Neurocutaneous disorders are characterized by a heterogeneous presentation where involvement of the skin and central nervous system prevails. Between these disorders, there are several overlapping signs and symptoms. The neurofibromatoses comprise three genetically distinctive disorders: Neurofibromatosis type 1 (NF1), Neurofibromatosis type 2 (NF2) and Schwanommatosis; all have predisposition to develop common multiple tumors, characteristic dermatologic presentation, alongside other systemic involvement. Initially, it was believed the etiology of these entities was the result of a defect of a single gene. With advances in molecular testing and current diagnostic tests, several genes have been found to be related to each of these disorders.

Neurofibromatosis type (NF1) was initially known as Von Recklinghausen's disease, named after a German pathologist Friedrich von Recklinghausen, who first described the disease as an entity in 1882.1 Subsequently, the National Institutes of Health (NIH) set the clinical criteria for diagnosis in 1988. The NF1 gene was mapped in the pericentromeric region of chromosome 17 in 1987. Later in 1989, the region of interest was determined to be in the long arm of the chromosome 17 (17q11.2), facilitating the gene isolation, cloning and characterization in 1990.2 NF1 is a tumor predisposition syndrome, caused by a mutation in the NF1 gene. NF1 encodes Neurofibromin, a protein that regulates the RAS-pathway activity involved in cellular proliferation.3

Neurofibromatosis type 1 (NF1, OMIM 162200) is one of the most common genetic conditions, with a prevalence ranging from 1 in 3000-6000.5 It is an inherited autosomal dominant disorder in about 50 % of the cases, but it can arise as a de novo mutation (sporadic) in about 40 % of the cases.6 The characteristic signs of NF1 include café-au-lait macules (CALMs), as well as freckles in the inguinal and axillary region. The original clinical criteria for NF1 were established by the National Institutes of Health (NIH) in 1987, then confirmed in 1997.7 These were recently updated in 2021. 4,8 The clinical diagnosis is based on the presence of two or more of the following:1.

CALMs: ≥ 6 with greatest diameter >5mm in prepubertal or ≥15mm in post-pubertal patients

2.

Freckles (inguinal and axillary), bilateral

3.

≥2 neurofibromas (cutaneous and/or subcutaneous), or ≥1 plexiform neurofibroma (PN)

4.

≥2 Lisch nodules (iris), and/or choroidal abnormalities

5.

Optic pathway glioma (OPG)

6.

Distinctive osseus lesion, i.e. sphenoid wing dysplasia, anterolateral bowing of the tibia, pseudoarthrosis of a long bone

7.One of the following:a.

Finding of a heterozygous pathogenic NF1 variant with a variant allele fraction of 50 % in apparently normal tissue

b.

A child of a parent, who meets the diagnostic criteria specified in above, merits a diagnosis of NF1 if 1 or more of the criteria, from above, are present

The disorder has a penetrance of 100 %, with a high heterogeneity of disease manifestations from patient to patient. There is no predilection for gender, race or ethnicity. Clinical criteria are key to establishing the diagnosis of NF1, and present with high variability. Some characteristic features might be present since birth (i.e CALMs), whereas others appear later in life (i.e. tumors) (Fig. 1).27