ESPE Abstracts

Aggrecan is a structural glycoprotein of the extracellular matrix of cartilage present in the articular cartilage, growth plate and cartilage of the intervertebral disc. Biallelic pathogenic variants are the cause of aggrecan type spondyloepiphyseal dysplasia (OMIM#612813) while the presence of heterozygous pathogenic variants determine Kimberley type spondyloepiphyseal dysplasia (OMIM#608361) and short stature associated or not with acceleration of bone maturation and early onset of osteoarthritis and familial osteochondritis dissecans (OMIM#165800). The clinical characteristics of 5 patients with heterozygous pathogenic variants in the ACAN gene are presented.

Patients: Family 1- index patient: 9,4 years old prepubertal girl with short stature (-2.2SD) disharmonious and bone age of 10 years. Father with disharmonious short stature (-2.7SD), maternal height (-1SD). A phenotype with retrognathia and low set ears stands out. Normal skeletal series. Exome sequencing identifies a heterozygous pathogenic variant in the ACAN gene (c.1097dup(p.(Glu367*)1),) confirmed by Sanger sequencing, not previously described.

Family 2 - index patient: 9,9 years old prepuberal boy with an idiopathic short stature family history. Presents disharmonious height (-2SD) and bone age 12.6 years. Also, non-severe genu varus and osteoarthritis in his right knee without other morphological alterations. Skeletal series: short cubes and curved rays and 4th metacarpal shortening. A 4.6 years old sister and 4.3 years old first cousin with harmonic short statures (-2.4SD and -3.0SD respectively). In both, the bone age is advanced. Normal phenotype. The skeletal series is normal in the sister, while in the first cousin there are widened distal femoral diaphysis. A pathogenic variant in ACAN (c.7276G>T;p.(Glu2426*)) is identified in the exome sequencing confirmed by Sanger sequencing in all of them, described in the literature.

Family 3 - index patient: 9.8 years old prepuberal girl with harmonic short stature (-2.6SD) and bone age of 10 years without assessable phenotypic characteristics. Harmonic short stature mother (-2.6SD) with repetitive knee osteochondritis. The paternal height is -1.1SD. Exome sequencing identifies a heterozygous pathogenic variant in the ACAN gene (c.11061_1062delp.(Phe354Cysfs*13)), confirmed by previously undescribed Sanger sequencing.

Conclusions: New patients and pathogenic variants of the ACAN gene have been identified with highly variable phenotypic and radiological characteristics, without the skeletal disproportion and the advance of bone maturation being constant. The ACAN gene study should be included in the study of patients with idiopathic short stature. More studies are required to establish the genotype-phenotype correlation in patients with genetic variants in the ACAN gene.