title: Jansen Metaphyseal Chondrodysplasia due to Heterozygous H223R-PTH1R Mutations With or Without Overt Hypercalcemia.
abstract: Jansen's metaphyseal chondrodysplasia (JMC) is a rare skeletal dysplasia characterized by abnormal endochondral bone formation and typically severe hypercalcemia despite normal/low levels of PTH. Five different heterozygous activating PTH/PTHrP receptor (PTH1R) mutations that change one of three different amino acid residues are known to cause JMC.
  
  
  
  Establishing the diagnosis of JMC during infancy or early childhood can be challenging, especially in the absence of family history and/or overt hypercalcemia. We therefore sought to provide radiographic findings supporting this diagnosis early in life.
  
  
  
  Three patients, a mother and her two sons, had radiographic evidence for JMC. However, obvious hypercalcemia and suppressed PTH levels were encountered only in both affected children. Sanger sequencing and endonuclease (SphI) digestion of PCR-amplified genomic DNA were performed to search for the H223R-PTH1R mutation.
  
  
  
  The heterozygous H223R mutation was identified in all three affected individuals. Surprisingly, however, the now 38-year-old mother was never overtly hypercalcemic and was therefore not diagnosed until her sons were found to be affected by JMC at the ages of 28 months and 40 days, respectively. The presented radiographic findings at different ages will help diagnose other infants/toddlers suspected of having JMC.
  
  
  
  The H223R mutation is typically associated with profound hypercalcemia despite low/normal PTH levels. However, the findings presented herein show that overt hypercalcemia is not always encountered in JMC, even if caused by this relatively frequent mutation, which is similar to observations with other PTH1R mutations that show less constitutive activity.
authors.affiliation: Department of Pediatric Genetics (S.N., D.Y.), Amrita Institute of Medical Sciences and Research Center, Aims Ponekkara PO, Cochin 682041, Kerala, India; Munroe-Meyer Institute for Genetics and Rehabilitation (E.T.R.), University of Nebraska Medical Center, Omaha, Nebraska 68198; Department of Kidney Diseases (C.B.L.), Lurie Children's Hospital of Chicago and Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611; and Endocrine Unit (E.F.-R., T.J.G., H.J.) and Pediatric Nephrology Unit (H.J.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Sheela
authors.initials: S
authors.lastname: Nampoothiri
authors.affiliation: Department of Pediatric Genetics (S.N., D.Y.), Amrita Institute of Medical Sciences and Research Center, Aims Ponekkara PO, Cochin 682041, Kerala, India; Munroe-Meyer Institute for Genetics and Rehabilitation (E.T.R.), University of Nebraska Medical Center, Omaha, Nebraska 68198; Department of Kidney Diseases (C.B.L.), Lurie Children's Hospital of Chicago and Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611; and Endocrine Unit (E.F.-R., T.J.G., H.J.) and Pediatric Nephrology Unit (H.J.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Fernández-Rebollo
authors.affiliation: Department of Pediatric Genetics (S.N., D.Y.), Amrita Institute of Medical Sciences and Research Center, Aims Ponekkara PO, Cochin 682041, Kerala, India; Munroe-Meyer Institute for Genetics and Rehabilitation (E.T.R.), University of Nebraska Medical Center, Omaha, Nebraska 68198; Department of Kidney Diseases (C.B.L.), Lurie Children's Hospital of Chicago and Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611; and Endocrine Unit (E.F.-R., T.J.G., H.J.) and Pediatric Nephrology Unit (H.J.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Dhanya
authors.initials: D
authors.lastname: Yesodharan
authors.affiliation: Department of Pediatric Genetics (S.N., D.Y.), Amrita Institute of Medical Sciences and Research Center, Aims Ponekkara PO, Cochin 682041, Kerala, India; Munroe-Meyer Institute for Genetics and Rehabilitation (E.T.R.), University of Nebraska Medical Center, Omaha, Nebraska 68198; Department of Kidney Diseases (C.B.L.), Lurie Children's Hospital of Chicago and Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611; and Endocrine Unit (E.F.-R., T.J.G., H.J.) and Pediatric Nephrology Unit (H.J.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Gardella
authors.affiliation: Department of Pediatric Genetics (S.N., D.Y.), Amrita Institute of Medical Sciences and Research Center, Aims Ponekkara PO, Cochin 682041, Kerala, India; Munroe-Meyer Institute for Genetics and Rehabilitation (E.T.R.), University of Nebraska Medical Center, Omaha, Nebraska 68198; Department of Kidney Diseases (C.B.L.), Lurie Children's Hospital of Chicago and Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611; and Endocrine Unit (E.F.-R., T.J.G., H.J.) and Pediatric Nephrology Unit (H.J.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Eric T
authors.initials: ET
authors.lastname: Rush
authors.affiliation: Department of Pediatric Genetics (S.N., D.Y.), Amrita Institute of Medical Sciences and Research Center, Aims Ponekkara PO, Cochin 682041, Kerala, India; Munroe-Meyer Institute for Genetics and Rehabilitation (E.T.R.), University of Nebraska Medical Center, Omaha, Nebraska 68198; Department of Kidney Diseases (C.B.L.), Lurie Children's Hospital of Chicago and Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611; and Endocrine Unit (E.F.-R., T.J.G., H.J.) and Pediatric Nephrology Unit (H.J.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Craig B
authors.initials: CB
authors.lastname: Langman
authors.affiliation: Department of Pediatric Genetics (S.N., D.Y.), Amrita Institute of Medical Sciences and Research Center, Aims Ponekkara PO, Cochin 682041, Kerala, India; Munroe-Meyer Institute for Genetics and Rehabilitation (E.T.R.), University of Nebraska Medical Center, Omaha, Nebraska 68198; Department of Kidney Diseases (C.B.L.), Lurie Children's Hospital of Chicago and Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611; and Endocrine Unit (E.F.-R., T.J.G., H.J.) and Pediatric Nephrology Unit (H.J.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Harald
authors.initials: H
authors.lastname: Jüppner
mesh_terms: D002675:Child, Preschool; D005260:Female; D006801:Humans; D006934:Hypercalcemia / Q000097:blood* / Q000209:etiology; D007223:Infant; D008297:Male; D010009:Osteochondrodysplasias / Q000097:blood / Q000150:complications / Q000000981:diagnostic imaging / Q000235:genetics*; D010281:Parathyroid Hormone / Q000097:blood*; D010375:Pedigree; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics*
chemical_list: C473449:PTH1R protein, human; D010281:Parathyroid Hormone; D044168:Receptor, Parathyroid Hormone, Type 1