CONTEXT: 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. PATIENTS AND 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.

Center for Personalized Medicine Children's Hospital of Los Angeles Los Angeles California 90027

Children's Hospital of Pittsburgh University of Pittsburgh Medical Center Pittsburgh Pennsylvania 15237

Cincinnati Center for Growth Disorders Division of Endocrinology Cincinnati Children's Hospital Medical Center Cincinnati Ohio 70941

Cottage Children's Medical Center Santa Barbara California 93111

Department of Endocrinology and Diabetes Women's and Children's Hospital North Adelaide South Australia 5006 Australia

Department of Immunology Genetics and Pathology Science for Life Laboratory Uppsala University Uppsala 75236 Sweden

Department of Medical Sciences Örebro University and University Hospital Örebro 70185 Sweden

Department of Pediatrics 2nd Faculty of Medicine Charles University Prague and University Hospital in Motol Prague 11636 Czech Republic

Department of Pediatrics Hospital Universitario Infanta Sofia Madrid 28703 Spain

Department of Pediatrics Oregon Health and Science University Portland Oregon 97239

Departments of Molecular and Human Genetics and

Division of Endocrinology Phoenix Children's Hospital Phoenix Arizona 85016

Division of Genetics Washington University St Louis Missouri 63130

Division of Pediatric Endocrinology Connecticut Children's Medical Center Hartford Connecticut 06106

Division of Pediatric Endocrinology Department of Women's and Children's Health Karolinska Institutet and Karolinska University Hospital Stockholm SE 171 76 Sweden

Divisions of Endocrinology and

El Rio Community Health Center Tucson Arizona 85745

Genetics Boston Children's Hospital Boston Massachusetts 02115

Hasbro Children's Hospital Providence Rhode Island 02903

Institute of Medical and Molecular Genetics and Skeletal Dysplasia Multidisciplinary Unit Hospital Universitario La Paz Universidad Autónoma de Madrid IdiPAZ and CIBERER ISCIII Madrid 20849 Spain

Laboratorio de Biología Molecular Departamento de Genética Humana Instituto Nacional de Pediatría Insurgentes Cuicuilco Coyoacán 04530 México

Pediatric Endocrinology and Metabolism Baylor College of Medicine Houston Texas 77030

Section on Growth and Development Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Bethesda Maryland 20892; and

Sunderby Hospital Sunderby 95442 Sweden

Unidade de Endocrinologia do Desenvolvimento Disciplina de Endocrinologia Faculdade de Medicina da Universidade de São Paulo São Paulo 05508 020 Brazil

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Monogenic causes of familial short stature