1 - Serviço de Genética Médica, Área de Pediatria, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central, Lisboa, Portugal
2 - Serviço de Genética Médica, Hospital Pediátrico, Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal
- Reunião nacional – 26.ª Reunião da Sociedade Portuguesa de Genética Humana (SPGH), sob a forma de comunicação oral
Introduction: A recurrent missense variant in the ERF gene has been associated to Chitayat syndrome (MIM 617180). On the other hand, variants in ERF leading to haploinsufficiency were recently related to a completely different phenotype, namely craniosynostosis 4 (MIM 600775), with or without facial dysmorphisms.
Aim: To describe two additional cases of ERF haploinsufficiency in order to explore challenges in phenotypic recognition.
Case reports: P1: A 4-year-old male presented with developmental delay, facial dysmorphisms (hypertelorism, depressed nasal bridge, and short/upturned nose), short stature, sagittal synostosis, webbed neck, and brachydactyly, resembling Noonan syndrome. Rasopathies NGS panel was negative. Clinical exome sequencing identified a pathogenic variant in ERF (NM_006494.3):c.1201_1202del, p.(Lys401Glufs*10), inherited from an apparently unaffected father. P2: A 3-year-old male was referred for feeding difficulties, recurrent vomiting, and failure to thrive. He had development delay, craniosynostosis, and dysmorphisms (triangular face, hypertelorism, mild exorbitism, thin/long nose, and low-set/posteriorly rotated ears). Clinical exome sequencing identified a pathogenic variant in ERF (NM_006494.3):c.697C>T, p.(Arg233*), maternally inherited. The mother had mild Crouzon-like facial dysmorphisms. Since failure to thrive was not explained by the ERF mutation, further testing was performed. Microarray showed a homozygosity in 7q11.21q22.3, and polymorphic markers indicated a maternal uniparental disomy, confirming Silver-Russel syndrome (MIM 618905).
Discussion: Both cases do not have a fully recognizable phenotype associated with ERF gene variants. The first patient has a Noonan-like phenotype, which is not surprising considering that ERF is a negative transcriptional regulator of the RAS pathway. The second patient has a dual diagnosis: ERF-related craniosynostosis superimposed with the Silver-Russel syndrome, reinforcing the importance of revisiting cases when the full phenotype is not concordant with the genotype. Additionally, this report reflects the wide intra and interfamilial variability, and incomplete penetrance of ERF mutations.
Palavras Chave: ERF haploinsuficiency, craniosynostosis