Anderson Peter J, Cox Timothy C, Roscioli Tony, Elakis George, Smithers Lisa, David David J, Powell Barry
Australian Craniofacial Unit, Women's and Children's Hospital, North Adelaide, and the University of Adelaide, Dental School, South Australia, Australia.
J Craniofac Surg. 2007 Mar;18(2):312-4. doi: 10.1097/scs.0b013e31802d6e76.
Pathogenic mutations in FGFR2 and TWIST genes are detected in the majority of individuals with Crouzon, Pfeiffer, Apert, and Saethre-Chotzen syndromes. In contrast, mutations have been identified rarely in cases of nonsyndromic, single suture craniosynostosis. Recently, two studies confirming somatic mosaicism with local expression of an FGFR mutation have been reported. This study investigates whether somatic mosaicism could account for nonsyndromic, single suture craniosynostosis. Eight individuals with single suture craniosynostosis who were negative for known mutations in FGFR1-3 and TWIST after screening in their leucocyte DNA were tested for the presence of pathogenic mutations in suture cell-derived DNA. Five had sagittal synostosis, two had metopic synostosis, and the other unicoronal synostosis. Osteoprogenitor cells from surgically excised fusing sutures and an adjacent open suture were cultured. DNA from the cultured cells grown to passage 3 was then examined for underlying FGFR and TWIST mutations. No mutations within the exons of the FGFR or TWIST genes studied were identified in any suture cells. This study found no evidence to support the notion that mosaicism for FGFR or TWIST mutations, normally associated with syndromal forms of craniosynostosis, occur in single suture craniosynostosis. Thus, any underlying genetic defects must occur in regions outside those normally implicated in syndromal craniosynostosis, or this disorder could arise as a consequence of some other epigenetic modification.
在大多数患有克鲁宗综合征、 Pfeiffer综合征、 Apert综合征和塞特雷-乔岑综合征的个体中检测到FGFR2和TWIST基因的致病性突变。相比之下，在非综合征性单缝颅缝早闭病例中很少发现突变。最近，有两项研究报道证实了FGFR突变的体细胞镶嵌现象及局部表达。本研究调查体细胞镶嵌现象是否可解释非综合征性单缝颅缝早闭。对8例单缝颅缝早闭个体进行检测，这些个体在白细胞DNA筛查后FGFR1-3和TWIST基因的已知突变呈阴性，检测其缝线细胞来源的DNA中是否存在致病性突变。其中5例为矢状缝早闭，2例为额缝早闭，另1例为单侧冠状缝早闭。培养手术切除的融合缝线和相邻开放缝线的骨祖细胞。然后检查传代至第3代的培养细胞的DNA，以寻找潜在的FGFR和TWIST突变。在所研究的FGFR或TWIST基因外显子中未在任何缝线细胞中鉴定到突变。本研究没有发现证据支持以下观点：通常与综合征性颅缝早闭形式相关的FGFR或TWIST突变的镶嵌现象发生在单缝颅缝早闭中。因此，任何潜在的遗传缺陷必定发生在通常与综合征性颅缝早闭相关区域以外的区域，或者这种疾病可能是由于其他一些表观遗传修饰而产生的。
