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. CONCLUSION: 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.
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. CONCLUSION: 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.
Authors: Eva-Lena Stattin; Fredrik Wiklund; Karin Lindblom; Patrik Onnerfjord; Björn-Anders Jonsson; Yelverton Tegner; Takako Sasaki; André Struglics; Stefan Lohmander; Niklas Dahl; Dick Heinegård; Anders Aspberg Journal: Am J Hum Genet Date: 2010-02-04 Impact factor: 11.025
Authors: P Cohen; A D Rogol; C L Deal; P Saenger; E O Reiter; J L Ross; S D Chernausek; M O Savage; J M Wit Journal: J Clin Endocrinol Metab Date: 2008-09-09 Impact factor: 5.958
Authors: Stuart W Tompson; Barry Merriman; Vincent A Funari; Maryline Fresquet; Ralph S Lachman; David L Rimoin; Stanley F Nelson; Michael D Briggs; Daniel H Cohn; Deborah Krakow Journal: Am J Hum Genet Date: 2008-12-24 Impact factor: 11.025
Authors: Michael H Guo; Yiping Shen; Emily C Walvoord; Timothy C Miller; Jennifer E Moon; Joel N Hirschhorn; Andrew Dauber Journal: Horm Res Paediatr Date: 2014-06-20 Impact factor: 2.852
Authors: M Crippa; S Giangiobbe; R Villa; I Bestetti; T De Filippis; L Fatti; J Taurino; L Larizza; L Persani; F Bellini; P Finelli; M T Bonati Journal: J Endocrinol Invest Date: 2018-01-04 Impact factor: 4.256