ESPEYB15 4 Growth and Growth Factors New perspectives (3 abstracts)
4.10 Genetic screening confirms heterozygous mutations in ACAN as a major cause of idiopathic short stature
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
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
To read the full abstract: Sci Rep 2017; 22(7):12225
The GH/IGF1 axis has historically been considered the most relevant regulator of growth. However, defects in the GH/IGF1 axis can be identified only in a minority of children with short stature. Human growth is dependent on chondrocyte proliferation and hypertrophy as well as structure and function of extracellular matrix in the growth plate [39]. The rate of growth plate chondrogenesis is regulated by many intracellular, paracrine and extracellular matrix factors, as well as endocrine mechanisms. Aggrecan, encoded by ACAN gene, is the most abundant proteoglycan of the growth plate cartilage and plays a key role in cartilage and bone morphogenesis. The ACAN gene mutation leads to aggrecan deficiency, abnormal structure of the cartilage extracellular matrix, decreased chondrocyte proliferation, and accelerated hypertrophic chondrocyte differentiation.
The clinical spectrum associated with ACAN mutations ranges from spondyloepimetaphyseal dysplasia, characterized by severe short stature, brachydactyly, and midface hypoplasia, to milder skeletal dysplasia, associated with variably compromised adult height. ISS has recently been associated with ACAN haploinsufficiency. Carriers of heterozygous mutations in ACAN have short stature with normal, delayed or advanced BA, early growth cessation, early-onset osteoarthritis and degenerative disc disease, suggesting dysfunction of the articular cartilage and intervertebral disc cartilage [40].
The present study identified heterozygous defects in ACAN in 6 of 428 patients with the “diagnosis” of ISS (1.4%), suggesting that ACAN mutations may be the most common cause of ISS after deletions and mutations of the SHOX gene, which account for ~2.4% of ISS patients [41]. The reported patients’ height varied between −0.9 and −5.9 SDS but a genotype-phenotype relationship was not found. Most of these patients presented an advanced bone age and proportionate or mildly disproportionate short stature. Three patients in this study showed delayed bone age, suggesting that bone age advancement has no predictive value for ACAN mutations. The identification of ACAN mutations may have therapeutic implications as anecdotal evidence suggests a modest response to GH, of a similar magnitude to that seen in ISS [40-42]. In conclusion, these findings suggest that ACAN mutations are a relatively common cause of short stature and have to be considered in the differential diagnosis of ISS.
39. Baron J, Sävendahl L, De Luca F, Dauber A, Phillip M, Wit JM, et al. Short and tall stature: a new paradigm emerges. Nat Rev Endocrinol. 2015;11:735-46.
40. Gkourogianni A, Andrew M, Tyzinski L, Crocker M, Douglas J, Dunbar N, et al. Clinical Characterization of Patients With Autosomal Dominant Short Stature due to Aggrecan Mutations. J Clin Endocrinol Metab. 2017;102:460-9.
41. Hu X, Gui B, Su J, Li H, Li N, Yu T, et al. Novel pathogenic ACAN variants in non-syndromic short stature patients. Clin Chim Acta. 2017;469:126-9.
42. van der Steen M, Pfundt R, Maas SJWH, Bakker-van Waarde WM, Odink RJ, Hokken-Koelega ACS. ACAN Gene Mutations in Short Children Born SGA and Response to Growth Hormone Treatment. J Clin Endocrinol Metab. 2017;102:1458-67.
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ESPE Yearbook of Paediatric Endocrinology
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