Identification of a heterozygous ACAN mutation in a 15-year old boy with familial short stature presenting an advanced bone age: A case report

Longitudinal bone growth is primarily mediated by the growth plate, which is a specialized cartilaginous structure. Aggrecan, encoded by ACAN, is a primary proteoglycan component of the extracellular matrix in the growth plate and articular cartilage. Aggrecanopathies have emerged as a phenotype of genetic skeletal disease in humans. A heterozygous ACAN mutation causes short stature, premature growth cessation, and accelerated bone age maturation. Here we report the case of a 15-year old boy with familial short stature. The patient's height was 149 cm (Korean standard deviation score [SDS] of -3.6), and 50.5 kg (-1.48 SDS), respectively. He also presented with mild mid-facial hypoplasia, frontal bossing, broad chest, and short neck. The father's and mother's height were 150 cm (-4.8 SDS) and 153 cm (-1.69 SDS), respectively. The subject's bone age was 2-3 years advanced than his chronological age, and no endocrine abnormalities were detected. Whole-exome sequencing followed by Sanger sequencing revealed a heterozygous ACAN mutation, c.512C>T (p.Ala171Val) in the proband and his father. Short stature is generally associated with a delayed bone age, and this case suggests that ACAN mutations may be the most likely etiology among patients with short stature and an advanced bone age, warranting early treatment.