ERF-related craniosynostosis: The phenotypic and developmental profile of a new craniosynostosis syndrome.

Graeme E Glass,Natalie Canham,Peter Noons,Tracy Lester,Deirdre Cilliers,Hiroshi Nishikawa,Caroleen Shipster,Pradeep Vasudevan,David Dunaway,Steven A Wall,Kemmy Schwiebert,David Johnson,Helen Lord,Aimée L Fenwick ,Owase Jeelani ,Andrew O.m Wilkie ,Alison Taylor-Beadling ,Jenny Morton ,Stephen R.f Twigg ,Justine O’hara ,Louise Wilson

doi:10.1002/ajmg.a.61073

Abstract

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.

Highlights

Prevalence estimates for craniosynostosis, defined as the premature fusion of one or more of the cranial vault sutures, have ranged from 3.1 to 6.4 per 10,000 livebirths (Cornelissen et al, 2016)
Of the genetically-related family members identified by family tree who consented for genetic testing, an additional 20 individuals with ERF mutations linked to those of the probands was found
Thirteen different heterozygous mutations were identified in the 16 families comprising one mutation within the translation initiation codon, three nonsense mutations, three frame-shifting mutations predicted to result in premature protein truncation, and six mutations predicted to result in missense substitutions (Figure 1)

Summary

Introduction

Prevalence estimates for craniosynostosis, defined as the premature fusion of one or more of the cranial vault sutures, have ranged from 3.1 to 6.4 per 10,000 livebirths (Cornelissen et al, 2016). We report our experience of 16 unrelated probands and 20 additional family members with heterozygous ERF mutations confirming that they contribute significantly to the craniosynostosis caseload, and highlight particular issues of importance in the clinical management of patients and their wider families.

Results

Conclusion