ESPE Abstracts (2022) 95 P1-325

1Pediatric Rare Disease Unit, IRCSS Azienda Ospedaliero-Universitaria S.Orsola, Bologna, Italy; 2Pediatric Endocrine Unit, IRCSS Azienda Ospedaliero-Universitaria S.Orsola, Bologna, Italy; 3Genetic Unit, IRCSS Azienda Ospedaliero-Universitaria S.Orsola, Bologna, Italy; 4Pediatric Clinic, IRCSS Azienda Ospedaliero-Universitaria S.Orsola, Bologna, Italy; 5University of Bologna, Bologna, Italy

ERF protein is a major binding target of ERK1/2 kinases, key effectors of the RAS–MEK–ERK signaling cascade. ERF has a role as a negative transcriptional regulator of RAS/MAPK mitogenic pathway (1) and, in theory, a loss-of-function mutation (LOF) in ERF could cause a Rasopathy phenotype. To date, LOF variants of ERF have been reported in 45 individuals with craniosynostosis but without a Noonan-like phenotype. There is only one case report describing a patient with a Noonan-like phenotype and craniosynostosis caused by a germline mutation in ERF. We report the case of a male with a Noonan syndrome-like phenotype, type 1 DM, focal epilepsy and a heterozygous ERF variant.

Case report: Firstborn child of healthy non consanguineous parents, born at term by CT for breech presentation after a normal pregnancy. Birth weight 3200 g (-0,69 SD), length 49 cm (-0.98 SD). Postnatal adaptation was normal. Severe language delay was observed. At the age of 13.5 yrs, he developed type 1 DM and subcutaneous insulin therapy was started. At 14 yrs, he suffered an episode of generalized tonic-clonic seizures. The EEG showed diffuse spikes and polyspikes, especially in centrotemporal regions and levetiracetam was initiated. No brain MRI abnormalities were detected. ECG showed high and asymmetric R waves. He was referred to our unit at 14 yrs of age for dysmorphic features and intellectual disability. Auxological parameters: height 152.8 cm (1.83 SD), weight 39.1 kg (-2.22 SD for height age), OFC 56.4 cm (+1.2 SD for height age). Physical examination showed dolichocephaly, hyperthelorism, pterigium colli, pectus excavatum, hypercheratotic skin. Due to the clinical signs and ECG pattern an NGS panel for Rasopathies was performed which revealed ERF variant (P.Lys401GlufsTer10).

Conclusion: In the literature, there has been a recent report of a patient with a Noonan-like phenotype, craniosynostosis and an ERF gene mutation [2]. Our patient has similar clinical characteristics such as dolicochephaly, a Noonan-like phenotype, and an ERF mutation, supporting a pathogenetic role for ERF in Rasopathies. Moreover, he had ECG anomalies and epilepsy which are frequently reported in these conditions, and type 1 DM, expanding the ERF mutant phenotype. Further studies are needed to clarify the genotype phenotype correlation.

1. Tartaglia, M. et al. Noonan syndrome and related disorders: genetics and pathogenesis. Annu. Rev. Genomics Hum. Genet. 2005,6:45-68.

2. Yamada M., et al. Noonan syndrome-like phenotype in a patient with heterozygous ERF truncating variant. Congenit Anom. 2021, 61:226-230.

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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