Idiopathic infantile arterial calcification

Idiopathic Infantile Arterial Calcification (IIAC) also known as Arterial Calcification of Infancy, Generalised Infantile Arterial Calcification (GACI), Idiopathic Arterial Calcification of Infancy (IACI), Occlusive Infantile Arterial Calcification, Occlusive Infantile Arteriopathy^[1] is an extremely rare,^[2] usually fatal genetic disorder, caused by mutations in the ENPP1 gene in 75% of the subjects.^[3] The condition affects infants during the first 6 months of life. This condition is inherited as an autosomal recessive pattern. It is characterized by generalised calcification of the arterial internal elastic lamina, leading to rupture of the lamina and occlusive changes in the tunica intima with stenosis and decreased elasticity of the vessel wall.^[4] Most infants die of vaso-occlusive disease, especially of the coronary arteries.^[5]

Symptoms

Clinical presentation is variable. First symptoms usually occur at birth but can take place in the first 6 months of life or in utero.^[2]

• Decreased fetal activity
• Gestation with an antenatal diagnosis of hydrops fetalis^[6][7]
• Polyhydramnios
• Low biophysical profile
• Marked cyanosis
• Edema^[8]
• Severe hypertension^[9]
• No or fade pulses
• Refusal of feeds^[10]
• Tachypnea
• Vomiting
• Abdominal distension
• General arterial rigidity^[11]
• Cardiac failure (most common clinical finding)
• Strain pattern

Cause

IIAC is inherited in an autosomal recessive pattern.

The disease results from an inactivating mutation in the ecto-nucleotide pyrophosphatase/phosphodiesterase-1 ENPP1 gene, leading to decreased inorganic pyrophosphate (PPi), a potent inhibitor of calcium deposition in the vessel wall. This mutation allows for unregulated calcium deposition within muscular arteries. The symptoms are caused by calcification of large and medium-sized arteries, including the aorta, coronary arteries, and renal arteries. Most of the patients die by 6 months of age because of heart failure. Recently, homozygous or compound heterozygous mutations for ENPP1 gene were reported as causative for the disorder. ENPP1 regulates extracellular inorganic pyrophosphate (PPi), a major inhibiter of extracellular matrix calcification.^[12]

Diagnosis

Idiopathic arterial calcification of infancy should always be considered in infants and children presenting with hypertension, cardiac failure, or sudden death.^[13] Plain radiography,^[14] sonography^[15] and MRI^[16] can aid in the diagnosis. Postnatal gray-scale and color Doppler echocardiographic and sonographic examinations allowed noninvasive diagnosis, assessment of severity, and monitoring of progression.^[17] Contrast-enhanced MR angiography with breath-hold and cardiac gating techniques can allow evaluation of the extent of the disease.^[18]

• Dilated and hypertrophied ventricles
• Extramedullary hematopoiesis of liver ^[19]
• Hypertrophy of myocardium
• Bright and hyper-reflective myocardium^[20]
• Periarticular calcifications in the wrists, ears, shoulders, ankles and hip^[21][22]
• Heart usually looks structurally normal
• Cardiomegaly and pulmonary plethora^[20]
• Diffuse arterial calcification involving aorta, carotid, cerebral, renal, mesenteric and cardiac arteries
• Echo-dense aortic annulus, ascending aorta, transverse arch, descending aorta, main pulmonary artery, and coronary arteries unusually.^[23]
• Abdominal ultrasound can reveal hepatosplenomegaly, ascites, renal echogenicity and diffused arterial calcifications involving the aorta, common iliac, splenic, and renal arteries, as well as peritoneal calcifications involving the visceral peritoneum overlying the liver and intestine
• Brain ultrasound can show dilated lateral ventricles, poorly developed corpus callosum, and leukomalacia
• Echocardiogram can reveal a structurally normal heart, normal ventricular function, however mild concentric ventricular hypertrophy and multiple intracardiac as well as vascular calcifications^[6]
• Idiopathic arterial calcification of infancy should be suspected when there is hyperechogenicity of vessel walls, evidence of polyhydramnios or a past history of early neonatal deaths.^[24]
• DNA testing can identify one of the mutations responsible for the condition^[25]

Prevention and early detection

• Potential role of genetic markers in the identification of persons at risk.^[26] There is a 75% probability to identify the two EPPN1 mutations (one paternal, one maternal) that cause IIAC. Once the mutations are identified, preimplantation genetic diagnosis (PGD) or chorionic villus sampling (CVS) are possible options to identify the condition, either before or during pregnancy.
• At week 20 of gestation, it is possible to detect an Echogenic intracardiac focus (EIF)^[27] or intravascular calcifications, particularly in the iliac and [abdominal aorta]. EIF is a small bright spot seen in the baby’s heart on an ultrasound exam. This is thought to represent mineralization, or small deposits of calcium hydroxyapatite,^[28] in the muscle of the heart. EIFs are found in about 3-5% of normal pregnancies and cause no health problems.
• Ultrasound can show subtle intravascular calcifications, particularly in the abdominal aorta at week 23.^[29]
• Calcification has been detected at 33 weeks' gestation.^[30]

Treatment

• Prenatal^[31] and postnatal treatment with low-dose, cyclical bisphosphonates, also called diphosphonate, resulted in a complete resolution of vascular calcifications in some cases using disodium pamidronate and risedronate.^{[32][33][33][34][35][36]}
• PGE1 infusion is a possible therapeutic alternative for babies with idiopathic arterial calcification complicated by severe hypertension refractory to conventional treatment.^[37]
• Infants must reach a certain weight to allow for a transplant, commonly not reached.^[38]

Prognosis

• Although survival to adulthood has been reported,^[39][40] sometimes with persistent hypertension and cardiovascular sequelae, most patients die within the first 6 months of life.
• Spontaneous regression of arterial calcifications can occur, and antihypertensive treatment can be tapered off gradually. In some patients, the natural course of GACI may be more favourable than previously assumed.^[41][42]
• Despite the same genotype and similar sonographic and radiographic features in early infancy, the phenotype of IIAC can vary to a great extent within one family.^[43]

See also

• ENPP1

References

1. Witzleben, C.L (1970). "Idiopathic infantile arterial calcification—A misnomer?". The American Journal of Cardiology 26 (3): 305–9. doi:10.1016/0002-9149(70)90798-8. PMID 4196111.
2. Chong, Curtis R.; Hutchins, Grover M. (2008). "Idiopathic Infantile Arterial Calcification: The Spectrum of Clinical Presentations". Pediatric and Developmental Pathology 11 (5): 405–15. doi:10.2350/07-06-0297.1. PMID 17990935.
3. Rutsch, Frank; Ruf, Nico; Vaingankar, Sucheta; Toliat, Mohammad R.; Suk, Anita; Höhne, Wolfgang; Schauer, Galen; Lehmann, Mandy; et al. (2003). "Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification". Nature Genetics 34 (4): 379–81. doi:10.1038/ng1221. PMID 12881724.
4. Greenberg, S. Bruce; Gibson, James (2005). "New Findings in Idiopathic Arterial Calcification of Infancy Detected by MDCT". American Journal of Roentgenology 185 (2): 530–2. doi:10.2214/ajr.185.2.01850530. PMID 16037532.
5. Rutsch, Frank; Boyer, Petra; Nitschke, Yvonne; Ruf, Nico; Lorenz-Depierieux, Bettina; Wittkampf, Tanja; Weissen-Plenz, Gabriele; Fischer, Rudolf-Josef; et al. (2008). "Hypophosphatemia, Hyperphosphaturia, and Bisphosphonate Treatment Are Associated with Survival Beyond Infancy in Generalized Arterial Calcification of Infancy". Circulation: Cardiovascular Genetics 1 (2): 133–40. doi:10.1161/CIRCGENETICS.108.797704. PMC 2794045. PMID 20016754.
6. Abu-Asbeh, J; Khan, J; Shallal, A (2006). "Idiopathic infantile arterial calcification associated with leukomalacia". Journal of the Arab Neonatology Forum 3 (1): 15–9.
7. Nagar, Arpit M.; Hanchate, Vijay; Tandon, Ankit; Thakkar, Hemangini; Chaubal, Nitin G. (2003-06-01). "Antenatal Detection of Idiopathic Arterial Calcification With Hydrops Fetalis". Journal of Ultrasound in Medicine 22 (6): 653–9. PMID 12795564.
8. Maayan, Ch.; Peleg, O.; Eyal, F.; Mogle, P.; Rosenmann, E.; Ziv, J. Bar (1984). "Idiopathic infantile arterial calcification: A case report and review of the literature". European Journal of Pediatrics 142 (3): 211–5. doi:10.1007/BF00442452. PMID 6468446.
9. Milner, Laurence S.; Heitner, René; Thomson, Peter D.; Levin, Solomon E.; Rothberg, Alan D.; Beale, Peter; Ninin, Daniel T. (1984). "Hypertension as the major problem of idiopathic arterial calcification of infancy". The Journal of Pediatrics 105 (6): 934–8. doi:10.1016/S0022-3476(84)80080-3. PMID 6502343.
10. Hunt, A. C.; Leys, D. G. (1957). "Generalized Arterial Calcification of Infancy". BMJ 1 (5015): 385–6. doi:10.1136/bmj.1.5015.385. PMC 1974337. PMID 13396267.
11. Thiaville, A.; Smets, A.; Clercx, A.; Perlmutter, N. (1994). "Idiopathic infantile arterial calcification: A surviving patient with renal artery stenosis". Pediatric Radiology 24 (7): 506–8. doi:10.1007/BF02015014. PMID 7885787.
12. Rutsch, Frank; Vaingankar, Sucheta; Johnson, Kristen; Goldfine, Ira; Maddux, Betty; Schauerte, Petra; Kalhoff, Hermann; Sano, Kimihiko; et al. (2001). "PC-1 Nucleoside Triphosphate Pyrophosphohydrolase Deficiency in Idiopathic Infantile Arterial Calcification". The American Journal of Pathology 158 (2): 543–54. doi:10.1016/S0002-9440(10)63996-X. PMC 1850320. PMID 11159191.
13. Hault, Kathrin; Sebire, Neil J.; Ho, Siew Y.; Sheppard, Mary N. (2008). "The difficulty in diagnosing idiopathic arterial calcification of infancy, its variation in presentation, and the importance of autopsy". Cardiology in the Young 18 (6): 624–7. doi:10.1017/S1047951108003168. PMID 18842162.
14. Lussier-Lazaroff, J.; Fletcher, B. D. (1973). "Idiopathic infantile arterial calcification: Roentgen diagnosis of a rare cause of coronary artery occlusion". Pediatric Radiology 1 (4): 224–8. doi:10.1007/BF00972856. PMID 4779072.
15. Rosenbaum, DM; Blumhagen, JD (1986). "Sonographic recognition of idiopathic arterial calcification of infancy". American Journal of Roentgenology 146 (2): 249–50. doi:10.2214/ajr.146.2.249. PMID 3510511.
16. Pao, D. G.; Deangelis, G. A.; Lovell, Mark A.; Hagspiel, Klaus D.; Hagspiel, KD (1998). "Idiopathic arterial calcification of infancy: Sonographic and magnetic resonance findings with pathologic correlation". Pediatric Radiology 28 (4): 256–9. doi:10.1007/s002470050344. PMID 9545482.
17. Whitehall, John; Smith, Mark; Altamirano, Louis (2003). "Idiopathic infantile arterial calcification: Sonographic findings". Journal of Clinical Ultrasound 31 (9): 497–501. doi:10.1002/jcu.10208. PMID 14595743.
18. Tran, Kim H.; Boechat, M. Ines (2006). "Idiopathic infantile arterial calcification: Imaging evaluation and the usefulness of MR angiography". Pediatric Radiology 36 (3): 247–53. doi:10.1007/s00247-005-0044-7. PMID 16429273.
19. Sharmila, N.; Prashant, S. Joshi; Ravikumar, Vani (Jan–Mar 2010). "Idiopathic Infantile arterial calcification–A Very rare case". Online Journal of Health and Allied Sciences 9 (1). ISSN 0972-5997.
20. Inwald, D P; Yen Ho, S; Shepherd, M N; Daubeney, P E F (2006). "Idiopathic infantile arterial calcification presenting as fatal hypertensive cardiomyopathy". Archives of Disease in Childhood 91 (11): 928. doi:10.1136/adc.2006.103093. PMC 2082956. PMID 17056867.
21. Vera, J.; Lucaya, J.; Garcia Conesa, J. A.; Aso, C.; Balaguer, A. (1990). "Idiopathic infantile arterial calcification: Unusual features". Pediatric Radiology 20 (8): 585–7. doi:10.1007/BF02129060. PMID 2251001.
22. Conn, Jessica; Hussaini, Shaheen; Greenberg, S. Bruce; Vanderzalm, Theodora; Klein, Sarah G. "Idiopathic Arterial Calcification of Infancy" (PDF). Little Rock, Arkansas: University of Arkansas for Medical Sciences and Arkansas Children's Hospital.
23. Levine, J. C.; Campbell, J.; Nadel, A. (2001). "Prenatal Diagnosis of Idiopathic Infantile Arterial Calcification". Circulation 103 (2): 325–6. doi:10.1161/01.CIR.103.2.325. PMID 11208697.
24. Sundaram, S; Kuruvilla, S; Thirupuram, S (2004). "Idiopathic arterial calcification of infancy - a case report". Images in paediatric cardiology 6 (1): 6–12. PMC 3232550. PMID 22368635.
25. Dlamini, Nomazulu; Splitt, Miranda; Durkan, Anne; Siddiqui, Ata; Padayachee, Soundrie; Hobbins, Sue; Rutsch, Frank; Wraige, Elizabeth (2009). "Generalized arterial calcification of infancy: Phenotypic spectrum among three siblings including one case without obvious arterial calcifications". American Journal of Medical Genetics Part A 149A (3): 456–60. doi:10.1002/ajmg.a.32646. PMID 19206175.
26. Eller, Philipp; Hochegger, Kathrin; Feuchtner, Gudrun M.; Zitt, Emanuel; Tancevski, Ivan; Ritsch, Andreas; Kronenberg, Florian; Rosenkranz, Alexander R.; et al. (2007). "Impact of ENPP1 genotype on arterial calcification in patients with end-stage renal failure". Nephrology Dialysis Transplantation 23 (1): 321–7. doi:10.1093/ndt/gfm566.
27. Nasrallah, F. K.; Baho, H.; Sallout, A.; Qurashi, M. (2009). "Prenatal diagnosis of idiopathic infantile arterial calcification with hydrops fetalis". Ultrasound in Obstetrics and Gynecology 34 (5): 601–4. doi:10.1002/uog.7438. PMID 19813208.
28. Meradji, M.; De Villeneuve, V.H.; Huber, J.; De Bruijn, W.C.; Pearse, R.G. (1978). "Idiopathic infantile arterial calcification in siblings: Radiologic diagnosis and successful treatment". The Journal of Pediatrics 92 (3): 401–5. doi:10.1016/S0022-3476(78)80427-2. PMID 416189.
29. http://www.sonoworld.com/Client/Cases/CaseDetails.aspx?CaseId=27[]
30. Stuart, G; Wren, C; Bain, H (1990). "Idiopathic infantile arterial calcification in two siblings: Failure of treatment with diphosphonate". Heart 64 (2): 156–9. doi:10.1136/hrt.64.2.156.
31. Bellah, Richard D.; Zawodniak, Len; Librizzi, Ronald J.; Harris, Mary Catherine (1992). "Idiopathic arterial calcification of infancy: Prenatal and postnatal effects of therapy in an infant". The Journal of Pediatrics 121 (6): 930–3. doi:10.1016/S0022-3476(05)80345-2. PMID 1447660.
32. Ramjan, Kim A; Roscioli, Tony; Rutsch, Frank; Sillence, David; Munns, Craig FJ (2009). "Generalized arterial calcification of infancy: Treatment with bisphosphonates". Nature Clinical Practice Endocrinology & Metabolism 5 (3): 167–72. doi:10.1038/ncpendmet1067.
33. Dyck, M.; Proesmans, W.; Hollebeke, E.; Marchal, G.; Moerman, Ph. (1989). "Idiopathic infantile arterial calcification with cardiac, renal and central nervous system involvement". European Journal of Pediatrics 148 (4): 374–7. doi:10.1007/BF00444138. PMID 2707283.
34. Ramjan, Kim; Munns, Craig; Roscioli, Tony; Sillence, David. "Successful treatment of infantile arterial calcification (IAC) with bisphosphonates" (PDF).
35. Sluis, Inge M.; Boot, Annemieke M.; Vernooij, Meike; Meradji, Morteza; Kroon, André A. (2006). "Idiopathic infantile arterial calcification: Clinical presentation, therapy and long-term follow-up". European Journal of Pediatrics 165 (9): 590–3. doi:10.1007/s00431-006-0146-8. PMID 16649023.
36. Culling, Bronwyn; Loughran-Fowlds, Alison; Munns, Craig; Sillence, David; Walsh, Corrina; Taylor, Peter; Buckley, Michael; Rutsch, Frank; Roscioli, Tony (August 6–10, 2006). Infantile Arterial Calcification: Successful Treatment with Bisphosphonate. 11th International Congress of Human Genetics. Brisbane, Australia. Archived from the original on May 12, 2006.
37. Ciana, G.; Colonna, F.; Forleo, V.; Brizzi, F.; Benettoni, A.; de Vonderweid, U. (1997). "Idiopathic Arterial Calcification of Infancy: Effectiveness of Prostaglandin Infusion for Treatment of Secondary Hypertension Refractory to Conventional Therapy: Case Report". Pediatric Cardiology 18 (1): 67–71. doi:10.1007/s002469900114. PMID 8960499.
38. Glatz, Andrew C.; Pawel, Bruce R.; Hsu, Daphne T.; Weinberg, Paul; Chrisant, Maryanne R. K. (2006). "Idiopathic infantile arterial calcification: Two case reports, a review of the literature and a role for cardiac transplantation". Pediatric Transplantation 10 (2): 225–33. doi:10.1111/j.1399-3046.2005.00414.x. PMID 16573612.
39. Sholler, Gary F.; Yu, John S.; Bale, Patricia M.; Hawker, Richard E.; Celermajer, John M.; Kozlowski, Kasimir (1984). "Generalized arterial calcification of infancy: Three case reports, including spontaneous regression with long-term survival". The Journal of Pediatrics 105 (2): 257–60. doi:10.1016/S0022-3476(84)80123-7. PMID 6747757.
40. Marrott, Pran K.; Newcombe, Ken D.; Becroft, David M. O.; Friedlander, Denis H. (1984). "Idiopathic infantile arterial calcification with survival to adult life". Pediatric Cardiology 5 (2): 119–22. doi:10.1007/BF02424963. PMID 6473121.
41. Ciana, Giovanni; Trappan, Antonella; Bembi, Bruno; Benettoni, Alessandra; Maso, Giampaolo; Zennaro, Floriana; Ruf, Nico; Schnabel, Dirk; Rutsch, Frank (2005). "Generalized arterial calcification of infancy: Two siblings with prolonged survival". European Journal of Pediatrics 165 (4): 258–63. doi:10.1007/s00431-005-0035-6. PMID 16315058.
42. Thomas, Philomena; Chandra, Manju; Kahn, Ellen; McVicar, Melinda; Naidich, James; Lacorte, Michael (1990). "Idiopathic arterial calcification of infancy: A case with prolonged survival". Pediatric Nephrology 4 (3): 233–5. doi:10.1007/BF00857661. PMID 2400650.
43. Cheng, Kun-Shan; Chen, Ming-Ren; Ruf, Nico; Lin, Shuan-Pei; Rutsch, Frank (2005). "Generalized arterial calcification of infancy: Different clinical courses in two affected siblings". American Journal of Medical Genetics Part A 136A (2): 210–3. doi:10.1002/ajmg.a.30800.

External links

• OMIM 208000