Abstract
Background: Vitamin D-dependent rickets type 1A (VDDR1A) is a rare autosomal recessive disorder caused by pathogenic variants in the CYP27B1 gene, typically characterized by growth failure, rickets, leg bowing, fracture, seizures, hyperparathyroidism, hypocalcemia, high-alkaline phosphatase, high or normal 25(OH)D3, and low 1,25(OH)2D3. Methods: We studied two siblings in a Mexican family with an atypical form of VDDR1A. In addition to the typical features of VDDR1A, the proband showed cafe au lait spots, small teeth, and grayish sclera, with hypophosphatemia, normocalcemia, and normal 25(OH)D3; the proband's brother showed grayish sclera. The proband underwent next generation sequencing. Sanger sequencing was performed in the proband, his brother, the parents, and 100 healthy controls validate the detected variant. Results: Both brothers presented with a recurrent variant NM_000785.3; c.1319_1325dupCCCACCC and a novel nonsense variant NM_000785.3; c.227G>A in the CYP27B1 gene. Conclusions: Calcitriol treatment had a better response in proband´s younger brother. We describe the first Mexican family with an atypical form of VDDR1A associated with a novel nonsense variant, the results contribute to the phenotypic spectrum and increase the pool of pathogenic variants in CYP27B1. Data suggest that nonsense-truncating variants play a significant role in the severity of VDDR1A.