ESPE Abstracts

Background: Homozygous aggrecan (ACAN) mutations have been described in a few skeletal dysplasias whilst more recently, heterozygous ACAN mutations have been reported in few families presenting with idiopathic short stature with advanced bone maturation and premature growth cessation.

Case presentation: We describe two novel heterozygous ACAN stop mutations, detected using a skeletal dysplasia NGS panel and confirmed by Sanger sequencing, in two Spanish families with unknown aetiology of autosomal dominant short stature. Case 1: an 18-year old male with disproportionate short stature (height 149 cm, −4.3 S.D.), limb shortening, frontal bosing and macrocephaly. Poor pubertal growth spurt. No evidence of endocrine disorders or advanced bone age during childhood. Short stature and a similar phenotype was present in four generations (heights −4.3/−5.3 S.D.). A heterozygous ACAN mutation in exon 16, c.7276G>T (p.Glu2426*), was identified in the proband and cosegregated with the short stature in the family. Case 2: a 2.5-year-old girl with proportionate short stature (height 85 cm, −0.14 S.D.), relative macrocephaly, midfacial hypoplasia, flat nasal bridge, frontal bosing and acromicria. Normal laboratory results. Skeletal survey revealed advanced bone maturation (BA 4 years, CA 2y) and cone-shaped phalanges. Familial history included short stature in four generations (heights −2.9/−5.8 S.D.). A heterozgyous ACAN mutation, c.61G>T in exon 1 (p.Glu21*) was detected in both child and affected mother.

Conclusions: Two novel ACAN mutations have been identified in two families with short stature, mild dysmorphic features and no or mild skeletal abnormalities. Whilst case 2 showed advanced bone maturation, as previously reported, case 1 did not. Thus, ACAN should be considered a candidate gene in cases with short stature and accelerated skeletal maturation but further studies are required to determine the frequency of ACAN mutations in other short stature phenotypes. In summary, our findings broaden the spectrum of disorders caused by mutations in ACAN.