Generalized arterial calcification of infancy: two siblings with prolonged survival

Area of Science:

• Genetics
• Pediatric Cardiology
• Biochemistry

Background:

• Generalized Arterial Calcification of Infancy (GACI) is a severe genetic disorder characterized by medial calcification and intimal proliferation, leading to arterial stenosis, hypertension, and early mortality.
• GACI is associated with mutations in the ENPP1 gene, which encodes ectonucleotide pyrophosphatase phosphodiesterase 1, a key enzyme in regulating extracellular matrix mineralization.
• The severe phenotype typically results in untreatable arterial hypertension and a fatal outcome within the first few months of life.

Observation:

• This report details two siblings diagnosed with GACI who presented with compound heterozygous mutations in ENPP1 (c.913C>A and c.1164+2T>A).
• Remarkably, both siblings exhibited spontaneous regression of arterial calcifications.
• Antihypertensive therapy was successfully tapered off in both affected individuals, indicating a significant improvement in their condition.

Findings:

• The identified compound heterozygous ENPP1 mutations c.913C>A and c.1164+2T>A were associated with a prolonged survival in the affected siblings.
• Spontaneous regression of arterial calcifications was observed in these patients, challenging the previously understood progressive nature of the disease.
• Successful tapering of antihypertensive medication suggests a potential for improved cardiovascular outcomes.

Implications:

• These findings suggest that the natural course of GACI may be more variable and potentially more favorable than previously assumed in certain genetic contexts.
• The observation of spontaneous regression highlights the complex pathophysiology of GACI and may offer insights into potential therapeutic targets.
• Further research into the specific ENPP1 mutations and their impact on disease progression is warranted to understand the variability in GACI phenotypes and to guide clinical management.