Neurofibromatosis type 1 (NF1) is a complex autosomal dominant disorder associated with germline mutations in the NF1 tumor suppressor gene. NF1 belongs to a class of congenital anomaly syndromes called RASopathies, a group of rare genetic conditions caused by mutations in the Ras/mitogen-activated protein kinase pathway. Generally, NF1 patients present with dermatologic manifestations. In this review the main features of café-au-lait macules, freckling, neurofibromas, juvenile xanthogranuloma, nevus anemicus and other cutaneous findings will be discussed.

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition, with a birth incidence of approximately 1:2000–3000, caused by germline pathogenic variants in NF1, a tumor suppressor gene encoding neurofibromin, a negative regulator of the RAS/MAPK pathway. This explains why NF1 is included in the group of RASopathies and shares several clinical features with Noonan syndrome. Here, we describe the main clinical characteristics and complications associated with NF1, particularly those occurring in pediatric age. NF1 has complete penetrance and shows wide inter- and intrafamilial phenotypic variability and age-dependent appearance of manifestations. Clinical presentation and history of NF1 are multisystemic and highly unpredictable, especially in the first years of life when penetrance is still incomplete. In this scenario of extreme phenotypic variability, some genotype–phenotype associations need to be taken into consideration, as they strongly impact on genetic counseling and prognostication of the disease. We provide a synthetic review, based on the most recent literature data, of all known genotype–phenotype correlations from a genetic and clinical perspective. Molecular diagnosis is fundamental for the confirmation of doubtful clinical diagnoses, especially in the light of recently revised diagnostic criteria, and for the early identification of genotypes, albeit few, that correlate with specific phenotypes.

A large body of literature reports the higher prevalence of epilepsy in subjects with Autism Spectrum Disorder (ASD) compared to the general population. Similarly, several studies report an increased rate of Subclinical Electroencephalographic Abnormalities (SEAs) in seizure-free patients with ASD rather than healthy controls, although with varying percentages. SEAs include both several epileptiform discharges and different non-epileptiform electroencephalographic abnormalities. They are more frequently associated with lower intellectual functioning, more serious dysfunctional behaviors, and they are often sign of severer forms of autism. However, SEAs clinical implications remain controversial, and they could represent an epiphenomenon of the neurochemical alterations of autism etiology. This paper provides an overview of the major research findings with two main purposes: to better delineate the state-of-the-art about EEG abnormalities in ASD and to find evidence for or against appropriateness of SEAs pharmacological treatment in ASD.

Pigmentary manifestations can represent an early clinical sign in children affected by Neurofibromatosis type 1 (NF1), Legius syndrome, and other neurocutaneous disorders. The differential molecular diagnosis of these pathologies is a challenge that can now be met by combining next generation sequencing of target genes with concurrent second-level tests, such as multiplex ligation-dependent probe amplification and RNA analysis. We clinically and genetically investigated 281 patients, almost all pediatric cases, presenting with either NF1 (n = 150), only pigmentary features (café au lait macules with or without freckling; (n = 95), or clinical suspicion of other RASopathies or neurocutaneous disorders (n = 36). The causative variant was identified in 239 out of the 281 patients analyzed (85.1%), while 42 patients remained undiagnosed (14.9%). The NF1 and SPRED1 genes were mutated in 73.3% and 2.8% of cases, respectively. The remaining 8.9% carried mutations in different genes associated with other disorders. We achieved a molecular diagnosis in 69.5% of cases with only pigmentary manifestations, allowing a more appropriate clinical management of these patients. Our findings, together with the increasing availability and sharing of clinical and genetic data, will help to identify further novel genotype–phenotype associations that may have a positive impact on patient follow-up.