title: Clinical Characterization of Patients With Autosomal Dominant Short Stature due to Aggrecan Mutations.
abstract: BACKGROUND
  Heterozygous mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with accelerated skeletal maturation.
  
  
  OBJECTIVE
  We sought to characterize the phenotypic spectrum and response to growth-promoting therapies.
  
  
  METHODS
  One hundred three individuals (57 females, 46 males) from 20 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 the medical records.
  
  
  RESULTS
  Identified ACAN variants showed perfect cosegregation with phenotype. Adult individuals had mildly disproportionate short stature [median height, -2.8 standard deviation score (SDS); range, -5.9 to -0.9] and a history of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). No apparent genotype-phenotype correlation was found between the type of ACAN mutation and the presence of joint complaints. Childhood height was less affected (median height, -2.0 SDS; range, -4.2 to -0.6). Most children with ACAN mutations had advanced bone age (bone age - chronologic age; median, +1.3 years; range, +0.0 to +3.7 years). Nineteen individuals had received growth hormone therapy 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. Many affected individuals developed early-onset osteoarthritis and degenerative disc disease, suggesting dysfunction of the articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients.
authors.affiliation: Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, Stockholm SE-171 76, Sweden.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gkourogianni
authors.affiliation: Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 70941.
authors.forename: Melissa
authors.initials: M
authors.lastname: Andrew
authors.affiliation: Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 70941.
authors.forename: Leah
authors.initials: L
authors.lastname: Tyzinski
authors.affiliation: Divisions of Endocrinology and.
authors.forename: Melissa
authors.initials: M
authors.lastname: Crocker
authors.affiliation: Genetics, Boston Children's Hospital, Boston, Massachusetts 02115.
authors.forename: Jessica
authors.initials: J
authors.lastname: Douglas
authors.affiliation: Division of Pediatric Endocrinology, Connecticut Children's Medical Center, Hartford, Connecticut 06106.
authors.forename: Nancy
authors.initials: N
authors.lastname: Dunbar
authors.affiliation: Department of Endocrinology and Diabetes, Women's and Children's Hospital, North Adelaide, South Australia 5006, Australia.
authors.forename: Jan
authors.initials: J
authors.lastname: Fairchild
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento (LIM/42), Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo 05508-020, Brazil.
authors.forename: Mariana F A
authors.initials: MF
authors.lastname: Funari
authors.affiliation: Institute of Medical and Molecular Genetics (INGEMM) and Skeletal Dysplasia Multidisciplinary Unit, Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, and CIBERER, ISCIII, Madrid 20849, Spain.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Heath
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento (LIM/42), Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo 05508-020, Brazil.
authors.forename: Alexander A L
authors.initials: AA
authors.lastname: Jorge
authors.affiliation: El Rio Community Health Center, Tucson, Arizona 85745.
authors.forename: Tracey
authors.initials: T
authors.lastname: Kurtzman
authors.affiliation: Department of Pediatrics, Oregon Health and Science University, Portland, Oregon 97239.
authors.forename: Stephen
authors.initials: S
authors.lastname: LaFranchi
authors.affiliation: Departments of Molecular and Human Genetics and.
authors.forename: Seema
authors.initials: S
authors.lastname: Lalani
authors.affiliation: Department of Pediatrics, Second Faculty of Medicine, Charles University in Prague and University Hospital in Motol, Prague 11636, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Lebl
authors.affiliation: Pediatric Endocrinology and Metabolism, Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Yuezhen
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Pediatrics, Oregon Health and Science University, Portland, Oregon 97239.
authors.forename: Evan
authors.initials: E
authors.lastname: Los
authors.affiliation: Division of Endocrinology, Phoenix Children's Hospital, Phoenix, Arizona 85016.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Newbern
authors.affiliation: Genetics, Boston Children's Hospital, Boston, Massachusetts 02115.
authors.forename: Catherine
authors.initials: C
authors.lastname: Nowak
authors.affiliation: Division of Endocrinology, Phoenix Children's Hospital, Phoenix, Arizona 85016.
authors.forename: Micah
authors.initials: M
authors.lastname: Olson
authors.affiliation: Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15237.
authors.forename: Jadranka
authors.initials: J
authors.lastname: Popovic
authors.affiliation: Department of Pediatrics, Second Faculty of Medicine, Charles University in Prague and University Hospital in Motol, Prague 11636, Czech Republic.
authors.forename: Štepánka
authors.initials: Š
authors.lastname: Pruhová
authors.affiliation: Department of Pediatrics, Second Faculty of Medicine, Charles University in Prague and University Hospital in Motol, Prague 11636, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Elblova
authors.affiliation: Hasbro Children's Hospital, Providence, Rhode Island 02903.
authors.forename: Jose Bernardo
authors.initials: JB
authors.lastname: Quintos
authors.affiliation: Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, Stockholm SE-171 76, Sweden.|Sunderby Hospital, Sunderby 95442, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Segerlund
authors.affiliation: Institute of Medical and Molecular Genetics (INGEMM) and Skeletal Dysplasia Multidisciplinary Unit, Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPAZ, and CIBERER, ISCIII, Madrid 20849, Spain.|Department of Pediatrics, Hospital Universitario Infanta Sofia, Madrid 28703, Spain.
authors.forename: Lucia
authors.initials: L
authors.lastname: Sentchordi
authors.affiliation: Division of Genetics, Washington University, St. Louis, Missouri 63130.
authors.forename: Marwan
authors.initials: M
authors.lastname: Shinawi
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala 75236, Sweden.
authors.forename: Eva-Lena
authors.initials: EL
authors.lastname: Stattin
authors.affiliation: Divisions of Endocrinology and.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Swartz
authors.affiliation: Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría, Insurgentes-Cuicuilco, Coyoacán 04530, México.
authors.forename: Ariadna González Del
authors.initials: AG
authors.lastname: Angel
authors.affiliation: Laboratorio de Biología Molecular, Departamento de Genética Humana, Instituto Nacional de Pediatría, Insurgentes-Cuicuilco, Coyoacán 04530, México.
authors.forename: Sinhué Diaz
authors.initials: SD
authors.lastname: Cuéllar
authors.affiliation: Cottage Children's Medical Center, Santa Barbara, California 93111.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Hosono
authors.affiliation: Center for Personalized Medicine, Children's Hospital of Los Angeles, Los Angeles, California 90027.
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Sanchez-Lara
authors.affiliation: Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 70941.
authors.forename: Vivian
authors.initials: V
authors.lastname: Hwa
authors.affiliation: Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; and.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Baron
authors.affiliation: Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, Stockholm SE-171 76, Sweden.|Section on Growth and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; and.|Department of Medical Sciences, Örebro University and University Hospital, Örebro 70185, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Nilsson
authors.affiliation: Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 70941.
authors.forename: Andrew
authors.initials: A
authors.lastname: Dauber
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053674:Aggrecans / Q000235:genetics*; D000886:Anthropometry / Q000379:methods; D059327:Brachydactyly / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods; D004392:Dwarfism / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D006128:Growth / Q000235:genetics; D013006:Growth Hormone / Q000627:therapeutic use; D006579:Heterozygote; D006801:Humans; D007223:Infant; D055959:Intervertebral Disc Degeneration / Q000235:genetics; D007405:Intervertebral Disc Displacement / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010008:Osteochondritis Dissecans / Q000151:congenital / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult
chemical_list: C508319:ACAN protein, human; D053674:Aggrecans; D013006:Growth Hormone