Nina Lenherr-Taube1, Edwin J Young2, Michelle Furman1, Yesmino Elia1, Esther Assor1, David Chitayat3,4, Tami Uster3, Susan Kirwin5, Katherine Robbins5, Kathleen M B Vinette5, Alan Daneman6, Christian R Marshall2,7, Carol Collins8, Kenneth Thummel8, Etienne Sochett1, Michael A Levine9. 1. Department of Pediatrics, Division of Endocrinology, The Hospital for Sick Children, University of Toronto, M5G 1X8 Toronto, Ontario, Canada. 2. Genome Diagnostics, Department of Paediatric Medicine, The Hospital for Sick Children, M5G 1X8 Toronto, Ontario, Canada. 3. Department of Obstetrics and Gynecology, The Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, University of Toronto, M5G 1X8 Toronto, Ontario, Canada. 4. Department of Pediatrics, Division of Clinical Genetics and Metabolism, The Hospital for Sick Children, University of Toronto, M5G 1X8 Toronto, Ontario, Canada. 5. Nemours Molecular Diagnostics Laboratory, Nemours Children's Health System, Wilmington, Delaware 19802, USA. 6. Department of Diagnostic Imaging, Division of General Radiology and Body Imaging, The Hospital for Sick Children, University of Toronto, M5G 1X8 Toronto, Ontario, Canada. 7. Department of Laboratory Medicine and Pathobiology, University of Toronto, M5S 1A8 Toronto, Ontario, Canada. 8. Department of Pharmaceutics, University of Washington, Seattle, Washington 98195, USA. 9. Division of Endocrinology and Diabetes and Center for Bone Health, Children's Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Abstract
CONTEXT: Idiopathic infantile hypercalcemia (IIH), an uncommon disorder characterized by elevated serum concentrations of 1,25 dihydroxyvitamin D (1,25(OH)2D) and low parathyroid hormone (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: This work aims to characterize the genetic associations and biochemical profile of mild IIH. METHODS: This is a cross-sectional study including children between age 6 months and 17 years with IIH who were followed in the Calcium Clinic at the Hospital for Sick Children (SickKids), Toronto, Canada. Twenty children with mild IIH on calcium-restricted diets were evaluated. We performed a dietary assessment and analyzed 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, whereas intact PTH was low normal (22.5 ng/L). Mean 1,25(OH)2D/PTH and 1,25(OH)2D/25(OH)D ratios were increased by comparison to healthy controls. Eleven individuals (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.
CONTEXT: Idiopathic infantile hypercalcemia (IIH), an uncommon disorder characterized by elevated serum concentrations of 1,25 dihydroxyvitamin D (1,25(OH)2D) and low parathyroid hormone (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: This work aims to characterize the genetic associations and biochemical profile of mild IIH. METHODS: This is a cross-sectional study including children between age 6 months and 17 years with IIH who were followed in the Calcium Clinic at the Hospital for Sick Children (SickKids), Toronto, Canada. Twenty children with mild IIH on calcium-restricted diets were evaluated. We performed a dietary assessment and analyzed 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, whereas intact PTH was low normal (22.5 ng/L). Mean 1,25(OH)2D/PTH and 1,25(OH)2D/25(OH)D ratios were increased by comparison to healthy controls. Eleven individuals (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.
Authors: Karl P Schlingmann; Martin Kaufmann; Stefanie Weber; Andrew Irwin; Caroline Goos; Ulrike John; Joachim Misselwitz; Günter Klaus; Eberhard Kuwertz-Bröking; Henry Fehrenbach; Anne M Wingen; Tülay Güran; Joost G Hoenderop; René J Bindels; David E Prosser; Glenville Jones; Martin Konrad Journal: N Engl J Med Date: 2011-06-15 Impact factor: 91.245
Authors: M Cools; S Goemaere; D Baetens; A Raes; A Desloovere; J M Kaufman; J De Schepper; I Jans; D Vanderschueren; J Billen; E De Baere; T Fiers; R Bouillon Journal: Bone Date: 2015-06-25 Impact factor: 4.398
Authors: Amy Fearn; Benjamin Allison; Sarah J Rice; Noel Edwards; Jan Halbritter; Soline Bourgeois; Eva M Pastor-Arroyo; Friedhelm Hildebrandt; Velibor Tasic; Carsten A Wagner; Nati Hernando; John A Sayer; Andreas Werner Journal: Physiol Rep Date: 2018-06