Idiopathic infantile hypercalcemia, type 1: clinical and genetic features of russian cohort of patients

Idiopathic infantile hypercalcemia, type 1 (IIH1) is a rare autosomal recessive disorder characterized by hypercalcemia, low parathyroid hormone (PTH) serum level, hypercalciuria, nephrocalcinosis (NC), and/or urolithiasis. IIH1 caused by mutations in the CYP24A1 gene that encodes a key enzyme responsible for the catabolism of active vitamin D. Aim: to evaluate clinical features and molecular characteristics of IIH1 in Russian children and search for phenotype features of the disease in children with their age and potential genotype-phenotypic associations. Materials and methods: we conducted a retrospective two-center longitudinal study of 20 children (9M/11F) with genetically confirmed IIH1. The median age of patients at the beginning of follow-up was 13 [10.0; 58.5] months. Genetic analysis was performed in all children using by next generation sequencing technology - complete exome sequencing (n=7), clinical exome sequencing with the study of mutations in 22 genes associated with rickets-like diseases (n=11), and direct automatic sequencing of the CYP24A1 gene (n=2). To identify age-related features of IIH1, patients were divided into 2 groups depending on their age at the time of the initial examination before diagnosis: group 1 included children <24 months (n=12), and group 2 - children ≥24 months (n=8). Results: the most prevalent features of IIH1 were medullary NC (100%) and low PTH serum level (90%). Hypercalcemia was found in 75% of children, hypercalciuria in 60% of patients, and urolithiasis in 20% of the children. According to the results of a molecular genetic study, the most common CYP24A1 variants were p.Arg396Trp (55%) and p.Glu143del (40%). Also 4 novel CYP24A1 variants were identified: p.Gly78Val, p.Arg396Gln, p.Met99Thr, p.Gln471SerfsTer21. In patients examined up to 24 months, serum levels of calcium (Ca2+ and total) were higher: 1.39 [1.35; 1.56] mmol/l vs. 1.31 [1.24; 1.34] mmol/l (p=0.013) and 2.9 [2.71; 3.74] mmol/l vs. 2.45 [2.36; 2.52] mmol/l (p=0.001), respectively, and serum level of PTH was lower: 7.9 [3.0; 12.7] pg/ml vs. 14.6 [8.25; 15.85] pg/ml (p=0.038) than in older children. Conclusion: a greater awareness of IIH1 phenotypes will increase clinical suspicion in patients presenting with NC or hypercalcemia. Testing for mutations in the CYP24A1 gene can establish a definitive diagnosis and clinical management by minimizing vitamin D intake to prevent the effects of vitamin D toxicity and dietary and lifestyle advice.

идиопатическая инфантильная гиперкальциемия, дети, нефрокальциноз, паратгормон, витамин Д, idiopathic infantile hypercalcemia, children, nephrocalcinosis, parathyroid hormone, vitamin D

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