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Clinical Characterization of Patients With Autosomal Dominant Short Stature due to Aggrecan Mutations
Karolinska Inst & Karolinska Univ Hosp, Div Pediat Endocrinol, Dept Womens & Childrens Hlth, S-17176 Stockholm, Sweden.
Cincinnati Childrens Hosp Med Ctr, Div Endocrinol, Cincinnati Ctr Growth Disorders, Cincinnati, OH 70941 USA.
Cincinnati Childrens Hosp Med Ctr, Div Endocrinol, Cincinnati Ctr Growth Disorders, Cincinnati, OH 70941 USA.
Boston Childrens Hosp, Endocrinol, Boston, MA USA.
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2017 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, no 2, p. 460-469Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS INC , 2017. Vol. 102, no 2, p. 460-469
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-359265DOI: 10.1210/jc.2016-3313ISI: 000397240900018PubMedID: 27870580OAI: oai:DiVA.org:uu-359265DiVA, id: diva2:1245799
Funder
Swedish Research Council, 521-2014-3063Swedish Research Council, 2015-02227VINNOVA, 2014-01438Available from: 2018-09-06 Created: 2018-09-06 Last updated: 2018-09-06Bibliographically approved

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Stattin, Evalena

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Jorge, Alexander A. L.Lebl, JanSentchordi, LuciaShinawi, MarwanStattin, EvalenaNilsson, Ola
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Medicinsk genetik och genomikScience for Life Laboratory, SciLifeLab
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Journal of Clinical Endocrinology and Metabolism
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