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Genotype-phenotype description of Vitamin-D Dependent Rickets 1A: CYP27B1 p.(Ala129Thr) variant induces a milder disease

Abstract : Abstract Introduction Vitamin D dependent rickets type 1A (VDDR1A) is a rare genetic disease associated with loss-of-function variations in the gene encoding the vitamin D activating enzyme 1α-hydroxylase (CYP27B1). Phenotype-genotype correlation is unclear. Long-term outcome data are lacking. The objective of this study was to describe characteristics and outcomes to search for a phenotype-genotype correlation. Methods We retrospectively collected clinical data, genetic features and outcomes from 24 genetically confirmed cases from 10 French centers; results are presented as median(min-max). Results Clinical symptoms at diagnosis (age 1.5(0.5-8.7) years) were mainly bone and neurological abnormalities, and laboratory data showed hypocalcemia (1.97(1.40-2.40) mmol/L), hypophosphatemia (- 3.4(-13.4-(-)0.2) SDS for age), low 25OHD and low 1,25(OH)2D3, secondary hyperparathyroidism with PTH at 6.6(1.3-13.7) times the upper limit for normal (ULN, PTH expressed as ULN to homogenize data presentation) and increased alkaline phosphatase (1968(521-7000) IU/L). Bone X-rays were abnormal in 83% of patients. We identified 17 variations (11 missense, 3 frameshift, 2 truncating and 1 acceptor splice site variations) in 19 families (homozygous state in 58% (11/19)). The partial loss-of-function variation p.(Ala129Thr) was associated with a milder phenotype: older age at diagnosis, higher serum calcium (2.26 vs 1.85 mmol/L), lower PTH (4.7 vs 7.5 ULN) and lower ALP (759 vs 2082IU/L). Patients were treated with alfacalcidol. Clinical (skeletal, neurological), biochemical and radiological outcomes were satisfactory, and complications occurred if bad adherence. Conclusion Overall, our findings highlight good outcomes under substitutive treatment and the need of a closer follow-up of eyes, teeth, kidneys and blood pressure in VDDR1A
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Submitted on : Monday, November 7, 2022 - 4:49:35 PM
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Marie-Noëlle Méaux, Jérôme Harambat, Anya Rothenbuhler, Juliane Léger, Peter Kamenicky, et al.. Genotype-phenotype description of Vitamin-D Dependent Rickets 1A: CYP27B1 p.(Ala129Thr) variant induces a milder disease. Journal of Clinical Endocrinology and Metabolism, 2022, ⟨10.1210/clinem/dgac639⟩. ⟨hal-03842659⟩



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