ESPE2024 Rapid Free Communications Bone, Growth Plate and Mineral Metabolism (6 abstracts)
CYP24A1 MUTATIONS: CLINICAL AND LABORATORY FEATURES IN PATIENTS PRESENTING WITH HYPERCALCEMIA
Ilknur Kurt 1 , Mehmet Eltan 1 , Zehra Yavas Abalı 1 , Ceren Alavanda 2 , Senol Demir 2 , Pınar Ata 2 , Belma Haliloglu 1 , Tulay Guran 1 , Abdullah Bereket 1 & Serap Turan 1
1Marmara University School of Medicine, Department of Pediatric Endocrinology, Istanbul, Turkey. 2Marmara University School of Medicine, Department of Medical Genetics, Istanbul, Turkey
Background: The inactivating mutations of CYP24A1 (OMIM*126065) were first identified in idiopathic infantile hypercalcemia (IH) and named IH-type1 (IH1). However, biallelic mutations were later associated with hypercalcemia at various ages. In our study, we aimed to present the clinical and laboratory findings of our patients who presented with hypercalcemia and were found to have a mutation in CYP24A1.
Methods and Results: Six patients from 5 families had been evaluated in a clinical exome analysis. The age at presentation ranged from 7 months to 7 years. Patients presented with vomiting(n = 3) and nephrocalcinosis (n = 2), while one patient was asymptomatic. The calcium levels at presentation ranged from 11.6 to 18.4 mg/dl, with suppressed parathyroid hormones levels. The 25-OH vitamin D levels were typically at intoxication levels, except levels of two patient (76 and 103ng/mL). Initial treatment for the patients with severe hypercalcemia (N:4) included hydration and forced diuresis; however, all patients eventually required bisphosphonate therapy. One patient was managed without treatment(n = 1). The vitamin D intake was documented as high dose in 2 patients and prophylactic dose in 4 patients. Molecular analysis revealed homozygous or compound heterozygous mutation in the CYP24A1 gene (Table).
| Case-1 | Case-2 | Case-3 | Case-4 | Case-5 | Case-6 | |
| Symptoms | Vomiting | Vomiting | Asymptomatic | Vomiting | Nephrocalcinosis | Nephrocalcinosis |
| Age | 20months | 3 years 8 months | 3 years 8 months | 7months | 7 years | 15 months |
| Family history | Grandfather/nephrocalcinosis | Mother/nephrolithiasis | Mother/nephrolithiasis | Grandmother/kidney disease | Father/nephrolithiasis- atrophic kidney | Nephrolithiasis:Father/p.two uncles/p.grandmother |
| 25OH vitamin Dtreatment(IU) | 600.000 | 300.000 | 400/day | 400/day | 400/day | 400/day |
| Ca(mg/dl) | 17.8 | 18.4 | 11.6 | 15.8 | 15.4 | 12.4 |
| 25OHD vit | 792 | 829 | 574 | 645 | 103 | 79 |
| 1,25(OH)2D vit (pg/ml) (N:15.1-72.4) | 200 | 105 | - | - | - | - |
| Treatment | Hydration, furosemide, pamidronate | Hydration, furosemide, alendronate | Treatment(-) | Hydration, furosemide, pamidronate | Hydration, furosemide, pamidronate | Hydration |
| Ultrasound | Nephrocalcinosis | Nephrocalcinosis | Nephrocalcinosis | Normal | Nephrocalcinosis | Nephrocalcinosis |
| CYP24A1 | Compound heterozygous c.1186C>T/p.Arg396Trp, c.640+5G>A/p.(?) |
Compound heterozygous c.37G>T/p.Ala13Thr, c.1157+58A>G/p.)?) |
Compound heterozygous c.37G>T/p.(Ala13Thr), c.1157+58A>G/p.(?) |
Homozygous c.990+204C>T/p(?) |
Homozygous c.428_430delAAG/p.(Glu143del) |
Compound heterozygous c.428_430delAAG/p.(Glu143del=), c.233G>T/p.Gly78Val |
Conclusion: Mutations in the CYP24A1 gene play an important role in the aetiology of hypercalcemia. CYP24A1 mutations should be suspected in patients with hypercalcemia who present at a young age, have nephrocalcinosis and/or family history of nephrocalcinosis. Additionally, CYP24A1 mutations should also be considered in patients who developed hypercalcemia as a result of prophylactic or high-dose vitamin D use, especially when 25-OH vitamin D levels are incompatible with the dose received. Detecting this mutation is crucial for limiting vitamin D supplementation in these patients and preventing nephrologic complications.
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