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Familial hypocalciuric hypercalcemia 2(FBH2; HHC2)

MedGen UID:
374447
•Concept ID:
C1840347
•
Disease or Syndrome
Synonyms: Familial benign hypercalcemia, type 2; FAMILIAL BENIGN HYPERCALCEMIA, TYPE II; Hypocalciuric hypercalcemia, familial, type II; Hypocalciuric hypercalcemia, type II
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
•Concept ID:
C0443147
•
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal dominant inheritance (Orphanet)
 
Gene (location): GNA11 (19p13.3)
 
Monarch Initiative: MONDO:0007792
OMIM®: 145981
Orphanet: ORPHA101049

Definition

Familial hypocalciuric hypercalcemia type II (HHC2) is an autosomal dominant disorder characterized by lifelong elevations of serum calcium concentrations with low urinary calcium excretion and normal circulating parathyroid hormone concentrations in most patients. Patients are generally asymptomatic (summary by Nesbit et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of hypocalciuric hypercalcemia, see HHC1 (145980). [from OMIM]

Clinical features

From HPO
Multiple lipomas
MedGen UID:
677074
•Concept ID:
C0745730
•
Finding
The presence of multiple lipomas (a type of benign tissue made of fatty tissue).
See: Feature record | Search on this feature
Hypocalciuria
MedGen UID:
9381
•Concept ID:
C0020599
•
Disease or Syndrome
An abnormally decreased calcium concentration in the urine.
See: Feature record | Search on this feature
Nephrolithiasis
MedGen UID:
98227
•Concept ID:
C0392525
•
Disease or Syndrome
The presence of calculi (stones) in the kidneys.
See: Feature record | Search on this feature
Parathormone-independent increased renal tubular calcium reabsorption
MedGen UID:
871133
•Concept ID:
C4025604
•
Finding
An increase in the reabsorption of calcium by the renal tubulus that is not associated with increased parathormone levels.
See: Feature record | Search on this feature
Peptic ulcer
MedGen UID:
45384
•Concept ID:
C0030920
•
Disease or Syndrome
The term peptic ulcer refers to acid peptic injury of the digestive tract, resulting in mucosal break reaching the submucosa. Peptic ulcers are usually located in the stomach or proximal duodenum, but they can also be found in the esophagus or Meckel's diverticulum. Infection with Helicobacter pylori and the use of non steroidal antiinflammatory drugs (NSAIDs) or aspirin are the main risk factors of both gastric and duodenal peptic ulcers.
See: Feature record | Search on this feature
Chondrocalcinosis
MedGen UID:
154303
•Concept ID:
C0553730
•
Disease or Syndrome
Radiographic evidence of articular calcification that represent calcium pyrophosphate depositions in soft tissue surrounding joints and at the insertions of tendons near joints (Entheses/Sharpey fibers) .
See: Feature record | Search on this feature
Pancreatitis
MedGen UID:
14586
•Concept ID:
C0030305
•
Disease or Syndrome
The presence of inflammation in the pancreas.
See: Feature record | Search on this feature
Hypercalcemia
MedGen UID:
5686
•Concept ID:
C0020437
•
Disease or Syndrome
An abnormally increased calcium concentration in the blood.
See: Feature record | Search on this feature
Hypermagnesemia
MedGen UID:
312005
•Concept ID:
C1522135
•
Finding
An abnormally increased magnesium concentration in the blood.
See: Feature record | Search on this feature
Primary hyperparathyroidism
MedGen UID:
66354
•Concept ID:
C0221002
•
Disease or Syndrome
A type of hyperparathyroidism caused by a primary abnormality of the parathyroid glands (e.g., adenoma, carcinoma, hyperplasia). Primary hyperparathyroidism is associated with hyercalcemia.
See: Feature record | Search on this feature
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Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVFamilial hypocalciuric hypercalcemia 2

Professional guidelines

PubMed

Genetic testing for familial hyperparathyroidism: clinical-genetic profile in a Mediterranean cohort.
Mazarico-Altisent I, Capel I, Baena N, Bella-Cueto MR, Barcons S, Guirao X, Pareja R, Muntean A, Arsentales V, Caixàs A, Rigla M
Front Endocrinol (Lausanne) 2023;14:1244361. Epub 2023 Sep 21 doi: 10.3389/fendo.2023.1244361. PMID: 37810884Free PMC Article
European Expert Consensus on Practical Management of Specific Aspects of Parathyroid Disorders in Adults and in Pregnancy: Recommendations of the ESE Educational Program of Parathyroid Disorders.
Bollerslev J, Rejnmark L, Zahn A, Heck A, Appelman-Dijkstra NM, Cardoso L, Hannan FM, Cetani F, Sikjær T, Formenti AM, Björnsdottir S, Schalin-Jantti C, Belaya Z, Gibb FW, Lapauw B, Amrein K, Wicke C, Grasemann C, Krebs M, Ryhänen EM, Makay O, Minisola S, Gaujoux S, Bertocchio JP, Hassan-Smith ZK, Linglart A, Winter EM, Kollmann M, Zmierczak HG, Tsourdi E, Pilz S, Siggelkow H, Gittoes NJ, Marcocci C, Kamenicky P; 2021 PARAT Working Group
Eur J Endocrinol 2022 Feb 1;186(2):R33-R63. Epub 2022 Jan 13 doi: 10.1530/EJE-21-1044. [Epub ahead of print] PMID: 34863037Free PMC Article
Is routine 24-hour urine calcium measurement useful during the evaluation of primary hyperparathyroidism?
Li SR, McCoy KL, Levitt HE, Kelley ML, Carty SE, Yip L
Surgery 2022 Jan;171(1):17-22. Epub 2021 Jul 27 doi: 10.1016/j.surg.2021.04.055. PMID: 34325903Free PMC Article

Recent clinical studies

Etiology

Genetic testing for familial hyperparathyroidism: clinical-genetic profile in a Mediterranean cohort.
Mazarico-Altisent I, Capel I, Baena N, Bella-Cueto MR, Barcons S, Guirao X, Pareja R, Muntean A, Arsentales V, Caixàs A, Rigla M
Front Endocrinol (Lausanne) 2023;14:1244361. Epub 2023 Sep 21 doi: 10.3389/fendo.2023.1244361. PMID: 37810884Free PMC Article
Personalised medicines for familial hypercalcemia and hyperparathyroidism.
Josephs TM, Zhang F, Dinh LV, Keller AN, Conigrave AD, Capuano B, Gregory KJ, Leach K
J Mol Endocrinol 2022 May 9;69(1):243-257. doi: 10.1530/JME-21-0263. PMID: 35318962
European Expert Consensus on Practical Management of Specific Aspects of Parathyroid Disorders in Adults and in Pregnancy: Recommendations of the ESE Educational Program of Parathyroid Disorders.
Bollerslev J, Rejnmark L, Zahn A, Heck A, Appelman-Dijkstra NM, Cardoso L, Hannan FM, Cetani F, Sikjær T, Formenti AM, Björnsdottir S, Schalin-Jantti C, Belaya Z, Gibb FW, Lapauw B, Amrein K, Wicke C, Grasemann C, Krebs M, Ryhänen EM, Makay O, Minisola S, Gaujoux S, Bertocchio JP, Hassan-Smith ZK, Linglart A, Winter EM, Kollmann M, Zmierczak HG, Tsourdi E, Pilz S, Siggelkow H, Gittoes NJ, Marcocci C, Kamenicky P; 2021 PARAT Working Group
Eur J Endocrinol 2022 Feb 1;186(2):R33-R63. Epub 2022 Jan 13 doi: 10.1530/EJE-21-1044. [Epub ahead of print] PMID: 34863037Free PMC Article
The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases.
Hannan FM, Kallay E, Chang W, Brandi ML, Thakker RV
Nat Rev Endocrinol 2018 Dec;15(1):33-51. doi: 10.1038/s41574-018-0115-0. PMID: 30443043Free PMC Article
Parathyroid glands in familial benign hypercalcemia (familial hypocalciuric hypercalcemia).
Law WM Jr, Carney JA, Heath H 3rd
Am J Med 1984 Jun;76(6):1021-6. doi: 10.1016/0002-9343(84)90852-0. PMID: 6731460

Diagnosis

European Expert Consensus on Practical Management of Specific Aspects of Parathyroid Disorders in Adults and in Pregnancy: Recommendations of the ESE Educational Program of Parathyroid Disorders.
Bollerslev J, Rejnmark L, Zahn A, Heck A, Appelman-Dijkstra NM, Cardoso L, Hannan FM, Cetani F, Sikjær T, Formenti AM, Björnsdottir S, Schalin-Jantti C, Belaya Z, Gibb FW, Lapauw B, Amrein K, Wicke C, Grasemann C, Krebs M, Ryhänen EM, Makay O, Minisola S, Gaujoux S, Bertocchio JP, Hassan-Smith ZK, Linglart A, Winter EM, Kollmann M, Zmierczak HG, Tsourdi E, Pilz S, Siggelkow H, Gittoes NJ, Marcocci C, Kamenicky P; 2021 PARAT Working Group
Eur J Endocrinol 2022 Feb 1;186(2):R33-R63. Epub 2022 Jan 13 doi: 10.1530/EJE-21-1044. [Epub ahead of print] PMID: 34863037Free PMC Article
Familial Hypocalciuric Hypercalcemia and Neonatal Severe Hyperparathyroidism.
Vannucci L, Brandi ML
Front Horm Res 2019;51:52-62. Epub 2018 Nov 19 doi: 10.1159/000491038. PMID: 30641521
Familial hypocalciuric hypercalcemia and related disorders.
Lee JY, Shoback DM
Best Pract Res Clin Endocrinol Metab 2018 Oct;32(5):609-619. Epub 2018 May 26 doi: 10.1016/j.beem.2018.05.004. PMID: 30449544Free PMC Article
Calcimimetic Use in Familial Hypocalciuric Hypercalcemia-A Perspective in Endocrinology.
Marx SJ
J Clin Endocrinol Metab 2017 Nov 1;102(11):3933-3936. doi: 10.1210/jc.2017-01606. PMID: 28945857Free PMC Article
Investigation of hypercalcemia.
Endres DB
Clin Biochem 2012 Aug;45(12):954-63. Epub 2012 May 5 doi: 10.1016/j.clinbiochem.2012.04.025. PMID: 22569596

Therapy

Cinacalcet Reverses Short QT Interval in Familial Hypocalciuric Hypercalcemia Type 1.
Cuny T, Romanet P, Goldsworthy M, Guérin C, Wilkin M, Roche P, Sebag F, van Summeren LE, Stevenson M, Howles SA, Deharo JC, Thakker RV, Taïeb D
J Clin Endocrinol Metab 2024 Jan 18;109(2):549-556. doi: 10.1210/clinem/dgad494. PMID: 37602721Free PMC Article
Cinacalcet therapy in a child with novel homozygous CASR p.Glu353Lys mutation causing familial hypocalciuric hypercalcemia type 1: case report and review of the literature.
Koca SB
Turk J Pediatr 2023;65(5):853-861. doi: 10.24953/turkjped.2022.1040. PMID: 37853976
Personalised medicines for familial hypercalcemia and hyperparathyroidism.
Josephs TM, Zhang F, Dinh LV, Keller AN, Conigrave AD, Capuano B, Gregory KJ, Leach K
J Mol Endocrinol 2022 May 9;69(1):243-257. doi: 10.1530/JME-21-0263. PMID: 35318962
The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases.
Hannan FM, Kallay E, Chang W, Brandi ML, Thakker RV
Nat Rev Endocrinol 2018 Dec;15(1):33-51. doi: 10.1038/s41574-018-0115-0. PMID: 30443043Free PMC Article
Calcimimetic Use in Familial Hypocalciuric Hypercalcemia-A Perspective in Endocrinology.
Marx SJ
J Clin Endocrinol Metab 2017 Nov 1;102(11):3933-3936. doi: 10.1210/jc.2017-01606. PMID: 28945857Free PMC Article

Prognosis

Genetics of hereditary forms of primary hyperparathyroidism.
English KA, Lines KE, Thakker RV
Hormones (Athens) 2024 Mar;23(1):3-14. Epub 2023 Dec 1 doi: 10.1007/s42000-023-00508-9. PMID: 38038882Free PMC Article
European Expert Consensus on Practical Management of Specific Aspects of Parathyroid Disorders in Adults and in Pregnancy: Recommendations of the ESE Educational Program of Parathyroid Disorders.
Bollerslev J, Rejnmark L, Zahn A, Heck A, Appelman-Dijkstra NM, Cardoso L, Hannan FM, Cetani F, Sikjær T, Formenti AM, Björnsdottir S, Schalin-Jantti C, Belaya Z, Gibb FW, Lapauw B, Amrein K, Wicke C, Grasemann C, Krebs M, Ryhänen EM, Makay O, Minisola S, Gaujoux S, Bertocchio JP, Hassan-Smith ZK, Linglart A, Winter EM, Kollmann M, Zmierczak HG, Tsourdi E, Pilz S, Siggelkow H, Gittoes NJ, Marcocci C, Kamenicky P; 2021 PARAT Working Group
Eur J Endocrinol 2022 Feb 1;186(2):R33-R63. Epub 2022 Jan 13 doi: 10.1530/EJE-21-1044. [Epub ahead of print] PMID: 34863037Free PMC Article
Familial Hypocalciuric Hypercalcemia and Neonatal Severe Hyperparathyroidism.
Vannucci L, Brandi ML
Front Horm Res 2019;51:52-62. Epub 2018 Nov 19 doi: 10.1159/000491038. PMID: 30641521
Familial hypocalciuric hypercalcemia and related disorders.
Lee JY, Shoback DM
Best Pract Res Clin Endocrinol Metab 2018 Oct;32(5):609-619. Epub 2018 May 26 doi: 10.1016/j.beem.2018.05.004. PMID: 30449544Free PMC Article
The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases.
Hannan FM, Kallay E, Chang W, Brandi ML, Thakker RV
Nat Rev Endocrinol 2018 Dec;15(1):33-51. doi: 10.1038/s41574-018-0115-0. PMID: 30443043Free PMC Article

Clinical prediction guides

Genetic testing for familial hyperparathyroidism: clinical-genetic profile in a Mediterranean cohort.
Mazarico-Altisent I, Capel I, Baena N, Bella-Cueto MR, Barcons S, Guirao X, Pareja R, Muntean A, Arsentales V, Caixàs A, Rigla M
Front Endocrinol (Lausanne) 2023;14:1244361. Epub 2023 Sep 21 doi: 10.3389/fendo.2023.1244361. PMID: 37810884Free PMC Article
GNA11 Variants Identified in Patients with Hypercalcemia or Hypocalcemia.
Howles SA, Gorvin CM, Cranston T, Rogers A, Gluck AK, Boon H, Gibson K, Rahman M, Root A, Nesbit MA, Hannan FM, Thakker RV
J Bone Miner Res 2023 Jun;38(6):907-917. Epub 2023 Apr 18 doi: 10.1002/jbmr.4803. PMID: 36970776Free PMC Article
Neurodevelopmental Abnormalities in Patients with Familial Hypocalciuric Hypercalcemia Type 3.
Chinoy A, Nicholson J, Skae M, Hannan FM, Thakker RV, Mughal MZ, Padidela R
J Pediatr 2023 Jun;257:113367. Epub 2023 Mar 2 doi: 10.1016/j.jpeds.2023.02.013. PMID: 36868303
European Expert Consensus on Practical Management of Specific Aspects of Parathyroid Disorders in Adults and in Pregnancy: Recommendations of the ESE Educational Program of Parathyroid Disorders.
Bollerslev J, Rejnmark L, Zahn A, Heck A, Appelman-Dijkstra NM, Cardoso L, Hannan FM, Cetani F, Sikjær T, Formenti AM, Björnsdottir S, Schalin-Jantti C, Belaya Z, Gibb FW, Lapauw B, Amrein K, Wicke C, Grasemann C, Krebs M, Ryhänen EM, Makay O, Minisola S, Gaujoux S, Bertocchio JP, Hassan-Smith ZK, Linglart A, Winter EM, Kollmann M, Zmierczak HG, Tsourdi E, Pilz S, Siggelkow H, Gittoes NJ, Marcocci C, Kamenicky P; 2021 PARAT Working Group
Eur J Endocrinol 2022 Feb 1;186(2):R33-R63. Epub 2022 Jan 13 doi: 10.1530/EJE-21-1044. [Epub ahead of print] PMID: 34863037Free PMC Article
Mutations in the human Ca(2+)-sensing-receptor gene that cause familial hypocalciuric hypercalcemia.
Chou YH, Pollak MR, Brandi ML, Toss G, Arnqvist H, Atkinson AB, Papapoulos SE, Marx S, Brown EM, Seidman JG
Am J Hum Genet 1995 May;56(5):1075-9. PMID: 7726161Free PMC Article

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      Clinical tests in GTR
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