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Journal of Pediatric Endocrinology and Metabolism

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Ed. by Bereket, Abdullah / Darendeliler, Feyza / Dattani, Mehul / Gustafsson, Jan / Luo, Fei Hong / Mericq, Veronica / Toppari, Jorma

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Volume 28, Issue 7-8


Idiopathic short stature due to novel heterozygous mutation of the aggrecan gene

Jose Bernardo Quintos
  • Division of Pediatric Endocrinology, Rhode Island Hospital/Hasbro Children’s Hospital – The Warren Alpert Medical School of Brown University, Providence, RI, USA
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Michael H. Guo / Andrew Dauber
  • Corresponding author
  • Division of Endocrinology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2015-03-04 | DOI: https://doi.org/10.1515/jpem-2014-0450


Background: Recently, whole exome sequencing identified heterozygous defects in the aggrecan (ACAN) gene in three families with short stature and advanced bone age.

Objective: We report a novel frameshift mutation in ACAN in a family with dominantly inherited short stature, advanced bone age, and premature growth cessation. This is the first case of targeted sequencing of ACAN in this phenotype and confirms that ACAN sequencing is warranted in patients with this rare constellation of findings.

Results: We present a 5 1/2-year-old male with a family history of short stature in three generations. The maternal grandfather stands 144.5 cm (Ht SDS –4.7), mother 147.7 cm (Ht SDS –2.6), and index case 99.2 cm (Ht SDS –2.7). Our prepubertal patient has significant bone age advancement (bone age 8 years at chronologic age 5 1/2 years) resulting in a poor predicted adult height of 142 cm (Ht SDS –5.1). DNA sequencing identified a novel heterozygous variant in ACAN, which encodes aggrecan, a proteoglycan in the extracellular matrix of growth plate and other cartilaginous tissues. The mutation (p.Gly1797Glyfs*52) results in premature truncation and presumed loss of protein function.

Conclusion: Mutations in the ACAN gene should be included in the differential diagnosis of the child with idiopathic short stature or familial short stature and bone age advancement.

This article offers supplementary material which is provided at the end of the article.

Keywords: aggrecan; bone age advancement; mutation; short stature


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About the article

Corresponding author: Andrew Dauber, MD, Division of Endocrinology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA, Phone: +513-803-7027, Fax: +513-803-1174, E-mail:

aDrafted the initial manuscript with further revisions, approved the final manuscript and was involved in the direct care of the patient described.

bPerformed the genetic analysis, reviewed and revised the manuscript, and approved the final manuscript as submitted.

cConceptualized, reviewed, revised, and approved the final manuscript for submission.

Received: 2014-11-03

Accepted: 2015-01-29

Published Online: 2015-03-04

Published in Print: 2015-07-01

Citation Information: Journal of Pediatric Endocrinology and Metabolism, Volume 28, Issue 7-8, Pages 927–932, ISSN (Online) 2191-0251, ISSN (Print) 0334-018X, DOI: https://doi.org/10.1515/jpem-2014-0450.

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