Genotype-phenotype description of Vitamin-D Dependent Rickets 1A: CYP27B1 p.(Ala129Thr) variant induces a milder disease
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EN
Article de revue
Ce document a été publié dans
Journal of Clinical Endocrinology and Metabolism. 2022-11-02, vol. 108, n° 4, p. 812-826
Résumé en anglais
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 ...Lire la suite >
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.< Réduire
Mots clés en anglais
CYP27B1
1-alpha hydroxylase
VDDR1A
Rickets
Genotype-phenotype
Unités de recherche