Aggrecan Mutations in Nonfamilial Short Stature and Short Stature Without Accelerated Skeletal Maturation

Abstract

Aggrecan, a proteoglycan, is an important component of cartilage extracellular matrix, including that of the growth plate. Heterozygous mutations in ACAN, the gene encoding aggrecan, cause autosomal dominant short stature, accelerated skeletal maturation, and joint disease. The inheritance pattern and the presence of bone age equal to or greater than chronological age have been consistent features, serving as diagnostic clues. From family 1, a 6-year-old boy presented with short stature [height standard deviation score (SDS), -1.75] and bone age advanced by 3 years. There was no family history of short stature (height SDS: father, -0.76; mother, 0.7). Exome sequencing followed by Sanger sequencing identified a de novo novel heterozygous frameshift mutation in ACAN (c.6404delC: p.A2135Dfs). From family 2, a 12-year-old boy was evaluated for short stature (height SDS, -3.9). His bone age at the time of genetic evaluation was approximately 1 year less than his chronological age. Family history was consistent with an autosomal dominant inheritance of short stature, with several affected members also showing early-onset osteoarthritis. Exome sequencing, confirmed by Sanger sequencing, identified a novel nonsense mutation in ACAN (c.4852C>T: p.Q1618X), which cosegregated with the phenotype. In conclusion, patients with ACAN mutations may present with nonfamilial short stature and with bone age less than chronological age. These findings expand the known phenotypic spectrum of heterozygous ACAN mutations and indicate that this diagnosis should be considered in children without a family history of short stature and in children without accelerated skeletal maturation.

Keywords: advanced bone age; aggrecan; exome sequencing; short stature.

Figure 1.

(a) Growth chart of proband in family 1. Height is shown as black circles, and height for bone age is shown as the tip of the arrows. The black line corresponds to the period of GH treatment. There is a discrepancy of 2 months between the height measurement at chronological age 5 years 11.5 months and the bone age x-ray performed at chronological age 6 years and 2 months (*). (b) Bone age radiograph of proband in family 1 obtained at chronological age 6 years and 2 months. The bone age was interpreted as 9 years and 9 months using the Greulich and Pyle atlas. (c) Growth chart of the proband in family 2. Height and weight are indicated with black circles and height for bone age as the tips of the black arrows. The black line corresponds to the period of GH treatment. (d) Bone age radiograph of proband in family 2 obtained at chronological age 12 years and 7 months. The bone age was interpreted as 11 years and 6 months using the Greulich and Pyle atlas and as 11 years and 9 months using the Tanner Whitehouse method. (e) Pedigree of proband in family 1. The affected proband (II:1) is shown with an arrow as a filled square. The height in SDS is shown below each symbol. (f) Pedigree of proband in family 2. The affected proband (IV:10)is indicated with an arrow. The family members with short stature are indicated with filled symbols. The height in SDS and the genotype for the members who underwent genetic testing are reported below each symbol. The three paternal aunts and one of their offspring were short as reported by the proband’s family, but no documentation of their height was available (*).