ACAN -related disorder, antenatal presentation and phenotypic variability: a case series

Background Pathogenic ACAN variants (‘aggrecanopathies’) are increasingly recognised as a non-syndromic cause of skeletal dysplasias and short stature. Unlike many other aetiologies, ACAN -related disorder is reportedly associated with advanced bone age due to early epiphysial fusion, although presentation can vary. This study aimed to further characterise skeletal findings in paediatric and adult patients. Methods A retrospective study of confirmed ACAN- related disorder cases from a tertiary genetics centre in England was performed. Data collected included patient demographics, antenatal ultrasound imaging (where available), auxology, endocrine investigations, skeletal imaging and genetic variant analysis. Using the Tanner-Whitehouse III method, bone age was calculated from left hand/wrist radiographs. Results Nine individuals from four families (paediatric=4, adult=5) were included. One individual presented antenatally with shortened long bones on ultrasound. The remaining cohort presented postnatally with short stature and unremarkable endocrine investigations. Of the paediatric patients, bone ages varied significantly: delayed (n=3) and advanced (n=1). Hypochondroplasia-like axial skeletal changes were more specific in affected parents than index children, for example, reduced interpedicular widening inferiorly in the lumbar spine and shortening of vertebral pedicles. Four had short fourth metacarpals. All individuals had pathogenic ACAN variants; two of the variants were novel. Conclusion Advanced bone age is not a consistent finding and should not be considered pathognomonic of ACAN -related disorder. Hypochondroplasia is a differential diagnosis with similar radiological findings in the axial skeleton. A short fourth metacarpal is a feature of this condition. Although skeletal features may become more pronounced in adulthood, early diagnosis can maximise future possible interventions.