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

Abstract

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.

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

“…(43) Also in 2009, other investigators reported their plan to stop risedronate therapy after 3 years of successful treatment of a GACI patient. (44) Hence, PPi-like effects of all BPs might reverse the AC of GACI. Of interest, nitrogen-containing BPs are now being assessed for calcific aortic stenosis.…”

A Tale of Two Sisters: Idiopathic Arterial Calcification of Infancy in Siblings

“…Ultrasound showed diffusely hyperechoic abdominal aorta, common iliac arteries and renal arteries, generalized and diffuse calcification of the carotid arteries and increased echogenicity in the anterior cerebral and middle cerebral arteries, all with normal Doppler velocities. DNA sequencing of the ENPP1 gene showed a homozygous mutation in exon 14 at c.1412A>G, a mutation previously reported as disease-causing for IACI [1][2][3]. DNA analysis in each parent demonstrated heterozygosity for the same defect.…”

“…Coronary artery involvement can be lethal within the first 6 months. Several case studies have described patients who survived into adulthood with persistent hypertension and cardiovascular squealae; however, approximately 85% of affected infants do not survive beyond 6 months of age [1].…”

“…IACI is inherited in an autosomal recessive pattern. Treatment with bisphosphonates, which are synthetic pyrophosphate analogues, has been proposed as a means of reducing arterial calcifications in IACI patients, but reported treatment regimens vary considerably both in terms of the specific bisphosphonate employed and the dose and duration of treatment [1][2][3].…”

Generalized Arterial Calcification of Infancy: Fatal Clinical Course Associated with a Novel Mutation in ENPP1

“…Myointimal proliferation is found to be associated with calcified spots, but may also occur in areas lacking calcification and vice versa. This suggests a separate pathological process involved in the development of GACI (Dlamini et al 2009). The aorta, renal, mesenteric, and carotid arteries are usually involved, while the cerebral vessels are commonly spared by the calcification process (Rutsch et al 2008).…”