Hypercalcemia due to CYP24A1 mutations: a systematic descriptive review

Abstract

Background and objectives: CYP24A1 encodes a 24-hydroxylase involved in vitamin D catabolism, whose loss-of-function results in vitamin D-dependent hypercalcemia. Since the identification of CYP24A1 variants as a cause of idiopathic infantile hypercalcemia (IIH), a large body of literature has emerged indicating heterogeneity in penetrance, symptoms, biochemistry, and treatments. The objectives of the present research work were to investigate the clinical heterogeneity of the disease, the possibility of a relevant phenotype for monoallelic carriers, and to compare the hypocalcemic effect of the available therapies. Methods: Two reviewers searched different databases for studies published between the identification of CYP24A1 variants and December 31st,2020. Eligible studies included clinical trials and reports describing carriers of CYP24A1 variants. Results: Fifty eligible studies were identified, accounting for 221 patients. Genetic data were retrieved and allele frequencies calculated. Acute hypercalcemia was the typical presentation during the first year of life (76%, P=0.0005), and nephrocalcinosis was more frequent in infancy (P<0.0001). Pregnancy was associated with symptomatic hypercalcemia in 81.8%, and high rates of obstetric complications. Monoallelic carriers displayed significant rates of nephrolithiasis (19.4%), nephrocalcinosis (4.9%), and symptomatic hypercalcemia (5.6%). The effect size of the most-used medications administered to control hypercalcemia ranged from 18 to 29%. Conclusions: CYP24A1 loss-of-function results in an age-dependent phenotype, which can be exacerbated by triggering factors, such as pregnancy. Although biallelic carriers present more significant clinical and biochemical features, monoallelic carriers have an increased risk of calcium-related conditions. The highly-variable tested therapeutic approaches did not allow to draw conclusions on preferable therapeutic regime.

Clinical Practice in the Prevention, Diagnosis and Treatment of Vitamin D Deficiency: A Central and Eastern European Expert Consensus Statement

“…Hypercalcemia does, however, usually not occur at 25(OH)D concentrations below 150 ng/mL (375 nmol/L) [ 46 ]. There are hardly any contraindications to correct vitamin D deficiency by vitamin D supplementation (e.g., kidney stones are per se no contraindication) except of rare conditions with an increased sensitivity to vitamin D treatment, such as inherited 24-hydroxylase-deficiency [ 47 ]. This is a rare genetic disorder in which catabolism of vitamin D metabolites is impaired, leading to hypercalcemia, low PTH concentrations, and relatively high serum 25(OH)D concentrations along with an increased risk of nephrolithiasis [ 47 ].…”

“…There are hardly any contraindications to correct vitamin D deficiency by vitamin D supplementation (e.g., kidney stones are per se no contraindication) except of rare conditions with an increased sensitivity to vitamin D treatment, such as inherited 24-hydroxylase-deficiency [ 47 ]. This is a rare genetic disorder in which catabolism of vitamin D metabolites is impaired, leading to hypercalcemia, low PTH concentrations, and relatively high serum 25(OH)D concentrations along with an increased risk of nephrolithiasis [ 47 ]. If such a disease is suspected, the measurement of 24,25-dihydroxyvitamin D, in a specialized laboratory, aids in the diagnosis as a high ratio of 25(OH)D to 24,25-dihydroxyvitamin D suggests this disease that is further confirmed by genetic analyses [ 47 ].…”

“…This is a rare genetic disorder in which catabolism of vitamin D metabolites is impaired, leading to hypercalcemia, low PTH concentrations, and relatively high serum 25(OH)D concentrations along with an increased risk of nephrolithiasis [ 47 ]. If such a disease is suspected, the measurement of 24,25-dihydroxyvitamin D, in a specialized laboratory, aids in the diagnosis as a high ratio of 25(OH)D to 24,25-dihydroxyvitamin D suggests this disease that is further confirmed by genetic analyses [ 47 ].…”

Hypercalcemia in Pregnancy Due to CYP24A1 Mutations: Case Report and Review of the Literature

“…Pregnant women with hypercalcemia and reduced PTH concentrations may suffer from a variety of diseases including, e.g., disorders of vitamin D metabolism, vitamin D intoxication per se, malignancy, granulomatous diseases (sarcoidosis and tuberculosis), pseudohyperparathyroidism (due to elevated PTH related peptide (PTHrP) levels), milk-alkali syndrome (due to excess intake of calcium and antacid drugs), etc. posing a diagnostic and therapeutic challenge [2][3][4][5][6].…”

“…Most patients with idiopathic infantile hypercalcemia probably remain unrecognized as there are only a few hundred cases described in the literature (i.e., 221 cases in a recent systematic review) with a Polish study suggesting a population disease frequency of 1 in 32,465 births [4,10]. Of note, the term idiopathic infantile hypercalcemia is meanwhile considered a misnomer for patients with pathogenic mutations of CYP24A1 as these patients can develop hypercalcemia across their whole life-span [4]. Due to the increasing use of vitamin D supplements and food fortification, knowledge on pathogenic CYP24A1 mutations in terms of their clinical relevance are of public health interest.…”