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

Abstract

Background: ERF-related craniosynostosis are a rare, complex, premature trisutural fusion associated with a broad spectrum of clinical features and heterogeneous aetiology. Here we describe two cases with the same pathogenic variant and a detailed description of their clinical course. Case presentation: Two subjects; a boy with a BLSS requiring repeated skull expansions and his mother who had been operated once for sagittal synostosis. Both developed intracranial hypertension at some point during the course, which was for both verified by formal invasive intracranial pressure monitoring. Exome sequencing revealed a pathogenic truncating frame shift variant in the ERF gene. Conclusions: Here we describe a boy and his mother with different craniosynostosis patterns, but both with verified intracranial hypertension and heterozygosity for a truncating variant of ERF c.1201_1202delAA (p.Lys401Glufs*10). Our work provides supplementary evidence in support of previous phenotypic descriptions of ERF-related craniosynostosis, particularly late presentation, an evolving synostotic pattern and variable expressivity even among affected family members.

Noonan syndrome‐like phenotype in a patient with heterozygous ERF truncating variant

“…No other de novo variants of any genes that could be responsible for the We reevaluated the phenotypic features of previously reported patients with definitive heterozygous loss-of-function variants in ERF (Table 1 and Table S1). [12][13][14][15][16][17][18][19] Such patients have deletions spanning various combinations of the three functional domains in ERF including ETS domain, ERK interaction domain, and Repressor domain. Some of the characteristic features of Noonan syndrome are indeed present in many patients.…”

“…[5][6][7][8][9][10][11] Loss-of-function variants of ERF (ETS2 Repressor Factor) resulting in craniosynostosis have been reported in 45 individuals. [12][13][14][15][16][17][18][19] ERF is a major binding target of extracellular signal-related kinases 1 and 2 (ERK1/2 kinases), which are key effectors of the RAS-MEK-ERK signaling cascade. ERK1/2 is an important protein that mediates a mitogen-activated protein kinase signaling downstream component of RAS.…”

Dissection of contiguous gene effects for deletions around ERF on chromosome 19

“…Disease‐causing heterozygous loss‐of‐function variants of ERF were first described in 2013, in 12 families segregating features of a newly recognized syndrome (termed ERF ‐related craniosynostosis or craniosynostosis type 4, OMIM# 600775), characterized by premature fusion of the cranial sutures (craniosynostosis), hypertelorism, and mild midface hypoplasia (Twigg et al, 2013). Confirmatory case reports have followed (Chaudhry et al, 2015; Korberg et al, 2020; Lee et al, 2018; Provenzano et al, 2021; Timberlake et al, 2017; Tønne et al, 2020; Yoon et al, 2020), and the clinical features of the disorder were further delineated and summarized in 16 additional families by Glass et al (2019). In addition to craniosynostosis and facial dysmorphism, additional frequently associated features included Chiari‐1 malformation, speech and language delay, poor gross and/or fine motor control, hyperactivity, and poor concentration.…”

Intrafamilial variability in six family members with ERF‐related craniosynostosis syndrome type 4

“…ERF mutations as the cause for syndromic craniosynostosis make up an estimated 2% (A. O. M. Wilkie et al, 2017). So far, information on 79 patients with CRS4 has been published (Balasubramanian et al, 2017; Chaudhry et al, 2015; Glass et al, 2019; Korberg et al, 2020; Twigg et al, 2013; Yadav & Hopkin, 2017).…”