Costantini Alice, Wallgren-Pettersson Carina, Mäkitie Outi
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
The Folkhälsan Institute of Genetics, Biomedicum, Helsinki, Finland; Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.
Eur J Med Genet. 2018 Oct;61(10):612-615. doi: 10.1016/j.ejmg.2018.04.004. Epub 2018 Apr 14.
Frontometaphyseal dysplasia 2 (FMD2) is a skeletal dysplasia with supraorbital hyperostosis combined with undermodeling of the bones, joint contractures and some extraskeletal features. It is caused by heterozygous mutations in MAP3K7, encoding the Mitogen-Activated Protein 3-Kinase 7. MAP3K7 is activated by TGF-β and plays an important role in osteogenesis. Less than 20 patients with FMD2 and MAP3K7 mutations have been described thus far. The majority of the patients harbor a recurrent missense mutation, NM_003188.3: c.1454C > T [NP_003179.1: p.(Pro485Leu)], which leads to a more severe phenotype than mutations in other domains. Here we describe an additional patient with FMD2 caused by the recurrent c.1454C > T MAP3K7 mutation, identified as a de novo variant by whole-genome sequencing. The 17-year-old boy has the characteristic skeletal and facial features of FMD2. However, some novel features were also observed, including growth retardation and spina bifida occulta. In line with other patients harboring the same mutation he also showed keloid scars and had no intellectual disability. This report expands the clinical spectrum of FMD2 caused by the recurrent c.1454C > T [p.(Pro485Leu)] mutation in MAP3K7.
额干骺端发育不良2型（FMD2）是一种骨骼发育不良疾病，其特征为眶上骨质增生，伴有骨骼塑形不足、关节挛缩及一些骨骼外表现。它由编码丝裂原活化蛋白3激酶7（MAP3K7）的基因杂合突变所致。MAP3K7由转化生长因子-β（TGF-β）激活，在骨生成中起重要作用。迄今为止，仅有不到20例FMD2患者及MAP3K7突变的病例被报道。大多数患者携带复发性错义突变，即NM_003188.3:c.1454C＞T [NP_003179.1:p.(Pro485Leu)]，该突变导致的表型比其他结构域的突变更为严重。在此，我们描述了另外1例由复发性c.1454C＞T MAP3K7突变引起的FMD2患者，该突变经全基因组测序鉴定为新发变异。这名17岁男孩具有FMD2典型的骨骼和面部特征。然而，我们也观察到了一些新特征，包括生长发育迟缓及隐性脊柱裂。与其他携带相同突变的患者一致，他也有瘢痕疙瘩，且无智力障碍。本报告扩展了由MAP3K7基因复发性c.1454C＞T [p.(Pro485Leu)]突变导致的FMD2的临床谱。
