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Abstract：
OBJECTIVE: To characterize the phenotype spectrum, diagnosis, and response to growth-promoting therapy in patients with ACAN variants causing familial short stature.
METHODS: Three families with ACAN variants causing short stature were reported. Similar cases in the literature were summarized, and the genotype and phenotype were analyzed.
RESULTS: Three novel heterozygous variants, c.757+1G>A, (splicing), c.6229delG, p.(Asp2078Tfs*1), and c.6679C>T, p.(Gln2227*) in the ACAN gene were identified. A total of 314 individuals with heterozygous variants from 105 families and 8 individuals with homozygous variants from 4 families were confirmed to have ACAN variants from literature and our 3 cases. Including our 3 cases, the variants reported comprised 33 frameshift, 39 missense, 23 nonsense, 5 splicing, 4 deletion, and 1 translocation variants. Variation points are scattered throughout the gene, while exons 12, 15, and 10 were most common (25/105, 11/105, and 10/105, respectively). Some identical variants existing in different families could be hot variants, c.532A>T, p.(Asn178Tyr), c.1411C>T, p.(Gln471*), c.1608C>A, p.(Tyr536*), c.2026+1G>A, (splicing), and c.7276G>T, p.(Glu2426*). Short stature, early-onset osteoarthritis, brachydactyly, midfacial hypoplasia, and early growth cessation were the common phenotypic features. The 48 children who received rhGH (and GnRHa) treatment had a significant height improvement compared with before (-2.18 ± 1.06 SD vs. -2.69 ± 0.95 SD, p < 0.001). The heights of children who received rhGH (and GnRHa) treatment were significantly improved compared with those of untreated adults (-2.20 ± 1.10 SD vs. -3.24 ± 1.14 SD, p < 0.001).
CONCLUSIONS: Our study achieves a new understanding of the phenotypic spectrum, diagnosis, and management of individuals with ACAN variants. No clear genotype-phenotype relationship of patients with ACAN variants was found. Gene sequencing is necessary to diagnose ACAN variants that cause short stature. In general, appropriate rhGH and/or GnRHa therapy can improve the adult height of affected pediatric patients caused by ACAN variants.
METHODS: Three families with ACAN variants causing short stature were reported. Similar cases in the literature were summarized, and the genotype and phenotype were analyzed.
RESULTS: Three novel heterozygous variants, c.757+1G>A, (splicing), c.6229delG, p.(Asp2078Tfs*1), and c.6679C>T, p.(Gln2227*) in the ACAN gene were identified. A total of 314 individuals with heterozygous variants from 105 families and 8 individuals with homozygous variants from 4 families were confirmed to have ACAN variants from literature and our 3 cases. Including our 3 cases, the variants reported comprised 33 frameshift, 39 missense, 23 nonsense, 5 splicing, 4 deletion, and 1 translocation variants. Variation points are scattered throughout the gene, while exons 12, 15, and 10 were most common (25/105, 11/105, and 10/105, respectively). Some identical variants existing in different families could be hot variants, c.532A>T, p.(Asn178Tyr), c.1411C>T, p.(Gln471*), c.1608C>A, p.(Tyr536*), c.2026+1G>A, (splicing), and c.7276G>T, p.(Glu2426*). Short stature, early-onset osteoarthritis, brachydactyly, midfacial hypoplasia, and early growth cessation were the common phenotypic features. The 48 children who received rhGH (and GnRHa) treatment had a significant height improvement compared with before (-2.18 ± 1.06 SD vs. -2.69 ± 0.95 SD, p < 0.001). The heights of children who received rhGH (and GnRHa) treatment were significantly improved compared with those of untreated adults (-2.20 ± 1.10 SD vs. -3.24 ± 1.14 SD, p < 0.001).
CONCLUSIONS: Our study achieves a new understanding of the phenotypic spectrum, diagnosis, and management of individuals with ACAN variants. No clear genotype-phenotype relationship of patients with ACAN variants was found. Gene sequencing is necessary to diagnose ACAN variants that cause short stature. In general, appropriate rhGH and/or GnRHa therapy can improve the adult height of affected pediatric patients caused by ACAN variants.
摘要：
目的：为了表征表型谱，诊断,以及ACAN变异导致家族性身材矮小的患者对促进生长治疗的反应。
方法：报道了三个具有导致身材矮小的ACAN变体的家族。对文献中的类似案例进行了总结，并对基因型和表型进行分析。
结果：三个新的杂合变体，c.757+1G>A，(拼接),c.6229delG,p.(Asp2078Tfs*1)，c.6679C>T，鉴定了ACAN基因中的p.(Gln2227*)。共有来自105个家庭的314个具有杂合变体的个体和来自4个家庭的8个具有纯合变体的个体被证实具有来自文献和我们的3个病例的ACAN变体。包括我们的3个案例，报告的变体包括33个移码，39错觉，23废话，5拼接，4删除，和1个易位变体。变异点分散在整个基因中，而外显子12、15和10最常见（分别为25/105、11/105和10/105）。不同家族中存在的一些相同变体可能是热门变体，c.532A>T，p.（Asn178Tyr），c.1411C>T，p.(Gln471*)，c.1608C>A，p.(Tyr536*)，c.2026+1G>A，(拼接),c.7276G>T，p.(Glu2426*)。身材矮小,早发性骨关节炎,Brachydactyly,面部中部发育不全,早期生长停止是常见的表型特征。与接受rhGH（和GnRHa）治疗的48名儿童相比，身高显着改善（-2.18±1.06SDvs.-2.69±0.95标准差，p<0.001)。与未经治疗的成年人相比，接受rhGH（和GnRHa）治疗的儿童的身高显着提高（-2.20±1.10SDvs.-3.24±1.14标准差，p<0.001)。
结论：我们的研究对表型谱有了新的认识，诊断,和管理具有ACAN变体的个人。未发现ACAN变异患者的明确基因型-表型关系。基因测序对于诊断导致身材矮小的ACAN变异是必要的。总的来说,适当的rhGH和/或GnRHa治疗可以改善由ACAN变异引起的儿童患者的成年身高.
方法：报道了三个具有导致身材矮小的ACAN变体的家族。对文献中的类似案例进行了总结，并对基因型和表型进行分析。
结果：三个新的杂合变体，c.757+1G>A，(拼接),c.6229delG,p.(Asp2078Tfs*1)，c.6679C>T，鉴定了ACAN基因中的p.(Gln2227*)。共有来自105个家庭的314个具有杂合变体的个体和来自4个家庭的8个具有纯合变体的个体被证实具有来自文献和我们的3个病例的ACAN变体。包括我们的3个案例，报告的变体包括33个移码，39错觉，23废话，5拼接，4删除，和1个易位变体。变异点分散在整个基因中，而外显子12、15和10最常见（分别为25/105、11/105和10/105）。不同家族中存在的一些相同变体可能是热门变体，c.532A>T，p.（Asn178Tyr），c.1411C>T，p.(Gln471*)，c.1608C>A，p.(Tyr536*)，c.2026+1G>A，(拼接),c.7276G>T，p.(Glu2426*)。身材矮小,早发性骨关节炎,Brachydactyly,面部中部发育不全,早期生长停止是常见的表型特征。与接受rhGH（和GnRHa）治疗的48名儿童相比，身高显着改善（-2.18±1.06SDvs.-2.69±0.95标准差，p<0.001)。与未经治疗的成年人相比，接受rhGH（和GnRHa）治疗的儿童的身高显着提高（-2.20±1.10SDvs.-3.24±1.14标准差，p<0.001)。
结论：我们的研究对表型谱有了新的认识，诊断,和管理具有ACAN变体的个人。未发现ACAN变异患者的明确基因型-表型关系。基因测序对于诊断导致身材矮小的ACAN变异是必要的。总的来说,适当的rhGH和/或GnRHa治疗可以改善由ACAN变异引起的儿童患者的成年身高.
