Abstract
Generalized arterial calcification of infancy (GACI) is a rare genetic disorder with high infantile mortality, described to be due to ENPP1, and less commonly ABCC6 mutations. Bisphosphonate treatment has been described to improve survival in ENPP1-positive GACI patients, but few studies have described bisphosphonate treatment in ABCC6-positive patients. Without therapy, patients will die before 6 months of age. Our patient is now 3 years old, former recipient twin of twin-to-twin transfusion syndrome (TTTS). Initial fetal echocardiogram at 19 weeks showed calcifications of the ascending aorta and pulmonary artery (PA). She underwent utero laser therapy, and despite resolution of the TTTS, her follow-up scans showed progressive calcification of the aorta and PA. Postnatal echocardiogram showed calcification and supravalvar stenosis of the aorta and PA. CT on day of life 6 showed calcifications in the PAs, aortic arch, and descending aorta. Quantification of valvular calcification can be difficult; in our patient, increasing outflow tract gradient on echocardiogram was used to monitor disease progression. Molecular testing revealed an ABCC6 gene mutation. She was started on weekly IV pamidronate (0.1–0.3 mg/kg/week) on day 8 of life then transitioned to oral etidronate (15–20 mg/kg/day). Given progressive supravalvar aortic and pulmonary stenosis, she underwent surgical repair with patch augmentation of the PA and ascending aorta at 4 months old. She has done well post-operatively, continuing on enteral bisphosphonate therapy with no side effects to date. Her identical twin was confirmed to have the same mutation and remains asymptomatic with no calcifications. Aggressive bisphosphonate therapy should be started as soon as possible in patients with infantile arterial calcinosis due to ABCC6 or ENPP1 mutations. Echocardiographic evaluation can be used to monitor disease progression by arterial gradients. Molecular testing is also essential to evaluate for possible co-morbidities in these patients and pregnancy management for the future.
Similar content being viewed by others
References
Ferreria C, Ziegler S, Gahl W. Gneralized arterial calcification of Infancy 2014 Nov 13. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2015
Bolster F, Ali Z, Southall P, Fowler D (2015) Generalized arterial calcification of infancy—findings at post-mortem computed tomography and autopsy. Forensic Sci Int 254:e7–e12
Bergen AA, Plomp AS, Hu X, de Jong PT, Gorgels TG (2007) ABCC6 and pseudoxanthoma elasticum. Pflügers Archiv-Eur J Physiol 453(5):685–691
Mastrolia SA, Weintraub AY, Baron J, Sciaky-Tamir Y, Koifman A, Loverro G, Hershkovitz R (2015) Antenatal diagnosis of idiopathic arterial calcification: a systematic review with a report of two cases. Arch Gynecol Obstet 291(5):977–986
Glatz AC, Pawel BR, Hsu DT, Weinberg P, Chrisant MR (2006) Idiopathic infantile arterial calcification: two case reports, a review of the literature and a role for cardiac transplantation. Pediatr Transplant 10(2):225–233
Rutsch, Frank, Petra Bïyer, Yvonne Nitschke, Nico Ruf, Bettina Lorenz-Deperieux, Tanja Wittkampf, Gabriele Weissen-Plenz et al. (2008) Hypophosphatemia, hyperphosphaturia and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy (GACI). Circ Cardiovasc Genet: CIRCGENETICS-108.)
Ramjan KA et al (2009) Generalized arterial calcification of infancy: treatment with bisphosphonates. Nat Rev Endocrinol 5(3):167–172
Edouard, Thomas, et al. Efficacy and safety of 2-year etidronate treatment in a child with generalized arterial calcification of infancy. Eur J Pediatr 170.12 (2011): 1585–1590
Giovannoni, Isabella, et al. Heart transplant and 2-year follow up in a child with generalized arterial calcification of infancy. Eur J Pediatr (2014) 173:1735–1740.
Nitschke Y, Baujat G, Botschen U et al (2012) Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. Am J Hum Genet 90(1):25–39. https://doi.org/10.1016/j.ajhg.2011.11.020
Li Q, Brodsky JL, Conlin LK et al (2014) Mutations in the ABCC6 gene as a cause of generalized arterial calcification of infancy – genotypic overlap with pseudoxanthoma elasticum. J Investig Dermatol 134(3):658–665. https://doi.org/10.1038/jid.2013.370.
Uitto J et al (2011) Pseudoxanthoma elasticum: progress in diagnostics and research towards treatment. Am J Med Genet Part A 155(7):1517–1526
Nitschke Y, Rutsch F (2017) Inherited arterial calcification syndromes: etiologies and treatment concepts. Curr Osteoporos Rep 15:255–270
LaRusso J, Li Q, Jiang Q, Uitto J. Elevated dietary magnesium prevents connective tissue mineralization in a mouse model of pseudoxanthoma elasticum (Abcc6(−/−)). J Investig Dermatol 2009;129(6):1388–1394
Stella J, Buers I, van de Wetering K, Höhne W, Rutsch F, Nitschke Y (2016) Effects of different variants in the ENPP1 gene on the functional properties of ectonucleotide. Pyrophosphatase/phosphodiesterase family member 1. Hum Mutat 37:1190–1201
Votava-Smith J,K, Pitukcheewanont P, Randolph L,M, Chmait R,H (2017) Generalized arterial calcification in a recipient twin: discordant fetal hemodynamics result in differing phenotypes in monozygotic twins with an ABCC6 mutation. Fetal Diagn Ther 41:234–236
Samon LM, Ash KM, Murdison KA (1995) Aorto-pulmonary calcification: an unusual manifestation of idiopathic calcification of infancy evident antenatally. Obstet Gynecol 85:863–865
Saxena A, Soni NR (2003) Pulmonary artery calcification in recipient twins of twin to twin transfusion syndrome: a report of three cases. Pediatr Cardiol 24:80–83
Inamura N, Nakajima T, Kayatani F, Kawata H, Takeuchi M (2003) Idiopathic arterial calcification in infancy with twin-twin transfusion syndrome. Pediatr Int 45:481–483
Towler DA, Demer LL (2011) Thematic series on the pathobiology of vascular calcification. Circulation. Research 108:1378–1380
Donepudi R et al (2017) Recipient umbilical artery elongation (redundancy) in twin-twin transfusion syndrome. Am J Obstet Gynecol 217(2):206.e1–206.e11
Barrea C et al (2005) Prenatal cardiovascular manifestations in the twin-to-twin transfusion syndrome recipients and the impact of therapeutic amnioreduction. Am J Obstet Gynecol 192(3):892–902
Verma V, Cronin DC II, Dachman AH (2001) Portal and Mesenteric Venous Calcification in Patients with Advanced Cirrhosis. Am J Roentgenol 176(2):489–492
Mahieu-Caputo D et al (2005) Paradoxic activation of the renin-angiotensin system in twin-twin transfusion syndrome: an explanation for cardiovascular disturbances in the recipient. Pediatr Res 58:685–688
Naouri M et al (2009) Manifestations of pseudoxanthoma elasticum in childhood. Br J Dermatol 161(3):635–639
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
None.
Rights and permissions
About this article
Cite this article
Akhtar Ali, S., Ng, C., Votava-Smith, J.K. et al. Bisphosphonate therapy in an infant with generalized arterial calcification with an ABCC6 mutation. Osteoporos Int 29, 2575–2579 (2018). https://doi.org/10.1007/s00198-018-4639-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00198-018-4639-x