ESPE Abstracts (2018) 89 P-P1-173

Clinical and Radiological Manifestations in a Large Swedish Family with a Pathogenic Heterozygous ACAN Variant

Alexandra Gkourogiannia, Emma Segerlundb, Sigrun Hallgrimsdottira, Ola Nilssona,c & Eva-Lena Stattind


aKarolinska Institutet and University Hospital, Stockholm, Sweden; bSunderby Hospital, Sunderbyn, Sweden; cÖrebro University and University Hospital, Örebro, Sweden; dDepartment of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden


Objectives: Heterozygous mutations in the aggrecan gene (ACAN) are associated with idiopathic short stature, with or without advanced bone age (BA), osteochondritis dissecans (OCD) and early onset of severe osteoarthritis (OA). Variable features also include midface hypoplasia, brachydactyly, short thumbs and intervertebral disc degenerative disease.

Methods: We reviewed 173 radiographs in 22 individuals (8F:14M), (three shoulders, 10 hands, 10 wrists, 17 spines, 10 pelvis, 31 hips, 79 knees, five lower-legs, four ankles, four feet). Furthermore two computed tomography scans (1 hip;1 knee), and 5 magnetic resonance scans (2 hips; 3 knees). All included individuals belong to a five generation Swedish family with short stature, OCD, and early onset OA (MIM#165800), caused by a pathogenic sequence variant, p.V2303M, in the C-type lectin domain of ACAN.

Results: In the group of children (n=6; age ≤15 yo; 3 F:3 M), six had moderately advanced BA (range:6-17.5 months). There was no clear sign of a metaphyseal or epiphyseal dysplasia, but subtle defects of the distal radial growth plate were present in four children. There were 3 males with OCD in the knees and one of them also presented OCD of the hip, scoliosis and schmorl’s nodes of intervertebral discs. Actually he went through a derotation osteotomy in both hips and later a proximal tibia osteotomy and distal fibula osteotomy. Among 16 adult patients (5 F:11 M), 16 had OCD (7 elbows,4 hips,13 knees, 5 patellas), 13 developed early onset (>40 y) OA, (1 shoulder, 5 elbows,3 spines, 1 metatarsophalangeal joint, 6 hips, 12 knees, 1 patella). Radiological manifestations of the spine were detected in 4 patients and included 1 scoliosis, 1 spina bifida occulta, 1 platyspondyly, 1 schmorl’s nodes, and 3 with lowering of the intervertebral discs. Moreover 8 adult patients (3 F:5 M) have been operated, 4 patients had hip replacement (1 F:3 M;3 bilateral;1 unilateral) and 5 knee arthroplasties (2 F:3 M; 3 bilateral; 2 unilateral) in particular 5 patients had tibia osteotomy of which one had combined tibia and fibula osteotomy. We measured all phalanges of eight adult hand X-rays and found no brachydactyly.

Conclusions: The pathogenic heterozygous p.V2303M variant in the ACAN gene causes mildly disproportionate short stature with early-onset OA and intervertebral disc degeneration often requiring multiple orthopedic interventions. Radiologic findings, included moderately advanced BA, OCD in knees, hips, and elbows as well as OA in 13 individuals. Further studies are needed to identify preventive measures that may slow the progression of OA and intervertebral disc disease and to determine the role of rhGH to improve final height.

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