ENPP1 deficiency in siblings with apparently discordant phenotypes: case report and a review of the literature

Objectives ENPP1 deficiency encompasses a phenotypic spectrum from generalized arterial calcification of infancy (GACI) to autosomal recessive hypophosphatemic rickets type 2 (ARHR2), and phenotypic variability has been reported even among individuals carrying the same variants; however, the extent of intrafamilial phenotypic concordance remains unclear. Case presentation Case 1, a 20-month-old boy, presented with genu varum and fibroblast growth factor 23-mediated hypophosphatemic rickets. Genetic testing identified compound heterozygous ENPP1 variants, c.937_938insT (p.Gln313LeufsTer18), and a deletion involving exons 8–13. Ultrasonography revealed valvular calcifications, carotid intimal irregularity, and nephrocalcinosis. Case 2, his younger brother, developed fetal hydrops, diffuse cardiovascular calcification, and severe cardiac dysfunction in late gestation and died shortly after preterm birth. Postmortem examination demonstrated extensive vascular calcification consistent with GACI; genetic testing identified the same variants. A sibling-based literature review of genetically confirmed cases with shared biallelic ENPP1 variants identified 21 publications describing 26 unrelated families. Including the present family, 27 families comprising 61 affected individuals were analyzed; 24 families (88.9 %) had concordant phenotypes, whereas three (11.1 %) had discordant phenotypes. Among 19 individuals who presented with hypophosphatemia or ARHR2 without a documented history of GACI and underwent cardiovascular, calcification, and/or hearing assessment, 14 had abnormal findings. Conclusions Documented GACI status was generally concordant among affected siblings. Frequent cardiovascular, calcification-related, and/or hearing abnormalities in patients presenting with hypophosphatemia or ARHR2 without a documented history of GACI highlight the importance of multisystem assessment and support GACI and ARHR2 as overlapping manifestations within the ENPP1 deficiency spectrum.