Idiopathic generalized epilepsy and café-au-lait macules as the predominant features in NF1 mild form

Abstract

Neurofibromatosis type 1 (NF1) is a complex autosomal dominant neurocutaneous disorder with a variable phenotype involving multiple body systems. It is due to a mutation in the NF1 gene, which results in the production of abnormal neurofibromin protein. According to the National Institutes of Health diagnostic criteria, hyperpigmented skin markings or café-au-lait macules (CALMs), axillary freckling, Lisch nodules, and neurofibromas are characteristic NF1 features. A milder phenotype, apparently manifesting with only pigmentary skin changes, has recently been associated with the c.2970_2972 in-frame deletion. Although neurological findings, including epilepsy and neurocognitive deficits, have been frequently described as a part of the classic NF1 form, they have not been properly characterized in this milder variant. We report for the first time the case of a patient harboring the c.2970_2972del of the NF1 gene and presenting with CALMs, idiopathic generalized epilepsy, and transient brain MRI alterations (so-called “unidentified bright objects”).

Keywords

NF1 mild form / idiopathic generalized epilepsy / café-au-lait macules / “unidentified bright objects” (UBOs)

References

[1] DastonMM,NordlundM,NissenLM.The protein product of the neurofibromatosis type 1 gene is expressed at highest abundance in neurons, Schwann cells, and oligodendrocytes.Neuron1992;8:415-28

[2] MalhotraR.Localization of neurofibromin to keratinocytes and melanocytes in developing rat and human skin.J Invest Dermatol1994;102:812-8

[3] MartinGA,BollagG.The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21.Cell1990;63:843-9

[4] Conference statement. National Institutes of Health Consensus Development Conference.Arch Neurol1988;45:575-8

[5] NixJS,RodriguezFJ.An update on the central nervous system manifestations of neurofibromatosis type 1.Acta Neuropathol2020;139:625-41 PMCID:PMC6819239

[6] PecoraroA,GallentineW.Epilepsy in neurofibromatosis type 1.Epilepsy Behav2017;73:137-41

[7] KoczkowskaM,GomesA.Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation.Genet Med2019;21:867-76 PMCID:PMC6752285

[8] QuintánsB,CamposB.Neurofibromatosis without neurofibromas: confirmation of a genotype-phenotype correlation and implications for genetic testing.Case Rep Neurol2011;3:86-90 PMCID:PMC3084038

[9] UpadhyayaM,DaviesM.An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation.Am J Hum Genet2007;80:140-51 PMCID:PMC1785321

[10] RojnueangnitK,GomesA.High incidence of Noonan syndrome features including short stature and pulmonic stenosis in patients carrying NF1 missense mutations affecting p.Arg1809: genotype-phenotype correlation.Hum Mutat2015;36:1052-63 PMCID:PMC5049609

[11] Muram-ZborovskiTM,ViskochilDH,MaoR.NF1 exon 22 analysis of individuals with the clinical diagnosis of neurofibromatosis type 1.Am J Med Genet A2010;152A:1973-8 PMCID:PMC2910813

[12] HsiehHY,WangCJ,WuT.Epileptic seizures in neurofibromatosis type 1 are related to intracranial tumors but not to neurofibromatosis bright objects.Seizure2011;20:606-11

[13] KurodaN,OkanishiT,NishimuraM.Epilepsy surgery for a patient with neurofibromatosis type 1 concomitant with moyamoya syndrome.J Clin Neurosci2019;61:307-10

[14] GriffithsPD,MukonoweshuroW,Milo-MasonG.Neurofibromatosis bright objects in children with neurofibromatosis type 1: a proliferative potential?.Pediatrics1999;104:e49

[15] GriffithJL,MahdiJ,HersheyT.Increased prevalence of brain tumors classified as T2 hyperintensities in neurofibromatosis 1.Neurol Clin Pract2018;8:283-91 PMCID:PMC6105062

[16] BillietT,D'ArcoF.Characterizing the microstructural basis of “unidentified bright objects" in neurofibromatosis type 1: A combined in vivo multicomponent T2 relaxation and multi-shell diffusion MRI analysis.Neuroimage Clin2014;4:649-58 PMCID:PMC4053637

[17] HeinzenEL,CavalleriGL.Exome sequencing followed by large-scale genotyping fails to identify single rare variants of large effect in idiopathic generalized epilepsy.Am J Hum Genet2012;91:293-302 PMCID:PMC3415540