Context Idiopathic Infantile Hypercalcemia (IIH), an uncommon disorder characterized by elevated serum concentrations of 1,25(OH)2D and low PTH levels, may present with mild to severe hypercalcemia during the first months of life. Biallelic variants in the CYP24A1 or SLC34A1 genes are associated with severe IIH. Little is known about milder forms. Objective To characterize the genetic associations and biochemical profile of mild IIH. Methods This is a cross-sectional study including children between 6 months and 17 years of age with IIH who were followed in the Calcium Clinic at the Hospital for Sick Children (SickKids), Toronto, Canada. 20 children with mild IIH on calcium-restricted diets were evaluated. We performed a dietary assessment and analysed biochemical measures including vitamin D metabolites and performed a stepwise molecular genetic analysis. Complementary biochemical assessments and renal ultrasounds were offered to first-degree family members of positive probands. Results The median age was 16 months. Median serum levels of calcium (2·69 mmol/L), urinary Calcium:Creatinine ratio (0·72 mmol/mmol) and 1,25(OH)2D (209 pmol/L) were elevated while intact PTH was low normal (22·5 ng/L). Mean1,25(OH)2D/PTH and 1,25(OH)2D/25(OH)D ratios were increased by comparison to healthy controls. Eleven subjects (55%) had renal calcification. Genetic variants were common (65%) with the majority being heterozygous variants in SLC34A1 and SLC34A3 while a minority showed variants of CYP24A1 and other genes related to hypercalciuria. Conclusion The milder form of IIH has a distinctive vitamin D metabolite profile and is primarily associated with heterozygous SLC34A1 and SLC34A3 variants.
Primary hyperparathyroidism is a condition that occurs infrequently in children. Parathyroid carcinoma, as the underlying cause of hyperparathyroidism in this age group, is extraordinarily rare, with only a few cases reported in the literature. We present a 13‐year‐old boy with musculoskeletal pain who was found to have brown tumors from primary hyperparathyroidism caused by parafibromin‐immunodeficient parathyroid carcinoma. Our patient had no clinical, biochemical, or radiographic evidence of pituitary adenomas, pancreatic tumors, thyroid tumors, pheochromocytoma, jaw tumors, renal abnormalities, or testicular lesions. Germline testing for AP2S1, CASR, CDC73/HRPT2, CDKN1B, GNA11, MEN1, PTH1R, RET, and the GCM2 gene showed no pathological variants, and a microarray of CDC73/HRPT2 did not reveal deletion or duplication. He was managed with i.v. fluids, calcitonin, pamidronate, and denosumab prior to surgery to stabilize hypercalcemia. After removal of a single parathyroid tumor, he developed severe hungry bone syndrome and required 3 weeks of continuous i.v. calcium infusion, in addition to oral calcium and activated vitamin D. Histopathological examination identified an angioinvasive parathyroid carcinoma with global loss of parafibromin (protein encoded by CDC73/HRPT2).HRpQCT and DXA studies were obtained prior to surgery and 18‐months postsurgery. HRpQCT showed a resolution of osteolytic lesions combined with structural improvement of cortical porosity and an increase in both cortical thickness and density compared with levels prior to treatment. These findings highlight the added value of HRpQCT in primary hyperparathyroidism. In addition to our case, we have provided a review of the published cases of parathyroid cancer in children. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Context Idiopathic Infantile Hypercalcemia (IIH) is an uncommon disorder with variable clinical features. The natural history and response to dietary calcium and vitamin D restriction in IIH remains unclear. Objective The aim of this study is to describe the clinical and biochemical response to dietary calcium and vitamin D restriction in a genetically characterized cohort of mild IIH. Methods This is a longitudinal, observational cohort study of 20 children with mild IIH monitored for a median of 21months. Biochemical measures, dietary assessment and yearly renal ultrasound results, since the time of diagnosis, were obtained and assessed prospectively every 4-6 months. Results Median age at initial diagnosis was 4·5 months. Median levels of serum calcium (2·82 mmol/l) and 1,25 (OH)2 D (192 pmol/l) were elevated whereas serum PTH was reduced (10 ng/l). Urinary calcium:creatinine ratio was elevated for some, but not all individuals (median 1·49 mmol/mmol). All patients who were managed with a low calcium diet showed an improvement in serum and urinary calcium measures, but the serum concentration of 1,25(OH)2D and 1,25(OH)2D/PTH ratio remained elevated. In 2 of the 11 subjects, renal calcification worsened. There were no differences in response between individuals with CYP24A1 or SLC34A1/A3 variants. Conclusion The clinical presentation of mild IIH is variable and dietary calcium and vitamin D restriction does not consistently normalize elevated 1,25(OH)2D concentrations or prevent worsening of renal calcification in all cases. Therapeutic options should target the defect in vitamin D metabolism.
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