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Aggrecan Mutations in Nonfamilial Short Stature and Short Stature Without Accelerated Skeletal Maturation
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda Maryland, USA.
Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
Department of Pediatrics, Otto-von-Guericke-University, Magdeburg, Germany.
Division of Pediatric Endocrinology, Children's Hospital of Pittsburgh of University of Pittsburg Medical Center, University of Pittsburgh, Pittsburgh Pennsylvania, USA.
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2017 (English)In: Journal of the Endocrine Society, E-ISSN 2472-1972, Vol. 1, no 8, p. 1006-1011Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Endocrine Society , 2017. Vol. 1, no 8, p. 1006-1011
Keywords [en]
aggrecan, short stature, advanced bone age, exome sequencing
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:oru:diva-65521DOI: 10.1210/js.2017-00229ISI: 000425350300002PubMedID: 29264551OAI: oai:DiVA.org:oru-65521DiVA, id: diva2:1187936
Funder
Swedish Research Council, K2015-54X-22736-01-4 2015-02227VINNOVA, 2014-01438Marianne and Marcus Wallenberg FoundationSwedish Society of Medicine
Note

Funding Agencies:

Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health (NIH)  

Clinical Center Genomics Opportunity, NIH  

Intramural Research Program of the National Human Genome Research Institute  

Common Fund, Office of the Director, NIH 

Stockholm County Council  

Byggmästare Olle Engkvist Stiftelse  

Novo Nordisk Foundation  NNF16OC0021508 

Erik och Edith Fernström Foundation for Medical Research  

HKH Kronprinsessan Lovisas förening  

Karolinska Institutet, Stockholm, Sweden  

Örebro University, Örebro, Sweden 

Available from: 2018-03-06 Created: 2018-03-06 Last updated: 2018-08-30Bibliographically approved

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