Background: Some children born small for gestational age (SGA) show advanced bone age (BA) maturation during growth hormone (GH) treatment. ACAN gene mutations have been described in children with short stature and advanced BA. Objective: To determine the presence of ACAN gene mutations in short SGA children with advanced BA and assess the response to GH treatment. Methods: BA assessment in 290 GH-treated SGA children. ACAN sequencing in 29 children with advanced BA $0.5 years compared with calendar age. Results: Four of 29 SGA children with advanced BA had an ACAN gene mutation (13.8%). Mutations were related to additional characteristics: Midface hypoplasia (P = 0.003), joint problems (P = 0.010), and broad great toes (P = 0.003). Children with one or fewer additional characteristic had no mutation. Of children with two additional characteristics, 50% had a mutation. Of children with three additional characteristics, 100% had a mutation. All GH-treated children with a mutation received gonadotropin-releasing hormone analog (GnRHa) treatment for 2 years from onset of puberty. At adult height, one girl was 5 cm taller than her mother and one boy was 8 cm taller than his father with the same ACAN gene mutation. Conclusion: This study expands the differential diagnosis of genetic variants in children born SGA and proposes a clinical scoring system for identifying subjects most likely to have an ACAN gene mutation. ACAN sequencing should be considered in children born SGA with persistent short stature, advanced BA, and midface hypoplasia, joint problems, or broad great toes. Our findings suggest that children with an ACAN gene mutation benefit from GH treatment with 2 years of GnRHa. (J Clin Endocrinol Metab 102: 1458-1467, 2017).

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Journal Journal of Clinical Endocrinology and Metabolism
Steen, M.V. (Manouk Vander), Pfundt, R, Maas, S.J.W.H. (Stephan J.W.H.), Bakker-VanWaarde, W.M. (Willie M.), Odink, R.J.H, & Hokken-Koelega, A.C.S. (2017). ACAN gene mutations in short children born SGA and response to growth hormone treatment. Journal of Clinical Endocrinology and Metabolism, 102(5), 1458–1467. doi:10.1210/jc.2016-2941