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Page 125 Fanella et al. J Transl Genet Genom 2021;5:124-9 https://dx.doi.org/10.20517/jtgg.2021.11

INTRODUCTION
Neurofibromatosis type 1 (NF1) (MIM No. 162200) is a complex autosomal dominant disorder involving
multiple body systems (with an estimated prevalence of 1/2500-1/3000 individuals). Neurofibromin protein,
encoded by NF1 gene, is highly expressed in neurons, glia, Schwann cells, and the early stage of melanocyte
[1,2]
development . Neurofibromin inhibits the activity of the proto-oncogene Ras, catalyzing the guanosine
triphosphate (GTP)-bound Ras hydrolysis to guanosine diphosphate (GDP)-bound Ras and thus preventing
[3]
tumor growth . In NF1, the absence of neurofibromin leads to unopposed GTPase activity, releasing the
downstream signals involved in cell proliferation and differentiation.

According to the National Institutes of Health (NIH) diagnostic criteria , NF1 clinical diagnosis is based on
[4]
the presence of at least two typical features or only one symptom with an affected first-degree relative.
Characteristic NF1 findings are hyperpigmented skin markings or café-au-lait macules (CALMs), which
typically develop in the first 2 years of life, axillary or inguinal freckling, distinctive bone anomalies, Lisch
nodules, and neurofibromas. Neurologic features, in particular mild neurocognitive deficits and epilepsy,
[5,6]
have been also frequently described in NF1 . A remarkable phenotype lacking both cutaneous
neurofibromas and visible plexiform neurofibromas has been associated with the in-frame
c.2970_2972del and the missense mutation at codon Arg 1809 mutations.
[10]
[7-9]
Here, we describe, for the first time, an interesting milder variant manifesting with idiopathic generalized
epilepsy (IGE) and typical pigmentary skin manifestations.

CASE REPORT
We report the case of a 27-year-old, right-handed man, who first presented typical absence seizures at the
age of 4. At that time, the electroencephalogram (EEG) showed 3-Hz generalized spike-and-wave
discharges. At 16 years, he was hospitalized following the occurrence of a generalized tonic-clonic seizure.
During his hospital stay, the EEG confirmed the previous findings and a brain magnetic resonance imaging
(MRI) showed focal bilateral subcortical signal alterations in the T2-weighted sequences [Figure 1A], which
had completely disappeared by the time the patient undertook a follow-up MRI scan 4 months later
[Figure 1B]. In addition, during hospitalization the physicians also observed pigmentary manifestations
similar to CALMs - eight café-au-lait macules of 10-20 mm located on the arms and the trunk - although no
other feature suggestive of NF1 was detected.

At the age of 26, the patient came to our observation for seizure persistence. He underwent a video-EEG
recording that showed the presence of generalized epileptiform abnormalities [Figure 2]. Brain MRI and
neurologic examination were normal. A complete neuropsychological evaluation (including
Phonemic/Semantic Alternate Fluency Test, Attentive Matrix, Trail Making Test, Rey Auditory Verbal
Learning Test, Rey-Osterrieth Complex Figure Test, Short-Story Recall Test, Stroop Test, Raven Colored
Progressive Matrices, Abstract Verbal Judgment, WAIS-IV Working Memory Scale, Tower of London Test,
and Ideomotor Apraxia Test) documented a normal cognitive profile except for a slight attention shifting
deficit. Seizure control was achieved thanks to a polytherapy with valproate 1500 mg/day, zonisamide
200 mg/day, and brivaracetam 150 mg/day. A dedicated team of specialists (i.e., orthopedists,
ophthalmologists, and dermatologists) examined our patient, and were unable to identify other typical
features of NF1. This included slit-lamp exam for Lisch nodules and plain film radiographs to screen for
bone dysplasias. Although all the clinical and instrumental evaluations did not reveal other peculiar aspects,
we performed Next Generation Sequencing (NGS) and Sanger sequencing that allowed us to detect the de
novo NM_000267.3: c.2970_2972delAAT p.(Met992del) in exon 22 of NF1 gene. Sanger sequencing did not
detect the deletion in parents.