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Ranzinger D, Schaefer T, Schauer F, Eyerich K, Pilz AC. Calcinosis cutis of the lower legs - hyperphosphatemic familial tumoral calcinosis in a patient with GALNT3 mutation. J Dtsch Dermatol Ges 2025. [PMID: 40317874 DOI: 10.1111/ddg.15716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 02/05/2025] [Indexed: 05/07/2025]
Affiliation(s)
- David Ranzinger
- Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany
| | - Tobias Schaefer
- Renal Division, Medical Center, University of Freiburg, Freiburg, Germany
| | - Franziska Schauer
- Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany
| | - Kilian Eyerich
- Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany
| | - Anna Caroline Pilz
- Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany
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Donati S, Palmini G, Aurilia C, Falsetti I, Marini F, Galli G, Zonefrati R, Iantomasi T, Margheriti L, Franchi A, Beltrami G, Masi L, Moro A, Brandi ML. Establishment and Molecular Characterization of a Human Stem Cell Line from a Primary Cell Culture Obtained from an Ectopic Calcified Lesion of a Tumoral Calcinosis Patient Carrying a Novel GALNT3 Mutation. Genes (Basel) 2025; 16:263. [PMID: 40149415 PMCID: PMC11942111 DOI: 10.3390/genes16030263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Revised: 02/21/2025] [Accepted: 02/21/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND/OBJECTIVES Tumoral calcinosis (TC) is an extremely rare inherited disease characterized by multilobulated, dense ectopic calcified masses, usually in the periarticular soft tissue regions. In a previous study, we isolated a primary cell line from an ectopic lesion of a TC patient carrying a previously undescribed GALNT3 mutation. Here, we researched whether a stem cell (SC) subpopulation, which may play a critical role in TC progression, could be present within these lesions. METHODS A putative SC subpopulation was initially isolated by the sphere assay (marked as TC1-SC line) and characterized for its stem-like phenotype through several cellular and molecular assays, including colony forming unit assay, immunofluorescence staining for mesenchymal SC (MSC) markers, gene expression analyses for embryonic SC (ESC) marker genes, and multidifferentiation capacity. In addition, a preliminary expression pattern of osteogenesis-related pathways miRNAs and genes were assessed in the TC1-SC by quantitative Real-Time PCR (qPCR). RESULTS These cells were capable of differentiating into both the adipogenic and the osteogenic lineages. Moreover, they showed the presence of the MSC and ESC markers, confirmed respectively by using immunofluorescence and qualitative reverse transcriptase PCR (RT-PCR), and a good rate of clonogenic capacity. Finally, qPCR data revealed a signature of miRNAs (i.e., miR-21, miR-23a-3p, miR-26a, miR-27a-3p, miR-27b-3p, and miR-29b-3p) and osteogenic marker genes (i.e., ALP, RUNX2, COLIA1, OPG, OCN, and CCN2) characteristic for the established TC1-SC line. CONCLUSIONS The establishment of this in vitro cell model system could advance the understanding of mechanisms underlying TC pathogenesis, thereby paving the way for the discovery of new diagnostic and novel gene-targeted therapeutic approaches for TC.
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Affiliation(s)
- Simone Donati
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy; (S.D.); (C.A.); (I.F.); (G.G.); (T.I.)
| | - Gaia Palmini
- FirmoLab, Fondazione F.I.R.M.O. Onlus and Stabilimento Chimico Farmaceutico Militare (SCFM), 50141 Florence, Italy; (G.P.); (F.M.); (R.Z.)
| | - Cinzia Aurilia
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy; (S.D.); (C.A.); (I.F.); (G.G.); (T.I.)
| | - Irene Falsetti
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy; (S.D.); (C.A.); (I.F.); (G.G.); (T.I.)
| | - Francesca Marini
- FirmoLab, Fondazione F.I.R.M.O. Onlus and Stabilimento Chimico Farmaceutico Militare (SCFM), 50141 Florence, Italy; (G.P.); (F.M.); (R.Z.)
| | - Gianna Galli
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy; (S.D.); (C.A.); (I.F.); (G.G.); (T.I.)
| | - Roberto Zonefrati
- FirmoLab, Fondazione F.I.R.M.O. Onlus and Stabilimento Chimico Farmaceutico Militare (SCFM), 50141 Florence, Italy; (G.P.); (F.M.); (R.Z.)
| | - Teresa Iantomasi
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy; (S.D.); (C.A.); (I.F.); (G.G.); (T.I.)
| | - Lorenzo Margheriti
- Stabilimento Chimico Farmaceutico Militare (SCFM)—Agenzia Industrie Difesa (AID), 50141 Florence, Italy; (L.M.); (A.M.)
| | - Alessandro Franchi
- Department of Translational Research and of New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy;
| | - Giovanni Beltrami
- Department of Orthopaedic Oncology and Reconstructive Surgery, Azienda Ospedaliero, Universitaria Careggi, 50134 Firenze, Italy;
| | - Laura Masi
- Metabolic Bone Diseases Unit, University Hospital of Florence, AOU Careggi, 50139 Florence, Italy;
| | - Arcangelo Moro
- Stabilimento Chimico Farmaceutico Militare (SCFM)—Agenzia Industrie Difesa (AID), 50141 Florence, Italy; (L.M.); (A.M.)
| | - Maria Luisa Brandi
- FirmoLab, Fondazione F.I.R.M.O. Onlus and Stabilimento Chimico Farmaceutico Militare (SCFM), 50141 Florence, Italy; (G.P.); (F.M.); (R.Z.)
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Cherian KE, Cherian J, Vinodhini D, Paul TV. Clinical Characteristics, Therapeutic Options, and Outcomes in Hyperphosphatemic Tumoral Calcinosis: A Systematic Review. Calcif Tissue Int 2024; 115:215-228. [PMID: 38951179 DOI: 10.1007/s00223-024-01247-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 06/15/2024] [Indexed: 07/03/2024]
Abstract
This systematic review was performed to understand better the myriad presentations, various therapeutic options, response to therapy, and its clinical outcomes in hyperphosphatemic tumoral calcinosis (HTC). Full texts were selected according to strict inclusion criteria. All case reports of HTC wherein baseline phosphate was measured, treatment offered was mentioned, and information on follow-up and response to therapy that were available were included. A total of 43 of 188 eligible studies (N = 63 patients) met the inclusion criteria. A list of desired data was extracted and graded for methodological quality. A total of 63 individuals (Males = 33) were included from the 43 eligible case studies. The median age of the patients was 18 (IQR 8-32) years. The most frequently involved sites were the hip/gluteal region (34/63; 53.9%) followed by the elbow/forearm (26/63; 41.2%), and the shoulder (18/63; 28.5%). Three patients had conjunctival calcific deposits. The mean (SD) phosphate was 6.9 (1.1) mg/dL. Among the subjects, 36/63 (57.1%) underwent surgical excision with some form of medical therapy. Two patients underwent only surgical excision (2.1%). One patient was maintained on follow-up (1.6%) and 24/63 (38.1%) patients were treated with medical measures. The median (IQR) follow-up duration was 3 (1-9) years. Regression or reduction in lesion size was reported in 19/63 (30.2%) subjects; 20/63 (31.7%) showed progression, 24/63 (38.1%) had features of stable disease, and mortality was reported in 3 patients (4.7%). We report for the first time a detailed description of the clinical and therapeutic response of HTC. A combination of medical measures aimed at lowering serum phosphate appears to be the cornerstone of treatment, although clinical responses may vary.
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Affiliation(s)
| | | | | | - Thomas Vizhalil Paul
- Department of Endocrinology, Christian Medical College, Vellore, Tamil Nadu, 632004, India.
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Wu A, Yang B, Yu X. A GALNT3 mutation causing Hyperphosphatemic familial Tumoral calcinosis. Mol Genet Metab Rep 2024; 40:101128. [PMID: 39185017 PMCID: PMC11342870 DOI: 10.1016/j.ymgmr.2024.101128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 07/26/2024] [Accepted: 07/27/2024] [Indexed: 08/27/2024] Open
Abstract
Aim Hyperphosphatemic Familial Tumoral Calcinosis (HFTC) is an autosomal recessive disorder. This study investigates the etiology of HFTC in offspring from consanguineous parents. Methods Clinical assessment, imaging, and direct sequencing were utilized to elucidate the condition. Previously reported cases were also reviewed. Result We identified a consanguineous Chinese family with HFTC caused by an interesting homozygous G to A substitution in GALNT3 (c.1626 + 1G > A). The parents were carriers. Conclusion This study represents the first report of HFTC in a consanguineous Chinese family due to an interesting GALNT3 mutation. We reviewed known GALNT3 variants and associated clinical features of calcification disorders. The phenotypic difference between homozygous and complex heterozygous mutations is not clinically significant. Gene mutations affect the function of proteins mainly by affecting their binding to polyvalent ligands.
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Affiliation(s)
- Aijia Wu
- Department of Endocrinology, Laboratory of Endocrinology and Metabolism, Rare Disease Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Bangxiang Yang
- Departement of Pain Management, West China Hospital, Sichuan University No 37, Guoxuexiang, Chengdu, Sichuan, PRC
| | - Xijie Yu
- Department of Endocrinology, Laboratory of Endocrinology and Metabolism, Rare Disease Center, West China Hospital, Sichuan University, Chengdu 610041, China
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Ivanova NG. A Sole Case of the FGF23 Gene Mutation c.202A>G (p.Thr68Ala) Associated with Multiple Severe Vascular Aneurysms and a Hyperphosphatemic Variant of Tumoral Calcinosis-A Case Report. Life (Basel) 2024; 14:613. [PMID: 38792634 PMCID: PMC11123361 DOI: 10.3390/life14050613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 05/02/2024] [Accepted: 05/08/2024] [Indexed: 05/26/2024] Open
Abstract
Tumoral calcinosis is an extremely rare genetic disease caused by mutations in three genes, GALNT3, FGF23, and KL, which disrupt phosphorus metabolism. The hallmark of this condition is the formation of tumors in the soft tissues around the joints. Other phenotypic features of tumoral calcinosis are dental involvement and brain and vascular calcifications. The clinical case reported herein presents for the first time to the scientific community the c.202A>G (p.Thr68Ala) mutation of the FGF23 gene, associated with a hyperphosphatemic variant of tumoral calcinosis and multiple severe vascular aneurysms. A female patient underwent multiple surgeries for tumor formations in her soft tissues that first appeared at the age of 12 months. On this occurrence, the patient was found to have hyperphosphatemia, low phosphate clearance, increased tubular reabsorption with normal levels of total and ionized calcium, vitamin D3, and parathyroid hormone, and no effect of treatment with sevelamer hydrochloride and a low-phosphate diet. At the age of 39, the patient underwent imaging studies due to edema and a pulsating formation in the neck area, which revealed multiple vascular aneurysms with thrombosis, for which she received operative and interventional treatment. In this connection, and because of the established phosphorus metabolism disturbance, a genetic disease was suspected. The sequence analysis and deletion/duplication testing of the 358 genes performed on this occasion revealed that the woman was homozygous for a variant of the c.202A>G (p.Thr68Ala) mutation of the FGF23 gene. The established mutation is not present in population databases. The presented clinical case is the first and only one in the world to demonstrate the role of this type of FGF23 gene mutation in the development of a hyperphosphatemic variant of tumoral calcinosis characterized by aggressive formation of multiple vascular aneurysms.
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Affiliation(s)
- Nevena Georgieva Ivanova
- Department of Urology and General Medicine, Faculty of Medicine, Medical University of Plovdiv, 4000 Plovdiv, Bulgaria; ; Tel.: +35-98-8913-0416
- St Karidad MHAT, Karidad Medical Health Center, 4004 Plovdiv, Bulgaria
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Jiang Q, Qin X, Moriishi T, Fukuyama R, Katsumata S, Matsuzaki H, Komori H, Matsuo Y, Sakane C, Ito K, Hojo H, Ohba S, Komori T. Runx2 Regulates Galnt3 and Fgf23 Expressions and Galnt3 Decelerates Osteoid Mineralization by Stabilizing Fgf23. Int J Mol Sci 2024; 25:2275. [PMID: 38396954 PMCID: PMC10889289 DOI: 10.3390/ijms25042275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 01/31/2024] [Accepted: 02/05/2024] [Indexed: 02/25/2024] Open
Abstract
Runx2 (runt related transcription factor 2) is an essential transcription factor for osteoblast proliferation and differentiation. Uridine diphosphate (UDP)-N-acetylgalactosamine (GalNAc): polypeptide GalNAc-transferase 3 (Galnt3) prevents proteolytic processing of fibroblast growth factor 23 (Fgf23), which is a hormone that regulates the serum level of phosphorus. Runx2 and Galnt3 were expressed in osteoblasts and osteocytes, and Fgf23 expression was restricted to osteocytes in bone. Overexpression and knock-down of Runx2 upregulated and downregulated, respectively, the expressions of Galnt3 and Fgf23, and Runx2 directly regulated the transcriptional activity of Galnt3 in reporter assays. The expressions of Galnt3 and Fgf23 in osteoblast-specific Runx2 knockout (Runx2fl/flCre) mice were about half those in Runx2fl/fl mice. However, the serum levels of phosphorus and intact Fgf23 in Runx2fl/flCre mice were similar to those in Runx2fl/fl mice. The trabecular bone volume was increased during aging in both male and female Galnt3-/- mice, but the osteoid was reduced. The markers for bone formation and resorption in Galnt3-/- mice were similar to the control in both sexes. Galnt3-/- mice exhibited hyperphosphatemia and hypercalcemia, and the intact Fgf23 was about 40% that of wild-type mice. These findings indicated that Runx2 regulates the expressions of Galnt3 and Fgf23 and that Galnt3 decelerates the mineralization of osteoid by stabilizing Fgf23.
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Affiliation(s)
- Qing Jiang
- Institute of Orthopaedics, Suzhou Medical College, Soochow University, Suzhou 215006, China
- Department of Molecular Bone Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan
| | - Xin Qin
- Institute of Orthopaedics, Suzhou Medical College, Soochow University, Suzhou 215006, China
- Department of Molecular Bone Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan
| | - Takeshi Moriishi
- Department of Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan
| | - Ryo Fukuyama
- Laboratory of Pharmacology, Hiroshima International University, Kure 737-0112, Japan
| | - Shinichi Katsumata
- Department of Nutritional Science, Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo 156-8502, Japan
| | - Hiroshi Matsuzaki
- Department of Nutritional Science, Faculty of Applied Bioscience, Tokyo University of Agriculture, Tokyo 156-8502, Japan
| | - Hisato Komori
- Department of Molecular Bone Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan
| | - Yuki Matsuo
- Department of Molecular Bone Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan
- Department of Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan
| | - Chiharu Sakane
- Research Center for Biomedical Models and Animal Welfare, Nagasaki University, Nagasaki 852-8523, Japan
| | - Kosei Ito
- Department of Molecular Bone Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan
| | - Hironori Hojo
- Laboratory of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Shinsuke Ohba
- Department of Tissue and Developmental Biology, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan
| | - Toshihisa Komori
- Department of Molecular Bone Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan
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Ochoa M, Jurencak R, Smit K, Carsen S, Sawyer SL, Robinson ME, Khatchadourian K, Cheng HP, Pagé M, Werier J, Ward LM. Canakinumab in addition to phosphate-binding and phosphaturia-inducing therapy were effective in achieving remission in a child with a large familial calcinotic tumour. Bone Rep 2023; 19:101695. [PMID: 37520934 PMCID: PMC10372364 DOI: 10.1016/j.bonr.2023.101695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 06/06/2023] [Accepted: 06/14/2023] [Indexed: 08/01/2023] Open
Abstract
We describe the clinical evolution of a patient with tumoral calcinosis due to a pathogenic variant in the GALNT3 gene presented with a large mass overlying her left hip associated complicated by inflammatory flares. Therapy (sevelamer, acetazolamide, and probenecid) was unsuccessful in preventing tumour surgeries, therefore, interleukin-1β monoclonal antibody therapy was added; this was successful in the prevention of tumour re-growth. This case highlights the importance of assessing and treating the inflammatory aspect of calcinotic tumour.
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Affiliation(s)
- Maria Ochoa
- The Ottawa Pediatric Bone Health Research Group, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
- Endocrinology Unit, Division of Pediatrics, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
- Pediatric Genetic and Metabolic Bone Disorders Program, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
| | - Roman Jurencak
- Department of Pediatrics, University of Ottawa, Division of Pediatric Rheumatology, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
| | - Kevin Smit
- The Ottawa Pediatric Bone Health Research Group, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
- Department of Surgery, University Of Ottawa, Division of Pediatric Orthopedic Surgery, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
| | - Sasha Carsen
- The Ottawa Pediatric Bone Health Research Group, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
- Pediatric Genetic and Metabolic Bone Disorders Program, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
| | - Sarah L. Sawyer
- Department of Pediatrics, University of Ottawa, Department of Medical Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
| | - Marie-Eve Robinson
- The Ottawa Pediatric Bone Health Research Group, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
- Pediatric Genetic and Metabolic Bone Disorders Program, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
- Department of Pediatrics, University Of Ottawa, Division of Endocrinology and Metabolism, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
| | - Karine Khatchadourian
- The Ottawa Pediatric Bone Health Research Group, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
- Pediatric Genetic and Metabolic Bone Disorders Program, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
- Department of Pediatrics, University Of Ottawa, Division of Endocrinology and Metabolism, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
| | - Hooi Peng Cheng
- The Ottawa Pediatric Bone Health Research Group, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
- Pediatric Genetic and Metabolic Bone Disorders Program, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
| | - Marika Pagé
- The Ottawa Pediatric Bone Health Research Group, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
- Pediatric Genetic and Metabolic Bone Disorders Program, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
| | - Joel Werier
- Pediatric Genetic and Metabolic Bone Disorders Program, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
- Department of Surgery, University Of Ottawa, Division of Adult Orthopedic Surgery, The Ottawa General Hospital, Ottawa, Ontario, Canada
| | - Leanne Marie Ward
- The Ottawa Pediatric Bone Health Research Group, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
- Pediatric Genetic and Metabolic Bone Disorders Program, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
- Department of Pediatrics, University Of Ottawa, Division of Endocrinology and Metabolism, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
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Seven Menevse T, Iwasaki Y, Yavas Abali Z, Gurpinar Tosun B, Helvacioglu D, Dogru Ö, Bugdayci O, Cyr SM, Güran T, Bereket A, Bastepe M, Turan S. Venous Thrombosis in a Pseudohypoparathyroidism Patient with a Novel GNAS Frameshift Mutation and Complete Resolution of Vascular Calcifications with Acetazolamide Treatment. Horm Res Paediatr 2023; 97:404-415. [PMID: 37906994 PMCID: PMC11058113 DOI: 10.1159/000534456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Accepted: 09/20/2023] [Indexed: 11/02/2023] Open
Abstract
INTRODUCTION Pseudohypoparathyroidism type IA (PHP1A) is characterized by end-organ resistance to multiple hormones and Albright's hereditary osteodystrophy (AHO). PHP1A is caused by inactivating mutations of the GNAS gene encoding the α-subunit of the stimulatory G protein (Gsα). In line with the underlying genetic defect, impaired inhibition of platelet aggregation has been demonstrated in some patients. However, no PHP1A case with thrombotic events has been described. Also, PHP1A cases typically have subcutaneous ossifications, but soft tissue calcifications are another common finding. Treatment options for those and other nonhormonal features of PHP1A are limited. CASE PRESENTATION A female patient presented with short stature, fatigue, and exercise-induced carpopedal spasms at age 117/12 years. Diagnosis of PHP1A was made based on hypocalcemia, hyperphosphatemia, elevated serum parathyroid hormone, and AHO features, including short stature and brachydactyly. A novel frameshift variant was detected in the last exon of GNAS (c.1065_1068delGCGT, p.R356Tfs*47), showing complete loss of baseline and receptor-stimulated activity in transfected cells. The patient developed venous thrombosis and vascular and subcutaneous calcifications on both forearms after venous puncture on the right and extravasation of calcium gluconate during treatment on the left. The thrombosis and calcifications completely resolved following treatment with low-molecular-weight heparin and acetazolamide for 5 and 8 months, respectively. CONCLUSIONS This case represents the first PHP1A patient displaying thrombosis and the first successful use of acetazolamide for PHP1A-associated soft tissue calcifications, thus providing new insights into the treatment of non-endocrinological features in this disease.
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Affiliation(s)
- Tuba Seven Menevse
- Department of Paediatric Endocrinology and Diabetes, Marmara University, School of Medicine, Istanbul, Turkey
| | - Yorihiro Iwasaki
- Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Zehra Yavas Abali
- Department of Paediatric Endocrinology and Diabetes, Marmara University, School of Medicine, Istanbul, Turkey
| | - Busra Gurpinar Tosun
- Department of Paediatric Endocrinology and Diabetes, Marmara University, School of Medicine, Istanbul, Turkey
| | - Didem Helvacioglu
- Department of Paediatric Endocrinology and Diabetes, Marmara University, School of Medicine, Istanbul, Turkey
| | - Ömer Dogru
- Department of Paediatric Haematology and Oncology, Marmara University, School of Medicine, Istanbul, Turkey
| | - Onur Bugdayci
- Department of Radiology, Marmara University, School of Medicine, Istanbul, Turkey
| | - Sajin M Cyr
- Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Tulay Güran
- Department of Paediatric Endocrinology and Diabetes, Marmara University, School of Medicine, Istanbul, Turkey
| | - Abdullah Bereket
- Department of Paediatric Endocrinology and Diabetes, Marmara University, School of Medicine, Istanbul, Turkey
| | - Murat Bastepe
- Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Serap Turan
- Department of Paediatric Endocrinology and Diabetes, Marmara University, School of Medicine, Istanbul, Turkey
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Li X, Lozovatsky L, Tommasini SM, Fretz J, Finberg KE. Bone marrow sinusoidal endothelial cells are a site of Fgf23 upregulation in a mouse model of iron deficiency anemia. Blood Adv 2023; 7:5156-5171. [PMID: 37417950 PMCID: PMC10480544 DOI: 10.1182/bloodadvances.2022009524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 06/16/2023] [Accepted: 07/05/2023] [Indexed: 07/08/2023] Open
Abstract
Iron deficiency is a potent stimulator of fibroblast growth factor 23 (FGF23), a hormonal regulator of phosphate and vitamin D metabolism, that is classically thought to be produced by bone-embedded osteocytes. Here, we show that iron-deficient transmembrane serine protease 6 knockout (Tmprss6-/-) mice exhibit elevated circulating FGF23 and Fgf23 messenger RNA (mRNA) upregulation in the bone marrow (BM) but not the cortical bone. To clarify sites of Fgf23 promoter activity in Tmprss6-/- mice, we introduced a heterozygous enhanced green fluorescent protein (eGFP) reporter allele at the endogenous Fgf23 locus. Heterozygous Fgf23 disruption did not alter the severity of systemic iron deficiency or anemia in the Tmprss6-/- mice. Tmprss6-/-Fgf23+/eGFP mice showed green fluorescence in the vascular regions of BM sections and showed a subset of BM endothelial cells that were GFPbright by flow cytometry. Mining of transcriptomic data sets from mice with normal iron balance revealed higher Fgf23 mRNA in BM sinusoidal endothelial cells (BM-SECs) than that in other BM endothelial cell populations. Anti-GFP immunohistochemistry of fixed BM sections from Tmprss6-/-Fgf23+/eGFP mice revealed GFP expression in BM-SECs, which was more intense than in nonanemic controls. In addition, in mice with intact Tmprss6 alleles, Fgf23-eGFP reporter expression increased in BM-SECs following large-volume phlebotomy and also following erythropoietin treatment both ex vivo and in vivo. Collectively, our results identified BM-SECs as a novel site for Fgf23 upregulation in both acute and chronic anemia. Given the elevated serum erythropoietin in both anemic models, our findings raise the possibility that erythropoietin may act directly on BM-SECs to promote FGF23 production during anemia.
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Affiliation(s)
- Xiuqi Li
- Department of Pathology, Yale School of Medicine, New Haven, CT
| | | | - Steven M. Tommasini
- Department of Orthopaedics & Rehabilitation, Yale School of Medicine, New Haven, CT
| | - Jackie Fretz
- Department of Orthopaedics & Rehabilitation, Yale School of Medicine, New Haven, CT
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Su T, Zhu Y, Wang X, Zhu Q, Duan X. Hereditary dentin defects with systemic diseases. Oral Dis 2023; 29:2376-2393. [PMID: 37094075 DOI: 10.1111/odi.14589] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 03/31/2023] [Accepted: 04/06/2023] [Indexed: 04/26/2023]
Abstract
OBJECTIVE This review aimed to summarize recent progress on syndromic dentin defects, promoting a better understanding of systemic diseases with dentin malformations, the molecules involved, and related mechanisms. SUBJECTS AND METHODS References on genetic diseases with dentin malformations were obtained from various sources, including PubMed, OMIM, NCBI, and other websites. The clinical phenotypes and genetic backgrounds of these diseases were then summarized, analyzed, and compared. RESULTS Over 10 systemic diseases, including osteogenesis imperfecta, hypophosphatemic rickets, vitamin D-dependent rickets, familial tumoral calcinosis, Ehlers-Danlos syndrome, Schimke immuno-osseous dysplasia, hypophosphatasia, Elsahy-Waters syndrome, Singleton-Merten syndrome, odontochondrodysplasia, and microcephalic osteodysplastic primordial dwarfism type II were examined. Most of these are bone disorders, and their pathogenic genes may regulate both dentin and bone development, involving extracellular matrix, cell differentiation, and metabolism of calcium, phosphorus, and vitamin D. The phenotypes of these syndromic dentin defects various with the involved genes, part of them are similar to dentinogenesis imperfecta or dentin dysplasia, while others only present one or two types of dentin abnormalities such as discoloration, irregular enlarged or obliterated pulp and canal, or root malformation. CONCLUSION Some specific dentin defects associated with systemic diseases may serve as important phenotypes for dentists to diagnose. Furthermore, mechanistic studies on syndromic dentin defects may provide valuable insights into isolated dentin defects and general dentin development or mineralization.
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Affiliation(s)
- Tongyu Su
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Oral Biology & Clinic of Oral Rare and Genetic Diseases, School of Stomatology, The Fourth Military Medical University, Xi'an, China
| | - Yulong Zhu
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Oral Biology & Clinic of Oral Rare and Genetic Diseases, School of Stomatology, The Fourth Military Medical University, Xi'an, China
| | - Xiangpu Wang
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Oral Biology & Clinic of Oral Rare and Genetic Diseases, School of Stomatology, The Fourth Military Medical University, Xi'an, China
| | - Qinglin Zhu
- Department of Operative Dentistry and Endodontics, School of Stomatology, The Fourth Military Medical University & State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, Xi'an, China
| | - Xiaohong Duan
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Oral Biology & Clinic of Oral Rare and Genetic Diseases, School of Stomatology, The Fourth Military Medical University, Xi'an, China
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11
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Clinkenbeard E. Fibroblast Growth Factor 23 Bone Regulation and Downstream Hormonal Activity. Calcif Tissue Int 2023; 113:4-20. [PMID: 37306735 DOI: 10.1007/s00223-023-01092-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Accepted: 05/01/2023] [Indexed: 06/13/2023]
Abstract
Mineral homeostasis of calcium and phosphate levels is one critical component to the maintenance of bone mineral density (BMD) and strength. Diseases that disrupt calcium and phosphate balanced have highlighted not only the role these minerals play in overall bone homeostasis, but also the factors, hormones and downstream transporters, responsible for mineral metabolism. The key phosphaturic hormone elucidated from studying rare heritable disorders of hypophosphatemia is Fibroblast Growth Factor 23 (FGF23). FGF23 is predominantly secreted from bone cells in an effort to maintain phosphate balance by directly controlling renal reabsorption and indirectly affecting intestinal uptake of this mineral. Multiple factors have been shown to enhance bone mRNA expression; however, FGF23 can also undergo proteolytic cleavage to control secretion of the biologically active form of the hormone. The review focuses specifically on the regulation of FGF23 and its secretion from bone as well as its hormonal actions under physiological and disease conditions.
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Affiliation(s)
- Erica Clinkenbeard
- Department of Medical and Molecular Genetics, School of Medicine, Indiana University, 635 Barnhill Drive MS 5023, Indianapolis, IN, 46202, USA.
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12
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Hassan N, Gregson CL, Tang H, van der Kamp M, Leo P, McInerney‐Leo AM, Zheng J, Brandi ML, Tang JCY, Fraser W, Stone MD, Grundberg E, Brown MA, Duncan EL, Tobias JH. Rare and Common Variants in GALNT3 May Affect Bone Mass Independently of Phosphate Metabolism. J Bone Miner Res 2023; 38:678-691. [PMID: 36824040 PMCID: PMC10729283 DOI: 10.1002/jbmr.4795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 02/15/2023] [Accepted: 02/22/2023] [Indexed: 02/25/2023]
Abstract
Anabolic treatment options for osteoporosis remain limited. One approach to discovering novel anabolic drug targets is to identify genetic causes of extreme high bone mass (HBM). We investigated a pedigree with unexplained HBM within the UK HBM study, a national cohort of probands with HBM and their relatives. Whole exome sequencing (WES) in a family with HBM identified a rare heterozygous missense variant (NM_004482.4:c.1657C > T, p.Arg553Trp) in GALNT3, segregating appropriately. Interrogation of data from the UK HBM study and the Anglo-Australasian Osteoporosis Genetics Consortium (AOGC) revealed an unrelated individual with HBM with another rare heterozygous variant (NM_004482.4:c.831 T > A, p.Asp277Glu) within the same gene. In silico protein modeling predicted that p.Arg553Trp would disrupt salt-bridge interactions, causing instability of GALNT3, and that p.Asp277Glu would disrupt manganese binding and consequently GALNT3 catalytic function. Bi-allelic loss-of-function GALNT3 mutations alter FGF23 metabolism, resulting in hyperphosphatemia and causing familial tumoral calcinosis (FTC). However, bone mineral density (BMD) in FTC cases, when reported, has been either normal or low. Common variants in the GALNT3 locus show genome-wide significant associations with lumbar, femoral neck, and total body BMD. However, no significant associations with BMD are observed at loci coding for FGF23, its receptor FGFR1, or coreceptor klotho. Mendelian randomization analysis, using expression quantitative trait loci (eQTL) data from primary human osteoblasts and genome-wide association studies data from UK Biobank, suggested increased expression of GALNT3 reduces total body, lumbar spine, and femoral neck BMD but has no effect on phosphate concentrations. In conclusion, rare heterozygous loss-of-function variants in GALNT3 may cause HBM without altering phosphate concentration. These findings suggest that GALNT3 may affect BMD through pathways other than FGF23 regulation, the identification of which may yield novel anabolic drug targets for osteoporosis. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Neelam Hassan
- Musculoskeletal Research Unit, Translational Health Sciences, Bristol Medical SchoolUniversity of BristolBristolUK
| | - Celia L. Gregson
- Musculoskeletal Research Unit, Translational Health Sciences, Bristol Medical SchoolUniversity of BristolBristolUK
- MRC Integrated Epidemiology Unit, Population Health Sciences, Bristol Medical SchoolUniversity of BristolBristolUK
| | - Haotian Tang
- MRC Integrated Epidemiology Unit, Population Health Sciences, Bristol Medical SchoolUniversity of BristolBristolUK
| | | | - Paul Leo
- Faculty of Health, Translational Genomics Group, Institute of Health and Biomedical InnovationQueensland University of TechnologyBrisbaneQueenslandAustralia
| | - Aideen M. McInerney‐Leo
- The Faculty of Medicine, Frazer InstituteThe University of QueenslandWoolloongabbaQueenslandAustralia
| | - Jie Zheng
- MRC Integrated Epidemiology Unit, Population Health Sciences, Bristol Medical SchoolUniversity of BristolBristolUK
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai National Clinical Research Center for metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR ChinaShanghai Jiao Tong University School of MedicineShanghaiChina
- Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | | | - Jonathan C. Y. Tang
- Norwich Medical SchoolUniversity of East AngliaNorwichUK
- Clinical Biochemistry, Departments of Laboratory MedicineNorfolk and Norwich University Hospital NHS Foundation TrustNorwichUK
| | - William Fraser
- Norwich Medical SchoolUniversity of East AngliaNorwichUK
- Department of Diabetes, Endocrinology and Clinical BiochemistryNorfolk and Norwich University Hospital NHS Foundation TrustNorwichUK
| | - Michael D. Stone
- University Hospital LlandoughCardiff & Vale University Health BoardCardiffUK
| | - Elin Grundberg
- Genomic Medicine CenterChildren's Mercy Kansas CityKansas CityMissouriUSA
| | | | | | - Emma L. Duncan
- Department of Twin Research and Genetic Epidemiology, School of Life Course & Population Sciences, Faculty of Life Sciences and MedicineKing's College LondonLondonUK
| | - Jonathan H. Tobias
- Musculoskeletal Research Unit, Translational Health Sciences, Bristol Medical SchoolUniversity of BristolBristolUK
- MRC Integrated Epidemiology Unit, Population Health Sciences, Bristol Medical SchoolUniversity of BristolBristolUK
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13
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Nishimura-Kinoshita N, Ohata Y, Sawai H, Izawa M, Takeyari S, Kubota T, Omae Y, Ozono K, Tokunaga K, Hamajima T. A case of hyperphosphatemic familial tumoral calcinosis due to maternal uniparental disomy of a GALNT3 variant. Clin Pediatr Endocrinol 2023; 32:161-167. [PMID: 37362161 PMCID: PMC10288290 DOI: 10.1297/cpe.2022-0071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 03/13/2023] [Indexed: 06/28/2023] Open
Abstract
Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare, inherited autosomal recessive disorder caused by fibroblast growth factor-23 (FGF23), N-acetylgalactosaminyltransferase 3 (GALNT3), or Klotho (KL) gene variants. Here, we report the case of a Japanese boy who presented with a mass in his left elbow at the age of three. Laboratory test results of the patient revealed normocalcemia (10.3 mg/dL) and hyperphosphatemia (8.7 mg/dL); however, despite hyperphosphatemia, serum intact FGF23 level was low, renal tubular reabsorption of phosphate (TRP) level was inappropriately increased, and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) level was inappropriately normal. Genetic analysis revealed maternal uniparental disomy (UPD) of chromosome 2, which included a novel GALNT3 variant (c.1780-1G>C). Reverse transcription-polymerase chain reaction (RT-PCR) analysis of GALNT3 mRNA confirmed that this variant resulted in the destruction of exon 11. We resected the mass when the patient was five years old, owing to its gradual enlargement. No relapse or new pathological lesions were observed four years after tumor resection. This is the first case report of a Japanese patient with HFTC associated with a novel GALNT3 variant, as well as the first case of HFTC caused by maternal UPD of chromosome 2 that includes the GALNT3 variant.
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Affiliation(s)
- Naoko Nishimura-Kinoshita
- Department of Pediatrics, Tango Central Hospital, Kyoto, Japan
- Department of Endocrinology and Metabolism, Aichi Children's Health and Medical Center, Aichi, Japan
| | - Yasuhisa Ohata
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hiromi Sawai
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masako Izawa
- Department of Endocrinology and Metabolism, Aichi Children's Health and Medical Center, Aichi, Japan
| | - Shinji Takeyari
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Takuo Kubota
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yosuke Omae
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Genome Medical Science Project (Toyama), National Center for Global Health and Medicine, Tokyo, Japan
| | - Keiichi Ozono
- Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Katsushi Tokunaga
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Genome Medical Science Project (Toyama), National Center for Global Health and Medicine, Tokyo, Japan
| | - Takashi Hamajima
- Department of Endocrinology and Metabolism, Aichi Children's Health and Medical Center, Aichi, Japan
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14
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Puar A, Donegan D, Helft P, Kuhar M, Webster J, Rao M, Econs M. Hyperphosphatemic Tumoral Calcinosis With Pemigatinib Use. AACE Clin Case Rep 2022; 8:217-220. [PMID: 36189136 PMCID: PMC9508588 DOI: 10.1016/j.aace.2022.07.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 06/30/2022] [Accepted: 07/07/2022] [Indexed: 02/06/2023] Open
Abstract
Background/Objective Pemigatinib, a fibroblast growth factor receptor (FGFR) 1-3 inhibitor, is a novel therapeutic approach for treating cholangiocarcinoma when an FGFR fusion or gene rearrangement is identified. Although the most reported side effect of pemigatinib is hyperphosphatemia, tumoral calcinosis with soft tissue calcifications is not widely recognized as a complication. We report a case of patient with hyperphosphatemic tumoral calcinosis on pemigatinib. Case Report A 59-year-old woman with progressive metastatic cholangiocarcinoma, despite receiving treatment with cisplatin and gemcitabine for 7 months, was found to have an FGFR2-BICC1 fusion in the tumor on next-generation sequencing. Pemigatinib was, therefore, initiated. Four months into the therapy, multiple subcutaneous nodules developed over the lower portion of her back, hips, and legs. Punch biopsies revealed deep dermal and subcutaneous calcifications. Investigations revealed elevated serum phosphorus (7.5 mg/dL), normal serum calcium (8.7 mg/dL), and elevated intact fibroblast growth factor-23 (FGF23, 1216 pg/mL; normal value <59 pg/mL) levels. Serum phosphorus levels improved with a low-phosphorus diet and sevelamer. Calcifications regressed with pemigatinib discontinuation. Discussion Inhibition or deficiency of FGF-23 results in hyperphosphatemia and can lead to ectopic calcification. Pemigatinib, a potent inhibitor of FGFR-1-3, blocks the effect of FGF-23 leading to hyperphosphatemia and tumoral calcinosis as observed in our case. Treatment is aimed primarily at lowering serum phosphate levels through dietary restriction or phosphate binders; however, the regression of tumoral calcinosis can occur with pemigatinib cessation, as seen in this case. Conclusion As the use of FGFR 1-3 inhibitors becomes more prevalent, we aim to raise attention to the potential side effects of tumoral calcinosis.
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15
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Abstract
Inorganic phosphate (Pi) in the mammalian body is balanced by its influx and efflux through the intestines, kidneys, bones, and soft tissues, at which several sodium/Pi co-transporters mediate its active transport. Pi homeostasis is achieved through the complex counter-regulatory feedback balance between fibroblast growth factor 23 (FGF23), 1,25-dihydroxyvitamin D (1,25(OH)2D), and parathyroid hormone. FGF23, which is mainly produced by osteocytes in bone, plays a central role in Pi homeostasis and exerts its effects by binding to the FGF receptor (FGFR) and αKlotho in distant target organs. In the kidneys, the main target, FGF23 promotes the excretion of Pi and suppresses the production of 1,25(OH)2D. Deficient and excess FGF23 result in hyperphosphatemia and hypophosphatemia, respectively. FGF23-related hypophosphatemic rickets/osteomalacia include tumor-induced osteomalacia and various genetic diseases, such as X-linked hypophosphatemic rickets. Coverage by the national health insurance system in Japan for the measurement of FGF23 and the approval of burosumab, an FGF23-neutralizing antibody, have had a significant impact on the diagnosis and treatment of FGF23-related hypophosphatemic rickets/osteomalacia. Some of the molecules responsible for genetic hypophosphatemic rickets/osteomalacia are highly expressed in osteocytes and function as local regulators of FGF23 production. A number of systemic factors also regulate FGF23 levels. Although the mechanisms responsible for Pi sensing in mammals have not yet been elucidated in detail, recent studies have suggested the involvement of FGFR1. The further clarification of the mechanisms by which osteocytes detect Pi levels and regulate FGF23 production will lead to the development of better strategies to treat hyperphosphatemic and hypophosphatemic conditions.
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Affiliation(s)
- Toshimi Michigami
- Department of Bone and Mineral Research, Research Institute, Osaka Women's and Children's Hospital, Osaka 594-1101, Japan
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16
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Pathogenesis of FGF23-Related Hypophosphatemic Diseases Including X-linked Hypophosphatemia. ENDOCRINES 2022. [DOI: 10.3390/endocrines3020025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Since phosphate is indispensable for skeletal mineralization, chronic hypophosphatemia causes rickets and osteomalacia. Fibroblast growth factor 23 (FGF23), which is mainly produced by osteocytes in bone, functions as the central regulator of phosphate metabolism by increasing the renal excretion of phosphate and suppressing the production of 1,25-dihydroxyvitamin D. The excessive action of FGF23 results in hypophosphatemic diseases, which include a number of genetic disorders such as X-linked hypophosphatemic rickets (XLH) and tumor-induced osteomalacia (TIO). Phosphate-regulating gene homologous to endopeptidase on the X chromosome (PHEX), dentin matrix protein 1 (DMP1), ectonucleotide pyrophosphatase phosphodiesterase-1, and family with sequence similarity 20c, the inactivating variants of which are responsible for FGF23-related hereditary rickets/osteomalacia, are highly expressed in osteocytes, similar to FGF23, suggesting that they are local negative regulators of FGF23. Autosomal dominant hypophosphatemic rickets (ADHR) is caused by cleavage-resistant variants of FGF23, and iron deficiency increases serum levels of FGF23 and the manifestation of symptoms in ADHR. Enhanced FGF receptor (FGFR) signaling in osteocytes is suggested to be involved in the overproduction of FGF23 in XLH and autosomal recessive hypophosphatemic rickets type 1, which are caused by the inactivation of PHEX and DMP1, respectively. TIO is caused by the overproduction of FGF23 by phosphaturic tumors, which are often positive for FGFR. FGF23-related hypophosphatemia may also be associated with McCune-Albright syndrome, linear sebaceous nevus syndrome, and the intravenous administration of iron. This review summarizes current knowledge on the pathogenesis of FGF23-related hypophosphatemic diseases.
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Parathyroidectomy May Cause Remission of Uraemic Tumoral Calcinosis in Haemodialysis Patients. Indian J Surg 2022. [DOI: 10.1007/s12262-022-03283-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
AbstractFew cases of uraemic tumoral calcinosis (UTC) have been reported. This study aimed to investigate the clinical efficacy of parathyroidectomy for UTC. Historical clinical data of patients with end-stage renal disease and UTC who underwent parathyroidectomy were analysed. Absorption of metastatic calcification was compared before and after operation. Changes in intact parathyroid hormone, serum calcium, phosphorus, and alkaline phosphatase levels were analysed before parathyroidectomy and at 1 week and 3, 6, and 12 months after parathyroidectomy. Eight patients met the enrolment criteria (men, 6; mean age, 38.6 SD 10.9 years). Uraemic tumoral calcinosis, which developed 2–8 years after dialysis began, was caused by secondary hyperparathyroidism. Massive calcium deposition was found in the shoulder (n = 6), hip (n = 3), and elbow (n = 2). Four patients had > 2 joints affected, and a single joint was involved for four patients. Seven patients had rapid remission (< 6 months) of the masses after parathyroidectomy. In one patient, the mass remained unabsorbed until 6 months postoperatively. Hypocalcaemia occurred in all patients where parathyroidectomy was successful, and calcium supplementation was required 1 year postoperatively. Serum intact parathyroid hormone levels on day 7 and at 3 and 6 months postoperatively decreased significantly from baseline and remained low 1 year postoperatively (22.015 SD33.134 pg/mL). Postoperative phosphorus levels were significantly lower than preoperative levels (p < 0.05), but no significant difference was found in alkaline phosphatase levels (p > 0.05). Parathyroidectomy has promising efficacy for UTC treatment and regulation of serum intact parathyroid hormone and phosphorus. Hypocalcaemia is a common complication after parathyroidectomy. Current Controlled Trials ChiCTR2000041311, date of registration: Dec. 23, 2020.
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18
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Kato K, Hansen L, Clausen H. Polypeptide N-acetylgalactosaminyltransferase-Associated Phenotypes in Mammals. Molecules 2021; 26:5504. [PMID: 34576978 PMCID: PMC8472655 DOI: 10.3390/molecules26185504] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 09/07/2021] [Accepted: 09/08/2021] [Indexed: 01/31/2023] Open
Abstract
Mucin-type O-glycosylation involves the attachment of glycans to an initial O-linked N-acetylgalactosamine (GalNAc) on serine and threonine residues on proteins. This process in mammals is initiated and regulated by a large family of 20 UDP-GalNAc: polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts) (EC 2.4.1.41). The enzymes are encoded by a large gene family (GALNTs). Two of these genes, GALNT2 and GALNT3, are known as monogenic autosomal recessive inherited disease genes with well characterized phenotypes, whereas a broad spectrum of phenotypes is associated with the remaining 18 genes. Until recently, the overlapping functionality of the 20 members of the enzyme family has hindered characterizing the specific biological roles of individual enzymes. However, recent evidence suggests that these enzymes do not have full functional redundancy and may serve specific purposes that are found in the different phenotypes described. Here, we summarize the current knowledge of GALNT and associated phenotypes.
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Affiliation(s)
- Kentaro Kato
- Department of Eco-Epidemiology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan
- School of Tropical Medicine and Global Health, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan
| | - Lars Hansen
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Mærsk Building, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark;
| | - Henrik Clausen
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Mærsk Building, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark;
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Wandall HH, Nielsen MAI, King-Smith S, de Haan N, Bagdonaite I. Global functions of O-glycosylation: promises and challenges in O-glycobiology. FEBS J 2021; 288:7183-7212. [PMID: 34346177 DOI: 10.1111/febs.16148] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 07/23/2021] [Accepted: 08/03/2021] [Indexed: 12/13/2022]
Abstract
Mucin type O-glycosylation is one of the most diverse types of glycosylation, playing essential roles in tissue development and homeostasis. In complex organisms, O-GalNAc glycans comprise a substantial proportion of the glycocalyx, with defined functions in hemostatic, gastrointestinal, and respiratory systems. Furthermore, O-GalNAc glycans are important players in host-microbe interactions, and changes in O-glycan composition are associated with certain diseases and metabolic conditions, which in some instances can be used for diagnosis or therapeutic intervention. Breakthroughs in O-glycobiology have gone hand in hand with the development of new technologies, such as advancements in mass spectrometry, as well as facilitation of genetic engineering in mammalian cell lines. High-throughput O-glycoproteomics have enabled us to draw a comprehensive map of O-glycosylation, and mining this information has supported the definition and confirmation of functions related to site-specific O-glycans. This includes protection from proteolytic cleavage, as well as modulation of binding affinity or receptor function. Yet, there is still much to discover, and among the important next challenges will be to define the context-dependent functions of O-glycans in different stages of cellular differentiation, cellular metabolism, host-microbiome interactions, and in disease. In this review, we present the achievements and the promises in O-GalNAc glycobiology driven by technological advances in analytical methods, genetic engineering, and systems biology.
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Affiliation(s)
- Hans H Wandall
- Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Copenhagen Center for Glycomics, University of Copenhagen, Copenhagen, Denmark
| | - Mathias A I Nielsen
- Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Copenhagen Center for Glycomics, University of Copenhagen, Copenhagen, Denmark
| | - Sarah King-Smith
- Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Copenhagen Center for Glycomics, University of Copenhagen, Copenhagen, Denmark
| | - Noortje de Haan
- Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Copenhagen Center for Glycomics, University of Copenhagen, Copenhagen, Denmark
| | - Ieva Bagdonaite
- Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, Copenhagen Center for Glycomics, University of Copenhagen, Copenhagen, Denmark
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Lee AE, Hartley IR, Roszko KL, Vanek C, Gafni RI, Collins MT. Hyperphosphatemic Familial Tumoral Calcinosis Hidden in Plain Sight for 73 Years: A Case Report. FRONTIERS IN DENTAL MEDICINE 2021. [DOI: 10.3389/fdmed.2021.719752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
While dental pulp calcifications and root anomalies may be inconsequential incidental findings in dental radiographs, they can, especially in combination, represent a clue, hidden in plain sight, for the diagnosis of hyperphosphatemic familial tumoral calcinosis (HFTC). HFTC is an autosomal recessive disease of mineral metabolism characterized by sometimes massive, painful calcification around large joints, systemic inflammation, dental pulp calcification, and thistle-shaped roots. This paper describes a woman with HFTC who endured not only the symptoms of HFTC for decades, but also the frustration of not knowing the cause. The diagnosis was finally made at the age of 73 years, when the connection between a large right shoulder calcification and hyperphosphatemia was made. The dental findings were likely present on her initial radiographs taken in childhood. Increased awareness of the association between characteristic dental findings and HFTC may allow for earlier diagnosis and interventions to improve the care of patients with this rare condition.
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21
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Freedman JD, Novak R, Bratman Morag S, Avitan-Hersh E, Nikomarov D. Bone Involvement in Hyperphosphatemic Familial Tumoral Calcinosis: A New Phenotypic Presentation. Rambam Maimonides Med J 2021; 12:RMMJ.10445. [PMID: 34270404 PMCID: PMC8284990 DOI: 10.5041/rmmj.10445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Mutations in FGF23, KL, and GALNT3 have been identified as the cause for the development of hyperphosphatemic familial tumoral calcinosis (HFTC). Patients with HFTC typically present in childhood or adolescence with periarticular soft tissue deposits that eventually progress to disrupt normal joint articulation. Mutations in the GALNT3 gene were shown to account for the hyperphosphatemic state in both HFTC and hyperostosis-hyperphosphatemia syndrome (HHS), the latter characterized by bone involvement. We present the case of a patient of a Druze ethnic origin with known HFTC that presented to our department with the first documented case of pathologic fracture occurring secondary to the disease. Our report introduces this new phenotypic presentation, suggests a potential role for prophylactic bone screening, and highlights the need for preconception genetic screening in selected populations.
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Affiliation(s)
- J. Daniel Freedman
- Department of Family Medicine, Henry Ford Health System, Detroit, Michigan, USA
- To whom correspondence should be addressed. E-mail:
| | - Rostislav Novak
- Orthopedic Surgery Section, Rambam Health Care Campus, Haifa, Israel
| | | | | | - David Nikomarov
- Musculoskeletal Oncology Surgery, Orthopedic Surgery Section, Rambam Health Care Campus, Haifa, Israel
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Soumya S, Prasad N, Jabbar PK, Hussain S, Jayakumari C, Nair A. Beneficial Response to Phosphate Lowering Therapy in Normophosphatemic Tumoral Calcinosis. Indian Pediatr 2021. [PMID: 33452789 PMCID: PMC7840380 DOI: 10.1007/s13312-021-2109-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022]
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Ito N, Fukumoto S. Congenital Hyperphosphatemic Conditions Caused by the Deficient Activity of FGF23. Calcif Tissue Int 2021; 108:104-115. [PMID: 31965220 DOI: 10.1007/s00223-020-00659-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 01/09/2020] [Indexed: 02/07/2023]
Abstract
Congenital diseases that could result in hyperphosphatemia at an early age include hyperphosphatemic familial tumoral calcinosis (HFTC)/hyperostosis-hyperphosphatemia syndrome (HHS) and congenital hypoparathyroidism/pseudohypoparathyroidism due to the insufficient activity of fibroblast growth factor (FGF) 23 and parathyroid hormone. HFTC/HHS is a rare autosomal recessive disease caused by inactivating mutations in the FGF23, UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), or Klotho (KL) genes, resulting in the excessive cleavage of active intact FGF23 (FGF23, GALNT3) or increased resistance to the action of FGF23 (KL). Massive ectopic calcification, known as tumoral calcinosis (TC), is seen in periarticular soft tissues, typically in the hip, elbow, and shoulder in HFTC/HHS, reducing the range of motion. However, other regions, such as the eye, intestine, vasculature, and testis, are also targets of ectopic calcification. The other symptoms of HFTC/HHS are painful hyperostosis of the lower legs, dental abnormalities, and systemic inflammation. Low phosphate diets, phosphate binders, and phosphaturic reagents such as acetazolamide are the treatment options for HFTC/HHS and have various consequences, which warrant the development of novel therapeutics involving recombinant FGF23.
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Affiliation(s)
- Nobuaki Ito
- Division of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan.
| | - Seiji Fukumoto
- Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
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24
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Mucin-Type O-GalNAc Glycosylation in Health and Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1325:25-60. [PMID: 34495529 DOI: 10.1007/978-3-030-70115-4_2] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Mucin-type GalNAc O-glycosylation is one of the most abundant and unique post-translational modifications. The combination of proteome-wide mapping of GalNAc O-glycosylation sites and genetic studies with knockout animals and genome-wide analyses in humans have been instrumental in our understanding of GalNAc O-glycosylation. Combined, such studies have revealed well-defined functions of O-glycans at single sites in proteins, including the regulation of pro-protein processing and proteolytic cleavage, as well as modulation of receptor functions and ligand binding. In addition to isolated O-glycans, multiple clustered O-glycans have an important function in mammalian biology by providing structural support and stability of mucins essential for protecting our inner epithelial surfaces, especially in the airways and gastrointestinal tract. Here the many O-glycans also provide binding sites for both endogenous and pathogen-derived carbohydrate-binding proteins regulating critical developmental programs and helping maintain epithelial homeostasis with commensal organisms. Finally, O-glycan changes have been identified in several diseases, most notably in cancer and inflammation, where the disease-specific changes can be used for glycan-targeted therapies. This chapter will review the biosynthesis, the biology, and the translational perspectives of GalNAc O-glycans.
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Clerin V, Saito H, Filipski KJ, Nguyen AH, Garren J, Kisucka J, Reyes M, Jüppner H. Selective pharmacological inhibition of the sodium-dependent phosphate cotransporter NPT2a promotes phosphate excretion. J Clin Invest 2020; 130:6510-6522. [PMID: 32853180 PMCID: PMC7685737 DOI: 10.1172/jci135665] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 08/20/2020] [Indexed: 12/16/2022] Open
Abstract
The sodium-phosphate cotransporter NPT2a plays a key role in the reabsorption of filtered phosphate in proximal renal tubules, thereby critically contributing to phosphate homeostasis. Inadequate urinary phosphate excretion can lead to severe hyperphosphatemia as in tumoral calcinosis and chronic kidney disease (CKD). Pharmacological inhibition of NPT2a may therefore represent an attractive approach for treating hyperphosphatemic conditions. The NPT2a-selective small-molecule inhibitor PF-06869206 was previously shown to reduce phosphate uptake in human proximal tubular cells in vitro. Here, we investigated the acute and chronic effects of the inhibitor in rodents and report that administration of PF-06869206 was well tolerated and elicited a dose-dependent increase in fractional phosphate excretion. This phosphaturic effect lowered plasma phosphate levels in WT mice and in rats with CKD due to subtotal nephrectomy. PF-06869206 had no effect on Npt2a-null mice, but promoted phosphate excretion and reduced phosphate levels in normophophatemic mice lacking Npt2c and in hyperphosphatemic mice lacking Fgf23 or Galnt3. In CKD rats, once-daily administration of PF-06869206 for 8 weeks induced an unabated acute phosphaturic and hypophosphatemic effect, but had no statistically significant effect on FGF23 or PTH levels. Selective pharmacological inhibition of NPT2a thus holds promise as a therapeutic option for genetic and acquired hyperphosphatemic disorders.
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Affiliation(s)
- Valerie Clerin
- Pfizer Inc., Worldwide Research, Development and Medical, Cambridge, Massachusetts, USA
| | | | - Kevin J. Filipski
- Pfizer Inc., Worldwide Research, Development and Medical, Cambridge, Massachusetts, USA
| | - An Hai Nguyen
- Pfizer Inc., Worldwide Research, Development and Medical, Cambridge, Massachusetts, USA
| | - Jeonifer Garren
- Pfizer Inc., Worldwide Research, Development and Medical, Cambridge, Massachusetts, USA
| | - Janka Kisucka
- Pfizer Inc., Worldwide Research, Development and Medical, Cambridge, Massachusetts, USA
| | | | - Harald Jüppner
- Endocrine Unit and
- Pediatric Nephrology Unit, Massachusetts General Hospital (MGH) and Harvard Medical School, Boston, Massachusetts, USA
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26
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Mahjoubi F, Ghadir M, Samanian S, Heydari I, Honardoost M. Hyperphosphatemic familial tumoral calcinosis caused by a novel variant in the GALNT3 gene. J Endocrinol Invest 2020; 43:1125-1130. [PMID: 32125652 DOI: 10.1007/s40618-020-01203-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Accepted: 02/19/2020] [Indexed: 10/24/2022]
Abstract
AIM Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare endocrine disorder caused by autosomal recessive variants in GALNT3, FGF23, and KL leading to progressive calcification of soft tissues and subsequent clinical effects. The aim of this was to study the cause of HFTC in an Iranian family. PATIENTS AND METHODS Four generations of a family with HFTC were studied for understanding the genetic pattern of the disease. Whole exome sequencing was applied on genomic DNA of the proband. Based on its result, genetically altered sequences were checked in his family through sanger sequencing. Then bioinformatics approaches as well as co-segregation analysis were applied to validate the genetic alteration. RESULTS A novel homozygous variant in exon four of GALNT3, namely p.R261Q was found. The parents and sister were carriers. CONCLUSION To our knowledge, it is the first-reported Iranian family with GALNT3-CDG novel variant.
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Affiliation(s)
- F Mahjoubi
- Genetic Foundation of Tehran, Solaleh Diagnostic Laboratory, Tehran, Iran
- Department of Clinical Genetics, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
| | - M Ghadir
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, No 10, Firoozeh St, Vali-asr Sq, Tehran, Iran
| | - S Samanian
- Genetic Foundation of Tehran, Solaleh Diagnostic Laboratory, Tehran, Iran
| | - I Heydari
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, No 10, Firoozeh St, Vali-asr Sq, Tehran, Iran
| | - M Honardoost
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, No 10, Firoozeh St, Vali-asr Sq, Tehran, Iran.
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27
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Hansen L, Husein DM, Gericke B, Hansen T, Pedersen O, Tambe MA, Freeze HH, Naim HY, Henrissat B, Wandall HH, Clausen H, Bennett EP. A mutation map for human glycoside hydrolase genes. Glycobiology 2020; 30:500-515. [PMID: 32039448 PMCID: PMC7372926 DOI: 10.1093/glycob/cwaa010] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 01/31/2020] [Accepted: 02/04/2020] [Indexed: 12/11/2022] Open
Abstract
Glycoside hydrolases (GHs) are found in all domains of life, and at least 87 distinct genes encoding proteins related to GHs are found in the human genome. GHs serve diverse functions from digestion of dietary polysaccharides to breakdown of intracellular oligosaccharides, glycoproteins, proteoglycans and glycolipids. Congenital disorders of GHs (CDGHs) represent more than 30 rare diseases caused by mutations in one of the GH genes. We previously used whole-exome sequencing of a homogenous Danish population of almost 2000 individuals to probe the incidence of deleterious mutations in the human glycosyltransferases (GTs) and developed a mutation map of human GT genes (GlyMAP-I). While deleterious disease-causing mutations in the GT genes were very rare, and in many cases lethal, we predicted deleterious mutations in GH genes to be less rare and less severe given the higher incidence of CDGHs reported worldwide. To probe the incidence of GH mutations, we constructed a mutation map of human GH-related genes (GlyMAP-II) using the Danish WES data, and correlating this with reported disease-causing mutations confirmed the higher prevalence of disease-causing mutations in several GH genes compared to GT genes. We identified 76 novel nonsynonymous single-nucleotide variations (nsSNVs) in 32 GH genes that have not been associated with a CDGH phenotype, and we experimentally validated two novel potentially damaging nsSNVs in the congenital sucrase-isomaltase deficiency gene, SI. Our study provides a global view of human GH genes and disease-causing mutations and serves as a discovery tool for novel damaging nsSNVs in CDGHs.
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Affiliation(s)
- Lars Hansen
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Mærsk Building, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark
| | - Diab M Husein
- Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Bünteweg 2, 30559 Hannover, Germany
| | - Birthe Gericke
- Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Bünteweg 2, 30559 Hannover, Germany
| | - Torben Hansen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Mærsk Building, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark
| | - Oluf Pedersen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Mærsk Building, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark
| | - Mitali A Tambe
- Human Genetics Program, Sanford-Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Hudson H Freeze
- Human Genetics Program, Sanford-Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
| | - Hassan Y Naim
- Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Bünteweg 2, 30559 Hannover, Germany
| | - Bernard Henrissat
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Mærsk Building, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark
- Architecture et Fonction des Macromolécules Biologiques, Centre National de la Recherche Scientifique (CNRS) and Aix-Marseille University Marseille, 163 Avenue de Luminy, 13288 Marseille CEDEX 09, France
| | - Hans H Wandall
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Mærsk Building, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark
| | - Henrik Clausen
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Mærsk Building, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark
| | - Eric P Bennett
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Mærsk Building, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark
- School of Dentistry, Faculty of Health Sciences, University of Copenhagen, Nørre Allé 20, DK-2200 Copenhagen N, Denmark
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28
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Boyce AM, Lee AE, Roszko KL, Gafni RI. Hyperphosphatemic Tumoral Calcinosis: Pathogenesis, Clinical Presentation, and Challenges in Management. Front Endocrinol (Lausanne) 2020; 11:293. [PMID: 32457699 PMCID: PMC7225339 DOI: 10.3389/fendo.2020.00293] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 04/20/2020] [Indexed: 02/02/2023] Open
Abstract
Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare and disabling disorder of fibroblast growth factor 23 (FGF23) deficiency or resistance. The disorder is manifest by hyperphosphatemia, inappropriately increased tubular reabsorption of phosphate and 1,25-dihydroxy-Vitamin D, and ectopic calcifications. HFTC has been associated with autosomal recessive pathogenic variants in: (1) the gene encoding FGF23; (2) GALNT3, which encodes a protein responsible for FGF23 glycosylation; and (3) KL, the gene encoding KLOTHO, a critical co-receptor for FGF23 signaling. An acquired autoimmune form of hyperphosphatemic tumoral calcinosis has also been reported. Periarticular tumoral calcinosis is the primary cause of disability in HFTC, leading to pain, reduced range-of-motion, and impaired physical function. Inflammatory disease is also prominent, including diaphysitis with cortical hyperostosis. Multiple treatment strategies have attempted to manage blood phosphate, reduce pain and inflammation, and address calcifications and their complications. Unfortunately, efficacy data are limited to case reports and small cohorts, and no clearly effective therapies have been identified. The purpose of this review is to provide a background on pathogenesis and clinical presentation in HFTC, discuss current approaches to clinical management, and outline critical areas of need for future research.
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29
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Lingappa L, Ichikawa S, Gray AK, Acton D, Evans MJ, Madarasu RC, Kekunnaya R, Siddaiahagari S. An Unusual Combination of Neurological Manifestations and Sudden Vision Loss in a Child with Familial Hyperphosphatemic Tumoral Calcinosis. Ann Indian Acad Neurol 2019; 22:327-331. [PMID: 31359949 PMCID: PMC6613414 DOI: 10.4103/aian.aian_191_18] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Hyperphosphatemia in the absence of renal failure is an unusual occurrence, particularly in children, but is a common primary feature of familial hyperphosphatemic tumor calcinosis. We report a child with hyperphosphatemia who presented with multiple episodes of neurologic dysfunction involving lower motor neuron facial nerve palsy along with sequential visual loss. He also had an episode of stroke. There was an extensive metastatic calcification of soft tissue and vasculature. Hyperphosphatemia with normal serum alkaline phosphatase, calcium, parathyroid hormone, and renal function was noted. He was managed with hemodialysis and sevelamer (3 months) without much success in reducing serum phosphate level, requiring continuous ambulatory peritoneal dialysis (3 years). Intact fibroblast growth factor 23 (FGF23) was undetectable, with C-terminal FGF23 fragments significantly elevated (2575 RU/ml, normal <180 RU/ml). Sequencing demonstrated homozygous c.486C >A (p.N162K) mutation in FGF23 exon 3, confirming the diagnoses of primary FGF23 deficiency, the first case to be reported from India.
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Affiliation(s)
- Lokesh Lingappa
- Department of Neurology and Hemato-Oncology, Rainbow Children's Hospital and Birthright, Hyderabad, Telangana, India
| | - Shoji Ichikawa
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Amie K Gray
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Dena Acton
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Michael J Evans
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | | | - Ramesh Kekunnaya
- Jasti V Ramanamma Children's Eye Care Centre, LV Prasad Eye Institute, Hyderabad, Telangana, India
| | - Sirisharani Siddaiahagari
- Department of Neurology and Hemato-Oncology, Rainbow Children's Hospital and Birthright, Hyderabad, Telangana, India
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30
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van Tol W, Wessels H, Lefeber DJ. O-glycosylation disorders pave the road for understanding the complex human O-glycosylation machinery. Curr Opin Struct Biol 2019; 56:107-118. [PMID: 30708323 DOI: 10.1016/j.sbi.2018.12.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 12/16/2018] [Accepted: 12/18/2018] [Indexed: 01/17/2023]
Abstract
Over 100 human Congenital Disorders of Glycosylation (CDG) have been described. Of these, about 30% reside in the O-glycosylation pathway. O-glycosylation disorders are characterized by a high phenotypic variability, reflecting the large diversity of O-glycan structures. In contrast to N-glycosylation disorders, a generic biochemical screening test is lacking, which limits the identification of novel O-glycosylation disorders. The emergence of next generation sequencing (NGS) and O-glycoproteomics technologies have changed this situation, resulting in significant progress to link disease phenotypes with underlying biochemical mechanisms. Here, we review the current knowledge on O-glycosylation disorders, and discuss the biochemical lessons that we can learn on 1) novel glycosyltransferases and metabolic pathways, 2) tissue-specific O-glycosylation mechanisms, 3) O-glycosylation targets and 4) structure-function relationships. Additionally, we provide an outlook on how genetic disorders, O-glycoproteomics and biochemical methods can be combined to answer fundamental questions regarding O-glycan synthesis, structure and function.
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Affiliation(s)
- Walinka van Tol
- Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands; Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Hans Wessels
- Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Dirk J Lefeber
- Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands; Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
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31
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Dauchez A, Souffir C, Quartier P, Baujat G, Briot K, Roux C. Hyperphosphatemic Familial Tumoral Calcinosis With Galnt3 Mutation: Transient Response to Anti-Interleukin-1 Treatments. JBMR Plus 2019; 3:e10185. [PMID: 31372591 PMCID: PMC6659445 DOI: 10.1002/jbm4.10185] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 02/04/2019] [Accepted: 02/06/2019] [Indexed: 01/12/2023] Open
Abstract
Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare autosomal recessive disease caused by mutations in genes involved in phosphate homeostasis and characterized by high serum phosphate concentration and occurrence of ectopic calcifications. Management of the disease includes lowering of phosphate concentration and, when clinically necessary, debulking surgery of calcifications. In addition, high inflammatory disease flares can occur. Our case is about a patient with GALNT3 mutation and several localizations of refractory calcinosis. Assuming HFTC acts like an auto-inflammatory syndrome, we report the effect of anti-interleukine-1 therapies on the evolution of the disease. Anakinra (100 mg, then 200 mg subcutaneous daily) and canakinumab (300 mg every 4 weeks) were sequentially given to the patient. Anti-IL-1 therapy was effective in controlling inflammatory flares; however, it did not prevent extension of calcinosis. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Astrid Dauchez
- Rheumatology Department Cochin Hospital Assistance Publique - Hôpitaux de Paris Paris France
| | - Camille Souffir
- Rheumatology Department Cochin Hospital Assistance Publique - Hôpitaux de Paris Paris France.,Paris Descartes University Paris France
| | - Pierre Quartier
- Paris Descartes University Paris France.,Paediatric Immunology - Haematology and Rheumatology Department Necker Hospital Assistance Publique - Hôpitaux de Paris Paris France.,IMAGINE Institute Paris France.,French National Reference Centre for Inflammatory Rheumatism and Autoimmune Systemic Disease in Children (RAISE)
| | - Geneviève Baujat
- IMAGINE Institute Paris France.,National Reference Center for Genetic Bone Diseases
| | - Karine Briot
- Rheumatology Department Cochin Hospital Assistance Publique - Hôpitaux de Paris Paris France.,National Reference Center for Genetic Bone Diseases
| | - Christian Roux
- Rheumatology Department Cochin Hospital Assistance Publique - Hôpitaux de Paris Paris France.,Paris Descartes University Paris France.,National Reference Center for Genetic Bone Diseases
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32
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Kışla Ekinci RM, Gürbüz F, Balcı S, Bişgin A, Taştan M, Yüksel B, Yılmaz M. Hyperphosphatemic Familial Tumoral Calcinosis in Two Siblings with a Novel Mutation in GALNT3 Gene: Experience from Southern Turkey. J Clin Res Pediatr Endocrinol 2019; 11:94-99. [PMID: 30015621 PMCID: PMC6398194 DOI: 10.4274/jcrpe.galenos.2018.2018.0134] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 07/17/2018] [Indexed: 12/01/2022] Open
Abstract
Inactivating autosomal recessive mutations in fibroblast growth factor 23 (FGF23), klotho (KL) and polypeptide N-acetylgalactosaminotransferase 3 (GALNT3) genes lead to a rare disorder, hyperphosphatemic familial tumoral calcinosis (HFTC). Patients with HFTC present with hyperphosphatemia and tumor like soft tissue calcifications. Although 78% of patients develop their first symptoms between the ages of 2-13 years, diagnosis is usually delayed until adulthood. Some individuals with the same genetic defect develop a condition named hyperphosphatemic hyperostosis syndrome. Herein we report two siblings suffering from periarticular, warm, hard and tender subcutaneous masses. Subcutaneous calcifications were present on X-ray and biopsy results were consistent with calcinosis in both patients. Laboratory results showed marked hyperphosphatemia and elevated renal tubular phosphate reabsorption rates, normal renal function tests and normal serum 25-hydroxyvitamin D levels. Thus, we suspected HFTC and performed next generation sequencing for the GALNT3 gene, reported as the most frequent cause. A novel homozygote P85Rfs*6 (c.254_255delCT) mutation in GALNT3 was identified in both siblings. Our report adds two new patients to the literature about this rare genetic disease and suggests that small deletions in the GALNT3 gene may be related with HFTC phenotype.
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Affiliation(s)
| | - Fatih Gürbüz
- Çukurova University Faculty of Medicine, Department of Pediatric Endocrinology, Adana, Turkey
| | - Sibel Balcı
- Çukurova University Faculty of Medicine, Department of Pediatric Rheumatology, Adana, Turkey
| | - Atıl Bişgin
- Çukurova University Faculty of Medicine, Department of Medical Genetics, Adana, Turkey
| | - Mehmet Taştan
- Çukurova University Faculty of Medicine, Department of Pediatric Endocrinology, Adana, Turkey
| | - Bilgin Yüksel
- Çukurova University Faculty of Medicine, Department of Pediatric Endocrinology, Adana, Turkey
| | - Mustafa Yılmaz
- Çukurova University Faculty of Medicine, Department of Pediatric Rheumatology, Adana, Turkey
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Chakhtoura M, Ramnitz MS, Khoury N, Nemer G, Shabb N, Abchee A, Berberi A, Hourani M, Collins M, Ichikawa S, El Hajj Fuleihan G. Hyperphosphatemic familial tumoral calcinosis secondary to fibroblast growth factor 23 (FGF23) mutation: a report of two affected families and review of the literature. Osteoporos Int 2018; 29:1987-2009. [PMID: 29923062 DOI: 10.1007/s00198-018-4574-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 05/14/2018] [Indexed: 01/20/2023]
Abstract
Hyperphosphatemic familial tumoral calcinosis (HFTC), secondary to fibroblast growth factor 23 (FGF23) gene mutation, is a rare genetic disorder characterized by recurrent calcified masses. We describe young Lebanese cousins presenting with HFTC, based on a retrospective chart review and a prospective case study. In addition, we present a comprehensive review on the topic, based on a literature search conducted in PubMed and Google Scholar, in 2014 and updated in December 2017. While the patients had the same previously reported FGF23 gene mutation (homozygous c.G367T variant in exon 3 leading to a missense mutation), they presented with variable severity and age of disease onset (at 4 years in patient 1 and at 23 years in patient 2). A review of the literature revealed several potential patho-physiologic pathways of HFTC clinical manifestations, some of which may be independent of hyperphosphatemia. Most available treatment options aim at reducing serum phosphate level, by stimulating renal excretion or by inhibiting intestinal absorption. HFTC is a challenging disease. While the available medical treatment has a limited and inconsistent effect on disease symptomatology, surgical resection of calcified masses remains the last resort. Research is needed to determine the safety and efficacy of FGF23 replacement or molecular therapy, targeting the specific genetic aberration. Hyperphosphatemic familial tumoral calcinosis is a rare genetic disorder characterized by recurrent calcified masses, in addition to other visceral, skeletal, and vascular manifestations. It remains a very challenging disease.
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Affiliation(s)
- M Chakhtoura
- Calcium Metabolism and Osteoporosis Program, WHO Collaborating Center for Metabolic Bone Disorders, American University of Beirut Medical Center, Beirut, Lebanon.
| | - M S Ramnitz
- Section on Skeletal Disorders and Mineral Homeostasis, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - N Khoury
- Department of Radiology, American University of Beirut Medical Center, Beirut, Lebanon
| | - G Nemer
- Department of Biochemistry and Molecular Genetics, American University of Beirut Medical Center, Beirut, Lebanon
| | - N Shabb
- Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - A Abchee
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - A Berberi
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - M Hourani
- Department of Radiology, American University of Beirut Medical Center, Beirut, Lebanon
| | - M Collins
- Section on Skeletal Disorders and Mineral Homeostasis, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - S Ichikawa
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - G El Hajj Fuleihan
- Calcium Metabolism and Osteoporosis Program, WHO Collaborating Center for Metabolic Bone Disorders, American University of Beirut Medical Center, Beirut, Lebanon
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34
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Affiliation(s)
- Allen W. Root
- Department of Pediatrics, Johns Hopkins Medicine – All Children’s Hospital, St. Petersburg, FL, USA
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35
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Goldenstein PT, Neves PD, Balbo BE, Elias RM, Pereira AC, Onuchic LF, Jüppner H, Jorgetti V, Abensur H, Moysés RM. Dialysis as a Treatment Option for a Patient With Normal Kidney Function and Familial Tumoral Calcinosis Due to a Compound Heterozygous FGF23 Mutation. Am J Kidney Dis 2018; 72:457-461. [PMID: 29548779 DOI: 10.1053/j.ajkd.2017.12.020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 12/24/2017] [Indexed: 11/11/2022]
Abstract
Primary tumoral calcinosis is a rare autosomal recessive disorder characterized by ectopic calcified tumoral masses. Mutations in 3 genes (GALNT3, FGF23, and KL) have been linked to this human disorder. We describe a case of a 28-year-old man with a history of painful firm masses over his right and left gluteal region, right clavicle region, knees, and left elbow. Biochemical analysis disclosed hyperphosphatemia (phosphate, 9.0 mg/dL) and normocalcemia (calcium, 4.8 mg/dL), with normal kidney function and fractional excretion of phosphate of 3%. Parathyroid hormone was suppressed (15 pg/mL), associated with a low-normal 25-hydroxyvitamin D (26 ng/mL) concentration but high 1,25-dihydroxyvitamin D concentration (92 pg/mL). Serum intact FGF-23 (fibroblast growth factor 23) was undetectable. Genetic analysis revealed tumoral calcinosis due to a compound heterozygous mutation in FGF23, c.201G>C (p.Gln67His) and c.466C>T (p.Gln156*). Due to lack of other treatment options and because the patient was facing severe vascular complications, we initiated a daily hemodialysis program even in the setting of normal kidney function. This unusual therapeutic option successful controlled hyperphosphatemia and reduced metastatic tumoral lesions. This is a report of a new mutation in FGF23 in which dialysis was an effective treatment option for tumoral calcinosis with normal kidney function.
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Affiliation(s)
| | - Precil D Neves
- Nephrology Division, University of São Paulo School of Medicine, Sao Paulo-SP, Brazil
| | - Bruno E Balbo
- Nephrology Division, University of São Paulo School of Medicine, Sao Paulo-SP, Brazil
| | - Rosilene M Elias
- Nephrology Division, University of São Paulo School of Medicine, Sao Paulo-SP, Brazil
| | - Alexandre C Pereira
- Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of Sao Paulo, Sao Paulo-SP, Brazil; Genetics Department, Harvard Medical School, Boston, MA
| | - Luiz F Onuchic
- Nephrology Division, University of São Paulo School of Medicine, Sao Paulo-SP, Brazil
| | - Harald Jüppner
- Endocrine, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Pediatric Nephrology Units, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Vanda Jorgetti
- Nephrology Division, University of São Paulo School of Medicine, Sao Paulo-SP, Brazil
| | - Hugo Abensur
- Nephrology Division, University of São Paulo School of Medicine, Sao Paulo-SP, Brazil
| | - Rosa Maria Moysés
- Nephrology Division, University of São Paulo School of Medicine, Sao Paulo-SP, Brazil; Universidade Nove de Julho, São Paulo-SP, Brazil.
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36
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Hussain MRM, Hoessli DC, Fang M. N-acetylgalactosaminyltransferases in cancer. Oncotarget 2018; 7:54067-54081. [PMID: 27322213 PMCID: PMC5288242 DOI: 10.18632/oncotarget.10042] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 05/30/2016] [Indexed: 12/11/2022] Open
Abstract
Aberrant mucin-type O-glycosylation by glycosyltransferases is a well-described hallmark of many cancers and is also associated with additional non-cancerous developmental and metabolic disorders. The current review focuses on N-acetylgalactosaminyltransferase genes (GALNTs) and proteins (GalNAcTs) to illustrate their importance in cancer biology. Aberrant O-glycosylation by GalNAcTs activates a wide range of proteins that carry out interactions of sessile and motile cells affecting organogenesis, responses to agonists and stimulating hyperproliferation and metastatisation of neoplastic cells. As genome-wide analyses have provided abundant clues regarding under- or over-expressed genes that characterize different types of cancers, GALNTs and their transferase products have attracted attention by being unexpected actors in neoplastic contexts. We intend to review the current knowledge on GALNTs and their encoded transferases in cancer and suggest what could be the significance of such information in cancer pathogenesis and management.
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Affiliation(s)
- Muhammad Ramzan Manwar Hussain
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Daniel C Hoessli
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | - Min Fang
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
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37
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Linglart A, Chaussain C. [Endocrine control of serum phosphate: from the discoveries of phosphatonins to novel therapies]. ANNALES D'ENDOCRINOLOGIE 2018. [PMID: 28645356 DOI: 10.1016/s0003-4266(17)30076-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Phosphate is absorbed through the gut, stored in the bone and reabsorbed through the proximal renal tubule. More importantly, PTH and FGF23 have been identified as the main phosphaturic factors that control the expression of the phosphate co-transporters NaPi-IIa et IIc. By allowing the adjustment of the urinary phosphate reabsorption, these two phosphatonins play a major role in bone and tooth mineralization and growth. Recently, novel therapies have successfully targeted the FGF23 signaling pathway to treat the hypophosphatemia in patients affected with molecular defects of this pathway (mutations in the PHEX gene).
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Affiliation(s)
- A Linglart
- APHP, Department of Pediatric Endocrinology, Bicêtre Paris Sud Hospital, Reference center for Rare Disorders of the Mineral Metabolism and Plateforme d'Expertise Paris Sud Maladies Rares, Bicêtre Paris Sud Hospital, 78 Rue du Général Leclerc, 94270 Le Kremlin Bicêtre, France.
| | - C Chaussain
- AP-HP Department of Odontology, Bretonneau Hospital, and Reference Center for Rare Diseases of Calcium and Phosphorus Metabolism, and EA 2496, Laboratory Orofacial Pathologies, Imaging and Biotherapies, School of Dentistry University Paris Descartes Sorbonne, 12 Rue de l'École de Médecine, 75006 Paris, France
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38
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A Case of Hyperphosphatemia and Elevated Fibroblast Growth Factor 23: A Brief Review of Hyperphosphatemia and Fibroblast Growth Factor 23 Pathway. Kidney Int Rep 2017; 2:1238-1242. [PMID: 29270533 PMCID: PMC5733768 DOI: 10.1016/j.ekir.2017.05.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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39
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Bader-Meunier B, Van Nieuwenhove E, Breton S, Wouters C. Bone involvement in monogenic autoinflammatory syndromes. Rheumatology (Oxford) 2017; 57:606-618. [DOI: 10.1093/rheumatology/kex306] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Indexed: 01/12/2023] Open
Affiliation(s)
- Brigitte Bader-Meunier
- Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, France
- INSERM UMR 1163, Laboratory of Immunogenetics of Pediatric Autoimmunity, Imagine Institut, Paris, France
| | - Erika Van Nieuwenhove
- Department of Microbiology and Immunology, KUL – University of Leuven, Belgium
- VIB Centre for Brain and Disease Research, KUL – University of Leuven, Belgium
- Laboratory of Pediatric Immunology, University Hospitals Leuven, Leuven, Belgium
| | - Sylvain Breton
- Pediatric Radiology Department, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Carine Wouters
- Department of Microbiology and Immunology, KUL – University of Leuven, Belgium
- Laboratory of Pediatric Immunology, University Hospitals Leuven, Leuven, Belgium
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40
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Ramadan AR, Shawar SM, Alghamdi MA. Development and Validation of a Simple Diagnostic Method to Detect Gain and Loss of Function Defects in Fibroblast Growth Factor-23. Horm Res Paediatr 2017; 86:45-52. [PMID: 27355663 DOI: 10.1159/000447113] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 05/26/2016] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Fibroblast growth factor-23 (FGF23) is a bone-derived hormone that regulates the homeostasis of phosphate and vitamin D. Three substitutions in the hormone are reported to cause autosomal dominant hypophosphatemic rickets and seven substitutions to cause autosomal recessive hyperphosphatemic familial tumoral calcinosis (HFTC). Both disorders are rare in the general population and occur most often in the Eastern Mediterranean region and Africa. None of the mutations could be identified using standard restriction fragment length polymorphism. The only technique currently available to confirm the clinical diagnosis is DNA sequencing. METHODS Using a tri-primer ARMS-PCR, in vitro site-directed mutagenesis and DNA sequencing, we developed, verified and validated a rapid and reliable diagnostic test for the ten mutations in FGF23. RESULTS We generated a test for all ten mutations and confirmed each test by DNA sequencing. We increased the specificity of the test by introducing a mismatch at position -2 in the 3'-terminus of the reverse primer of the normal and the mutant sequences. Finally, using DNA sequencing, we validated the technique for FGF23/S129F substitution by testing samples from 80 individuals from two unrelated Arab families harboring HFTC. CONCLUSIONS This inexpensive and specific method could be adopted where DNA sequencing is not available or affordable.
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Affiliation(s)
- Ahmad R Ramadan
- Department of Life Sciences, Medical Biotechnology, Arabian Gulf University, Manama, Bahrain
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41
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Shawar SM, Ramadan AR, Ali BR, Alghamdi MA, John A, Hudaib FM. FGF23-S129F mutant bypasses ER/Golgi to the circulation of hyperphosphatemic familial tumoral calcinosis patients. Bone 2016; 93:187-195. [PMID: 26620085 DOI: 10.1016/j.bone.2015.11.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Revised: 11/15/2015] [Accepted: 11/21/2015] [Indexed: 02/05/2023]
Abstract
FGF23 is essential for the homeostasis of phosphate, and vitamin D. Loss-of-function mutations in this hormone cause hyperphosphatemic familial tumoral calcinosis (HFTC). Earlier reports suggested that intact FGF23 from loss of function mutants such as FGF23/S129F (iFGF23/S129F) is retained intracellularly while the carboxy-terminal fragment is secreted. We sought to investigate the fate of iFGF23/S129F mutant hormone in vivo and in vitro. Five patients clinically diagnosed with HFTC and confirmed by DNA sequencing to carry the c.386 C>T; p.S129F mutation in the homozygous state were studied. Healthy and heterozygous individuals were used as controls in the study. Using ELISA assays, we showed that iFGF23/S129F was 2-5 folds higher in patients' plasma, compared to heterozygous or healthy controls. Importantly, the mutant hormone could not be detected in the patients' sera. However, using proteinase inhibition profiling, we found that a serum metalloproteinase degraded the iFGF23/S129F explaining our failure to detect it in sera. The serum metalloproteinase degrades the WT and the mutant at different rates. Also, confocal microscopy imaging using wild-type (WT) FGF23 or FGF23/S129F mutant in transiently transfected HEK293 and HeLa cells showed weak staining of the Golgi complex with some vesicular staining resembling the ER. Additionally, FGF23 variants (FGF23/WT, FGF23/S129F, FGF23/S71G, and FGF23/R176Q) from stably transfected HEK293 cells secreted high levels into a serum-free medium that can be detected by ELISA and Western blot. Our results suggest that iFGF23/S129F mutant bypasses the ER/Golgi quality control system to the circulation of HFTC patients by an unknown pathway. Finally, we hypothesize that either the mutant hormone is unable to bind α-Klotho-FGFR1c, or it binds the dyad receptor with low affinity and, therefore, incapable of initiating maximal intracellular signaling. Our findings raise the potential use of the WT hormone in therapies of some HFTC patients.
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Affiliation(s)
- Said M Shawar
- Life Sciences Department, Medical Biotechnology, Arabian Gulf University, Manama, Bahrain.
| | - Ahmad R Ramadan
- Life Sciences Department, Medical Biotechnology, Arabian Gulf University, Manama, Bahrain
| | - Bassam R Ali
- Pathology Department, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Manal A Alghamdi
- Life Sciences Department, Medical Biotechnology, Arabian Gulf University, Manama, Bahrain
| | - Anne John
- Pathology Department, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Ferial M Hudaib
- Life Sciences Department, Medical Biotechnology, Arabian Gulf University, Manama, Bahrain
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42
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Identification of two novel mutations in the GALNT3 gene in a Chinese family with hyperphosphatemic familial tumoral calcinosis. Bone Res 2016; 4:16038. [PMID: 27867679 PMCID: PMC5100662 DOI: 10.1038/boneres.2016.38] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Accepted: 08/23/2016] [Indexed: 12/15/2022] Open
Abstract
Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare, autosomal recessive genetic disease. This disease is characterized by the progressive calcification of soft tissues leading to symptoms of pressure and hyperphosphatemia but normal concentrations of serum calcium with or without an elevation of 1,25-dihydroxyvitamin D3 levels.HFTC is caused by loss-of-function mutations in the GALNT3, FGF23 or KL genes. Here, we identified two novel mutations in the GALNT3 gene in a Chinese family with HFTC. Identification of a novel genotype in HFTC provides clues for understanding the phenotype-genotype relationships in HFTC and may assist not only in the clinical diagnosis of HFTC but also in the interpretation of the genetic information used for prenatal diagnosis and genetic counseling.
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43
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Ramnitz MS, Gourh P, Goldbach-Mansky R, Wodajo F, Ichikawa S, Econs MJ, White KE, Molinolo A, Chen MY, Heller T, Del Rivero J, Seo-Mayer P, Arabshahi B, Jackson MB, Hatab S, McCarthy E, Guthrie LC, Brillante BA, Gafni RI, Collins MT. Phenotypic and Genotypic Characterization and Treatment of a Cohort With Familial Tumoral Calcinosis/Hyperostosis-Hyperphosphatemia Syndrome. J Bone Miner Res 2016; 31:1845-1854. [PMID: 27164190 PMCID: PMC5071128 DOI: 10.1002/jbmr.2870] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 04/22/2016] [Accepted: 05/09/2016] [Indexed: 01/05/2023]
Abstract
Familial tumoral calcinosis (FTC)/hyperostosis-hyperphosphatemia syndrome (HHS) is a rare disorder caused by mutations in the genes encoding fibroblast growth factor-23 (FGF23), N-acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO. The result is functional deficiency of, or resistance to, intact FGF23 (iFGF23), causing hyperphosphatemia, increased renal tubular reabsorption of phosphorus (TRP), elevated or inappropriately normal 1,25-dihydroxyvitamin D3 (1,25D), ectopic calcifications, and/or diaphyseal hyperostosis. Eight subjects with FTC/HHS were studied and treated. Clinical manifestations varied, even within families, ranging from asymptomatic to large, disabling calcifications. All subjects had hyperphosphatemia, increased TRP, and elevated or inappropriately normal 1,25D. C-terminal FGF23 was markedly elevated whereas iFGF23 was comparatively low, consistent with increased FGF23 cleavage. Radiographs ranged from diaphyseal hyperostosis to massive calcification. Two subjects with severe calcifications also had overwhelming systemic inflammation and elevated C-reactive protein (CRP). GALNT3 mutations were identified in seven subjects; no causative mutation was found in the eighth. Biopsies from four subjects showed ectopic calcification and chronic inflammation, with areas of heterotopic ossification observed in one subject. Treatment with low phosphate diet, phosphate binders, and phosphaturia-inducing therapies was prescribed with variable response. One subject experienced complete resolution of a calcific mass after 13 months of medical treatment. In the two subjects with systemic inflammation, interleukin-1 (IL-1) antagonists significantly decreased CRP levels with resolution of calcinosis cutis and perilesional inflammation in one subject and improvement of overall well-being in both subjects. This cohort expands the phenotype and genotype of FTC/HHS and demonstrates the range of clinical manifestations despite similar biochemical profiles and genetic mutations. Overwhelming systemic inflammation has not been described previously in FTC/HHS; the response to IL-1 antagonists suggests that anti-inflammatory drugs may be useful adjuvants. In addition, this is the first description of heterotopic ossification reported in FTC/HHS, possibly mediated by the adjacent inflammation. © 2016 American Society for Bone and Mineral Research.
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Affiliation(s)
- Mary Scott Ramnitz
- Skeletal Clinical Studies Unit, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Pravitt Gourh
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Raphaela Goldbach-Mansky
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Felasfa Wodajo
- Musculoskeletal Tumor Surgery, Virginia Cancer Specialists, Fairfax, VA, USA
| | - Shoji Ichikawa
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Michael J Econs
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Kenneth E White
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Alfredo Molinolo
- Skeletal Clinical Studies Unit, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Marcus Y Chen
- National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
| | - Theo Heller
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Jaydira Del Rivero
- National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Patricia Seo-Mayer
- Division of Nephrology and Hypertension, Pediatric Specialists of Virginia and Georgetown University School of Medicine, Fairfax, VA, USA
| | - Bita Arabshahi
- Department of Rheumatology, Pediatric Specialists of Virginia, Fairfax, VA, USA
| | - Malaka B Jackson
- Department of Pediatric Endocrinology, University of South Carolina School of Medicine, Columbia, SC, USA
| | - Sarah Hatab
- Department of Pediatric Endocrinology, Emory University School of Medicine, Atlanta, GA, USA
| | - Edward McCarthy
- Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Lori C Guthrie
- Skeletal Clinical Studies Unit, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Beth A Brillante
- Skeletal Clinical Studies Unit, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Rachel I Gafni
- Skeletal Clinical Studies Unit, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Michael T Collins
- Skeletal Clinical Studies Unit, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
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Imel EA, Liu Z, McQueen AK, Acton D, Acton A, Padgett LR, Peacock M, Econs MJ. Serum fibroblast growth factor 23, serum iron and bone mineral density in premenopausal women. Bone 2016; 86:98-105. [PMID: 26965530 PMCID: PMC4839198 DOI: 10.1016/j.bone.2016.03.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Revised: 01/25/2016] [Accepted: 03/05/2016] [Indexed: 10/22/2022]
Abstract
Fibroblast growth factor 23 (FGF23) circulates as active protein and inactive fragments. Low iron status increases FGF23 gene expression, and iron deficiency is common. We hypothesized that in healthy premenopausal women, serum iron influences C-terminal and intact FGF23 concentrations, and that iron and FGF23 associate with bone mineral density (BMD). Serum iron, iron binding capacity, percent iron saturation, phosphorus, and other biochemistries were measured in stored fasting samples from healthy premenopausal white (n=1898) and black women (n=994), age 20-55years. Serum C-terminal and intact FGF23 were measured in a subset (1631 white and 296 black women). BMD was measured at the lumbar spine and femur neck. Serum phosphorus, calcium, alkaline phosphatase and creatinine were lower in white women than black women (p<0.001). Serum iron (p<0.0001) and intact FGF23 (p<0.01) were higher in white women. C-terminal FGF23 did not differ between races. Phosphorus correlated with intact FGF23 (white women, r=0.120, p<0.0001; black women r=0.163, p<0.01). However, phosphorus correlated with C-terminal FGF23 only in black women (r=0.157, p<0.01). Intact FGF23 did not correlate with iron. C-terminal FGF23 correlated inversely with iron (white women r=-0.134, p<0.0001; black women r=-0.188, p<0.01), having a steeper slope at iron <50mcg/dl than ≥50mcg/dl. Longitudinal changes in iron predicted changes in C-terminal FGF23. Spine BMD correlated with iron negatively (r=-0.076, p<0.01) in white women; femur neck BMD correlated with iron negatively (r=-0.119, p<0.0001) in black women. Both relationships were eliminated in weight-adjusted models. BMD did not correlate with FGF23. Serum iron did not relate to intact FGF23, but was inversely related to C-terminal FGF23. Intact FGF23 correlated with serum phosphorus. In weight-adjusted models, BMD was not related to intact FGF23, C-terminal FGF23 or iron. The influence of iron on FGF23 gene expression is not important in determining bone density in healthy premenopausal women.
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Affiliation(s)
- Erik A Imel
- Department of Medicine, Indiana University School of Medicine, USA; Department of Pediatrics, Indiana University School of Medicine, USA.
| | - Ziyue Liu
- Indiana University School of Public Health, Department of Biostatistics, USA
| | - Amie K McQueen
- Department of Medicine, Indiana University School of Medicine, USA
| | - Dena Acton
- Department of Medicine, Indiana University School of Medicine, USA
| | - Anthony Acton
- Department of Medicine, Indiana University School of Medicine, USA
| | - Leah R Padgett
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, USA
| | - Munro Peacock
- Department of Medicine, Indiana University School of Medicine, USA
| | - Michael J Econs
- Department of Medicine, Indiana University School of Medicine, USA; Medical and Molecular Genetics, Indiana University School of Medicine, USA
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45
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Fatehi M, Ahuja CS, Wang S, Ginsberg HJ. Uremic tumoral calcinosis in the cervical spine: case report. J Neurosurg Spine 2016; 25:26-30. [PMID: 26943247 DOI: 10.3171/2015.12.spine151085] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Tumoral calcinosis is an uncommon condition characterized by the calcification of periarticular soft tissue. In uremic patients the disease is secondary to metabolic disturbances in predisposed patients. The authors report the case of a 73-year-old woman who presented with a new painful cervical mass while undergoing continuous ambulatory peritoneal dialysis for long-standing end-stage renal disease (ESRD). A CT scan of the neck showed a lobulated, calcified mass in the left paraspinal soft tissue at C2-3. This mass affected the facet joint and also extended into the neural foramen but did not cause any neurological compromise. Due to the patient's significant medical comorbidities, resection was deferred and the patient was followed in the clinic. Subsequent repeat imaging has shown a significant decrease in the size of the mass. In the context of ESRD, a diagnosis of uremic tumoral calcinosis (UTC) was made. The authors conducted a search of the PubMed and EMBASE databases and identified 7 previously reported cases of UTC of the cervical spine. They present a summary of these cases and discuss the etiology, diagnosis, and management of the condition. Although the metabolic disturbances seen in patients undergoing dialysis can lead to tumoral calcinosis, most reported cases involve large joints such as the shoulder or the hip; however, the spine can also be affected and should be considered in the differential diagnosis of patients with uremia as it can mimic aggressive bone-forming neoplasms.
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Affiliation(s)
- Mostafa Fatehi
- Division of Neurosurgery, Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada; and
| | - Christopher S Ahuja
- Division of Neurosurgery, Department of Surgery, University of Toronto;,Institute of Medical Science, University of Toronto
| | - Shelly Wang
- Division of Neurosurgery, Department of Surgery, University of Toronto;,Department of Biostatistics and Epidemiology, Harvard School of Public Health, Boston, Massachusetts
| | - Howard J Ginsberg
- Division of Neurosurgery, Department of Surgery, University of Toronto;,Department of Surgery and Institute of Biomaterials and Biomedical Engineering, University of Toronto;,Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Ontario
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46
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Kinoshita S, Kawai M. The FGF23/KLOTHO Regulatory Network and Its Roles in Human Disorders. VITAMINS AND HORMONES 2016; 101:151-74. [PMID: 27125741 DOI: 10.1016/bs.vh.2016.02.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The functions of Klotho (KL) are multifaceted and include the regulation of aging and mineral metabolism. It was originally identified as the gene responsible for premature aging-like symptoms in mice and was subsequently shown to function as a coreceptor in the fibroblast growth factor (FGF) 23 signaling pathway. The discovery of KL as a partner for FGF23 led to significant advances in understanding of the molecular mechanisms underlying phosphate and vitamin D metabolism, and simultaneously clarified the pathogenic roles of the FGF23 signaling pathway in human diseases. These novel insights led to the development of new strategies to combat disorders associated with the dysregulated metabolism of phosphate and vitamin D, and clinical trials on the blockade of FGF23 signaling in X-linked hypophosphatemic rickets are ongoing. Molecular and functional insights on KL and FGF23 have been discussed in this review and were extended to how dysregulation of the FGF23/KL axis causes human disorders associated with abnormal mineral metabolism.
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Affiliation(s)
- S Kinoshita
- Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Japan
| | - M Kawai
- Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Japan.
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47
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Kawai M. The FGF23/Klotho axis in the regulation of mineral and metabolic homeostasis. Horm Mol Biol Clin Investig 2016; 28:55-67. [DOI: 10.1515/hmbci-2015-0068] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Accepted: 01/07/2016] [Indexed: 11/15/2022]
Abstract
AbstractThe function of fibroblast growth factor (FGF) 23 has been suggested to be multifaceted beyond its canonical function as a regulator of mineral metabolism. FGF23 was originally shown to play a central role in phosphate (Pi) and vitamin D metabolism, and a number of diseases associated with dysregulated Pi metabolism have been attributed to abnormal FGF23 signaling activities. The discovery of Klotho as a co-receptor for FGF23 signaling has also accelerated understanding on the molecular mechanisms underlying Pi and vitamin D metabolism. In addition to these canonical functions, FGF23 has recently been implicated in a number of metabolic diseases including chronic kidney disease-associated complications, cardiovascular diseases, and obesity-related disorders; however, the physiological significance and molecular mechanisms of these emerging roles of FGF23 remain largely unknown. Molecular and functional insights into the FGF23 pathway will be discussed in the present review, with an emphasis on its role in human disorders related to dysregulated Pi metabolism as well as metabolic disorders.
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Vilder EYGD, Vanakker OM. From variome to phenome: Pathogenesis, diagnosis and management of ectopic mineralization disorders. World J Clin Cases 2015; 3:556-574. [PMID: 26244149 PMCID: PMC4517332 DOI: 10.12998/wjcc.v3.i7.556] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2014] [Revised: 02/27/2015] [Accepted: 05/18/2015] [Indexed: 02/05/2023] Open
Abstract
Ectopic mineralization - inappropriate biomineralization in soft tissues - is a frequent finding in physiological aging processes and several common disorders, which can be associated with significant morbidity and mortality. Further, pathologic mineralization is seen in several rare genetic disorders, which often present life-threatening phenotypes. These disorders are classified based on the mechanisms through which the mineralization occurs: metastatic or dystrophic calcification or ectopic ossification. Underlying mechanisms have been extensively studied, which resulted in several hypotheses regarding the etiology of mineralization in the extracellular matrix of soft tissue. These hypotheses include intracellular and extracellular mechanisms, such as the formation of matrix vesicles, aberrant osteogenic and chondrogenic signaling, apoptosis and oxidative stress. Though coherence between the different findings is not always clear, current insights have led to improvement of the diagnosis and management of ectopic mineralization patients, thus translating pathogenetic knowledge (variome) to the phenotype (phenome). In this review, we will focus on the clinical presentation, pathogenesis and management of primary genetic soft tissue mineralization disorders. As examples of dystrophic calcification disorders Pseudoxanthoma elasticum, Generalized arterial calcification of infancy, Keutel syndrome, Idiopathic basal ganglia calcification and Arterial calcification due to CD73 (NT5E) deficiency will be discussed. Hyperphosphatemic familial tumoral calcinosis will be reviewed as an example of mineralization disorders caused by metastatic calcification.
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Masi L, Beltrami G, Ottanelli S, Franceschelli F, Gozzini A, Zonefrati R, Galli G, Ciuffi S, Mavilia C, Giusti F, Marcucci G, Cioppi F, Colli E, Fossi C, Franchi A, Casentini C, Capanna R, Brandi ML. Human Preosteoblastic Cell Culture from a Patient with Severe Tumoral Calcinosis-Hyperphosphatemia Due to a New GALNT3 Gene Mutation: Study of In Vitro Mineralization. Calcif Tissue Int 2015; 96:438-52. [PMID: 25899975 DOI: 10.1007/s00223-015-9974-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Accepted: 02/24/2015] [Indexed: 02/08/2023]
Abstract
Human disorders of phosphate (Pi) handling and skeletal mineralization represent a group of rare bone diseases. One of these disease is tumoral calcinosis (TC). In this study, we present the case of a patient with TC with a new GALNT3 gene mutation. We also performed functional studies using an in vitro cellular model. Genomic DNA was extracted from peripheral blood collected from a teenage Caucasian girl affected by TC, and from her parents. A higher capability to form mineralization nodules in vitro was found in human preosteoblastic cells of mutant when compared to wild-type controls. We found a novel homozygous inactivating splice site mutation in intron I (c.516-2a>g). A higher capability to form mineralization nodules in vitro was found in the mutant cells in human preosteoblastic cells when compared to wild-type controls. Understanding the functional significance and molecular physiology of this novel mutation will help to define the role of FGF23 in the control of Pi homeostasis in normal and in pathological conditions.
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Affiliation(s)
- L Masi
- Metabolic Bone Diseases Unit AOUC-Careggi, Department of Orthopedics, University of Florence, Largo Palagi, 1, 50134, Florence, Italy
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Esapa CT, Hannan FM, Babinsky VN, Potter P, Thomas GP, Croucher PI, Brown MA, Brown SDM, Cox RD, Thakker RV. N-ethyl-N-Nitrosourea (ENU) induced mutations within the klotho gene lead to ectopic calcification and reduced lifespan in mouse models. PLoS One 2015; 10:e0122650. [PMID: 25860694 PMCID: PMC4393098 DOI: 10.1371/journal.pone.0122650] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2014] [Accepted: 02/11/2015] [Indexed: 11/18/2022] Open
Abstract
Ectopic calcification (EC), which is the pathological deposition of calcium and phosphate in extra-skeletal tissues, may be associated with hypercalcaemic and hyperphosphataemic disorders, or it may occur in the absence of metabolic abnormalities. In addition, EC may be inherited as part of several monogenic disorders and studies of these have provided valuable insights into the metabolic pathways regulating mineral metabolism. For example, studies of tumoural calcinosis, a disorder characterised by hyperphosphataemia and progressive EC, have revealed mutations of fibroblast growth factor 23 (FGF23), polypeptide N-acetyl galactosaminyltransferase 3 (GALNT3) and klotho (KL), which are all part of a phosphate-regulating pathway. However, such studies in humans are limited by the lack of available large families with EC, and to facilitate such studies we assessed the progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) for EC. This identified two mutants with autosomal recessive forms of EC, and reduced lifespan, designated Ecalc1 and Ecalc2. Genetic mapping localized the Ecalc1 and Ecalc2 loci to a 11.0 Mb region on chromosome 5 that contained the klotho gene (Kl), and DNA sequence analysis identified nonsense (Gln203Stop) and missense (Ile604Asn) Kl mutations in Ecalc1 and Ecalc2 mice, respectively. The Gln203Stop mutation, located in KL1 domain, was severely hypomorphic and led to a 17-fold reduction of renal Kl expression. The Ile604Asn mutation, located in KL2 domain, was predicted to impair klotho protein stability and in vitro expression studies in COS-7 cells revealed endoplasmic reticulum retention of the Ile604Asn mutant. Further phenotype studies undertaken in Ecalc1 (kl203X/203X) mice demonstrated elevations in plasma concentrations of phosphate, FGF23 and 1,25-dihydroxyvitamin D. Thus, two allelic variants of Kl that develop EC and represent mouse models for tumoural calcinosis have been established.
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Affiliation(s)
- Christopher T. Esapa
- Academic Endocrine Unit, Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Oxford, United Kingdom
- Medical Research Council (MRC) Mammalian Genetics Unit and Mary Lyon Centre, MRC Harwell, Harwell Science and Innovation Campus, Harwell, United Kingdom
| | - Fadil M. Hannan
- Academic Endocrine Unit, Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Oxford, United Kingdom
- Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom
| | - Valerie N. Babinsky
- Academic Endocrine Unit, Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Oxford, United Kingdom
| | - Paul Potter
- Medical Research Council (MRC) Mammalian Genetics Unit and Mary Lyon Centre, MRC Harwell, Harwell Science and Innovation Campus, Harwell, United Kingdom
| | - Gethin P. Thomas
- University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, University of Queensland, Brisbane, Australia
| | | | - Matthew A. Brown
- University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, University of Queensland, Brisbane, Australia
| | - Steve D. M. Brown
- Medical Research Council (MRC) Mammalian Genetics Unit and Mary Lyon Centre, MRC Harwell, Harwell Science and Innovation Campus, Harwell, United Kingdom
| | - Roger D. Cox
- Medical Research Council (MRC) Mammalian Genetics Unit and Mary Lyon Centre, MRC Harwell, Harwell Science and Innovation Campus, Harwell, United Kingdom
| | - Rajesh V. Thakker
- Academic Endocrine Unit, Radcliffe Department of Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Oxford, United Kingdom
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