Phenotypic and genotypic diversity in patients with Chinese aggrecan gene-related short stature

The clinical manifestations, progression and therapeutic outcomes associated with ACAN variants exhibit considerable heterogeneity, rendering identification difficult. This characterizes the phenotypic profiles, genotypic spectrum and treatment strategies of Chinese patients with ACAN-related short stature.

We identified 20 short stature patients from a large single-center cohort who carried heterozygous ACAN variants. Among them, 15 patients received recombinant human growth hormone (rhGH) and/or gonadotropin-releasing hormone analog (GnRHa) therapy.

All 20 patients had proportionally short stature, with or without mild facial dysmorphism and skeletal abnormalities. Furthermore, a less common characteristic was identified, that is 27.3% (3/11) of the female patients presented with central precocious puberty (CPP). Notably, intellectual disability/global developmental delay (ID/GDD) was observed in four males, a feature hardly documented in ACAN-related disorders. We identified 16 variants, of which 14 were novel. In addition, height improved in all 15 patients after treated with rhGH alone or combined with GnRHa. The clinical spectrum of ACAN variants exhibits extensive heterogeneity.

This study underscores the significant clinical heterogeneity of ACAN-related disorders. Cognitive impairment and signs of early pubertal development were identified in a subset of patients in our cohort, suggesting that the clinical manifestations of ACAN variants may be broader than previously recognized. These observations warrant further evaluation in larger cohorts.

We explored the characteristics and genetic profile of ACAN variants. ACAN-related disorders had a diversity of clinical manifestations. ACAN variants should be considered in children with short stature, including those showing subnormal GH responses on stimulation testing, particularly with a family history.