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Current Osteoporosis Reports
Erschienen in: Current Osteoporosis Reports 3/2020

14.03.2020 | Rare Bone Disease (C Langman and E Shore, Section Editors)

Generalized Arterial Calcification of Infancy: New Insights, Controversies, and Approach to Management

verfasst von: Alison M. Boyce, Rachel I. Gafni, Carlos R. Ferreira

Erschienen in: Current Osteoporosis Reports | Ausgabe 3/2020

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Abstract

Purpose of Review

This review summarizes current understanding of generalized arterial calcification of infancy (GACI), emphasizing pathophysiology, clinical presentation, and approaches and controversies in management.

Recent Findings

Identification of causative ENPP1 mutations revealed that GACI arises from deficiencies in inorganic pyrophosphate (leading to calcifications) and adenosine monophosphate (leading to intimal proliferation). Identification of genotypic and phenotypic overlap with pseudoxanthoma elasticum and autosomal recessive hypophosphatemic rickets further advanced understanding of GACI as a complex, multisystemic disease. Clinical data is limited to small, retrospective samples; it is therefore unknown whether commonly used medications, such as bisphosphonates and hypophosphatemia treatment, are therapeutic or potentially harmful. ENPP1-Fc replacement represents a promising approach warranting further study.

Summary

Knowledge gaps in natural history place clinicians at high risk of assigning causality to interventions that are correlated with changes in clinical status. There is thus a critical need for improved natural history studies to develop and test targeted therapies.
Literatur
1.
Durante G. Athérome congénital de l’aorte et de l’artère pulmonaire. Bull Soc Anat Paris. 1899;74:97–101.
2.
Okawa A, Nakamura I, Goto S, Moriya H, Nakamura Y, Ikegawa S. Mutation in Npps in a mouse model of ossification of the posterior longitudinal ligament of the spine. Nat Genet. 1998;19(3):271–3.PubMedCrossRef
3.
Rutsch F, Vaingankar S, Johnson K, Goldfine I, Maddux B, Schauerte P, et al. PC-1 nucleoside triphosphate pyrophosphohydrolase deficiency in idiopathic infantile arterial calcification. Am J Pathol. 2001;158(2):543–54.PubMedPubMedCentralCrossRef
4.
Rutsch F, Ruf N, Vaingankar S, Toliat MR, Suk A, Hohne W, et al. Mutations in ENPP1 are associated with ‘idiopathic’ infantile arterial calcification. Nat Genet. 2003;34(4):379–81.PubMedCrossRef
5.
Rutsch F, Boyer P, Nitschke Y, Ruf N, Lorenz-Depierieux B, Wittkampf T, et al. Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy. Circ Cardiovasc Genet. 2008;1(2):133–40.PubMedPubMedCentralCrossRef
6.
Ruf N, Uhlenberg B, Terkeltaub R, Nurnberg P, Rutsch F. The mutational spectrum of ENPP1 as arising after the analysis of 23 unrelated patients with generalized arterial calcification of infancy (GACI). Hum Mutat. 2005;25(1):98.PubMedCrossRef
7.
Orriss IR, Arnett TR, Russell RG. Pyrophosphate: a key inhibitor of mineralisation. Curr Opin Pharmacol. 2016;28:57–68.PubMedCrossRef
8.
•• Nitschke Y, Yan Y, Buers I, Kintziger K, Askew K, Rutsch F. ENPP1-Fc prevents neointima formation in generalized arterial calcification of infancy through the generation of AMP. Exp Mol Med. 2018;50(10):–139 This study demonstrated that ENPP1 inhibits neointima formation by generating AMP and that administration of recombinant human ENPP1-Fc protein prevented neointimal formation in an animal model of GACI. CrossRef
9.
Lorenz-Depiereux B, Schnabel D, Tiosano D, Hausler G, Strom TM. Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets. Am J Hum Genet. 2010;86(2):267–72.PubMedPubMedCentralCrossRef
10.
Levy-Litan V, Hershkovitz E, Avizov L, Leventhal N, Bercovich D, Chalifa-Caspi V, et al. Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. Am J Hum Genet. 2010;86(2):273–8.PubMedPubMedCentralCrossRef
11.
Hajjawi MO, MacRae VE, Huesa C, Boyde A, Millan JL, Arnett TR, et al. Mineralisation of collagen rich soft tissues and osteocyte lacunae in Enpp1(−/−) mice. Bone. 2014;69:139–47.PubMedPubMedCentralCrossRef
12.
Nitschke Y, Baujat G, Botschen U, Wittkampf T, du Moulin M, Stella J, et al. Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. Am J Hum Genet. 2012;90(1):25–39.PubMedPubMedCentralCrossRef
13.
Li Q, Brodsky JL, Conlin LK, Pawel B, Glatz AC, Gafni RI, et al. Mutations in the ABCC6 gene as a cause of generalized arterial calcification of infancy: genotypic overlap with pseudoxanthoma elasticum. J Invest Dermatol. 2014;134(3):658–65.PubMedCrossRef
14.
St Hilaire C, Ziegler SG, Markello TC, Brusco A, Groden C, Gill F, et al. NT5E mutations and arterial calcifications. N Engl J Med. 2011;364(5):432–42.PubMedPubMedCentralCrossRef
15.
Jin H, St Hilaire C, Huang Y, Yang D, Dmitrieva NI, Negro A, et al. Increased activity of TNAP compensates for reduced adenosine production and promotes ectopic calcification in the genetic disease ACDC. Sci Signal. 2016;9(458):ra121.PubMedPubMedCentralCrossRef
16.
Chong CR, Hutchins GM. Idiopathic infantile arterial calcification: the spectrum of clinical presentations. Pediatr Dev Pathol : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society. 2008;11(5):405–15.CrossRef
17.
Witzleben CL. Idiopathic infantile arterial calcification--a misnomer? Am J Cardiol. 1970;26(3):305–9.PubMedCrossRef
18.
Lussier-Lazaroff J, Fletcher BD. Idiopathic infantile arterial calcification: roentgen diagnosis of a rare cause of coronary artery occlusion. Pediatr Radiol. 1973;1(4):224–8.PubMedCrossRef
19.
Attia TH, Abd Alhamed MM, Selim MF, Haggag MS, Fathalla D. Idiopathic arterial calcification of infancy: case report. J Radiol Case Rep. 2015;9(11):32–40.PubMedPubMedCentral
20.
Shaireen H, Howlett A, Amin H, Yusuf K, Kamaluddeen M, Lodha A. The mystery of persistent pulmonary hypertension: an idiopathic infantile arterial calcification. BMC Pediatr. 2013;13:107.PubMedPubMedCentralCrossRef
21.
Sawyer T, Stacey M, Mulreany M, Thompson M, Nitschke Y, Rutsch F, et al. Generalized arterial calcification of infancy associated with meconium peritonitis: a case report and review of the literature. Am J Perinatol. 2009;26(10):711–6.PubMedCrossRef
22.
van der Sluis IM, Boot AM, Vernooij M, Meradji M, Kroon AA. Idiopathic infantile arterial calcification: clinical presentation, therapy and long-term follow-up. Eur J Pediatr. 2006;165(9):590–3.PubMedCrossRef
23.
Glatz AC, Pawel BR, Hsu DT, Weinberg P, Chrisant MR. Idiopathic infantile arterial calcification: two case reports, a review of the literature and a role for cardiac transplantation. Pediatr Transplant. 2006;10(2):225–33.PubMedCrossRef
24.
Galletti S, Nitschke Y, Malavolti AM, Aquilano G, Faldella G, Corvaglia L, et al. Generalized arterial calcification of infancy: fatal clinical course associated with a novel mutation in ENPP1. JIMD Reports. 2011;1:23–7.PubMedPubMedCentralCrossRef
25.
Hault K, Sebire NJ, Ho SY, Sheppard MN. The difficulty in diagnosing idiopathic arterial calcification of infancy, its variation in presentation, and the importance of autopsy. Cardiol Young. 2008;18(6):624–7.PubMedCrossRef
26.
Brachet C, Mansbach AL, Clerckx A, Deltenre P, Heinrichs C. Hearing loss is part of the clinical picture of ENPP1 loss of function mutation. Horm Res Paediatr. 2014;81(1):63–6.PubMedCrossRef
27.
Vera J, Lucaya J, Garcia Conesa JA, Aso C, Balaguer A. Idiopathic infantile arterial calcification: unusual features. Pediatr Radiol. 1990;20(8):585–7.PubMedCrossRef
28.
Terry SF, Bercovitch L. Pseudoxanthoma elasticum. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, et al., editors. GeneReviews((R)). Seattle (WA): University of Washington, Seattle University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.; 1993
29.
Li Q, Schumacher W, Jablonski D, Siegel D, Uitto J. Cutaneous features of pseudoxanthoma elasticum in a patient with generalized arterial calcification of infancy due to a homozygous missense mutation in the ENPP1 gene. Br J Dermatol. 2012;166(5):1107–11.PubMedPubMedCentralCrossRef
30.
Ferreira CR, Ziegler SG, Gupta A, Groden C, Hsu KS, Gahl WA. Treatment of hypophosphatemic rickets in generalized arterial calcification of infancy (GACI) without worsening of vascular calcification. Am J Med Genet A. 2016;170a(5):1308–11.PubMedCrossRef
31.
Thumbigere-Math V, Alqadi A, Chalmers NI, Chavez MB, Chu EY, Collins MT, et al. Hypercementosis associated with ENPP1 mutations and GACI. J Dent Res. 2018;97(4):432–41.PubMedCrossRef
32.
Staretz-Chacham O, Shukrun R, Barel O, Pode-Shakked B, Pleniceanu O, Anikster Y, et al. Novel homozygous ENPP1 mutation causes generalized arterial calcifications of infancy, thrombocytopenia, and cardiovascular and central nervous system syndrome. Am J Med Genet A. 2019;179(10):2112–8.PubMedPubMedCentralCrossRef
33.
Dlamini N, Splitt M, Durkan A, Siddiqui A, Padayachee S, Hobbins S, et al. Generalized arterial calcification of infancy: phenotypic spectrum among three siblings including one case without obvious arterial calcifications. Am J Med Genet A. 2009;149a(3):456–60.PubMedCrossRef
34.
Cheng KS, Chen MR, Ruf N, Lin SP, Rutsch F. Generalized arterial calcification of infancy: different clinical courses in two affected siblings. Am J Med Genet A. 2005;136(2):210–3.PubMedCrossRef
35.
Otero JE, Gottesman GS, McAlister WH, Mumm S, Madson KL, Kiffer-Moreira T, et al. Severe skeletal toxicity from protracted etidronate therapy for generalized arterial calcification of infancy. J Bone Miner Res. 2013;28(2):419–30.PubMedCrossRef
36.
Ciana G, Trappan A, Bembi B, Benettoni A, Maso G, Zennaro F, et al. Generalized arterial calcification of infancy: two siblings with prolonged survival. Eur J Pediatr. 2006;165(4):258–63.PubMedCrossRef
37.
Thomas P, Chandra M, Kahn E, McVicar M, Naidich J, LaCorte M. Idiopathic arterial calcification of infancy: a case with prolonged survival. Pediatr Nephrol (Berlin, Germany). 1990;4(3):233–5.CrossRef
38.
Ciana G, Colonna F, Forleo V, Brizzi F, Benettoni A, de Vonderweid U. Idiopathic arterial calcification of infancy: effectiveness of prostaglandin infusion for treatment of secondary hypertension refractory to conventional therapy: case report. Pediatr Cardiol. 1997;18(1):67–71.PubMedCrossRef
39.
Sholler GF, Yu JS, Bale PM, Hawker RE, Celermajer JM, Kozlowski K. Generalized arterial calcification of infancy: three case reports, including spontaneous regression with long-term survival. J Pediatr. 1984;105(2):257–60.PubMedCrossRef
40.
Marrott PK, Newcombe KD, Becroft DM, Friedlander DH. Idiopathic infantile arterial calcification with survival to adult life. Pediatr Cardiol. 1984;5(2):119–22.PubMedCrossRef
41.
Thiaville A, Smets A, Clercx A, Perlmutter N. Idiopathic infantile arterial calcification: a surviving patient with renal artery stenosis. Pediatr Radiol. 1994;24(7):506–8.PubMedCrossRef
42.
Meradji M, de Villeneuve VH, Huber J, de Bruijn WC, Pearse RG. Idiopathic infantile arterial calcification in siblings: radiologic diagnosis and successful treatment. J Pediatr. 1978;92(3):401–5.PubMedCrossRef
43.
44.
Stuart AG. Idiopathic arterial calcification of infancy and pyrophosphate deficiency. J Pediatr. 1993;123(1):170–1.PubMedCrossRef
45.
Etidronate [package insert]. Cincinatti, OH: Procter & Gamble Pharmaceuticals. 2009.
46.
Macedo G, Azevedo F, Ribeiro T. Ulcerative esophagitis caused by etidronate. Gastrointest Endosc. 2001;53(2):250–1.PubMedCrossRef
47.
van Staa T, Abenhaim L, Cooper C. Upper gastrointestinal adverse events and cyclical etidronate. Am J Med. 1997;103(6):462–7.PubMedCrossRef
48.
Boivin G, Farlay D, Bala Y, Doublier A, Meunier PJ, Delmas PD. Influence of remodeling on the mineralization of bone tissue. Osteoporos Int. 2009;20(6):1023–6.PubMedPubMedCentralCrossRef
49.
Reade MC, Davies SR, Morley PT, Dennett J, Jacobs IC. Review article: management of cyanide poisoning. Emerg Med Australas. 2012;24(3):225–38.PubMedCrossRef
50.
Adirekkiat S, Sumethkul V, Ingsathit A, Domrongkitchaiporn S, Phakdeekitcharoen B, Kantachuvesiri S, et al. Sodium thiosulfate delays the progression of coronary artery calcification in haemodialysis patients. Nephrol Dial Transplant. 2010;25(6):1923–9.PubMedCrossRef
51.
Arabshahi B, Silverman RA, Jones OY, Rider LG. Abatacept and sodium thiosulfate for treatment of recalcitrant juvenile dermatomyositis complicated by ulceration and calcinosis. J Pediatr. 2012;160(3):520–2.PubMedPubMedCentralCrossRef
52.
Jost J, Bahans C, Courbebaisse M, Tran TA, Linglart A, Benistan K, et al. Topical sodium thiosulfate: a treatment for calcifications in Hyperphosphatemic familial tumoral calcinosis? J Clin Endocrinol Metab. 2016;101(7):2810–5.PubMedCrossRef
53.
Omarjee L, Nitschke Y, Verschuere S, Bourrat E, Vignon MD, Navasiolava N, et al. Severe early-onset manifestations of pseudoxanthoma elasticum resulting from the cumulative effects of several deleterious mutations in the ENPP1, ABCC6 and HBB genes: transient improvement in ectopic calcification with sodium thiosulfate. Br J Dermatol 2019.
54.
Selk N, Rodby RA. Unexpectedly severe metabolic acidosis associated with sodium thiosulfate therapy in a patient with calcific uremic arteriolopathy. Semin Dial. 2011;24(1):85–8.PubMedCrossRef
55.
Poterucha TJ, Goldhaber SZ. Warfarin and vascular calcification. Am J Med. 2016;129(6):635.e1–4.CrossRef
56.
Giovannoni I, Callea F, Travaglini L, Amodeo A, Cogo P, Secinaro A, et al. Heart transplant and 2-year follow up in a child with generalized arterial calcification of infancy. Eur J Pediatr. 2014;173(12):1735–40.PubMedCrossRef
57.
Murali SK, Andrukhova O, Clinkenbeard EL, White KE, Erben RG. Excessive Osteocytic Fgf23 secretion contributes to pyrophosphate accumulation and mineralization defect in Hyp mice. PLoS Biol. 2016;14(4):e1002427.PubMedPubMedCentralCrossRef
58.
Beck-Nielsen SS, Mughal Z, Haffner D, Nilsson O, Levtchenko E, Ariceta G, et al. FGF23 and its role in X-linked hypophosphatemia-related morbidity. Orphanet J Rare Dis. 2019;14(1):58.PubMedPubMedCentralCrossRef
59.
Linglart A, Biosse-Duplan M, Briot K, Chaussain C, Esterle L, Guillaume-Czitrom S, et al. Therapeutic management of hypophosphatemic rickets from infancy to adulthood. Endocr Connect. 2014;3(1):R13–30.PubMedPubMedCentralCrossRef
60.
Freychet C, Gay C, Lavocat MP, Teyssier G, Patural H, Bacchetta J, et al. GACI syndrome: a case report with a neonatal beginning. Arch Pediatr. 2014;21(6):632–6.PubMedCrossRef
61.
•• Albright RA, Stabach P, Cao W, Kavanagh D, Mullen I, Braddock AA, et al. ENPP1-Fc prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy. Nat Commun. 2015;6:10006 This study demonstrated that administration of a recombinant ENPP1-Fc fusion protein prevented vascular calcifications and mortality in an animal model of GACI. PubMedPubMedCentralCrossRef
62.
Khan T, Sinkevicius KW, Vong S, Avakian A, Leavitt MC, Malanson H, et al. ENPP1 enzyme replacement therapy improves blood pressure and cardiovascular function in a mouse model of generalized arterial calcification of infancy. Dis Model Mech. 2018;11(10):dmm035691.PubMedPubMedCentralCrossRef
Metadaten
Titel
Generalized Arterial Calcification of Infancy: New Insights, Controversies, and Approach to Management
verfasst von
Alison M. Boyce
Rachel I. Gafni
Carlos R. Ferreira
Publikationsdatum
14.03.2020
Verlag
Springer US
Erschienen in
Current Osteoporosis Reports / Ausgabe 3/2020
Print ISSN: 1544-1873
Elektronische ISSN: 1544-2241
DOI
https://doi.org/10.1007/s11914-020-00577-4

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