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  • 1.
    Andrade, Anenisia C.
    et al.
    Karolinska Inst, Stockholm, Sweden; Karolinska Univ Hosp, Stockholm, Sweden.
    Gkourogianni, Alexandra
    Karolinska Inst, Stockholm, Sweden; Karolinska Univ Hosp, Stockholm, Sweden.
    Segerlund, Emma
    Sunderby Hosp, Sunderby, Sweden.
    Werner-Sperker, Antje
    Sunderby Hosp, Sunderby, Sweden.
    Horemuzova, Eva
    Karolinska Inst, Stockholm, Sweden; Karolinska Univ Hosp, Stockholm, Sweden.
    Dahlgren, Jovanna
    Sahlgrenska Acad, Univ Gothenburg, Gothenburg, Sweden.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Karolinska Inst, Stockholm, Sweden; Karolinska Univ Hosp, Stockholm, Sweden.
    Short Stature Due To Two Novel Heterozygous Igf1r Mutations and Response To Gh Treatment2017In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 88, no Suppl. 1, p. 130-131, article id P1-842Article in journal (Other academic)
  • 2.
    Andrade, Anenisia C.
    et al.
    Division of Pediatric Endocrinology, Department of Women’s and Children’s Health, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Jee, Youn Hee
    Section of Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, USA.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Division of Pediatric Endocrinology, Department of Women’s and Children’s Health, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Örebro University Hospital, Örebro, Sweden.
    New Genetic Diagnoses of Short Stature Provide Insights into Local Regulation of Childhood Growth2017In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 88, no 1, p. 22-37Article, review/survey (Refereed)
    Abstract [en]

    Idiopathic short stature is a common condition with a heterogeneous etiology. Advances in genetic methods, including genome sequencing techniques and bioinformatics approaches, have emerged as important tools to identify the genetic defects in families with monogenic short stature. These findings have contributed to the understanding of growth regulation and indicate that growth plate chondrogenesis, and therefore linear growth, is governed by a large number of genes important for different signaling pathways and cellular functions, including genetic defects in hormonal regulation, paracrine signaling, cartilage matrix, and fundamental cellular processes. In addition, mutations in the same gene can cause a wide phenotypic spectrum depending on the severity and mode of inheritance of the mutation.

  • 3.
    Beck-Nielsen, Signe Sparre
    et al.
    Centre for Rare Diseases, Aarhus University Hospital, Aarhus, Denmark.
    Mughal, Zulf
    Royal Manchester Children's Hospital, Manchester, UK.
    Haffner, Dieter
    Hannover Medical School, Hannover, Germany.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Karolinska Institutet, Stockholm, Sweden .
    Levtchenko, Elena
    Katholieke Universiteit Leuven, Leuven, Belgium.
    Ariceta, Gema
    Hospital Universitario Materno-Infantil Vall d'Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain.
    de Lucas Collantes, Carmen
    Hospital Niño Jesús, Madrid, Spain.
    Schnabel, Dirk
    University Children's Hospital of Berlin, Berlin, Germany.
    Jandhyala, Ravi
    Medialis Ltd, Banbury, UK.
    Mäkitie, Outi
    Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
    FGF23 and its role in X-linked hypophosphatemia-related morbidity2019In: Orphanet Journal of Rare Diseases, ISSN 1750-1172, E-ISSN 1750-1172, Vol. 14, no 1, article id 58Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: X-linked hypophosphatemia (XLH) is an inherited disease of phosphate metabolism in which inactivating mutations of the Phosphate Regulating Endopeptidase Homolog, X-Linked (PHEX) gene lead to local and systemic effects including impaired growth, rickets, osteomalacia, bone abnormalities, bone pain, spontaneous dental abscesses, hearing difficulties, enthesopathy, osteoarthritis, and muscular dysfunction. Patients with XLH present with elevated levels of fibroblast growth factor 23 (FGF23), which is thought to mediate many of the aforementioned manifestations of the disease. Elevated FGF23 has also been observed in many other diseases of hypophosphatemia, and a range of animal models have been developed to study these diseases, yet the role of FGF23 in the pathophysiology of XLH is incompletely understood.

    METHODS: The role of FGF23 in the pathophysiology of XLH is here reviewed by describing what is known about phenotypes associated with various PHEX mutations, animal models of XLH, and non-nutritional diseases of hypophosphatemia, and by presenting molecular pathways that have been proposed to contribute to manifestations of XLH.

    RESULTS: The pathophysiology of XLH is complex, involving a range of molecular pathways that variously contribute to different manifestations of the disease. Hypophosphatemia due to elevated FGF23 is the most obvious contributor, however localised fluctuations in tissue non-specific alkaline phosphatase (TNAP), pyrophosphate, calcitriol and direct effects of FGF23 have been observed to be associated with certain manifestations.

    CONCLUSIONS: By describing what is known about these pathways, this review highlights key areas for future research that would contribute to the understanding and clinical treatment of non-nutritional diseases of hypophosphatemia, particularly XLH.

  • 4.
    Gkourogianni, Alexandra
    et al.
    Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet, Stocholm, Sweden; Karolinska University Hospital, Stockholm, Sweden.
    Andrew, Melissa
    Division of Endocrinology, Cincinnati Center for Growth Disorders, Cincinnati Children's Hospital Medical Center, Cincinnati OH, USA.
    Tyzinski, Leah
    Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati OH, USA.
    Crocker, Melissa
    Division of Endocrinology, Boston Children's Hospital, Boston MA, USA.
    Douglas, Jessica
    Division of Genetics, Boston Children's Hospital, Boston MA, USA.
    Dunbar, Nancy
    Division of Pediatric Endocrinology, Connecticut Children's Medical Center, Hartford CT, USA.
    Fairchild, Jan
    Department of Endocrinology and Diabetes, Women's and Children's Hospital, Adelaide, Australia.
    Funari, Mariana F. A.
    Unidade de Endocrinologia do Desenvolvimento (LIM/42), Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de Sao Paulo (USP), Sao Paulo, Brazil.
    Heath, Karen E.
    Institute of Medical & Molecular Genetics (INGEMM) and Skeletal dysplasia Multidisciplinary Unit (UMDE), Hospital La Paz Institute for Health Research (IdiPAZ), Hospital Universitario La Paz, Universidad Autónoma de Madrid, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain; Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Pediatrics, Hospital Universitario Infanta Sofia, Madrid, Spain.
    Jorge, Alexander A. L.
    Unidade de Endocrinologia do Desenvolvimento (LIM/42), Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de Sao Paulo (USP), Sao Paulo, Brazil.
    Kurtzman, Tracey
    El Rio Community Health Center, Tucson AZ, USA.
    LaFranchi, Stephen
    Department of Pediatrics, Oregon Health and Science University, Portland OR, USA.
    Lalani, Seema
    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston TX, USA.
    Lebl, Jan
    Department of Pediatrics, 2nd Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czech Republic.
    Lin, Yuezhen
    Pediatric Endocrinology and Metabolism, Baylor College of Medicine, Houston TX, USA.
    Los, Evan
    Department of Pediatrics, Oregon Health and Science University, Portland OR, USA.
    Newbern, Dorothee
    Division of Endocrinology, Phoenix Children's Hospital, Phoenix AZ, USA.
    Nowak, Catherine
    Division of Genetics, Boston Children's Hospital, Boston MA, USA.
    Olson, Micah
    Division of Endocrinology, Phoenix Children's Hospital, Phoenix AZ, USA.
    Popovic, Jadranka
    Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh PA, USA.
    Průhová, Štěpánka
    Department of Pediatrics, 2nd Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czech Republic.
    Elblova, Lenka
    Department of Pediatrics, 2nd FacultDepartment of Pediatrics, 2nd Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czech Republic.
    Quintos, Jose Bernardo
    Hasbro Children's Hospital, Providence RI, USA.
    Segerlund, Emma
    Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Sunderby Hospital, Sunderbyn, Sweden.
    Sentchordi, Lucia
    Institute of Medical & Molecular Genetics (INGEMM) and Skeletal dysplasia Multidisciplinary Unit (UMDE), Hospital Universitario La Paz, Universidad Autónoma de Madrid, (IdiPAZ), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain; Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Pediatrics, Hospital Universitario Infanta Sofia, Madrid, Spain.
    Shinawi, Marwan
    Division of Genetics, Washington University, St. Louis MO, USA.
    Stattin, Eva-Lena
    Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Swartz, Jonathan
    Division of Endocrinology, Boston Children's Hospital, Boston MA, USA.
    Ariadna, González-Del Angel
    Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría, Mexico City, México.
    Sinhué, Díaz-Cuéllar
    Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría, Insurgentes-Cuicuilco, Coyoacán, México.
    Hosono, Hidekazu
    Cottage Children's Medical Center, Santa Barbara CA, USA.
    Sanchez-Lara, Pedro A.
    Center for Personalized Medicine, Children's Hospital of Los Angeles, Los Angeles CA, USA.
    Hwa, Vivian
    Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati OH, USA.
    Baron, Jeffrey
    Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, USA.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Karolinska University Hospital, Stockholm, Sweden; Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, USA; Örebro University Hospital, Örebro, Sweden.
    Dauber, Andrew
    Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati OH, USA.
    Clinical characterization of patients with autosomal dominant short stature due to aggrecan mutations2017In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, no 2, p. 460-469Article in journal (Refereed)
    Abstract [en]

    Context: Heterozygous mutations in the Aggrecan gene (ACAN) cause autosomal dominant short stature with bone age (BA) acceleration, premature growth cessation and minor skeletal abnormalities.

    Objective: Characterize the phenotypic spectrum, associated conditions and response to growth-promoting therapies.

    Design: Retrospective international cohort study.

    Patients: Information from 103 individuals (57 female, 46 male) from 20 families with confirmed heterozygous ACAN mutations were included.

    Methods: Families with autosomal dominant short stature and heterozygous ACAN mutations were identified and confirmed using whole-exome sequencing, targeted next generation sequencing, and/or Sanger sequencing. Clinical information was collected from medical records.

    Results: Identified ACAN variants showed perfect co-segregation with phenotype. Adult individuals had mildly disproportionate short stature (median height: -2.8 SDS, range: -5.9 to -0.9) and histories of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). There was no apparent genotype-phenotype correlation between type of ACAN mutation and presence of joint complaints. During childhood, height was less affected (median height: -2.0 SDS, range: -4.2 to -0.6). In contrast to most children with short stature, the majority of children had advanced BA (BA - CA, median: +1.3y; range +0.0 to +3.7y) reflecting a reduction in remaining growth potential. Nineteen individuals had received GH with some evidence of increased growth velocity.

    Conclusions Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly. In several of the families, affected individuals developed early-onset osteoarthritis and degenerative disc disease requiring intervention, suggesting dysfunction of articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients.

  • 5.
    Gkourogianni, Alexandra
    et al.
    Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Segerlund, Emma
    Sunderby Hospital, Sunderbyn, Sweden.
    Hallgrimsdottir, Sigrun
    Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Karolinska Institutet and University Hospital, Stockholm, Sweden.
    Stattin, Eva-Lena
    Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Clinical and Radiological Manifestations in a Large Swedish Family with a Pathogenic Heterozygous ACAN Variant2018In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 90, no Suppl.1, p. 424-424Article in journal (Other academic)
    Abstract [en]

    Objectives: Heterozygous mutations in the aggrecan gene (ACAN) are associated with idiopathic short stature, with or without advanced bone age (BA), osteochondritis dissecans (OCD) and early onset of severe osteoarthritis (OA). Variable features also include midface hypoplasia, brachydactyly, short thumbs and intervertebral disc degenerative disease.

    Methods: We reviewed 173 radiographs in 22 individuals (8F:14M), (3shoulders, 10hands, 10wrists, 17spines, 10pelvis, 31hips, 79knees, 5 lower-legs, 4ankles, 4feet).Furthermore 2 computed tomography scans (1hip; 1knee), and 5 magnetic resonance scans (2hips; 3knees). All included individuals belong to a five generation Swedish family with short stature, OCD, and early onset OA (MIM#165800), caused by a pathogenic sequence variant, p.V2303M, in the C-type lectin domain of ACAN.

    Results: In the group of children (n=6; age ≤15yo; 3F:3M), six had moderately advanced BA (range:6-17.5months). There was no clear sign of a metaphyseal or epiphyseal dysplasia, but subtle defects of the distal radial growth plate were present in four children. There were 3 males with OCD in the knees and one of them also present-ed OCD of the hip, scoliosis and schmorl’s nodes of intervertebral discs. Actually he went through a derotation osteotomy in both hips and later a proximal tibia osteotomy and distal fibula osteotomy.Among 16 adult patients (5F:11M), 16 had OCD (7elbows,4 hips,13 knees, 5 patellas), 13 developed early onset (>40y) OA, (1shoulder, 5elbows, 3 spines, 1 metatarsophalangeal joint, 6 hips, 12 knees, 1 patella). Radiological manifestations of the spine were detected in 4 patients and included 1 scoliosis, 1 spina bifida occulta, 1 platyspondyly, 1 schmorl’s nodes, and 3 with lowering of the intervertebral discs.Moreover 8 adult patients (3F:5M) have been operated, 4 pa-tients had hip replacement (1F:3M;3bilateral;1unilateral) and 5 knee arthroplasties (2F:3M; 3bilateral;2unilateral) in particular 5 patients had tibia osteotomy of which one had combined tibia and fibula osteotomy. We measured all phalanges of eight adult hand x-rays and found no brachydactyly.

    Conclusions: The pathogenic heterozygous p.V2303M variant in the ACAN gene causes mildly disproportionate short stature with early-onset OA and intervertebral disc degeneration often requiring multiple orthopedic interventions. Radiologic findings, included moderately advanced BA, OCD in knees, hips, and elbows as well as OA in 13 individuals. Further studies are needed to identify preventive measures that may slow the progression of OA and intervertebral disc disease and to determine the role of rhGH to improve final height

  • 6.
    Högler, W.
    et al.
    Dept of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz, Linz, Austria.
    Imel, A.
    Indiana University School of Medicine, Indianapolis, USA.
    Whyte, P.
    Shriners Hospitals for Children, St.Louis, USA.
    Munns, C.
    The Children’s Hospital at Westmead, Sydney, Australia.
    Anthony, P.
    University of California, San Francisco, San Francisco, USA.
    Ward, L.
    University of Ottawa, Ontario, Canada.
    Simmons, H.
    Vanderbilt University School of Medicine, Nashville, USA.
    Padidela, R.
    Royal Manchester Children's Hospital, Manchester, UK.
    Namba, N.
    Osaka Hospital, Japan Community Healthcare Organization and Osaka University Graduate School of Medicine, Osaka, Japan.
    Cheong, H.
    Seoul National University Children’s Hospital, Seoul, South Korea,.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Karolinska Institutet, Stockholm, Sweden.
    Mao, M.
    Ultragenyx Pharmaceutical Inc., Novato, USA.
    Skrinar, A.
    Ultragenyx Pharmaceutical Inc., Novato, USA.
    Chen, C. -Y
    Ultragenyx Pharmaceutical Inc., Novato, USA.
    San Martin, J.
    Ultragenyx Pharmaceutical Inc., Novato, USA.
    Glorieux, F.
    Shriners Hospital for Children-Canada, McGill University, Montreal, Canada.
    BUROSUMAB RESULTED IN GREATER IMPROVEMENT IN PHOSPHATE METABOLISM, RICKETS, GROWTH, AND MOBILITY THAN CONTINUATION WITH CONVENTIONAL THERAPY IN CHILDREN WITH X-LINKED HYPOPHOSPHATEMIA (XLH)2019In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 30, no Suppl. 2, p. S409-S410Article in journal (Other academic)
  • 7.
    Imel, Erik A.
    et al.
    Department of Medicine and Department of Pediatrics, Indiana University School of Medicine, Indianapolis IN, USA.
    Glorieux, Francis H.
    Shriners Hospital for Children — Canada, McGill University, Montreal QC, Canada.
    Whyte, Michael P.
    Shriners Hospitals for Children — St Louis, St Louis MO, USA.
    Munns, Craig F.
    The University of Sydney Children's Hospital Westmead Clinical School, The Children's Hospital at Westmead, Westmead, NSW, Australia; Department of Endocrinology, The Children's Hospital at Westmead, Westmead NSW, Australia.
    Ward, Leanne M.
    Department of Pediatrics, Faculty of Medicine, University of Ottawa, Ottawa ON, Canada.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Simmons, Jill H.
    Department of Pediatrics, Division of Endocrinology and Diabetes, Vanderbilt University School of Medicine, Vanderbilt University, Nashville TN, USA.
    Padidela, Raja
    Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Manchester, UK.
    Namba, Noriyuki
    Department of Pediatrics, Osaka Hospital, Japan Community Healthcare Organization, Osaka, Japan; Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.
    Cheong, Hae Il
    Seoul National University Children's Hospital, Seoul, Korea.
    Pitukcheewanont, Pisit
    Center of Endocrinology, Diabetes and Metabolism, Children's Hospital of Los Angeles, Los Angeles CA, USA.
    Sochett, Etienne
    Department of Pediatrics, Hospital for Sick Children, Toronto ON, Canada.
    Högler, Wolfgang
    Department of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz, Linz, Austria; Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK.
    Muroya, Koji
    Kanagawa Children's Medical Center, Yokohama, Japan.
    Tanaka, Hiroyuki
    Okayama Saiseikai General Hospital Outpatient Center, Okayama, Japan.
    Gottesman, Gary S.
    Shriners Hospitals for Children — St Louis, St Louis MO, USA.
    Biggin, Andrew
    The University of Sydney Children's Hospital Westmead Clinical School, The Children's Hospital at Westmead, Westmead NSW, Australia.
    Perwad, Farzana
    Department of Pediatrics, University of California, San Francisco, San Francisco CA, USA.
    Mao, Meng
    Ultragenyx Pharmaceutical, Novato CA, USA.
    Chen, Chao-Yin
    Ultragenyx Pharmaceutical, Novato CA, USA.
    Skrinar, Alison
    Ultragenyx Pharmaceutical, Novato CA, USA.
    San Martin, Javier
    Ultragenyx Pharmaceutical, Novato CA, USA.
    Portale, Anthony A.
    Department of Pediatrics, University of California, San Francisco, San Francisco CA, USA.
    Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial2019In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 393, no 10189, p. 2416-2427Article in journal (Refereed)
    Abstract [en]

    Background: X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia.

    Methods: In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1-12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2.0, fasting serum phosphorus lower than 0.97 mmol/L (3.0 mg/dL), confirmed PHEX (phosphate-regulating endopep-tidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1: 1) to receive either subcutaneous burosumab starting at 0.8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705.

    Findings: Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1.9 [SE 0.1] with burosumab vs +0.8 [0.1] with conventional therapy; difference 1.1, 95% CI 0.8-1.5; p<0.0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved.

    Interpretation: Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

  • 8.
    Jee, Youn Hee
    et al.
    Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, CRC, Bethesda MD, United States.
    Andrade, Anenisia C.
    Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Solna, Sweden.
    Baron, Jeffrey
    Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, CRC, Bethesda MD, United States.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital, Solna, Sweden.
    Genetics of Short Stature2017In: Endocrinology and metabolism clinics of North America (Print), ISSN 0889-8529, E-ISSN 1558-4410, Vol. 46, no 2, p. 259-281Article in journal (Refereed)
    Abstract [en]

    Short stature is a common and heterogeneous condition that is often genetic in etiology. For most children with genetic short stature, the specific molecular causes remain unknown; but with advances in exome/genome sequencing and bioinformatics approaches, new genetic causes of growth disorders have been identified, contributing to the understanding of the underlying molecular mechanisms of longitudinal bone growth and growth failure. Identifying new genetic causes of growth disorders has the potential to improve diagnosis, prognostic accuracy, and individualized management, and help avoid unnecessary testing for endocrine and other disorders.

  • 9.
    Jee, Youn Hee
    et al.
    Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda Maryland, USA.
    Baron, Jeffrey
    Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda Maryland, USA.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    New developments in the genetic diagnosis of short stature2018In: Current opinion in pediatrics, ISSN 1040-8703, E-ISSN 1531-698X, Vol. 30, no 4, p. 541-547Article, review/survey (Refereed)
    Abstract [en]

    Purpose of review: Genome-wide approaches including genome-wide association studies as well as exome and genome sequencing represent powerful new approaches that have improved our ability to identify genetic causes of human disorders. The purpose of this review is to describe recent advances in the genetic causes of short stature.

    Recent findings: In addition to SHOX deficiency which is one of the most common causes of isolated short stature, PAPPA2, ACAN, NPPC, NPR2, PTPN11 (and other rasopathies), FBN1, IHH and BMP2 have been identified in isolated growth disorders with or without other mild skeletal findings. In addition, novel genetic causes of syndromic short stature have been discovered, including pathogenic variants in BRCA1, DONSON, AMMECR1, NFIX, SLC25A24, and FN1.

    Summary: Isolated growth disorders are often monogenic. Specific genetic causes typically have specific biochemical and/or phenotype characteristics which are diagnostically helpful. Identification of additional subjects with a specific genetic cause of short stature often leads to a broadening of the known clinical spectrum for that condition. The identification of novel genetic causes of short stature has provided important insights into the underlying molecular mechanisms of growth failure.

  • 10.
    Jee, Youn Hee
    et al.
    Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, United States.
    Wang, Jinhee
    Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, United States.
    Yue, Shanna
    Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, United States.
    Jennings, Melissa
    Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, United States.
    Clokie, Samuel J. H.
    Birmingham Women's and Children's NHS Foundation Trust, Birmingham, United Kingdom.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Lui, Julian
    Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, United States.
    Baron, Jeffrey
    Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, United States.
    Mir-374-5p, mir-379-5p, and mir-503-5p regulate proliferation and hypertrophic differentiation of growth plate chondrocytes in male rats2018In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 159, no 3, p. 1469-1478Article in journal (Refereed)
    Abstract [en]

    Growth plate chondrocytes undergo sequential differentiation to form the resting (RZ), proliferative (PZ), and hypertrophic zones (HZ). The important role of microRNAs (miRNAs) in the growth plate was previously revealed by cartilage-specific ablation of Dicer, an enzyme essential for biogenesis of many miRNAs. To identify specific miRNAs that regulate differentiation of PZ chondrocytes to HZ chondrocytes, we microdissected individual growth plate zones from juvenile rats and performed miRNA profiling using a solution hybridization method and also miRNA-seq. Thirty-four miRNAs were differentially expressed between PZ and HZ and we hypothesized that some of the miRNAs that are preferentially expressed in PZ may serve to promote proliferation and inhibit hypertrophic differentiation. Consistent with this hypothesis, transfection of inhibitors for four of these miRNAs (mir-369-3p, mir-374-5p, mir-379-5p, mir-503-5p) decreased proliferation in primary epiphyseal chondrocytes. The inhibitors for three of these miRNAs (mir-374-5p, mir-379-5p, mir-503-5p) also increased expression of multiple genes that are associated with chondrocyte hypertrophic differentiation. We next hypothesized that preferential expression of these miRNAs in PZ is driven by the PTHrP concentration gradient across the growth plate. Consistent with this hypothesis, treatment of primary chondrocytes with a PTH/PTHrP receptor agonist, PTH1-34, increased expression of mir-374-5p, mir-379-5p, and mir-503-5p. Taken together, our findings suggest that the PTHrP concentration gradient across the growth plate induces differential expression of mir-374-5p, mir-379-5p and mir-503-5p between PZ and HZ. In PZ, the higher expression levels of these miRNAs promote proliferation and inhibit hypertrophic differentiation. In HZ, downregulation of these miRNAs inhibits proliferation and promotes hypertrophic differentiation.

  • 11.
    Lodefalk, Maria
    et al.
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Paediatrics, Örebro University Hospital, Örebro, Sweden; University Health Care Research Center, Region Örebro County, Örebro, Sweden.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Department of Paediatrics, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden; Division of Paediatric Endocrinology, Department of Women’s and Children’s Health, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    To Prime or Not to Prime - Is That Still a Question?: A Comment on the US Guidelines on Growth Hormone and Insulin-Like Growth Factor-I Treatment in Children and Adolescents2017In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 88, no 2, p. 179-180Article in journal (Refereed)
  • 12.
    Lui, Julian C.
    et al.
    National Institutes of Health, .
    Barnes, Kevin M.
    Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, USA.
    Dong, Lijin
    Genetic Engineering Core, National Eye Institute, National Institutes of Health, Bethesda MD, USA.
    Yue, Shanna
    Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, USA.
    Graber, Evan
    Division of Pediatric Endocrinology and Diabetes, Ichan School of Medicine at Mount Sinai, New York NY, USA.
    Rapaport, Robert
    Division of Pediatric Endocrinology and Diabetes, Ichan School of Medicine at Mount Sinai, New York NY, USA.
    Dauber, Andrew
    Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati OH, USA.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, USA; Center for Molecular Medicine and Pediatric Endocrinology Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Karolinska University Hospital, Stockholm, Sweden; Örebro University Hosptial, Örebro, Sweden.
    Baron, Jeffrey
    Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, USA.
    Ezh2 mutations found in the Weaver overgrowth syndrome cause a partial loss of H3K27 histone methyltransferase activity2018In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, no 4, p. 1470-1478Article in journal (Refereed)
    Abstract [en]

    Context: Weaver syndrome is characterized by tall stature, advanced bone age, characteristic facies, and variable intellectual disability. It is caused by heterozygous mutations in EZH2, a histone methyltransferase responsible for H3K27 trimethylation. However, no early truncating mutations have been identified, suggesting that null mutations do not cause Weaver syndrome.

    Objective: To test alternative hypotheses that EZH2 variants found in Weaver syndrome either cause a gain of function or a partial loss of function.

    Design: Exome sequencing was performed in a boy with tall stature, advanced bone age, and mild dysmorphic features. Mutant or wild-type EZH2 protein was expressed in mouse growth plate chondrocytes with or without endogenous EZH2, and enzymatic activity was measured. A mouse model was generated, and histone methylation was assessed in heterozygous and homozygous embryos.

    Results: A de novo missense EZH2 mutation (c.1876G>A (p.Val626Met)) was identified in the proband. When expressed in growth plate chondrocytes, the mutant protein showed decreased histone methyltransferase activity. A mouse model carrying this EZH2 mutation was generated using CRISPR/Cas9. Homozygotes showed perinatal lethality while heterozygotes were viable, fertile, and showed mild overgrowth. Both homozygous and heterozygous embryos showed decreased H3K27 methylation.

    Conclusion: We generated a mouse model with the same mutation as our patient and found that it recapitulates the Weaver overgrowth phenotype, and demonstrated that EZH2 mutations found in Weaver syndrome cause a partial loss of function.

  • 13.
    Lui, Julian C.
    et al.
    Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Collaborative Research Centers (CRC),National Institutes of Health, Bethesda MD, USA.
    Garrison, Presley
    Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Collaborative Research Centers (CRC), National Institutes of Health, Bethesda MD, USA.
    Nguyen, Quang
    Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Collaborative Research Centers (CRC), National Institutes of Health, Bethesda MD, USA.
    Ad, Michal
    Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Collaborative Research Centers (CRC), National Institutes of Health, Bethesda MD, USA.
    Keembiyehetty, Chithra
    Genomic Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda MD, USA.
    Chen, Weiping
    Genomic Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda MD, USA.
    Jee, Youn Hee
    Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Collaborative Research Centers (CRC), National Institutes of Health, Bethesda MD, USA.
    Landman, Ellie
    Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; University Hospital, Stockholm, Sweden.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. University Hospital, Örebro, Sweden; Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; University Hospital, Stockholm, Sweden.
    Barnes, Kevin M.
    Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Collaborative Research Centers (CRC), National Institutes of Health, Bethesda, Maryland, USA.
    Baron, Jeffrey
    Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Collaborative Research Centers (CRC), National Institutes of Health, Bethesda MD, USA.
    EZH1 and EZH2 promote skeletal growth by repressing inhibitors of chondrocyte proliferation and hypertrophy2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 13685Article in journal (Refereed)
    Abstract [en]

    Histone methyltransferases EZH1 and EZH2 catalyse the trimethylation of histone H3 at lysine 27 (H3K27), which serves as an epigenetic signal for chromatin condensation and transcriptional repression. Genome-wide associated studies have implicated EZH2 in the control of height and mutations in EZH2 cause Weaver syndrome, which includes skeletal overgrowth. Here we show that the combined loss of Ezh1 and Ezh2 in chondrocytes severely impairs skeletal growth in mice. Both of the principal processes underlying growth plate chondrogenesis, chondrocyte proliferation and hypertrophy, are compromised. The decrease in chondrocyte proliferation is due in part to derepression of cyclin-dependent kinase inhibitors Ink4a/b, while ineffective chondrocyte hypertrophy is due to the suppression of IGF signalling by the increased expression of IGF-binding proteins. Collectively, our findings reveal a critical role for H3K27 methylation in the regulation of chondrocyte proliferation and hypertrophy in the growth plate, which are the central determinants of skeletal growth.

  • 14.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Örebro University Hospital, Örebro, Sweden; Division of Pediatric Endocrinology and Center for Molecular Medicine, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Growth and growth disorders in 2017: Genetic and epigenetic regulation of childhood growth2018In: Nature Reviews Endocrinology, ISSN 1759-5029, E-ISSN 1759-5037, Vol. 14, no 2, p. 71-72Article in journal (Refereed)
    Abstract [en]

    Studies of rare growth disorders taken together with large-scale genetic studies of adult height variability have uncovered a large genetic network regulating childhood growth. Advances in technology and experimental model systems will help decipher the molecular mechanisms of this complex network and lead to novel treatment approaches for growth disorders.

  • 15.
    Nilsson, Ola
    Örebro University, School of Medical Sciences.
    It Is Not Just the Growth Hormone-IGF-I Axis2018In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 90, no Suppl.1, p. 12-13Article in journal (Other academic)
    Abstract [en]

    For decades, the dominant conceptual framework for understanding short and tall stature was centered on the GH-IGF-I axis. However, recent findings in basic molecular and cellular biology and in clinical genetics have uncovered a vast array of other regulatory systems that control skeletal growth and an accompanying vast array of genetic defects outside the GH-IGF-I axis that can cause disorders of linear growth. As a result, the traditional view of short or tall stature that is centered on the GH-IGF-I axis is now far too narrow to encompass the ever-growing number of defects that cause abnormal linear growth. A much broader conceptual framework can be based on the simple concept that linear growth disorders are necessarily due to dysfunction of the growth plate, the structure responsible for bone elongation and therefore overall body size. Consequently, short stature can more generally be conceptualized as a primary or secondary disorder of the growth plate chondrocytes. The wide array of genetic defects, many newly-discovered, that affect growth plate chondrocyte function and thereby cause childhood growth disorders will be reviewed. A novel concept that has emerged from recent findings is that sequence variants in a single gene can produce a phenotypic spectrum that ranges from a severe skeletal dysplasia to disproportionate or proportionate short stature, to normal variation in height, to tall stat-ure. The recent advances reviewed in this paper are steadily dimin-ishing the number of children who receive the unhelpful diagnoses of severe idiopathic short stature or tall stature.

  • 16.
    Nilsson, Ola
    Örebro University, School of Medical Sciences.
    PRO - To Prime Or Not to Prime?2018In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 90, no Suppl.1, p. 18-19Article in journal (Other academic)
    Abstract [en]

    Recent progress in the understanding of growth disorders has further emphasized that growth hormone deficiency is only one of many causes for growth failure and that growth hormone deficiency (GHD) is over-diagnosed in children with short stature. Over-diagnosis of GHD is problematic as it incorrectly labels children with pituitary disease, leads to overtreatment and misin-formation of patients and families, and may sometimes prevent doctors from making the correct diagnosis. Methods that can im-prove the specificity of GH testing are therefore urgently needed. Estrogen priming of prepubertal children is safe and inexpensive. Available data suggest that it increases specificity and therefore improves testing performance. In this presentation, I will discuss estrogen priming and argue that it should be used if the purpose of testing is to accurately determine whether the child is GH deficient.

  • 17.
    Nilsson, Ola
    et al.
    Örebro University, School of Medical Sciences. Karolinska Institutet, Stockholm, Sweden.
    Whyte, Michael P.
    Shriners Hospitals for Children, St Louis, USA.
    Imel, Erik A.
    Indiana University School of Medicine, Indianapolis, USA.
    Munns, Craig
    The Children’s Hospital at Westmead, Sydney, Australia.
    Portale, Anthony A.
    University of California, San Francisco, USA.
    Ward, Leanne
    University of Ottawa, Ontario, Canada.
    Simmons, Jill H.
    Vanderbilt University School of Medicine, Nashville, USA.
    Padidela, Raja
    Royal Manchester Children’s Hospital, Manchester, UK.
    Namba, Noriyuki
    Osaka Hospital, Japan Community, Healthcare Organization, Osaka, Japan; Osaka University Graduate School of Medicine, Osaka, Japan.
    Cheong, Hae Il
    Seoul National University Children’s Hospital, Seoul, South Korea.
    Mao, Meng
    Ultragenyx Pharmaceutical Inc., Novato, USA.
    Skrinar, Alison
    Ultragenyx Pharmaceutical Inc., Novato, USA.
    Chen, Chao-Yin
    Ultragenyx Pharmaceutical Inc., Novato, USA.
    Martin, Javier San
    Ultragenyx Pharmaceutical Inc., Novato, USA.
    Glorieux, Francis
    Shriners Hospital for Children-Canada, McGill University, Montreal, Canada.
    Burosumab Improved Rickets, Phosphate Metabolism, and Clinical Outcomes Compared to Conventional Therapy in Children with X-Linked Hypophosphatemia (XLH) - A Randomized Controlled Phase 3 Study2018In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 90, no Suppl.1, p. 57-58Article in journal (Other academic)
    Abstract [en]

    In children with XLH, high circulating levels of FGF23 cause hypophosphatemia with consequent rickets, skeletal deformities, and growth impairment. Conventional therapy consists of multiple daily doses of oral phosphate and active vitamin D (Pi/D). Burosumab is a fully human monoclonal antibody against FGF23 indicated for the treatment of XLH.

    In the active-control study CL301 (NCT02915705), 61 children with XLH (1-12 years old) were randomized (1:1) to receive subcutaneous burosumab starting at 0.8 mg/kg every 2 weeks (Q2W) or Pi/D as prescribed by investigators. Eligibility criteria included a Total Rickets Severity Score (RSS) ≥2.0 and prior receipt of Pi/D. The primary endpoint was healing of rickets at Week 40 assessed by radiologists blinded to treatment using the Radiographic Global Impression of Change (RGI-C).

    At Week 40, burosumab significantly improved rickets compared with Pi/D (RGI-C global score least squares [LS] mean ± SE: +1.92 ± 0.11 vs +0.77 ± 0.11; p<0.0001). More subjects in the burosumab group had substantial healing (RGI-C ≥+2.0) at Week 40, compared with the Pi/D group (21/29, 72% vs 2/32, 6%; odds ratio of 39.1, p<0.0001). Additional evidence for improvement of rickets included decreased Total RSS (LS mean ± SE change, burosumab vs Pi/D: -2.04 ± 0.145 vs -0.71 ± 0.138; p<0.0001), decreased alkaline phosphatase (-131 ± 13 vs -35 ± 19; p<0.0001), and improved RGI-C lower limb deformity score (+0.62 ± 0.12 vs +0.21 ± 0.12; p=0.020). At Week 40, increases in serum phosphorous (p<0.0001) and TmP/GFR (p<0.0001) were significantly greater with burosumab compared with Pi/D. Standing height Z-score increased in both treatment groups from baseline to Week 40 with an LS mean change of +0.15 (95% CI: 0.05, 0.25) for burosumab and +0.08 (-0.02, 0.19) for Pi/D. Percent predicted distance walked in six minutes increased with burosumab (Baseline to Week 40: 62% to 72%) and was unchanged with Pi/D (76% to 75%). Pre-defined adverse events (AEs) of interest, including hypersensitivity and injection site reaction, were higher in the burosumab group, but were mild to moderate in severity overall, with no discontinuations. There were 4 serious AEs (3 burosumab, 1 Pi/D); none were treatment-related and all resolved.

    In this randomized Phase 3 clinical trial, burosumab Q2W re-sulted in significantly greater improvements in rickets and phosphate metabolism compared with conventional therapy in 1-12 year-old children with XLH.

  • 18.
    Tatsi, Christina
    et al.
    Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda Maryland, USA.
    Gkourogianni, Alexandra
    Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Mohnike, Klaus
    Department of Pediatrics, Otto-von-Guericke-University, Magdeburg, Germany.
    DeArment, Diana
    Division of Pediatric Endocrinology, Children's Hospital of Pittsburgh of University of Pittsburg Medical Center, University of Pittsburgh, Pittsburgh Pennsylvania, USA.
    Witchel, Selma
    Division of Pediatric Endocrinology, Children's Hospital of Pittsburgh of University of Pittsburg Medical Center, University of Pittsburgh, Pittsburgh Pennsylvania, USA.
    Andrade, Anenisia C.
    Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Markello, Thomas C.
    Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda Maryland, USA.
    Baron, Jeffrey
    Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda Maryland, USA.
    Nilsson, Ola
    Örebro University, School of Medical Sciences. Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Jee, Youn Hee
    Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda Maryland, USA.
    Aggrecan Mutations in Nonfamilial Short Stature and Short Stature Without Accelerated Skeletal Maturation2017In: Journal of the Endocrine Society, E-ISSN 2472-1972, Vol. 1, no 8, p. 1006-1011Article in journal (Refereed)
    Abstract [en]

    Aggrecan, a proteoglycan, is an important component of cartilage extracellular matrix, including that of the growth plate. Heterozygous mutations in ACAN, the gene encoding aggrecan, cause autosomal dominant short stature, accelerated skeletal maturation, and joint disease. The inheritance pattern and the presence of bone age equal to or greater than chronological age have been consistent features, serving as diagnostic clues. From family 1, a 6-year-old boy presented with short stature [height standard deviation score (SDS), -1.75] and bone age advanced by 3 years. There was no family history of short stature (height SDS: father, -0.76; mother, 0.7). Exome sequencing followed by Sanger sequencing identified a de novo novel heterozygous frameshift mutation in ACAN (c.6404delC: p.A2135Dfs). From family 2, a 12-year-old boy was evaluated for short stature (height SDS, -3.9). His bone age at the time of genetic evaluation was approximately 1 year less than his chronological age. Family history was consistent with an autosomal dominant inheritance of short stature, with several affected members also showing early-onset osteoarthritis. Exome sequencing, confirmed by Sanger sequencing, identified a novel nonsense mutation in ACAN (c.4852C>T: p.Q1618X), which cosegregated with the phenotype. In conclusion, patients with ACAN mutations may present with nonfamilial short stature and with bone age less than chronological age. These findings expand the known phenotypic spectrum of heterozygous ACAN mutations and indicate that this diagnosis should be considered in children without a family history of short stature and in children without accelerated skeletal maturation.

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