Phenotypic Variability in Vitamin D-Dependent Rickets Type 1a: A Case Report of Two Children With the Same CYP27B1 Mutation.

Abstract

Background: Vitamin D-dependent rickets Type 1A (VDDR1A) is a rare autosomal recessive disorder caused by pathogenic variants in CYP27B1, resulting in impaired renal 1α-hydroxylation of 25-hydroxyvitamin D. The consequent deficiency of active vitamin D disrupts calcium-phosphate homeostasis and causes rickets. Although VDDR1A is monogenic, clinical severity may vary considerably even among patients with the same mutation.

Case presentation: We describe two unrelated Saudi boys with genetically confirmed VDDR1A who both harbored the same homozygous CYP27B1 c.1286G > C (p.Arg429Pro) variant but exhibited markedly different clinical courses. The first child presented at 7 months of age with hypocalcemic seizures and classical radiographic features of rickets but preserved growth. Early initiation of alphacalcidol and calcium supplementation was associated with biochemical improvement, resolution of seizures, and favorable clinical recovery by 2.5 years of age. In contrast, the second child was diagnosed at 16 months after developmental delay, recurrent respiratory infections, growth failure, and early skeletal deformities. Long-term follow-up into adolescence revealed severe bowing deformities, kyphoscoliosis, osteopenia, and healed fractures in the setting of delayed diagnosis and inconsistent treatment adherence, despite receiving the same therapy.

Conclusion: These cases highlight substantial phenotypic variability in VDDR1A even in children harboring the same CYP27B1 mutation. Early recognition and sustained treatment with active vitamin D therapy are crucial to prevent severe skeletal complications and optimize growth, particularly in populations with high rates of consanguinity.