Generalized arterial calcification of infancy: different clinical courses in two affected siblings

Area of Science:

• Genetics and Molecular Biology
• Pediatrics
• Cardiovascular Medicine

Background:

• Generalized arterial calcification of infancy (GACI) is a rare, severe autosomal recessive disorder.
• It is characterized by extensive arterial calcification, intimal proliferation, and vascular occlusion, often leading to early mortality.
• Mutations in the ENPP1 gene are the primary cause of GACI.

Observation:

• This report details two Taiwanese siblings with identical compound heterozygous ENPP1 mutations (c.1025G > T [p.Gly342Val] and c.1112A > T [Tyr371Phe]).
• Both siblings presented with similar early infantile sonographic and radiographic findings characteristic of GACI.
• Despite the shared genotype and initial presentation, their clinical courses diverged significantly.

Findings:

• The male sibling experienced severe heart failure and hypertension, succumbing at 6 weeks of age despite aggressive medical management.
• The female sibling, with close prenatal and postnatal monitoring, has maintained an uncomplicated clinical course to 1.5 years of age.
• This case series underscores the significant intrafamilial phenotypic variability in GACI.

Implications:

• The findings suggest that factors beyond ENPP1 genotype influence GACI's clinical manifestation and severity.
• Understanding these modulating factors is crucial for predicting disease progression and optimizing therapeutic strategies.
• This variability emphasizes the need for individualized patient monitoring and management in rare genetic disorders like GACI.