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

Area of Science:

• Genetics
• Skeletal Dysplasias
• Pediatric Endocrinology

Background:

• Pathogenic variants in the Aggrecan (ACAN) gene, termed aggrecanopathies, are increasingly recognized as a cause of non-syndromic skeletal dysplasias and short stature.
• While ACAN-related disorder is often associated with advanced bone age due to early epiphyseal fusion, presentations can vary.

Purpose of the Study:

• To further characterize the skeletal findings in pediatric and adult patients with ACAN-related disorder.
• To investigate the variability in bone age presentation and associated skeletal features.

Main Methods:

• Retrospective study of nine individuals from four families with confirmed ACAN-related disorder.
• Data collection included demographics, imaging (ultrasound, skeletal radiographs), auxology, endocrine tests, and genetic analysis.
• Bone age was calculated using the Tanner-Whitehouse III method from hand/wrist radiographs.

Main Results:

• Nine individuals (4 pediatric, 5 adult) with pathogenic ACAN variants were included.
• Bone ages varied significantly in pediatric patients (delayed in 3, advanced in 1).
• Hypochondroplasia-like axial skeletal changes were noted, including reduced interpedicular widening and shortened vertebral pedicles, particularly in adults. Short fourth metacarpals were present in four individuals.

Conclusions:

• Advanced bone age is not a consistent or pathognomonic feature of ACAN-related disorder.
• Hypochondroplasia is a differential diagnosis with overlapping axial skeletal radiological findings.
• A short fourth metacarpal is a characteristic feature; early diagnosis is crucial for potential interventions.