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.

A progressive and complex clinical course in two family members with ERF-related craniosynostosis: a case report

“…In total 13 different heterozygous ERF-variants were reported ( Table 1). These studies suggest a wide spectrum of pathogenic variants causing ERF-related CS [9,10,12]. The phenotype in the mother and son presented here is consistent with the phenotype previously described.…”

“…An interesting observation is the pansynostosis (including coronal sutures) that developed over time in the index patient. ERF-related pansynostosis has been described in previously reported cases [9,12]. Thus, the postoperative pansynostosis observed here could be a postnatal progression of the sutural fusion, similarly to what is seen in Crouzon syndrome.…”

“…Furthermore, the patient presented with brachydactyly of hands and feet, broad halluces and dysplastic ears, thus syndromic CS [9]. Patient 19 presented with pansynostosis and Chari-1 malformation, he had orbital hypertelorism, malar hypoplasia, frontal bossing, long philtrum, high palate, low set ears, inverted nipples and clinodactyly [12].…”

“…In 2015, Chaudhry et al sequenced 40 patients, and heterozygous mutations in ERF were detected in 2 patients (5%), one patient with bicoronal and metopic synostosis, and the other with pansynostosis [10]. Glass et al reported 16 unrelated probands and 20 family members with multi sutural synostosis, predominantly BLSS [12]. In total 13 different heterozygous ERF-variants were reported ( Table 1).…”

“…The aetiology of CS is heterogeneous, and several chromosomal hotspot loci and candidate genes have been associated with CS [6][7][8]. One of the most recent addition is ETS2 repressor factor (ERF), in which pathogenic variants have been identified in patients presenting with CS [9][10][11][12].…”