Low levels of urinary inorganic pyrophosphate indicating systemic pyrophosphate deficiency in a boy with idiopathic infantile arterial calcification

Rutsch, Frank; Schauerte, P; Kalhoff, H.; Petrarulo, Michele; August, Christian; Diekmann, L

doi:10.1111/j.1651-2227.2000.tb00747.x

Cited by 49 publications

(26 citation statements)

References 12 publications

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“…The disease is inherited in an autosomal recessive manner so that it is not uncommon for siblings to be affected [3,13,14]. In the past, GACI was also referred to as "Idiopathic Infantile Arterial Calcification (IIAC)" [11,16]. Recently, mutations in ENPP1 encoding ecto-nucleotide pyrophosphatase/ phosphodiesterase 1 (E-NPP1) have been identified as the underlying genetic defect in most of the cases studied [10].…”

Section: Discussionmentioning

confidence: 98%

“…Generalized arterial calcification of infancy (GACI) is associated with the deposition of hydroxyapatite crystals in the media of the large-and medium-sized muscular arteries and in peri-articular soft tissue [11,12]. The disease is inherited in an autosomal recessive manner so that it is not uncommon for siblings to be affected [3,13,14].…”

Section: Discussionmentioning

confidence: 99%

“…Coronary artery involvement can lead to death within the first 6 months of life [6,15] and, in general, the prognosis is considered to be poor, although occasional long-term survival has been reported [4,14]. The disease has recently been found to be caused by mutations in the ENPP1 gene [13] which encodes for ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (E-NPP1), an enzyme that generates inorganic pyrophosphate, a potent inhibitor of hydroxyapatite crystal formation [11,12].…”

Section: Introductionmentioning

confidence: 98%

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Generalized arterial calcification of infancy: two siblings with prolonged survival

et al. 2005

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In generalized arterial calcification of infancy (OMIM no. 208000), calcification of the media and proliferation of the intima lead to arterial stenoses. Most affected patients present with untreatable arterial hypertension and die within the first months of life. The disease has recently been linked to mutations in ENPP1. We report two siblings with prolonged survival, both of whom carry the compound heterozygous ENPP1 mutations c.913C>A and c.1164+2T>A. In both siblings, spontaneous regression of arterial calcifications occurred, and antihypertensive treatment could be tapered off gradually. In some patients, the natural course of GACI may be more favourable than previously assumed.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Generalized arterial calcification of infancy: two siblings with prolonged survival

et al. 2005

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“…(33) EHDP binds to the surface of matrix vesicles, and impairs their crystallization of calcium and phosphate. (34) Hence, EHDP was used to treat GACI (16) long before low levels of PPi were identified in its pathogenesis (35,36) and its genetic basis was discovered in 2003. (6) EHDP treatment for GACI was supported by two clinical observations: (1) hydroxyapatite (HA) was found in specimens of arteries from GACI patients postmortem, (3) and (2) EHDP seemed promising as an inhibitor of ectopic bone formation in fibrodysplasia ossificans progressiva (FOP).…”

Section: Discussionmentioning

confidence: 99%

Severe skeletal toxicity from protracted etidronate therapy for generalized arterial calcification of infancy

Otero

Gottesman

McAlister

et al. 2012

Journal of Bone and Mineral Research

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Generalized arterial calcification (AC) of infancy (GACI) is an autosomal recessive disorder that features hydroxyapatite deposition within arterial elastic fibers. Untreated, approximately 85% of GACI patients die by 6 months of age from cardiac ischemia and congestive heart failure. The first-generation bisphosphonate etidronate (EHDP; ethane-1-hydroxy-1,1-diphosphonic acid, also known as 1-hydroxyethylidene-bisphosphonate) inhibits bone resorption and can mimic endogenous inorganic pyrophosphate by blocking mineralization. With EHDP therapy for GACI, AC may resolve without recurrence upon treatment cessation. Skeletal disease is not an early characteristic of GACI, but rickets can appear from acquired hypophosphatemia or prolonged EHDP therapy. We report a 7-year-old boy with GACI referred for profound, acquired, skeletal disease. AC was gone after 5 months of EHDP therapy during infancy, but GACI-related joint calcifications progressed. He was receiving EHDP, 200 mg/day orally, and had odynodysphagia, diffuse opioid-controlled pain, plagiocephaly, facial dysmorphism, joint calcifications, contractures, and was wheelchair bound. Biochemical parameters of mineral homeostasis were essentially normal. Serum osteocalcin was low and the brain isoform of creatine kinase and tartrate-resistant acid phosphatase 5b (TRAP-5b) were elevated as in osteopetrosis. Skeletal radiographic findings resembled pediatric hypophosphatasia with pancranial synostosis, long-bone bowing, widened physes, as well as metaphyseal osteosclerosis, cupping and fraying, and ''tongues'' of radiolucency. Radiographic features of osteopetrosis included osteosclerosis and femoral Erlenmeyer flask deformity. After stopping EHDP, he improved rapidly, including remarkable skeletal healing and decreased joint calcifications. Profound, but rapidly reversible, inhibition of skeletal mineralization with paradoxical calcifications near joints can occur in GACI from protracted EHDP therapy. Although EHDP treatment is lifesaving in GACI, surveillance for toxicity is crucial. ß

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“…There are reports in the literature of long-term survival with resolution of calcification associated with bisphosphonate treatment [Meradji et al, 1978;Van Dyck et al, 1989;Rutsch et al, 2000] but there are also reports of spontaneous resolution of calcification [Marrott et al, 1984;Ciana et al, 2006;van der Sluis et al, 2006] and of fatal outcome despite treatment [Stuart et al, 1990]. Arterial stenosis due to intimal proliferation may also occur in areas devoid of calcification [Witzleben, 1970;Thomas et al, 1990] and persist despite resolution of calcification indicating it may be independent of calcification [Thiaville et al, 1994;Rutsch et al, 2000].…”

Section: Discussionmentioning

confidence: 90%

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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Low levels of urinary inorganic pyrophosphate indicating systemic pyrophosphate deficiency in a boy with idiopathic infantile arterial calcification

Cited by 49 publications

References 12 publications

Generalized arterial calcification of infancy: two siblings with prolonged survival

Generalized arterial calcification of infancy: two siblings with prolonged survival

Severe skeletal toxicity from protracted etidronate therapy for generalized arterial calcification of infancy

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

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