Acute encephalopathy related to cardio-facio-cutaneous syndrome with KRAS mutation

Background: Cardio-facio-cutaneous syndrome (CFC) is a rare genetic condition affecting up to 300 people globally. The cardinal features of CFC are congenital cardiac anomalies, distinctive facial appearances and skin changes, however, it is also associated with feeding problems, short stature, macrocephaly, hypotonia, speech delay, learning disability and seizures. CFC has phenotypic overlap with Noonan and Costello Syndrome and these are all considered RASopathies. CFC is associated with variants in genes involved in the RAS/MAPK intracellular signalling pathway and is most frequently caused by mutations in BRAF (approximately 75%), MAP2K1 and MAP2K2 (approximately 25%) and infrequently KRAS (approximately 2%). Case report: We describe a 7 year old girl with CFC caused by a pathogenic KRAS variant. She has distinctive facial features, pulmonary stenosis and atrial septal defect, multiple pigmented naevi and lymphoedema. She also has Dandy-Walker Syndrome with hydrocephalus, poor feeding and faltering growth requiring gastrostomy feeding. She has right eye amblyopia and right optic nerve atrophy. She is able to speak and walk independently but required additional educational support. She presented with fever without a prodrome and a prolonged focal seizure affecting the left side of her body. She had a marked left-sided hemiplegia. Magnetic resonance imaging showed extensive right hemispheric high T2 intensity, swelling of the grey matter structures, and initial restricted diffusion. Infective, auto-immune, and metabolic causes were excluded. Acute encephalopathy with brain oedema has been previously reported in cases of CFC associated with BRAF mutations, but this is the first report in a patient with CFC due to a KRAS mutation. It is postulated that aberrant ERK signalling may lead to excessive central nervous system cytokine production leading to neurotoxicity and encephalopathy. KRAS is upstream from BRAF and this case suggests that aberrant signalling upstream from BRAF can also lead to acute encephalopathy.

Citation

Monaghan et al (2021). Acute encephalopathy related to cardio-facio-cutaneous syndrome with KRAS mutation. Developmental Medicine & Child Neurology. 63 (S1): 13-102.

DOI

10.1111/dmcn.14749

URI

https://hdl.handle.net/20.500.14709/1067

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