Genetic hypercalcemia |
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| Institution: | 1. CHU de Caen, department of rheumatology, avenue de la Côte de Nacre, Caen, 14000, France;2. AP–HM, department of medical genetics, La Timone Children''s hospital, 264, rue Saint-Pierre, 13385 Marseille cedex 5, France;3. CHU de Caen, department of genetics, avenue de la Cote de Nacre, Caen, 14000, France;4. Université Caen Normandie, medical School, Caen, 14000, France;1. Department of Clinical and Experimental Sciences, University of Brescia, Viale Europa 11, 25123 Brescia, Italy;2. Rheumatology and Clinical Immunology Unit, ASST Spedali Civili, Piazzale Spedali Civili, 1, 25123 Brescia, Italy;3. Centro Hospitalar de Leiria (CHL), Hospital de Santo André (HSA), R. de Santo André, 2410-197 Leiria, Portugal;4. Rheumatology Research Unit, Department of Clinical Medicine and Surgery, University Federico II of Naples, Via Sergio Pansini, 5, 80131 Naples, Italy;5. Unit of Medicine and Clinical Immunology, IRCCS San Raffaele Scientific Institute, Via Olgettina, 60, 20132 Milan, Italy;6. Rheumatology Unit, Department of Medicine, University of Perugia, Piazzale Gambuli, 1, 06132 Perugia, Italy;7. Unit of Allergology, Clinical Immunology and Rheumatology, University Campus Biomedico Rome, Via Álvaro del Portillo, 21, 00128 Rome, Italy;8. Rheumatology Unit, Policlinico “Le Scotte” and University of Siena, Via Mario Bracci-Loc.Le Scotte, 53100 Siena, Italy;9. Rheumatology Unit, Department of Medical Sciences, University of Ferrara and Azienda Ospedaliero-Universitaria S. Anna, Via Aldo Moro, 8, 44124 Cona, Ferrara, Italy;10. Rheumatology Clinic, Department of Medical and Surgical Sciences, University of Foggia, Rione Biccari, 71122 Foggia, Italy;11. Division of Rheumatology, University of Pavia and IRCCS Policlinico San Matteo Foundation, Viale Camillo Golgi, 19, 27100 Pavia, Italy;12. Division of Rheumatology and Clinical Immunology, Humanitas Research Hospital; BIOMETRA Department, University of Milan, Via Manzoni, 56, 20089 Rozzano (Milano), Milan, Italy;13. Department of Clinical Sciences and Community Health, University of Milan, Via Festa del Perdono, 7, 20122 Milano, Italy;14. Unit of Rheumatology, Istituto Auxologico Italiano, Via Mosè Bianchi, 90, 20149 Milan, Italy;15. Rheumatology, Allergy and Clinical Immunology, University of Rome Tor Vergata, Via Oxford, 81, 00133 Rome, Italy;p. Research Laboratory and Division of Rheumatology, Postgraduate School of Rheumatology, Department of Internal Medicine, University of Genova, Viale Benedetto XV, 16, 16132 Genova, Italy;q. Rheumatology Institute of Lucania (IReL)–Rheumatology Department of Lucania, San Carlo Hospital of Potenza and Madonna delle Grazie Hospital of Matera; Basilicata Ricerca Biomedica (BRB) Foundation, Via Potito Petrone, 1, 85100 Potenza, Italy;r. Rheumatology Unit, Department of Medicine-DIMED, University of Padua, Via Nicolò Giustiniani, 2, 35128 Padua, Italy;s. Clinica Medica, Università Politecnica delle Marche, Via Tronto, 10/a, 60126 Ancona, Italy 15;t. Rheumatology Unit, A.O.U. Policlinico Vittorio Emanuele, Via S. Sofia, 78, 95123 Catania, Italy;u. Department of Rheumatology, ASST Istituto Gaetano Pini & CTO, Piazza Cardinale Andrea Ferrari, 1, 20122 Milan, Italy;v. Rheumatology Outpatient Clinic, Internal Medicine Department, Hospital of Bolzano, Via Lorenz Böhler, 5, 39100 Bolzano, Italy;w. Rheumatology Unit, Internal Medicine, Policlinico S. Orsola-Malpighi, Azienda Ospedaliero-Universitaria di Bologna, Via Pietro Albertoni, 15, 40138 Bologna, Italy;x. Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 67, 56126 Pisa, Italy;y. Department of Rheumatology, S. Chiara Hospital, Largo Medaglie D’oro, 9, 38122 Trento, Italy;z. Rheumatology Unit, Azienda USL-IRCCS of Reggio Emilia, University of Modena and Reggio Emilia, Viale Risorgimento, 80, 42123 Reggio-Emilia, Italy;11. Unit of Rheumatology, S. Croce e Carle Hospital, Via Michele Coppino, 26, 12100 Cuneo, Italy;12. Rheumatology Unit, San Camillo Hospital, Circonvallazione Gianicolense, 87, 00152 Rome, Italy;13. Rheumatology Unit, Department of Internal Medicine and Medical Specialties, La Sapienza University, Piazzale Aldo Moro, 5, 00185 Roma, Italy;1. Rheumatology, Xarxa Universitària Fundació Althaia, Manresa, Joan Soler, 1–3, Manresa 08243, Barcelona, Spain;2. Rheumatology, Hospital Universitari de Girona Doctor Josep Trueta, Girona 17007, Spain;3. Radiology, Xarxa Universitària Fundació Althaia, Manresa 08243, Barcelona, Spain;1. Center for Clinical Research (CKF) Dalarna, Uppsala University, Falun, Sweden;2. Department of Rheumatology, Falun General Hospital, Falun, Sweden;1. Services de rhumatologie, hôpitaux civils de Colmar, 39, avenue de la liberté, 68000 Colmar, France;2. Service de radiologie, CHU de Hautepierre, 67000 Strasbourg, France;3. Service de rhumatologie, CHU de Hautepierre, 67000 Strasbourg, France;1. Department of infectious and tropical diseases, hôpital Pellegrin, CHU de Bordeaux, 33076 Bordeaux, France;2. Centre de référence infections ostéo-articulaires complexes du Grand Sud-Ouest (Crioac GSO), 33076 Bordeaux, France;3. Service de médecine nucléaire, hôpital Pellegrin, 33076 Bordeaux, France;4. INCIA, UMR, CNRS 5287, université de Bordeaux, 33076 Bordeaux, France;5. Inserm U1219 Bordeaux population health, ISPED, university of Bordeaux, 33076 Bordeaux, France;6. Spine unit one, orthopaedic surgery, hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France;7. Department of infectious and tropical diseases, CHU de Toulouse, Toulouse, France;8. Department of infectious and tropical diseases, CHU de Limoges, Limoges, France |
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| Abstract: | A genetic disorder should be suspected in patients with hypercalcemia, notably those who are young; have family members with hypercalcemia; or have had a tumor of the endocrine pancreas, thyroid, pituitary, adrenal gland, or jaw bone. All forms of hypercalcemia should be interpreted according to the serum level of parathyroid hormone (PTH). Genetic forms are thus classified as related or unrelated to a parathyroid gland disorder. When the PTH level is elevated or is not depressed despite the hypercalcemia, findings that suggest family history of hypercalcemia due to a genetic cause include syndromic manifestations in the patient or family members, parathyroid cancer (either suspected before surgery or confirmed during parathyroidectomy), multiple or recurrent parathyroid tumors, a family history of primary hyperparathyroidism, and the onset of primary hyperthyroidism before 50 years of age. In patients with moderate hypercalcemia, a normal PTH level, and relative hypocalciuria, the first hypothesis is a mutation in the calcium-sensing receptor gene, which is often difficult to distinguish from primary hyperparathyroidism, particularly when there is no known family history of hyperparathyroidism, as is often the case. A low PTH level suggests non-parathyroid hypercalcemia due to a genetic defect in patients with no evidence of other conditions associated with hypercalcemia and low PTH levels and in those whose calcitriol levels are elevated or normal (instead of depressed as expected when PTH is elevated). Patients with hypercalciuria but no evidence of conditions such as granulomatous diseases should be evaluated for increased vitamin D sensitivity due to a CYP 4A1 mutation. Other very rare causes include hypophosphatasia due to ALPL mutations, which is characterized by a low alkaline phosphatase level; and renal phosphate wasting due to an NPT2A mutation, in which serum phosphate levels are low. A thorough analysis of the clinical and laboratory data can point toward a genetic disorder in patients with hypercalcemia. The diagnosis is then confirmed by obtaining genetic tests tailored to the clinical and laboratory test abnormalities. The current development of diagnostic genetic testing is shedding new light on the phenotypes, thereby improving their management. |
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| Keywords: | Genetic hypercalcemia Syndromic hypercalcemia Familial hypercalcemia Hypercalcemia in young patients |
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