Department of Surgery, Sidra Medicine, Doha, Qatar.
Division of Clinical Surgery, Weill Cornell Medical College, Doha, Qatar.
Am J Med Genet A. 2019 Apr;179(4):615-627. doi: 10.1002/ajmg.a.61073. Epub 2019 Feb 13.
Mutations in the ERF gene, coding for ETS2 repressor factor, a member of the ETS family of transcription factors cause a recently recognized syndromic form of craniosynostosis (CRS4) with facial dysmorphism, Chiari-1 malformation, speech and language delay, and learning difficulties and/or behavioral problems. The overall prevalence of ERF mutations in patients with syndromic craniosynostosis is around 2%, and 0.7% in clinically nonsyndromic craniosynostosis. Here, we present findings from 16 unrelated probands with ERF-related craniosynostosis, with additional data from 20 family members sharing the mutations. Most of the probands exhibited multisutural (including pan-) synostosis but a pattern involving the sagittal and lambdoid sutures (Mercedes-Benz pattern) predominated. Importantly the craniosynostosis was often postnatal in onset, insidious and progressive with subtle effects on head morphology resulting in a median age at presentation of 42 months among the probands and, in some instances, permanent visual impairment due to unsuspected raised intracranial pressure (ICP). Facial dysmorphism (exhibited by all of the probands and many of the affected relatives) took the form of orbital hypertelorism, mild exorbitism and malar hypoplasia resembling Crouzon syndrome but, importantly, a Class I occlusal relationship. Speech delay, poor gross and/or fine motor control, hyperactivity and poor concentration were common. Cranial vault surgery for raised ICP and/or Chiari-1 malformation was expected when multisutural synostosis was observed. Variable expressivity and nonpenetrance among genetically affected relatives was encountered. These observations form the most complete phenotypic and developmental profile of this recently identified craniosynostosis syndrome yet described and have important implications for surgical intervention and follow-up.
ERF 基因突变,导致 ETS2 抑制因子编码异常,ETS2 抑制因子是 ETS 转录因子家族的成员,引起一种最近被认识的颅缝早闭综合征(CRS4),伴有颅面畸形、Chiari-1 畸形、言语和语言延迟以及学习困难和/或行为问题。在综合征性颅缝早闭症患者中,ERF 突变的总体患病率约为 2%,而在临床非综合征性颅缝早闭症中为 0.7%。在这里,我们介绍了 16 例 ERF 相关颅缝早闭症的无关联先证者的发现,并提供了 20 例携带突变的家族成员的附加数据。大多数先证者表现为多缝(包括全)早闭,但以涉及矢状缝和人字缝(梅赛德斯-奔驰模式)为主的模式为主。重要的是,颅缝早闭症通常在出生后开始,隐匿性和进行性进展,对头骨形态的影响很小,导致先证者的平均就诊年龄为 42 个月,在某些情况下,由于未被怀疑的颅内压升高(ICP)导致永久性视力损害。颅面畸形(所有先证者和许多受影响的亲属都有表现)表现为眶距增宽、轻度眼球突出和颧骨发育不良,类似于 Crouzon 综合征,但重要的是,存在 I 类咬合关系。言语延迟、精细和/或粗大运动控制不良、多动和注意力不集中很常见。当观察到多缝早闭时,预期需要进行颅骨穹窿手术以治疗 ICP 升高和/或 Chiari-1 畸形。在遗传受影响的亲属中,存在可变表达性和不完全外显率。这些观察结果形成了迄今为止对这种最近被识别的颅缝早闭综合征最完整的表型和发育概况,并对手术干预和随访具有重要意义。