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Familial hypocalciuric hypercalcemia 3(FBH3; HHC3)

MedGen UID:
322173
Concept ID:
C1833372
Disease or Syndrome
Synonyms: Familial benign hypercalcemia, Oklahoma variant; Familial benign hypercalcemia, type 3; FAMILIAL BENIGN HYPERCALCEMIA, TYPE III; FBHOk; Hypercalcemia, familial benign, Oklahoma type; Hypocalciuric hypercalcemia, familial, type III; Hypocalciuric hypercalcemia, type III
 
Gene (location): AP2S1 (19q13.32)
 
Monarch Initiative: MONDO:0010926
OMIM®: 600740
Orphanet: ORPHA101050

Definition

Any familial hypocalciuric hypercalcemia in which the cause of the disease is a mutation in the AP2S1 gene. [from MONDO]

Clinical features

From HPO
Fatigue
MedGen UID:
41971
Concept ID:
C0015672
Sign or Symptom
A subjective feeling of tiredness characterized by a lack of energy and motivation.
Bone pain
MedGen UID:
57489
Concept ID:
C0151825
Sign or Symptom
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to bone.
Multiple lipomas
MedGen UID:
677074
Concept ID:
C0745730
Finding
The presence of multiple lipomas (a type of benign tissue made of fatty tissue).
Hypocalciuria
MedGen UID:
9381
Concept ID:
C0020599
Disease or Syndrome
An abnormally decreased calcium concentration in the urine.
Nephrolithiasis
MedGen UID:
98227
Concept ID:
C0392525
Disease or Syndrome
The presence of calculi (stones) in the kidneys.
Renal insufficiency
MedGen UID:
332529
Concept ID:
C1565489
Disease or Syndrome
A reduction in the level of performance of the kidneys in areas of function comprising the concentration of urine, removal of wastes, the maintenance of electrolyte balance, homeostasis of blood pressure, and calcium metabolism.
Multiple small medullary renal cysts
MedGen UID:
892386
Concept ID:
C4024644
Disease or Syndrome
The presence of many cysts in the medulla of the kidney.
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.
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.
Depression
MedGen UID:
4229
Concept ID:
C0011581
Mental or Behavioral Dysfunction
Frequently experiencing feelings of being down, miserable, and/or hopeless; struggling to recover from these moods; having a pessimistic outlook on the future; feeling a pervasive sense of shame; having a low self-worth; experiencing thoughts of suicide and engaging in suicidal behavior.
Headache
MedGen UID:
9149
Concept ID:
C0018681
Sign or Symptom
Cephalgia, or pain sensed in various parts of the head, not confined to the area of distribution of any nerve.
Osteomalacia
MedGen UID:
14533
Concept ID:
C0029442
Disease or Syndrome
Osteomalacia is a general term for bone weakness owing to a defect in mineralization of the protein framework known as osteoid. This defective mineralization is mainly caused by lack in vitamin D. Osteomalacia in children is known as rickets.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
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) .
Pancreatitis
MedGen UID:
14586
Concept ID:
C0030305
Disease or Syndrome
The presence of inflammation in the pancreas.
Hypercalcemia
MedGen UID:
5686
Concept ID:
C0020437
Disease or Syndrome
An abnormally increased calcium concentration in the blood.
Hypophosphatemia
MedGen UID:
39327
Concept ID:
C0085682
Disease or Syndrome
An abnormally decreased phosphate concentration in the blood.
Hypermagnesemia
MedGen UID:
312005
Concept ID:
C1522135
Finding
An abnormally increased magnesium concentration in the blood.
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.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVFamilial hypocalciuric hypercalcemia 3
Follow this link to review classifications for Familial hypocalciuric hypercalcemia 3 in Orphanet.

Professional guidelines

PubMed

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
Appelman-Dijkstra NM, Ertl DA, Zillikens MC, Rjenmark L, Winter EM
Endocrine 2021 Mar;71(3):604-610. Epub 2021 Feb 5 doi: 10.1007/s12020-021-02615-2. PMID: 33544354Free PMC Article
Bhangu JS, Selberherr A, Brammen L, Scheuba C, Riss P
Head Neck 2019 May;41(5):1372-1378. Epub 2018 Dec 15 doi: 10.1002/hed.25568. PMID: 30554440

Recent clinical studies

Etiology

Tőke J, Czirják G, Enyedi P, Tóth M
Endocrine 2021 Mar;71(3):611-617. Epub 2021 Feb 2 doi: 10.1007/s12020-021-02620-5. PMID: 33528764Free PMC Article
Dershem R, Gorvin CM, Metpally RPR, Krishnamurthy S, Smelser DT, Hannan FM, Carey DJ, Thakker RV, Breitwieser GE; Regeneron Genetics Center
Am J Hum Genet 2020 Jun 4;106(6):734-747. Epub 2020 May 7 doi: 10.1016/j.ajhg.2020.04.006. PMID: 32386559Free PMC Article
Hovden S, Rejnmark L, Ladefoged SA, Nissen PH
Eur J Endocrinol 2017 Feb;176(2):177-185. Epub 2016 Nov 15 doi: 10.1530/EJE-16-0842. PMID: 27913609
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
J Clin Endocrinol Metab 2016 May;101(5):2185-95. Epub 2016 Mar 10 doi: 10.1210/jc.2015-3442. PMID: 26963950
Brown EM
Endocrinol Metab Clin North Am 2000 Sep;29(3):503-22. doi: 10.1016/s0889-8529(05)70148-1. PMID: 11033758

Diagnosis

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
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
Lemoine S, Figueres L, Bacchetta J, Frey S, Dubourg L
Ann Endocrinol (Paris) 2022 Aug;83(4):237-243. Epub 2022 May 19 doi: 10.1016/j.ando.2022.05.003. PMID: 35598638
Appelman-Dijkstra NM, Ertl DA, Zillikens MC, Rjenmark L, Winter EM
Endocrine 2021 Mar;71(3):604-610. Epub 2021 Feb 5 doi: 10.1007/s12020-021-02615-2. PMID: 33544354Free PMC Article
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

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
Koca SB
Turk J Pediatr 2023;65(5):853-861. doi: 10.24953/turkjped.2022.1040. PMID: 37853976
Sanada J, Kamei S, Shimoda M, Tatsumi F, Kimura T, Obata A, Kohara K, Nakanishi S, Kaku K, Mune T, Kaneto H
Medicine (Baltimore) 2021 Oct 22;100(42):e27579. doi: 10.1097/MD.0000000000027579. PMID: 34678905Free PMC Article
Tenhola S, Hendy GN, Valta H, Canaff L, Lee BS, Wong BY, Välimäki MJ, Cole DE, Mäkitie O
J Clin Endocrinol Metab 2015 Jul;100(7):2515-8. Epub 2015 May 20 doi: 10.1210/jc.2015-1518. PMID: 25993639
Watanabe H, Sutton RA
Kidney Int 1983 Sep;24(3):353-7. doi: 10.1038/ki.1983.166. PMID: 6645209

Prognosis

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
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
Dershem R, Gorvin CM, Metpally RPR, Krishnamurthy S, Smelser DT, Hannan FM, Carey DJ, Thakker RV, Breitwieser GE; Regeneron Genetics Center
Am J Hum Genet 2020 Jun 4;106(6):734-747. Epub 2020 May 7 doi: 10.1016/j.ajhg.2020.04.006. PMID: 32386559Free PMC Article
Boisen IM, Mos I, Lerche-Black EM, Juul A, Bräuner-Osborne H, Blomberg Jensen M
J Clin Endocrinol Metab 2020 Apr 1;105(4) doi: 10.1210/clinem/dgz205. PMID: 32160303
Nesbit MA, Hannan FM, Howles SA, Babinsky VN, Head RA, Cranston T, Rust N, Hobbs MR, Heath H 3rd, Thakker RV
N Engl J Med 2013 Jun 27;368(26):2476-2486. doi: 10.1056/NEJMoa1300253. PMID: 23802516Free PMC Article

Clinical prediction guides

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
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
Lemoine S, Figueres L, Bacchetta J, Frey S, Dubourg L
Ann Endocrinol (Paris) 2022 Aug;83(4):237-243. Epub 2022 May 19 doi: 10.1016/j.ando.2022.05.003. PMID: 35598638
Dershem R, Gorvin CM, Metpally RPR, Krishnamurthy S, Smelser DT, Hannan FM, Carey DJ, Thakker RV, Breitwieser GE; Regeneron Genetics Center
Am J Hum Genet 2020 Jun 4;106(6):734-747. Epub 2020 May 7 doi: 10.1016/j.ajhg.2020.04.006. PMID: 32386559Free PMC Article
Nesbit MA, Hannan FM, Howles SA, Babinsky VN, Head RA, Cranston T, Rust N, Hobbs MR, Heath H 3rd, Thakker RV
N Engl J Med 2013 Jun 27;368(26):2476-2486. doi: 10.1056/NEJMoa1300253. PMID: 23802516Free PMC Article

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