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


CONCLUSIONS
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.
Jose Bernardo
JB
Quintos
Michael H
MH
Guo
Andrew
A
Dauber
D000328:Adult; D053674:Aggrecans / Q000235:genetics*; D001827:Body Height / Q000235:genetics*; D002675:Child, Preschool; D004392:Dwarfism / Q000235:genetics*; D005190:Family; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011379:Prognosis
C508319:ACAN protein, human; D053674:Aggrecans