ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Endocr Soc 2017;1:1006-1011

Besides its structural role in the extracellular matrix, aggrecan orchestrates a plethora of key mechanisms in endochondral ossification, such as embryonic morphogen distribution, regular indian hedgehog (IHH) / Sox9 expression and columnar chondrocyte orientation. Thus, homozygous loss-of-function mutations in the ACAN gene, encoding aggrecan, cause severe skeletal phenotypes with strong affection of linear growth and chondrocyte maturation. Heterozygous ACAN mutations feature a milder, variable phenotypic spectrum of skeletal disorders and short stature. Recently, the prevalence of ACAN mutations was described as high as 1.4% in European and Chinese idiopathic short stature (ISS) cohorts (1,2).

Here, Tatsi et al. report a detailed case that extends the known clinical characteristics of patients with ACAN mutations. The authors report novel heterozygous ACAN mutations in two unrelated ISS patients not fulfilling the classical strong criteria for ACAN-related disease, such as familial occurrence and advanced bone age. The absence of these features may easily lead to clinical exclusion of ACAN mutations as the underlying cause. The findings of this study suggest that a high rate of underdiagnosis may exist and that the recent prevalence studies may underestimate the prevalence. It is therefore important that the threshold to investigate ACAN should be lowered in genetic diagnostics for ISS.

1. Hauer NN, Sticht H, Boppudi S, Büttner C, Kraus C, Trautmann U, Zenker M, Zweier C, Wiesener A, Jamra RA, Wieczorek D, Kelkel J, Jung AM, Uebe S, Ekici AB, Rohrer T, Reis A, Dörr HG, Thiel CT. Genetic screening confirms heterozygous mutations in ACAN as a major cause of idiopathic short stature. Sci Rep. 2017 Sep 22;7(1):12225.

2. Hu X, Gui B, Su J, Li H, Li N, Yu T, Zhang Q, Xu Y, Li G, Chen Y, Qing Y; Chinese Genetic Short Stature Consortium, Li C, Luo J, Fan X, Ding Y, Li J, Wang J, Wang X, Chen S, Shen Y. Novel pathogenic ACAN variants in non-syndromic short stature patients. Clin Chim Acta. 2017;469:126-129.