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Tumoral calcinosis, hyperphosphatemic, familial, 1(HFTC1)

MedGen UID:
1642611
Concept ID:
C4692564
Disease or Syndrome
Synonyms: CALCINOSIS, TUMORAL, WITH HYPERPHOSPHATEMIA; Cortical hyperostosis with hyperphosphatemia; FGF23-Related Familial Hyperphosphatemic Tumoral Calcinosis; Hyperostosis with hyperphosphatemia; Hyperostosis-hyperphosphatemia syndrome; LIPOCALCINOGRANULOMATOSIS; MORBUS TEUTSCHLAENDER; TEUTSCHLAENDER DISEASE, FAMILIAL; TUMORAL CALCINOSIS, PRIMARY HYPERPHOSPHATEMIC
 
Gene (location): GALNT3 (2q24.3)
 
Monarch Initiative: MONDO:0100252
OMIM®: 211900

Disease characteristics

Excerpted from the GeneReview: Hyperphosphatemic Familial Tumoral Calcinosis
Hyperphosphatemic familial tumoral calcinosis (HFTC) is characterized by: Ectopic calcifications (tumoral calcinosis) typically found in periarticular soft tissues exposed to repetitive trauma or prolonged pressure (e.g., hips, elbows, and shoulders); and Painful swellings (referred to as hyperostosis) in the areas overlying the diaphyses of the tibiae (and less often the ulna, metacarpal bones, and radius). The dental phenotype unique to HFTC includes enamel hypoplasia, short and bulbous roots, obliteration of pulp chambers and canals, and pulp stones. Less common are large and small vessel calcifications that are often asymptomatic incidental findings on radiologic studies but can also cause peripheral vascular insufficiency (e.g., pain, cold extremities, and decreased peripheral pulses). Less frequently reported findings include testicular microlithiasis and angioid streaks of the retina. [from GeneReviews]
Authors:
Mary Scott Ramnitz  |  Rachel I Gafni  |  Michael T Collins   view full author information

Additional descriptions

From OMIM
Hyperphosphatemic familial tumoral calcinosis is a rare autosomal recessive metabolic disorder characterized by the progressive deposition of basic calcium phosphate crystals in periarticular spaces, soft tissues, and sometimes bone (Chefetz et al., 2005). The biochemical hallmark of tumoral calcinosis is hyperphosphatemia caused by increased renal absorption of phosphate due to loss-of-function mutations in the FGF23 (605380) or GALNT3 gene. The term 'hyperostosis-hyperphosphatemia syndrome' is sometimes used when the disorder is characterized by involvement of the long bones associated with the radiographic findings of periosteal reaction and cortical hyperostosis. Although some have distinguished HHS from FTC by the presence of bone involvement and the absence of skin involvement (Frishberg et al., 2005), Ichikawa et al. (2010) concluded that the 2 entities represent a continuous spectrum of the same disease, best described as familial hyperphosphatemic tumoral calcinosis. HFTC is considered to be the clinical converse of autosomal dominant hypophosphatemic rickets (ADHR; 193100), an allelic disorder caused by gain-of-function mutations in the FGF23 gene and associated with hypophosphatemia and decreased renal phosphate absorption (Chefetz et al., 2005; Ichikawa et al., 2005). Genetic Heterogeneity of Hyperphosphatemic Familial Tumoral Calcinosis Also see HFTC2 (617993), caused by mutation in the FGF23 gene (605380) on chromosome 12p13, and HFTC3 (617994), caused by mutation in the KL gene (604824) on chromosome 13q13. Most cases are caused by mutation in the GALNT3 gene.  http://www.omim.org/entry/211900
From MedlinePlus Genetics
Hyperphosphatemic familial tumoral calcinosis (HFTC) is a condition characterized by an increase in the levels of phosphate in the blood (hyperphosphatemia) and abnormal deposits of phosphate and calcium (calcinosis) in the body's tissues. Calcinosis typically develops in early childhood to early adulthood, although in some people the deposits first appear in infancy or in late adulthood. Calcinosis usually occurs in and just under skin tissue around the joints, most often the hips, shoulders, and elbows. Calcinosis may also develop in the soft tissue of the feet, legs, and hands. Rarely, calcinosis occurs in blood vessels or in the brain and can cause serious health problems. The deposits develop over time and vary in size. Larger deposits form masses that are noticeable under the skin and can interfere with the function of joints and impair movement. These large deposits may appear tumor-like (tumoral), but they are not tumors or cancerous. The number and frequency of deposits varies among affected individuals; some develop few deposits during their lifetime, while others may develop many in a short period of time.

Other features of HFTC include eye abnormalities such as calcium buildup in the clear front covering of the eye (corneal calcification) or angioid streaks that occur when tiny breaks form in the layer of tissue at the back of the eye called Bruch's membrane. Inflammation of the long bones (diaphysis) or excessive bone growth (hyperostosis) may occur. Some affected individuals have dental abnormalities. In males, small crystals of cholesterol can accumulate (microlithiasis) in the testicles, which usually causes no health problems.

A similar condition called hyperphosphatemia-hyperostosis syndrome (HHS) results in increased levels of phosphate in the blood, excessive bone growth, and bone lesions. This condition used to be considered a separate disorder, but it is now thought to be a mild variant of HFTC.  https://medlineplus.gov/genetics/condition/hyperphosphatemic-familial-tumoral-calcinosis

Clinical features

From HPO
Nephrocalcinosis
MedGen UID:
10222
Concept ID:
C0027709
Disease or Syndrome
Nephrocalcinosis is the deposition of calcium salts in renal parenchyma.
Decreased renal tubular phosphate excretion
MedGen UID:
409704
Concept ID:
C1968899
Finding
Increased renal tubular phosphate reabsorption
MedGen UID:
368914
Concept ID:
C1968910
Finding
Vascular calcification
MedGen UID:
90990
Concept ID:
C0342649
Disease or Syndrome
Abnormal calcification of the vasculature.
Calcinosis
MedGen UID:
709
Concept ID:
C0006663
Finding
Formation of calcium deposits in any soft tissue.
Hyperostosis
MedGen UID:
9366
Concept ID:
C0020492
Disease or Syndrome
Excessive growth or abnormal thickening of bone tissue.
Subperiosteal bone formation
MedGen UID:
393241
Concept ID:
C2674853
Finding
The formation of new bone along the cortex and underneath the periosteum of a bone.
Hypercalcemia
MedGen UID:
5686
Concept ID:
C0020437
Disease or Syndrome
An abnormally increased calcium concentration in the blood.
Hyperphosphatemia
MedGen UID:
39326
Concept ID:
C0085681
Disease or Syndrome
An abnormally increased phosphate concentration in the blood.
Elevated circulating alkaline phosphatase concentration
MedGen UID:
727252
Concept ID:
C1314665
Finding
Abnormally increased serum levels of alkaline phosphatase activity.
High serum calcitriol
MedGen UID:
1619023
Concept ID:
C4531136
Finding
An increased concentration of calcitriol in the blood. Calcitriol is also known as 1,25-dihydroxycholecalciferol or 1,25-dihydroxyvitamin D3.
Enamel hypoplasia
MedGen UID:
3730
Concept ID:
C0011351
Disease or Syndrome
Developmental hypoplasia of the dental enamel.
Taurodontism
MedGen UID:
75596
Concept ID:
C0266039
Disease or Syndrome
Increased volume of dental pulp of permanent molar characterized by a crown body-root ratio equal or larger than 1:1 or an elongated pulp chambers and apical displacement of the bifurcation or trifurcation of the roots.
Denticles
MedGen UID:
315928
Concept ID:
C1527284
Disease or Syndrome
Dentin dysplasia type II (DTDP2) is a defect of dentin formation in which the clinical appearance of the secondary teeth is normal, but the primary teeth may appear opalescent, similar to teeth affected by dentinogenesis imperfecta. The roots of the teeth are of normal shape and morphologic character. The pulp chambers and root canals of the anterior teeth and the premolars are shaped like thistle tubes because of the radicular extension of the pulp chamber. Most teeth show accumulations of pulp stones in these unusually shaped pulp chambers (summary by Kalk et al., 1998). Also see dentin dysplasia type I (DTDP1; 125400).
Conjunctival whitish salt-like deposits
MedGen UID:
368912
Concept ID:
C1968901
Finding
The presence of whitish deposits in the conjunctiva resembling salt. May be related to calcinosis.
Hyperparathyroidism
MedGen UID:
6967
Concept ID:
C0020502
Disease or Syndrome
Excessive production of parathyroid hormone (PTH) by the parathyroid glands.
Angioid streaks
MedGen UID:
1541
Concept ID:
C0002982
Disease or Syndrome
Angioid streaks are irregular tapering linear breaks in the Bruch membrane that typically emanate from the optic disk (summary by Karacorlu et al., 2002).

Professional guidelines

PubMed

Boyce AM, Lee AE, Roszko KL, Gafni RI
Front Endocrinol (Lausanne) 2020;11:293. Epub 2020 May 8 doi: 10.3389/fendo.2020.00293. PMID: 32457699Free PMC Article
Nitschke Y, Rutsch F
Curr Osteoporos Rep 2017 Aug;15(4):255-270. doi: 10.1007/s11914-017-0370-3. PMID: 28585220

Recent clinical studies

Etiology

Chakhtoura M, Ramnitz MS, Khoury N, Nemer G, Shabb N, Abchee A, Berberi A, Hourani M, Collins M, Ichikawa S, El Hajj Fuleihan G
Osteoporos Int 2018 Sep;29(9):1987-2009. Epub 2018 Jun 20 doi: 10.1007/s00198-018-4574-x. PMID: 29923062
Nitschke Y, Rutsch F
Curr Osteoporos Rep 2017 Aug;15(4):255-270. doi: 10.1007/s11914-017-0370-3. PMID: 28585220
Ramnitz MS, Gourh P, Goldbach-Mansky R, Wodajo F, Ichikawa S, Econs MJ, White KE, Molinolo A, Chen MY, Heller T, Del Rivero J, Seo-Mayer P, Arabshahi B, Jackson MB, Hatab S, McCarthy E, Guthrie LC, Brillante BA, Gafni RI, Collins MT
J Bone Miner Res 2016 Oct;31(10):1845-1854. Epub 2016 Sep 20 doi: 10.1002/jbmr.2870. PMID: 27164190Free PMC Article
Masi L, Beltrami G, Ottanelli S, Franceschelli F, Gozzini A, Zonefrati R, Galli G, Ciuffi S, Mavilia C, Giusti F, Marcucci G, Cioppi F, Colli E, Fossi C, Franchi A, Casentini C, Capanna R, Brandi ML
Calcif Tissue Int 2015 May;96(5):438-52. Epub 2015 Apr 23 doi: 10.1007/s00223-015-9974-8. PMID: 25899975

Diagnosis

Sheppard AJ, Theng EH, Paravastu SS, Wojnowski NM, Farhadi F, Morris MA, Hartley IR, Gafni RI, Roszko KL, Collins MT, Saboury B
Arterioscler Thromb Vasc Biol 2024 Jun;44(6):1432-1446. Epub 2024 Apr 25 doi: 10.1161/ATVBAHA.123.320455. PMID: 38660800Free PMC Article
Pallone SG, Kunii IS, da Silva REC, Lazaretti-Castro M
Calcif Tissue Int 2022 Jul;111(1):102-106. Epub 2022 Mar 25 doi: 10.1007/s00223-022-00969-x. PMID: 35338393
Huang J, Cao LG, Zhang TR, Li SM, Meng QQ
Osteoporos Int 2022 Jan;33(1):309-312. Epub 2021 Jul 10 doi: 10.1007/s00198-021-06056-5. PMID: 34245344
Albaramki J, Dmour H, Shboul M, Bonnard C, Venkatesh B, Odeh R
Turk J Pediatr 2019;61(1):130-133. doi: 10.24953/turkjped.2019.01.022. PMID: 31559735
Kışla Ekinci RM, Gürbüz F, Balcı S, Bişgin A, Taştan M, Yüksel B, Yılmaz M
J Clin Res Pediatr Endocrinol 2019 Feb 20;11(1):94-99. Epub 2018 Jul 17 doi: 10.4274/jcrpe.galenos.2018.2018.0134. PMID: 30015621Free PMC Article

Therapy

Pallone SG, Kunii IS, da Silva REC, Lazaretti-Castro M
Calcif Tissue Int 2022 Jul;111(1):102-106. Epub 2022 Mar 25 doi: 10.1007/s00223-022-00969-x. PMID: 35338393
Ovejero D, Hartley IR, de Castro Diaz LF, Theng E, Li X, Gafni RI, Collins MT
J Bone Miner Res 2022 Feb;37(2):179-184. Epub 2021 Sep 15 doi: 10.1002/jbmr.4429. PMID: 34464000
Suzuki Y, Kuzina E, An SJ, Tome F, Mohanty J, Li W, Lee S, Liu Y, Lax I, Schlessinger J
Proc Natl Acad Sci U S A 2020 Dec 15;117(50):31800-31807. Epub 2020 Nov 30 doi: 10.1073/pnas.2018554117. PMID: 33257569Free PMC Article
Ramnitz MS, Gourh P, Goldbach-Mansky R, Wodajo F, Ichikawa S, Econs MJ, White KE, Molinolo A, Chen MY, Heller T, Del Rivero J, Seo-Mayer P, Arabshahi B, Jackson MB, Hatab S, McCarthy E, Guthrie LC, Brillante BA, Gafni RI, Collins MT
J Bone Miner Res 2016 Oct;31(10):1845-1854. Epub 2016 Sep 20 doi: 10.1002/jbmr.2870. PMID: 27164190Free PMC Article
Folsom LJ, Imel EA
Curr Osteoporos Rep 2015 Apr;13(2):78-87. doi: 10.1007/s11914-015-0254-3. PMID: 25656441

Prognosis

Sheppard AJ, Theng EH, Paravastu SS, Wojnowski NM, Farhadi F, Morris MA, Hartley IR, Gafni RI, Roszko KL, Collins MT, Saboury B
Arterioscler Thromb Vasc Biol 2024 Jun;44(6):1432-1446. Epub 2024 Apr 25 doi: 10.1161/ATVBAHA.123.320455. PMID: 38660800Free PMC Article

Clinical prediction guides

Sheppard AJ, Paravastu SS, Farhadi F, Donnelly E, Hartley IR, Gafni RI, Saboury B, Collins MT, Roszko KL
J Bone Miner Res 2024 Sep 2;39(9):1327-1339. doi: 10.1093/jbmr/zjae115. PMID: 39046425Free PMC Article
Sheppard AJ, Theng EH, Paravastu SS, Wojnowski NM, Farhadi F, Morris MA, Hartley IR, Gafni RI, Roszko KL, Collins MT, Saboury B
Arterioscler Thromb Vasc Biol 2024 Jun;44(6):1432-1446. Epub 2024 Apr 25 doi: 10.1161/ATVBAHA.123.320455. PMID: 38660800Free PMC Article
Ovejero D, Hartley IR, de Castro Diaz LF, Theng E, Li X, Gafni RI, Collins MT
J Bone Miner Res 2022 Feb;37(2):179-184. Epub 2021 Sep 15 doi: 10.1002/jbmr.4429. PMID: 34464000
Huang J, Cao LG, Zhang TR, Li SM, Meng QQ
Osteoporos Int 2022 Jan;33(1):309-312. Epub 2021 Jul 10 doi: 10.1007/s00198-021-06056-5. PMID: 34245344
Ramnitz MS, Gourh P, Goldbach-Mansky R, Wodajo F, Ichikawa S, Econs MJ, White KE, Molinolo A, Chen MY, Heller T, Del Rivero J, Seo-Mayer P, Arabshahi B, Jackson MB, Hatab S, McCarthy E, Guthrie LC, Brillante BA, Gafni RI, Collins MT
J Bone Miner Res 2016 Oct;31(10):1845-1854. Epub 2016 Sep 20 doi: 10.1002/jbmr.2870. PMID: 27164190Free PMC Article

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