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| {{CMG}}; {{AE}} {{Ajay}} | | {{CMG}}; {{AE}} {{Ajay}} |
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| {{SK}} | | {{SK}} FHH, Familial benign hypocalciuric hypercalcemia, Hypercalcemia |
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| ==[[Familial hypocalciuric hypercalcemia overview|Overview]]== | | ==[[Familial hypocalciuric hypercalcemia overview|Overview]]== |
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| ==[[Familial hypocalciuric hypercalcemia classification|Classification]]== | | ==[[Familial hypocalciuric hypercalcemia classification|Classification]]== |
| Three genetically heterogeneous variants are reported so far for familial hypocalciuric hypercalcemia.
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| Type 1 - due to loss-of-functional mutations of the calcium-sensing receptor (encoded by CASR). Type 2 - unknown cause.
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| Type 3 - associated with adaptor-related protein complex 2, sigma 1 subunit (AP2S1) mutations, which alter calcium-sensing receptor endocytosis<ref name="pmid1682230">{{cite journal |vauthors=Garioch JJ, Mackie RM, Campbell I, Forsyth A |title=Keratinocyte expression of intercellular adhesion molecule 1 (ICAM-1) correlated with infiltration of lymphocyte function associated antigen 1 (LFA-1) positive cells in evolving allergic contact dermatitis reactions |journal=Histopathology |volume=19 |issue=4 |pages=351–4 |year=1991 |pmid=1682230 |doi= |url=}}</ref><ref name="urlMutations Affecting G-Protein Subunit α11 in Hypercalcemia and Hypocalcemia — NEJM">{{cite web |url=http://www.nejm.org/doi/full/10.1056/NEJMoa1300253#t=article |title=Mutations Affecting G-Protein Subunit α11 in Hypercalcemia and Hypocalcemia — NEJM |format= |work= |accessdate=}}</ref>
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| ==[[Familial hypocalciuric hypercalcemia pathophysiology|Pathophysiology]]== | | ==[[Familial hypocalciuric hypercalcemia pathophysiology|Pathophysiology]]== |
| The pathophysiology of [Familial hypocalciuric hypercalcemia] is due to an inactivating missense mutation in the calcium sensing receptor (CaSR)<ref name="urlMarkedly reduced activity of mutant calcium-sensing receptor with an inserted Alu element from a kindred with familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.">{{cite web |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC508016/ |title=Markedly reduced activity of mutant calcium-sensing receptor with an inserted Alu element from a kindred with familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. |format= |work= |accessdate=}}</ref><ref name="urlRecent advances in understanding the extracellular calcium-sensing receptor">{{cite web |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5074356/ |title=Recent advances in understanding the extracellular calcium-sensing receptor |format= |work= |accessdate=}}</ref><ref name="pmid8317484">{{cite journal |vauthors=Heath H, Jackson CE, Otterud B, Leppert MF |title=Genetic linkage analysis in familial benign (hypocalciuric) hypercalcemia: evidence for locus heterogeneity |journal=Am. J. Hum. Genet. |volume=53 |issue=1 |pages=193–200 |year=1993 |pmid=8317484 |pmc=1682230 |doi= |url=}}</ref> located on the short arm of the chromosome 3 (FBHH3q)<ref name="urlMutations in the calcium-sensing receptor and their clinical implications. - PubMed - NCBI">{{cite web |url=https://www.ncbi.nlm.nih.gov/pubmed/9362389 |title=Mutations in the calcium-sensing receptor and their clinical implications. - PubMed - NCBI |format= |work= |accessdate=}}</ref>. The mutation of CaSR is associated with two inherited conditions FBHH and neonatal hyperparathyroidism<ref name="urlMutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. - PubMed - NCBI">{{cite web |url=https://www.ncbi.nlm.nih.gov/pubmed/7916660 |title=Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. - PubMed - NCBI |format= |work= |accessdate=}}</ref>. 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.
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| ==[[Familial hypocalciuric hypercalcemia causes|Causes]]== | | ==[[Familial hypocalciuric hypercalcemia causes|Causes]]== |
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| ==[[Familial hypocalciuric hypercalcemia differential diagnosis|Differentiating Xyz from other Diseases]]== | | ==[[Familial hypocalciuric hypercalcemia differential diagnosis|Differentiating Familial Hypocalciuric Hypercalcemia from other Diseases]]== |
| Familial hypocalciuric hypercalcemia should be differentiated from other causes of hypercalcemia. Causes of hypercalcemia include:
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| Parathyroid-related
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| Hyperparathyroidism
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| Primary hyperparathyroidism
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| Secondary hyperparathyroidism
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| Tertiary hyperparathyroidism
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| Familial hypocalciuric hypercalcemia
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| Non-parathyroid related
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| Malignancy
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| Humoral hypercalcemia of malignancy
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| Osteolytic tumors
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| Production of calcitriol by tumors
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| Ectopic parathyroid hormone production
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| Medication-induced
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| Thiazide diuretics
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| Lithium
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| Nutritional
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| Milk-alkali syndrome
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| Vitamin D toxicity
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| Granulomatous disease
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| Sarcoidosis
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| Surgical
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| Immobilization
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| ==[[Familial hypocalciuric hypercalcemia epidemiology and demographics|Epidemiology and Demographics]]== | | ==[[Familial hypocalciuric hypercalcemia epidemiology and demographics|Epidemiology and Demographics]]== |
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| ==[[Familial hypocalciuric hypercalcemia screening|Screening]]== | | ==[[Familial hypocalciuric hypercalcemia screening|Screening]]== |
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| Prenatal testing for FHH is not recommended routinely.
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| In both parents with type-1 FHH their offsprings are screened for CASR mutation<ref name="pmid21697018">{{cite journal |vauthors=Fernández López I, Fernández Peña I, Cózar León MV, Viloria Peñas MM, Martínez De Pinillos Gordillo G, Fernández-Ladreda MT, Duran García S |title=[Usefulness of genetic tests in familial hypocalciuric hypercalcemia with atypical clinical presentation] |language=Spanish; Castilian |journal=Endocrinol Nutr |volume=58 |issue=7 |pages=325–30 |year=2011 |pmid=21697018 |doi=10.1016/j.endonu.2011.04.004 |url=}}</ref>.
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| Genetic screening for the CASR familial mutation is also offered to family members of affected individuals, CaSR and AP2S1 sequencing is done in patients with familial hyperparathyroidism and phenotype suggesting FHH. GNA11 mutations seem much rarer.
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| Learning disabilities in these patients, associated with higher serum calcium and magnesium levels may suggest the presence of AP2S1 rather than CaSR mutation and may guide the first step in the genetic evaluation.<ref name="pmid21697018">{{cite journal |vauthors=Fernández López I, Fernández Peña I, Cózar León MV, Viloria Peñas MM, Martínez De Pinillos Gordillo G, Fernández-Ladreda MT, Duran García S |title=[Usefulness of genetic tests in familial hypocalciuric hypercalcemia with atypical clinical presentation] |language=Spanish; Castilian |journal=Endocrinol Nutr |volume=58 |issue=7 |pages=325–30 |year=2011 |pmid=21697018 |doi=10.1016/j.endonu.2011.04.004 |url=}}</ref><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>.
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| ==[[Familial hypocalciuric hypercalcemia natural history, complications and prognosis|Natural History, Complications and Prognosis]]== | | ==[[Familial hypocalciuric hypercalcemia natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |