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

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.

Keywords: Chiari-1 malformation; ERF; craniosynostosis; facial dysmorphism; intracranial pressure; phenotype.

Figure 1

Domain structure of the ERF protein and the mutations identified. The mutations identified in the present cohort are shown underneath and the previously described mutations are shown above. †Refers to the heterozygous ERF missense substitution found to cause Chitayat syndrome (Balasubramanian et al., 2017)

Figure 2

Craniosynostosis in the patient cohort. (a) The synostotic patterns identified among the 23 individuals evaluated radiologically. (b) The frequency of involvement of each suture or paired sutures

Figure 3

Selected 3D‐CT scan views from two probands illustrating the progressive nature of the craniosynostosis. (a) and (b) Patient 14 (K3): 3D‐CT images taken at age 0.8 and 2.7 years, respectively. At 0.8 years only the squamosal sutures were noted to be closed, progressing to pansynostosis with associated papilledema by 2.7 years. The site of the neurosurgical evacuation of a presumed spontaneous extradural bleed is also visible. Note the relatively normal skull shape. (c) and (d) Patient 8 (K3): 3D‐CT images taken at ages 1.9 and 4.7 years, respectively. At 1.9 years there was a scaphocephalic head shape with an indistinct sagittal suture suspicious of synostosis. By 4.7 years when clinical evidence of raised intracranial pressure became apparent, the craniosynostosis had progressed with clear involvement of the sagittal, superior bilambdoid, left inferior coronal, and left squamosal sutures

Figure 4

Spectrum of facial phenotypes in patients with ERF‐related craniosynostosis. (a) Patient 1 aged 3 years and (b) Patient 24 (adult) illustrating typical mild orbital hypertelorism and exorbitism with normal mid‐facial development. (c) Patient 35 aged 24 weeks illustrating scaphocephaly with a narrow occiput, mild orbital hypertelorism, and down‐slanting palpebral fissures with normal mid‐facial development. (d) Patient 8 aged 4 years illustrating a mildly elongated skull but normal facial appearance