMID 28176280.
- ↑ Hendy GN, Canaff L, Newfield RS, Tripto-Shkolnik L, Wong BY, Lee BS, Cole DE (2014). "Codon Arg15 mutations of the AP2S1 gene: common occurrence in familial hypocalciuric hypercalcemia cases negative for calcium-sensing receptor (CASR) mutations". J. Clin. Endocrinol. Metab. 99 (7): E1311–5. doi:10.1210/jc.2014-1120. PMID 24731014.
- ↑ Mayr B, Schnabel D, Dörr HG, Schöfl C (2016). "GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts". Eur. J. Endocrinol. 174 (5): R189–208. doi:10.1530/EJE-15-1028. PMID 26646938.
- ↑ 9.0 9.1 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 (4): 281–96. doi:10.1002/1098-1004(200010)16:4<281::AID-HUMU1>3.0.CO;2-A. PMID 11013439.
- ↑ Pidasheva S, D'Souza-Li L, Canaff L, Cole DE, Hendy GN (2004). "CASRdb: calcium-sensing receptor locus-specific database for mutations causing familial (benign) hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia". Hum. Mutat. 24 (2): 107–11. doi:10.1002/humu.20067. PMID 15241791.
- ↑ Felderbauer P, Hoffmann P, Klein W, Bulut K, Ansorge N, Epplen JT, Schmitz F, Schmidt WE (2005). "Identification of a novel calcium-sensing receptor gene mutation causing familial hypocalciuric hypercalcemia by single-strand conformation polymorphism analysis". Exp. Clin. Endocrinol. Diabetes. 113 (1): 31–4. doi:10.1055/s-2004-830523. PMID 15662592.
- ↑ Law WM, Heath H (1985). "Familial benign hypercalcemia (hypocalciuric hypercalcemia). Clinical and pathogenetic studies in 21 families". Ann. Intern. Med. 102 (4): 511–9. PMID 3977197.
- ↑ Heath H (1989). "Familial benign (hypocalciuric) hypercalcemia. A troublesome mimic of mild primary hyperparathyroidism". Endocrinol. Metab. Clin. North Am. 18 (3): 723–40. PMID 2673770.
- ↑ Brachet C, Boros E, Tenoutasse S, Lissens W, Andry G, Martin P, Bergmann P, Heinrichs C (2009). "Association of parathyroid adenoma and familial hypocalciuric hypercalcaemia in a teenager". Eur. J. Endocrinol. 161 (1): 207–10. doi:10.1530/EJE-09-0257. PMID 19423559.
- ↑ 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 (5): 2042–7. doi:10.1210/jcem.85.5.6477. PMID 10843194.