ESPE Abstracts

Background: Hereditary hypophosphatemic rickets (HHR) comprises a group of rare disorders characterized by renal phosphate wasting and impaired vitamin D metabolism. Numerous genetic defects can underlie this condition, with the X-linked dominant form (XLHR) being the most prevalent (1 in 20,000 individuals) resulting from inactivating variants in the PHEX gene.

Aim: To characterize a large cohort of 99 argentinian patients with HHR.

Patients and Methods: Molecular studies were performed on 80 individuals (including patients and affected family members) from 60 unrelated families, suspected of suffering from HHR based on clinical, radiological, and laboratory criteria followed by our interdisciplinary team between 2017-2023. Initially, Sanger sequencing of the PHEX gene was performed. In female cases where no alterations were detected, MLPA analysis was pursued. Patients lacking proven variations were analyzed using an NGS custom panel including CLCN5, CYP24A1, OCRL, PHEX, CYP27B1, CYP2R1, DMP1, ENPP1, FAM20C, FGF23, MEPE, SLC34A1, SLC34A3, SLC9A3R1, and VDR genes. Immediate relatives of confirmed XLHR patients with compatible phenotype and inheritance pattern were considered positive for the same variant.

Results: Pathogenic variants were identified in 53 out of 60 unrelated families (88.3%): 49 exhibited mutations in PHEX, 3 in SLC34A3, and 1 in the ENPP1 gene. No pathogenic variants were found in 7 unrelated families. Among the 49 XLHR cases: 28 were sporadic, and 21 were familial cases affecting 56 members (patients and relatives), with a female-to-male ratio of 3:1. Among the 3 cases with HHR with hypercalciuria (SLC34A3): 2 were sporadic, and 1 was a familial case involving 2 affected brothers, with a female-to-male ratio of 0:4. All 6 parents were heterozygous carriers. The median pretreatment phosphatemia and calciuria levels in these patients were significantly higher compared to children with XLHR, while median PTH levels were lower. The only case with the autosomal recessive form (ENPP1) was a girl exhibiting a phenotype similar to XLHR, her parents were heterozygous carriers. Among the 7 cases without identified pathogenic variants: 5 were sporadic, and 2 were familial cases involving 2 and 3 affected members respectively, with a female-to-male ratio of 1:1.

Conclusion: Our findings underscore the importance of careful clinical selection and an intelligent genetic approach, resulting in a molecular diagnosis in 88.3% of HHR cases. In our cohort, HHR with hypercalciuria emerged as the second most commonly confirmed subtype, presenting with distinct familial history, clinical, and biochemical features that distinguish it from XLHR and the exceptionally rare autosomal recessive forms