Clinical Characterization of Children with Autosomal Dominant Short Stature due to Aggrecan Mutations Broadens the Phenotypic Spectrum

Background: Heterozygous mutations in the Aggrecan gene (ACAN) cause autosomal dominant short stature with bone age (BA) acceleration, and premature growth cessation.

Objective and methods: To characterize the phenotypic spectrum, associated conditions and describe response to growth-promoting therapies, detailed clinical evaluation of 73 mutation positive individuals from 16 families different families with heterozygous ACAN mutations was performed.

Results: Adult individuals have mildly disproportionate short stature (average SDS height −2,8, range −0.9 to −4.5) with sitting height indices at the upper part of the normal range or slightly elevated (SDS average: 2.0, range: 0.4–3.8) and histories of early growth cessation and/or lack of pubertal growth spurt. Growth of upper extremities is often less affected with arm spans greater than height (arm span – height: median 5 cm, range −5 to +13.3). The condition is associated with early-onset osteoarthritis (nine families) and degenerative disc disease (six families). Before puberty, height is less affected and often in the lower part of the normal range (average height SDS: −2.1). In contrast to most children with short stature, many children with ACAN mutations have an advanced bone age (BA – CA, median: +1.3; range +0 to +3.8yr) reflecting a reduction in the remaining growth potential. Twelve patients have been treated with GH. In addition, three girls and one boy have received GnRH analog and two boys letrozole in order to slow down bone age advancement and increase final height.

Conclusion: Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a distinct skeletal dysplasia with disproportionate short stature and brachydactyly. Several of the mutations also cause articular/intervertebral disc cartilage dysfunction leading to early-onset osteoarthritis and degenerative disc disease requiring intervention. Careful monitoring of patients with ACAN mutations will reveal the full spectrum of this condition and may identify important genotype-phenotype correlations.