Novel Mutation in CYP2R1 Causing Vitamin D-Dependent Rickets Type 1b

Area of Science:

• Genetics
• Endocrinology
• Pediatrics

Background:

• Monogenic forms of rickets are increasingly recognized.
• Vitamin D-dependent rickets 1b (VDDR1b) is a rare condition caused by CYP2R1 gene mutations.
• Nutritional rickets is common, but resistance to treatment suggests underlying genetic causes.

Observation:

• A 4.5-year-old girl and her sibling presented with rickets unresponsive to standard vitamin D therapy.
• Clinical, radiological, and biochemical findings were initially suggestive of nutritional rickets.
• Genetic evaluation revealed a novel homozygous CYP2R1 variant (c.50_51insTCGGCGGCGC; p.Leu18ArgfsTer79).

Findings:

• The identified CYP2R1 variant is a novel cause of VDDR1b.
• Affected siblings showed a good clinical and radiological response to calcium and cholecalciferol therapy.
• Treatment was titrated to maintain normal levels of alkaline phosphatase, 25-hydroxyvitamin D, and parathyroid hormone.

Implications:

• This case underscores the importance of genetic testing for suspected nutritional rickets with treatment resistance or family history.
• Early identification of VDDR1b enables targeted therapy and prevents long-term complications.
• This is the first reported case of VDDR1b due to CYP2R1 mutation from Asia, expanding the geographic and genetic understanding of the condition.