Short stature, accelerated bone maturation, and early growth cessation due to heterozygous aggrecan mutations.
BACKGROUND
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.


METHODS
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.
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.
Ola
O
Nilsson
Michael H
MH
Guo
Nancy
N
Dunbar
Jadranka
J
Popovic
Daniel
D
Flynn
Christina
C
Jacobsen
Julian C
JC
Lui
Joel N
JN
Hirschhorn
Jeffrey
J
Baron
Andrew
A
Dauber
D000293:Adolescent; D000328:Adult; D000365:Age Determination by Skeleton; D053674:Aggrecans / Q000235:genetics*; D001827:Body Height / Q000235:genetics; D001846:Bone Development / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004392:Dwarfism / Q000235:genetics*; D005190:Family; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree
C508319:ACAN protein, human; D053674:Aggrecans