Distinct phenotypes associated with the same homozygous ENPP1 c.26dup variant

ENPP1 pathogenic variants have been associated with a wide phenotypic spectrum, ranging from generalized arterial calcification of infancy to vascular stenoses and autosomal recessive hypophosphatemic rickets.

This study presents two cases of cousins who are homozygous for the c.26dup (p.Gly10ArgfsTer67) variant in the ENPP1 gene, but who exhibit distinct clinical features. The first patient developed hypophosphatemic rickets in early childhood. He was subsequently diagnosed with hypertension due to multiple arterial stenoses. In the second case, prenatal monitoring revealed generalized vascular calcification of intrauterine onset. Postnatally, the patient was diagnosed with heart failure, for which medical therapy was initiated, and early parenteral pamidronate was administered. However, the infant died during infancy due to a respiratory infection.

These findings suggest that ENPP1 variants may manifest with heterogeneous phenotypes and modifying factors may influence the variant's clinical expression. Case 1 was previously reported with limited clinical information as part of a national Turkish cohort of patients with autosomal recessive hypophosphatemic rickets type 2 caused by ENPP1 deficiency. However, as the study was a cohort analysis, it did not comprehensively describe the patient's clinical course, cardiovascular involvement, long-term follow-up, or the intrafamilial phenotypic variability observed within the affected family. Our report contributes to a better understanding of this rare genetic disorder's clinical spectrum and to clarifying the genotype-phenotype correlation.