Neurofibromatosis type I (NF-1), or von Recklinghausen syndrome, is a complex multi-system human disorder caused by the mutation of neurofibromin 1 (NF-1).

NF-1 is a gene on chromosome 17 that is responsible for production of a protein (neurofibromin) which is needed for normal function in many human cell types.

NF-1 is an autosomal dominant disorder, which means that mutation or deletion of one copy (or allele) of the NF-1 gene is sufficient for the development of NF-1, although presentation varies widely and is often different even between relatives affected by NF-1.

[5] The following is a list of conditions and complications associated with NF-1, and, where available, age range of onset and progressive development, occurrence percentage of NF-1 population, method of earliest diagnosis, and treatments and related medical specialties.

[7][8] The progression of the condition is roughly as follows: Musculoskeletal abnormalities affecting the skull include sphenoid bone dysplasia, congenital hydrocephalus and associated neurologic impairment.

[11] Clinical findings in people with NF-1 include: Studies in genetically modified mice have thus far confirmed that the NF1 gene is vital for normal muscle development and metabolism.

[14] It is likely that impaired muscle function in these disorders is linked to altered Ras/MAPK signalling, however, the precise molecular mechanisms remain unknown.

These cognitive problems have been shown to be present in approximately 90% of children and adults with NF-1 and have significant effects on their schooling and everyday life.

[19] These cognitive problems have been shown to be stable into adulthood mainly in the mid 20s to early 30s and do not get worse unlike some of the other physical symptoms of NF-1.

Neurofibroma conditions are progressive and include: Intracranially, NF-1 patients have a predisposition to develop glial tumors of the central nervous system, primarily optic nerve gliomas and associated blindness.

[25] Another CNS manifestation of NF-1 is the so-called "unidentified bright object" or UBO, which is a lesion which has increased signal on a T2 weighted sequence of a magnetic resonance imaging examination of the brain.

These UBOs are typically found in the Cerebral peduncle, pons, midbrain, globus pallidus, thalamus, and optic radiations.

Weakness of the dura leads to focal enlargement due to chronic exposure to the pressures of CSF pulsation, and typically presents as paraesthesia or loss of motor or sensory function.

[43] This homologous sequence is in the central portion of neurofibromin and being similar to the GAP family is recognized as a negative regulator of the Ras kinase.

[47] Together, likely with domains yet to be discovered, neurofibromin regulates many of the pathways responsible for overactive cell proliferation, learning impairments, skeletal defects and plays a role in neuronal development.

[48] The mutant gene is transmitted with an autosomal dominant pattern of inheritance, but up to 50% of NF-1 cases arise due to spontaneous mutation.

[54] In addition to physical manifestations, patients with NF1 are at high risk of developing neurodevelopmental disorders, which result in learning difficulties, attention problems, and other behavioral or social challenges.

[55] A significant number of children with NF-1 exhibit symptoms commonly associated with Autism Spectrum Disorder (ASD), which can impact daily functioning.

[57] These differences include stronger eye contact, fewer repetitive behaviors, and more pronounced autistic mannerisms compared to non-syndromic ASD.

[57] Research suggests that Neurofibromatosis Type 1 and Tuberous Sclerosis (TSC) exhibit similarities in the symptomatology associated with Autism Spectrum Disorder.

Due to their fewer observed repetitive behaviors and improved eye contact, these children may not exhibit the typical characteristics of idiopathic autism in clinical settings, increasing the likelihood that they will be overlooked by clinicians.

[56] Individuals with neurofibromatosis type 1 often exhibit certain brain abnormalities known as T2 hyperintensities (visible on MRI scans), referred to as Unidentified Bright Objects (UBOs), which are located in specific brain regions such as the cerebellum, brainstem, thalamus, and basal ganglia—areas involved in motor signal processing and cognitive functions.

[60] Some of these brain regions are also connected to attention-related networks, particularly those involved in cognitive flexibility and motor inhibition, which are essential for attention and behavior.

[60] Studies suggest that while ADHD symptoms may partially explain attention problems in NF-1, such as impulsivity, they do not fully account for other deficits like cognitive control.

Selumetinib, is a drug produced by Astra Zeneca sold under the brand name Koselugo, and was approved by the FDA in April 2020[62] for the treatment of NF-1 in the pediatric population who are two or more years of age.

It is a mitogen-activated protein kinase inhibitor (MEKi) and is indicated for use in pediatric patients who are symptomatic and have inoperable plexiform neurofibromas.

In an open-label, phase 2 trial of selumetinib with 50 children: NF-1 is a progressive and diverse condition, making the prognosis difficult to predict.

However, there are many more severe complications caused by NF-1 like increased cancer risk, a plexiform neurofibroma has a 10-15% chance of developing into a MPNST (Malignant Peripheral Nerve Sheath Tumour) Epidemiology NF-1 is estimated to affect around 25,000 people in the UK.