Journal
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
Volume 99, Issue 8, Pages E1510-E1518Publisher
OXFORD UNIV PRESS INC
DOI: 10.1210/jc.2014-1332
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Funding
- Harvard Catalyst The Harvard Clinical and Translational Science Center (National Institutes of Health Award from Harvard University) [UL1 TR001102]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health [1K23HD073351]
- Pediatric Endocrine Society Clinical Scholar Award
- Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
- ESPE Research Fellowship Grant
- Swedish Research Council [K2012-99X-21998-01-3]
- Swedish Society of Medicine
- Her Royal Highness Crown Princess Lovisa's Foundation for Pediatric Care
- Wera Ekstrom's Foundation for Pediatric Research
- Marta och Gunnar V Philipson's Foundation
- Sallskapet Barnavard
- Stiftelsen Frimurare Barnhuset i Stockholm
- Karolinska Institutet
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Context: Many children with idiopathic short stature have a delayed bone age. Idiopathic short stature with advanced bone age is far less common. Objective: The aim was to identify underlying genetic causes of short stature with advanced bone age. Setting and Design: We used whole-exome sequencing to study three families with autosomal-dominant short stature, advanced bone age, and premature growth cessation. Results: Affected individuals presented with short stature [adult heights -2.3 to -4.2 standard deviation scores (SDS)] with histories of early growth cessation or childhood short stature (height SDS -1.9 to -3.5 SDS), advancement of bone age, and normal endocrine evaluations. Whole-exome sequencing identified novel heterozygous variants in ACAN, which encodes aggrecan, a proteoglycan in the extracellular matrix of growth plate and other cartilaginous tissues. The variants were present in all affected, but in no unaffected, family members. In Family 1, a novel frameshift mutation in exon 3 (c.272delA) was identified, which is predicted to cause early truncation of the aggrecan protein. In Family 2, a base-pair substitution was found in a highly conserved location within a splice donor site (c. 2026 + 1G>A), which is also likely to alter the amino acid sequence of a large portion of the protein. In Family 3, a missense variant (c.7064T>C) in exon 14 affects a highly conserved residue (L2355P) and is strongly predicted to perturb protein function. Conclusions: Our study demonstrates that heterozygous mutations in ACAN can cause a mild skeletal dysplasia, which presents clinically as short stature with advanced bone age. The accelerating effect on skeletal maturation has not previously been noted in the few prior reports of human ACAN mutations. Our findings thus expand the spectrum of ACAN defects and provide a new molecular genetic etiology for the unusual child who presents with short stature and accelerated skeletal maturation.
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