Moderate to Severe Short Stature and Joint Involvement in Individuals With ACAN Deletions

In recent years, numerous heterozygous ACAN variants have been identified in individuals with short stature. The phenotypic spectrum includes mild to moderate short stature, advanced to delayed bone age, mild dysmorphic features, brachydactyly and/or other mild skeletal defects and joint pathology in early adulthood which often requires surgery. However, only one multiexonic ACAN deletion has been reported to date, in a family with short stature, advanced bone age in childhood and early osteoarthritis and spine deformity in the father. Here, we describe 15 individuals from 6 families with ACAN deletions.

All probands were referred for short stature to paediatric endocrinology and genetic clinics in different European hospitals. After molecular studies detected the deletion, segregation studies were performed when available. Clinical and radiological features were evaluated in all cases.

Three complete and three intragenic deletions were detected. Patients present with moderate to severe short stature, mildly disproportionate growth and mild dysmorphic features. The majority suffer from joint involvement (osteochondritis dissecans and/or early onset osteoarthritis) which has required early surgical intervention.

Although individuals with heterozygous ACAN deletions exhibit phenotypic variability, it is noticeable that they present with a quite homogeneous and age-dependent phenotype with a high proportion of severe joint problems.