ESPE Abstracts (2018) 89 P-P2-048

Infantile Arterial Calcification and Subsequent Hypophosphatemia due to ENPP1 Mutation - A Case Followed through to Adulthood

Munier Noura, Mark Inmana & Terra Arnasonb


aDivision of Pediatric Endocrinology, Department of Pediatrics, University of Saskatchewan, Saskatoon, Canada; bDivision of Endocrinology, Department of Medicine, University of Saskatchewan, Saskatoon, Canada


Introduction: Infantile Arterial Calcification (IAC) is a rare and frequently lethal condition. Children who survive the infantile period may develop fibroblast growth factor 23 (FGF23) mediated hypophosphatemia and rickets when IAC is due to mutations in the ENPP1 gene.

Case: We present a female patient born to a family whose previous child died at birth with extensive vascular calcifications. Akin to the first sibling, our case presented with extensive calcifications noted antenatally, involving the coronary arteries and cardiac valves. The patient survived infancy, treated compassionately with a first-generation bisphosphonate (Etidronate). However, by 4-months-of-age, hypophosphatemia and rickets developed requiring phosphate and calcitriol treatment while calcifications remained stable. During puberty, new calcifications developed and hypophosphatemia therapy was discontinued. Calcifications remained stable as an adult until the initiation of an oral contraceptive pill (OCP), where acute worsening of calcifications was noted necessitating exploration of further therapies. A compound heterozygous genetic mutations in the ENPP1 gene was confirmed.

Discussion: Patients with ENPP1 mutations that survive infancy present a unique balance between bone hypomineralization paradoxically coexisting with extraskeletal calcifications. In our patient, the onset of new calcifications during puberty, followed by further exacerbation upon OCP initiation, has led the authors to query if estrogen may modulate extraskeletal calcifications. Symptoms and calcifications seemingly occurred exclusively during three distinct periods of predicted increased estrogen concentrations: early infancy, puberty and with OCP initiation. There is no literature to support this hypothesis to our knowledge, yet it is an intriguing avenue of exploration. While a great deal remains to be delineated in FGF23 regulation, clear differences have been observed in infancy, adolescence and between sexes that may offer understanding in mineral homeostasis. Experimental therapies to minimize calcium deposits and reverse systemic calcifications in IAC and other conditions have been proposed. These therapies include first-generation bisphosphonates, oral sodium thiosulfate and oral acetazolamide, although little literature support exists for these therapies outside of isolated case reports and series.

Conclusion: IAC is a rare and often fatal condition in infancy. Here, we present an adult survivor of IAC arising from a proven ENPP1 mutation, allowing a unique look at possible exacerbating and mitigating factors for calcium-phosphate deposition. The apparent exacerbation of calcification formation during times of increased estrogen exposures prompts consideration for a mechanistic link. Further analysis of the disease course may offer insights into the underlying mechanisms of mineral homeostasis and opportunities for future therapeutic targets.

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