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

Abstract

ERF-related craniosynostosis syndrome type 4 (CRS4, OMIM #600775) is a rare autosomal dominant malformation syndrome, caused by pathogenic variants in the ERF gene and characterized by craniosynostosis, developmental delay, and dysmorphic features such as hypertelorism, exophthalmos, depressed nasal bridge, and retrognathia. So far, there are mostly individual reports and only a few descriptions of families with more than two affected patients, allowing statements about the penetrance of a certain variant and its variability only to a limited extent. In this study, we report an in-depth analysis of the clinical course of six family members from three generations with the novel heterozygous nonsense variant c.286A>T (p.Lys96*) in the ERF gene. At the time of examination, all of the six patients showed mild dysmorphic features and brachydactyly, five were overweight/obese and had delayed speech development, and four were short in stature. Hyperactivity, a short concentration span and a history of learning difficulties were found in half of the affected family members. To this day, none of the patients developed increased intracranial hypertension that would require surgical intervention. This work provides further information on the expressive variability of an ERF variant in six members of one family and focuses on the need for close neuropediatric surveillance.

Noonan syndrome‐like phenotype associated with an ERF frameshift variant

“…Yamada et al (2021) reported a patient with a Noonan syndrome-like phenotype associated with an ERF truncating variant. Other previous reports of ERF-related disorders did not describe a Noonan syndrome-like phenotype, but in some patients, overlapping phenotypes were noted retrospectively (Chaudhry et al, 2015;Glass et al, 2019;Körberg et al, 2020;Moddemann et al, 2022;Twigg et al, 2013;Yamada et al, 2021). A summary of the reported characteristics of patients with ERF variants is presented in Table 1.…”

“…Yumi Enomoto and Takuya Naruto performed the bioinformatics experiments and contributed to the genetics experiments. Yasuhiro Hirano and Yukiko Kuroda recruited T A B L E 1 Summary of the clinical data for reported patients with pathogenic ERF variants (Chaudhry et al, 2015;Glass et al, 2019;Körberg et al, 2020;Moddemann et al, 2022;Twigg et al, 2013;Yamada et al, 2021).…”