Description
Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is a common autosomal dominant disorder characterised by multiple cutaneous neurofibromas, café-au-lait spots, axillary and inguinal freckling, optic gliomas, and distinctive osseous lesions.
Pathogenesis
NF1 is caused by mutations in the NF1 gene located on chromosome 17, which encodes for neurofibromin, a protein involved in the regulation of the Ras/MAPK pathway. This pathway plays a crucial role in cell growth and differentiation. Mutations in the NF1 gene lead to decreased function of neurofibromin, resulting in uncontrolled cell growth and the formation of tumours along the nerves, skin, and other parts of the body.
Epidemiology, Risk Factors & Associations
NF1 affects approximately 1 in 3,000 to 4,000 individuals worldwide, making it one of the most common inherited neurological disorders. The condition occurs in all ethnic groups with equal sex distribution. While it’s inherited in an autosomal dominant manner, up to 50% of cases are due to de novo mutations. There’s an association between advanced paternal age and the risk of new mutations.
NF1 is more common than NF2 (1 in over 200,000).
Clinical Features
Clinical manifestations of NF1 are diverse and may vary greatly between individuals, even within the same family. Features include:
- Six or more café-au-lait spots larger than 5mm in prepubertal individuals and over 15mm in postpubertal individuals.
- Two or more neurofibromas of any type or one plexiform neurofibroma.
- Freckling in the axillary or inguinal regions.
- Optic pathway glioma.
- Two or more Lisch nodules (iris hamartomas).
- Distinctive osseous lesions such as sphenoid dysplasia or thinning of the long bone cortex with or without pseudarthrosis.
- A first-degree relative (parent, sibling, or child) with NF1 as per the above criteria.
Pathological Features
Histopathology
- Macroscopic: Involvement of multiple cutaneous, subcutaneous, and plexiform neurofibromas.
- Microscopic: These are composed of a mixture of cell types, including Schwann cells, fibroblasts, perineural cells, and mast cells.
Biochemistry
Typically, there’s a loss of neurofibromin expression in NF1 lesions.
Radiological Features
General Features
- Neurofibromas
- MRI: Cutaneous and subcutaneous neurofibromas are seen as well-defined, round to oval, hyperintense lesions on T2-weighted images and show intense enhancement after administration of gadolinium-based contrast.
- Plexiform Neurofibromas
- MRI: Plexiform neurofibromas have a characteristic ‘bag of worms’ appearance on MRI. They are typically hyperintense on T2-weighted images and can be large, extending along the length of a nerve.
- Ultrasound: Plexiform neurofibromas may appear as hypoechoic masses with variable echotexture.
- CT: On CT, plexiform neurofibromas may be seen as soft tissue masses that displace adjacent structures.
- PET/CT: Plexiform neurofibromas, when undergoing malignant transformation into malignant peripheral nerve sheath tumours, typically show increased uptake of the radiotracer.
- Optic Pathway Gliomas
- MRI: Optic pathway gliomas are typically seen as fusiform enlargements of the optic nerve with hyperintensity on T2-weighted images. They may enhance following contrast administration.
- FASI (Focal Areas of Signal Intensity)
- Also known as Unidentified Bright Objects, bright areas in basal ganglia (globus pallidus), thalamus, brainstem (pons) and cerebellum.
- MRI: T1/T2/FLAIR hyperintense foci, usually with no enhancement.
- Osseous Lesions
- MRI: Osseous lesions may be identified as areas of abnormal signal intensity within the bone marrow.
- CT: CT can identify distinctive osseous lesions such as sphenoid wing dysplasia and thinning of the long bone cortex.
- Plain Radiography: Plain radiographs can be useful for identifying skeletal abnormalities associated with NF1, including sphenoid wing dysplasia, tibial dysplasia, and scoliosis.
- Lisch Nodules (Iris Hamartomas)
- These are typically identified during ophthalmologic examinations rather than through radiologic imaging.
Grading and Staging
There’s no formal staging system for NF1. However, disease progression is monitored based on the number, size, and location of neurofibromas, the presence of other tumours such as optic gliomas, and the development of skeletal abnormalities.
Diagnosis
The diagnosis of NF1 is primarily clinical, based on the presence of characteristic features as outlined in the Clinical Features section.
Differential Diagnosis
The differential diagnosis for NF1 includes other phakomatoses such as NF2 and schwannomatosis. Legius syndrome, an autosomal dominant condition characterised by café-au-lait spots and freckling, may also resemble NF1 but lacks the tumour predisposition seen in NF1.
Management
Management of NF1 is multidisciplinary and mainly focuses on surveillance and symptom management. Regular assessments are recommended to monitor for complications. This may include annual physical examinations, ophthalmologic assessments, and imaging studies. For symptomatic neurofibromas, surgical removal may be considered. Malignant peripheral nerve she