2018 Volume 50 Issue 5 Pages 350-354
The RAS/MAPK syndromes, including Noonan syndrome, Costello syndrome, and cardio-facio-cutaneous (CFC) syndrome, are congenital developmental disorders caused by germline mutations in genes involved in the RAS/MAPK pathway. Neuroblastoma RAS viral oncogene homolog (NRAS) is one of the causative genes for Noonan syndrome. Here, we report a case of an NRAS mutation associated with a phenotype analogous to that of CFC syndrome. A 16-year-old Japanese girl with severe psychomotor developmental delay was born without complications, and was the second child of healthy and nonconsanguineous parents. However, she was hypotonic, had no head control, and had microcephalus. Brain MRI scans showed agenesis of the corpus callosum and hypoplasia of the frontal lobe. Onset of epilepsy occurred at 1 year and 4 months of age. Interictal EEG showed no abnormal findings, but epilepsy was intractable. Sodium valproate and phenobarbital were not effective, and levetiracetam resulted in worsening of seizures. Seizures are currently controlled with phenytoin, phenobarbital, sodium valproate, and nitrazepam. Whole exome sequencing identified a de novo somatic mutation in NM_002524.4 (NRAS) : c.34G>A (p.Gly12Ser). This mutation was confirmed in 7/46 alleles in blood leukocytes, but not in the hair roots or nails.
This is a report of a CFC-like syndrome associated with an NRAS mutation and provides further evidence supporting the phenotypic diversity of RAS/MAPK syndromes.
