Ola Nilsson1, Michael H Guo, Nancy Dunbar, Jadranka Popovic, Daniel Flynn, Christina Jacobsen, Julian C Lui, Joel N Hirschhorn, Jeffrey Baron, Andrew Dauber. 1. Program in Developmental Endocrinology and Genetics (O.N., J.C.L., J.B.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Center for Molecular Medicine and Pediatric Endocrinology Unit, Department of Women's and Children's Health (O.N.), Karolinska Institutet and Karolinska University Hospital, SE-171 76 Stockholm, Sweden; Program in Biological and Biomedical Sciences (M.H.G.), Harvard Medical School, Boston, Massachusetts 02115; Connecticut Children's Medical Center (N.D.), Hartford, Connecticut 06106; Children's Hospital of Pittsburgh (J.P., D.F.), University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15224; Division of Endocrinology (M.H.G., C.J., J.N.H., A.D.), Boston Children's Hospital, Boston, Massachusetts 02115; Department of Genetics (M.H.G., J.N.H.), Harvard Medical School, Boston, Massachusetts 02115; and Program in Medical and Population Genetics (J.N.H., A.D.), Broad Institute, Cambridge, Massachusetts 02142.
Abstract
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.
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 humanACAN 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.
Authors: E Rao; B Weiss; M Fukami; A Rump; B Niesler; A Mertz; K Muroya; G Binder; S Kirsch; M Winkelmann; G Nordsiek; U Heinrich; M H Breuning; M B Ranke; A Rosenthal; T Ogata; G A Rappold Journal: Nat Genet Date: 1997-05 Impact factor: 38.330
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