Vitamin D dependency rickets type 1B (VDDR-1B) is a rare condition classified as rickets due to inadequate 25-hydroxylation of vitamin D. In this study, we describe rickets and loss-of-function CYP2R1 mutations in 6/10 individuals tested from two unrelated families. Five patients in family 1 (F1) have homozygous L99P mutations; while one member of family 2 (F2) has novel homozygous mutations at G42_L46del insR. The mutations, as well as another variant M248I found in the French population, were recreated and tested using an in vitro mammalian expression system described previously (JBiolChem 286:28729). L99P and G42_L46del insR showed <5% of wild type CYP2R1 enzyme activity and are presumed to be loss-of-function mutations, while the M284I variant had 75% activity and is thus likely a polymorphism. In F1, the eldest child presented with marked limb amyotrophy and genu valgum also found in his younger 7 year brother; his youngest 4 year sister was asymptomatic. At diagnosis, all children had hypocalcemia, hypo-/normo-phosphatemia; high PTH and alkaline phosphatase (ALP) levels. Serum 1,25-(OH)2D levels were within the normal range (48182 pmol/l), but 25-OH-D levels were undetectable (<4 ng/ml). The aunt and uncle had genu valgum during infancy and were treated with 25-OH-D3 but were free of treatment for many years until the molecular investigation was made at 32 and 34 years respectively. Both had normocalcemia and slightly elevated PTH levels, normal 1,25-(OH)2D, but undetectable 25-OH D levels. In F2, the child presented with typical vitamin D deficiency rickets: short stature, genu varum deformity and hypotonia. He was given high doses of alfacalcidol (1α-OH-D3) and calcium supplementation. Serum calcium normalized, but PTH and ALP levels remained elevated. 1,25-(OH)2D levels were supranormal (194 pmol/l up to 383 pmol/l), while 25-OH-D was 2.7 ng/mL by LC-MS/MS. Calcifediol (25-OH-D3) therapy resulted in complete normalization of biochemical and bone defects. The major finding of the present study is identification of six new patients with VDDR-1B rickets harboring known (L99P) or novel (G42_L46del insR) mutations of the CYP2R1 gene and very low serum 25-OH-D3 which when corrected by 25-OH-D3 therapy cures the bone defect.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology