What is von Recklinghausen's (Neurofibromatosis type 1) disease?

From the Guidelines

Von Recklinghausen's disease, also known as Neurofibromatosis Type 1 (NF1), is a genetic disorder that requires a multidisciplinary approach for optimal management, focusing on monitoring for complications and treating specific symptoms as they arise. This condition is characterized by skin changes including café-au-lait spots (light brown patches), freckling in the armpits or groin, and soft bumps on or under the skin (neurofibromas) 1. NF1 is caused by mutations in the NF1 gene and is typically diagnosed in childhood. Management focuses on monitoring for complications through regular check-ups, including eye exams, blood pressure measurements, and imaging studies when needed.

Some key considerations in the management of NF1 include:

• Regular eye exams to monitor for optic pathway gliomas, glaucoma, and other ophthalmologic conditions that can result in visual loss 1
• Monitoring for malignant peripheral nerve sheath tumor (MPNST), breast cancer, cutaneous neurofibromas, and significant psychiatric and neurologic diagnoses, which are common problems in patients with NF1 1
• Surgical removal of problematic neurofibromas, such as plexiform neurofibromas (PNs) involving the eyelid, orbit, periorbital and facial structures, which can cause vision loss, proptosis, ptosis, and facial disfigurement 1
• Pain medications to manage discomfort, and educational support for learning disabilities, which affect about 50% of patients 1
• Regular follow-up with specialists including neurologists, dermatologists, and geneticists is essential for optimal management 1.

Overall, the goal of management is to improve quality of life, reduce morbidity, and prevent mortality in patients with NF1, while also addressing the physical and emotional challenges associated with this condition 1.

From the Research

Definition and Prevalence of von Recklinghausen's Disease

• von Recklinghausen's disease, also known as Neurofibromatosis 1 (NF1), is a neurocutaneous genetic disorder with a prevalence of approximately 1:2500 to 1:3500 individuals worldwide 2.
• It is an autosomal dominant genetic disorder, meaning that half of the affected individuals have NF1 as a result of a new gene NF1 mutation, and the offspring of an affected individual have a 50% risk of inheriting the altered NF1 gene 3.

Clinical Manifestations

• The disease is characterized by multiple café au lait spots, axillary and inguinal freckling, multiple discrete dermal neurofibromas, and iris Lisch nodules 3, 4.
• Other common manifestations include learning disabilities, plexiform neurofibromas, optic and other central nervous system gliomas, malignant peripheral nerve sheath tumors, vasculopathy, and osseous lesions 3, 2.
• The clinical diagnosis of NF1 is based on the presence of two or more specific criteria, including six or more café au lait spots, neurofibromas, freckling in the axillary or inguinal region, optic glioma, and distinctive osseous lesions 4.

Molecular Mechanism and Pathogenesis

• The NF1 gene is a megagene localized on the long arm of the 17th chromosome at the position 17q11.2, and its mutation rate is high, with half of all cases resulting from new mutations 4.
• The gene protein product, neurofibromin, plays an important role in tumorogenesis as a tumor-suppressor gene, and its inactivation leads to the growth of several neoplasms, mainly in the skin and central nervous system 5.
• The development of NF1 is a consequence of the inactivation of the NF1 gene, resulting in the overactivation of the RAS/MAPK pathway and leading to neurocutaneous manifestations and osseous abnormalities 6.

Management and Treatment

• NF1 requires life-long management adapted to age, and multidisciplinary structures are particularly well adapted to the diversity of the manifestations of this pathology 3.
• Molecular genetic evaluation for the identification of disease-causing mutations is possible in approximately 20% of patients, and patient care is best done in specialized neurofibromatosis centers 4.
• Recent progress in diagnosis, clinical characteristics, and treatment of NF1 includes the approval of selumetinib, an oral selective MEK1/2 inhibitor, for use in children with inoperable, symptomatic plexiform neurofibromas in Japan 6.