Clinical phenotype and musculoskeletal characteristics of patients with aggrecan deficiency

Abstract

Aggrecan is a proteoglycan within the physeal and articular cartilage. Aggrecan deficiency, due to heterozygous mutations in the ACAN gene, causes dominantly inherited short stature and, in many patients, early‐onset osteoarthritis and degenerative disc disease. We aimed to further characterize this phenotypic spectrum with an emphasis on musculoskeletal health. Twenty‐two individuals from nine families were enrolled. Histories and examinations focused on joint health, gait analysis, joint specific patient reported outcomes, and imaging studies were performed. All patients had dominantly inherited short stature, with the exception of a de novo mutation. Short stature was worse in adults versus children (median height −3.05 SD vs. −2.25 SD). ACAN mutations were not always associated with bone age advancement (median advancement +1.1 years, range 0 to +2 years). Children had subtle disproportionality and clinically silent joint disease—25% with osteochondritis dissecans (OD). Adults had a high prevalence of joint symptomatology–decline in knee function, disability from spinal complaints, and lower physical activity on outcome measures. Osteoarthritis (OA) and OD was detected in 90% of adults, and orthopedic surgeries were reported in 60%. Aggrecan deficiency leads to short stature with progressive decline in height SD, mild skeletal dysplasia, and increasing prevalence of joint pathology over time. Optimal musculoskeletal health and quality of life can be attained with timely identification of pathology and intervention.

From “ACAN” to “I CAN”: Restoring wellness in a boy with severe osteochondritis dissecans through diagnostic precision combined with optimal medical, surgical and rehabilitation management

“…The subchondral lesions can cause separation of cartilage and subchondral bone, and develop into instability and degenerative changes of the cartilage. The incidence of osteochondritis dissecans is estimated to be 6.09 per 100,000 person-years in the general population ( Pareek et al, 2017 ); the typical location of the lesions is the knee, with a distribution of approximately two-thirds in the medial and one-third in the lateral femoral condyles ( Pareek et al, 2017 ; Alexandrou et al, 2022 ).…”

Análise genética prospectiva de uma coorte de pacientes classificados como tendo baixa estatura idiopática

“…A maturação prematura de condrócitos hipertróficos e a invasão precoce da placa de crescimento por vasos sanguíneos e osteoblastos são mecanismos propostos para idade óssea avançada, fusão epifisária precoce e parada prematura do crescimento em pacientes com mutações ACAN 49 . Apesar de ser uma característica marcante, não é encontrada em todos os pacientes 123 . Devido à sua presença na cartilagem articular, os pacientes também podem apresentar osteoartrite de início precoce, mais comum na quarta década de vida, afetando principalmente os joelhos, com grau de gravidade variável 122 .…”