Phenotypic Diversity in Autosomal Recessive Hypophosphatemic Rickets Type 2.

Abstract

Autosomal Recessive Hypophosphatemic Rickets Type 2 (ARHR2) caused by biallelic ENPP1 mutations is a rare disorder with a broad phenotypic spectrum. We describe three affected siblings from a consanguineous family who presented with markedly heterogeneous clinical features. The proband exhibited classical signs of rickets with progressive lower-limb deformities, short stature, and elevated alkaline phosphatase. Her older sister demonstrated limited elbow extension, conductive hearing loss, and vascular stenoses, while the youngest sibling developed early biochemical abnormalities before overt skeletal manifestations of rickets emerged. All affected children had hypophosphatemia, reduced TmP/GFR, and elevated or inappropriately normal FGF23 concentrations, consistent with FGF23-mediated phosphate wasting. Notably, plasma inorganic pyrophosphate (PPi) levels were markedly reduced in the affected children and mildly reduced in the carriers of monoallelic mutation. Genetic testing identified a homozygous ENPP1 variant, c.2559_2561del p.(Leu854del), which was essential for establishing the diagnosis and distinguishing ARHR2 from other hereditary forms of hypophosphatemic rickets. The father had low lumbar spine bone mineral density. These cases highlight the clinical heterogeneity of ENPP1 deficiency and reinforce the essential role of genetic testing in establishing the correct diagnosis.