Phenotypes and Genotypes of Children with Vitamin D-Dependent Rickets Type 1A: A Single Tertiary Pediatric Center in...

Background: Vitamin D-dependent rickets type 1A (VDDR1A) is a rare autosomal recessive disorder caused by mutations in the CYP27B1 gene, leading to a deficiency in active vitamin D (1,25-dihydroxyvitamin D). This study examines the genotypic and phenotypic characteristics of VDDR1A in Vietnamese children. Patients and Methods: A retrospective analysis was conducted on 19 Vietnamese children diagnosed with VDDR1A. Clinical, radiological, biochemical, and molecular data were collected. Rickets Severity Scores (RSSs), biochemical parameters, and height standard deviation scores (HtSDSs) were used to assess the severity of the condition. Results: The study included 19 children from 17 families (ten males and nine females). The median age of rickets diagnosis was 19.2 months, while with VDDR1A, the median time of diagnosis was 7.5 months. Common symptoms among the children included thickened wrists and ankles (19/19), genu varum or genu valgum (18/19), failure to thrive (18/19), rachitic rosary (12/19), and delayed walking (11/19). The radiographic features showed that all children had cupping, splaying, and fraying, twelve children had rachitic rosary, and six exhibited pseudofractures. The biochemical findings showed severe hypocalcemia, normal or mildly low serum phosphate, elevated alkaline phosphatase and parathyroid hormone levels, and normal serum 25-hydroxyvitamin D levels. Genetic analysis identified biallelic CYP27B1 variants, including one known pathogenic frameshift mutation, c.1319_1325dup p.(Phe443Profs*24), one novel likely pathogenic missense variant, c.616C>T p.(Arg206Cys), and one novel pathogenic frameshift mutation, c.96_97del p.(Ala33Thrfs*299). The c.1319_1325dup p.(Phe443Profs*24) variant was the most common, present in 18 out of 19 children. Conclusions: The children with VDDR1A in this study presented with growth failure and skeletal deformities. Key findings included severe hypocalcemia, elevated alkaline phosphatase and parathyroid hormone levels, normal or elevated 25(OH)D, and high RSSs. Predominant frameshift mutations in CYP27B1, especially c.1319_1325dup, highlighted the importance of early genetic diagnosis for optimal management. Additionally, two novel CYP27B1 variants were identified, expanding the known mutation spectrum of VDDR1A.