Idiopathic arterial calcification in infancy

Morton, R E

doi:10.1111/j.1365-2559.1978.tb01736.x

Cited by 42 publications

(25 citation statements)

References 10 publications

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“…Patient history and clinical data were gathered through a standardized questionnaire, which was sent to the referring physician or geneticist. Diagnosis of GACI was based on the presence of cardiovascular symptoms associated with evidence of arterial calcification with or without periarticular calcification on x-ray or sonography in infancy,1 or typical histology20 (Figure 1). Diagnosis of GACI is exemplified in the following case report: The male infant (case 6 of our study) was born to consanguineous Turkish parents.…”

Section: Methodsmentioning

confidence: 99%

Hypophosphatemia, Hyperphosphaturia, and Bisphosphonate Treatment Are Associated With Survival Beyond Infancy in Generalized Arterial Calcification of Infancy

Rutsch

Böyer

Nitschke

et al. 2008

Circ Cardiovasc Genet

198

294

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, MD; the GACI Study GroupBackground-Generalized arterial calcification of infancy has been reported to be frequently lethal, and the efficiency of any therapy, including bisphosphonates, is unknown. A phosphate-poor diet markedly increases survival of NPP1 null mice, a model of generalized arterial calcification of infancy. Methods and Results-We performed a multicenter genetic study and retrospective observational analysis of 55 subjects affected by generalized arterial calcification of infancy to identify prognostic factors. Nineteen (34%) patients survived the critical period of infancy. In all 8 surviving patients tested, hypophosphatemia due to reduced renal tubular phosphate reabsorption developed during childhood. Eleven of 17 (65%) patients treated with bisphosphonates survived. Of 26 patients who survived their first day of life and were not treated with bisphosphonates only 8 (31%) patients survived beyond infancy. Forty different homozygous or compound heterozygous mutations, including 16 novel mutations in ENPP1, were found in 41 (75%) of the 55 patients. Twenty-nine (71%) of these 41 patients died in infancy (median, 30 days). Seven of the 14 (50%) patients without ENPP1 mutations died in infancy (median, 9 days). When present on both alleles, the mutation p.P305T was associated with death in infancy in all 5 cases; otherwise, no clear genotype-phenotype correlation was seen. Conclusion-ENPP1 coding region mutations are associated with generalized arterial calcification of infancy in Ϸ75% of subjects. Except for the p.P305T mutation, which was universally lethal when present on both alleles, the identified ENPP1 mutations per se have no discernable effect on survival. However, survival seems to be associated with hypophosphatemia linked with hyperphosphaturia and also with bisphosphonate treatment. ENPP1 encodes a type II transmembrane glycoprotein ectoenzyme that forms homodimers of identical disulfidebonded subunits. 7 NPP1 has an extracellular catalytic domain as well as somatomedin B-like and substrate-binding or substrate-specifying nuclease-like domains. 8 NPP1 regulates soft tissue calcification and bone and joint cartilage mineralization by generating PP i , which not only serves as an essential physiological inhibitor of hydroxyapatite crystal growth 9 but also is a suppressor of chondrogenesis. 10 In artery smooth muscle cells, deficiencies of NPP1 (or of extracellular PP i without NPP1 deficiency in ank/ank mice homozygous for functional inactivation of the PP i transporter ANK) promote chondrogenic transdifferentiation in vivo and also in vitro under circumstances where excess of an inorganic phosphate (P i ) source is provided. 10,11 Although the pathophysiologic role of NPP1-mediated PP i generation in GACI has come to light within recent years, the factors accounting for the variation of the GACI phenotype including the presence or absence of intracerebral artery calcification and periarticular calcification, early death in utero and long-term survival are not known. 12 PP i and ...

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Section: Methodsmentioning

confidence: 99%

Hypophosphatemia, Hyperphosphaturia, and Bisphosphonate Treatment Are Associated With Survival Beyond Infancy in Generalized Arterial Calcification of Infancy

Rutsch

Böyer

Nitschke

et al. 2008

Circ Cardiovasc Genet

198

294

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“…The pathogenesis of GACI is related to reduced NPP1 enzymatic activity leading to low extracellular PP i levels. [13–15]…”

Section: Discussionmentioning

confidence: 99%

Molecular diagnosis of generalized arterial calcification of infancy (GACI)

Kalal¹,

Dayakar²,

Panda³

et al. 2012

Journal of Cardiovascular Disease Research

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Generalized arterial calcification of infancy (GACI) is a life-threatening disorder in young infants. Cardiovascular symptoms are usually apparent within the first month of life. 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 the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene were reported as causative for the disorder. ENPP1 regulates extracellular inorganic pyrophosphate (PPi), a major inhibitor of extracellular matrix calcification. A newborn was diagnosed with GACI. The infant died at the age of 7 weeks of cardiac failure and the parents were referred to Molecular Biology and Cytogenetic lab for further workup. Cytogenetics analysis was performed on the parents, which showed normal karyotypes and mutational analysis for the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene was also performed. The mutational analysis showed that both father and mother of the deceased infant were heterozygous carriers of the mutation c.749C>T (p.P250L) in exon 7 of ENPP1 and it was likely, that the deceased child carried the same mutation homozygous on both alleles and died of GACI resulting from this ENPP1 mutation. The couple was counseled and monitored for the second pregnancy. Amniocentesis was performed at 15 weeks of gestation for mutational analysis of the same gene in the second pregnancy. The analysis was negative for the parental mutations. One month after the birth of a healthy infant, peripheral blood was collected from the baby and sent for reconfirmation. The results again were negative for the mutation and the baby was on 6 months follow up and no major symptoms were seen. The parents of the child benefited enormously by learning about the disease much in advance and also its risk of recurrence. The main aim of this study is to emphasize on two aspects: (i) the importance of modern molecular techniques in diagnosis such a syndrome and (2) the difficulties faced by the physician to provide appropriate diagnosis and the adequate genetic counseling to the family without molecular facilities.

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“…Calcification may also occur in areas devoid of intimal thickening [Morton, 1978]. Exceptional case reports have indicated that calcification identified in earlier life is not always persistent [Marrott et al, 1984;Sholler et al, 1984;Ciana et al, 2006].…”

Section: Discussionmentioning

confidence: 99%

Generalized arterial calcification of infancy: Phenotypic spectrum among three siblings including one case without obvious arterial calcifications

Dlamini

Splitt

Durkan

et al. 2009

American J of Med Genetics Pt A

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Generalized arterial calcification of infancy (GACI) (OMIM no. 208000) is characterized by calcification of the major arteries and soft tissues and associated with mutations in the ENPP1 gene. Most affected patients die within the first 6 months of life although prolonged survival is increasingly recognized. We report on three siblings with GACI and striking phenotypic variability. Two siblings (including the sibling survivor) were compound heterozygotes for mutations in exon 7 (c.783C>G (p.Y261X)) and exon 8 (c. 878_879delAA (p.K293fsX5)) of the ENPP1 gene confirming the diagnosis of GACI. The sibling survivor did not have calcification on X-ray studies or evidence of hypophosphatemic rickets. GACI may be under recognized and we emphasize consideration of this condition in patients with multiple arterial stenosis even in the absence of radiographic calcification. This adds to the expanding phenotype of GACI and supports a potential role for modifying genes.

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Idiopathic arterial calcification in infancy

Cited by 42 publications

References 10 publications

Hypophosphatemia, Hyperphosphaturia, and Bisphosphonate Treatment Are Associated With Survival Beyond Infancy in Generalized Arterial Calcification of Infancy

Hypophosphatemia, Hyperphosphaturia, and Bisphosphonate Treatment Are Associated With Survival Beyond Infancy in Generalized Arterial Calcification of Infancy

Molecular diagnosis of generalized arterial calcification of infancy (GACI)

Generalized arterial calcification of infancy: Phenotypic spectrum among three siblings including one case without obvious arterial calcifications

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