MON-749 - Long-Term Survival and Phenotypic Expansion in Siblings with Generalized Arterial Calcification of Infancy

Generalized arterial calcification of infancy (GACI) provides a rare model of dysregulated pyrophosphate and phosphate metabolism, with profound implications for vascular mineralization, FGF23 biology, and long-term skeletal outcomes .
GACI is a rare, often fatal disorder caused by biallelic pathogenic ENPP1 or ABCC6 variants, leading to severe neonatal vascular calcification. Mortality in the first year of life ranges from 55-85%, and long-term survivors frequently develop hypophosphatemic rickets and pseudoxanthoma elasticum (PXE)-like skin changes.
We describe two siblings with a rarely reported homozygous ENPP1 variant (c.1367G>A, p.Arg456Gln) and provide a detailed longitudinal clinical, biochemical, and imaging characterization. The family previously had one child who died at four months from genetically confirmed GACI and one miscarriage (affected status unknown). The two surviving siblings were diagnosed shortly after birth and presented in the neonatal period with extensive vascular calcifications involving the aorta, coronary arteries, and major branch vessels. Both received early bisphosphonate therapy and survived into adolescence and school age (currently 12 and 8 years old).
Echocardiography and CT angiography showed persistent large-vessel and coronary calcifications rather than the regression described in prior series. Both children developed hypertension requiring medical therapy, however, they remain clinically asymptomatic and hemodynamically stable. One sibling experienced significant orthopedic morbidity with right hip dysplasia requiring adductor release surgery, whereas the other had no skeletal deformities.
Both developed extravascular manifestations unusually early, including PXE-like skin lesions (onset ages 2 and 7), auricular cartilage calcifications, and retinal vascular changes. Persistent hypophosphatemia with elevated or high-normal FGF23 was present in both, yet neither shows radiographic rickets. One sibling demonstrated an unusual improvement in tubular phosphate reabsorption over time despite elevated FGF23, suggesting a potential compensatory mechanism or variant-specific modifier effect. These findings differ from conventional ENPP1-related GACI phenotypes and suggest variant-specific biochemical and tissue-level effects.

These cases illustrate how ENPP1 deficiency disrupts pyrophosphate and phosphate homeostasis across multiple tissues, resulting in persistent vascular calcification and hypophosphatemia without rickets. The unique FGF23-TRP dissociation in one sibling suggests previously unrecognized compensatory adaptations. Together, these findings broaden the clinical spectrum of GACI and emphasize the importance of ongoing endocrine, cardiovascular, and dermatologic surveillance as well as emerging ENPP1-based therapeutics.

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