Neurofibromatosis

Neurofibromatosis

Definition: an autosomal dominant genetic disorder affecting cells of neural crest origin (e.g. melanocytes, craniofacial cartilage and bone, smooth muscle, peripheral and enteric neurones and glia), resulting in development of multiple neurocutaneous tumours.

Type 1 neurofibromatosis (NF1, von Recklinghausen’s disease)- characterised by peripheral and spinal neurofibromas, multiple café-au-lait spots, freckling, optic nerve glioma, Lisch nodules, skeletal deformities, phaeochromocytomas and renal artery stenosis.

Type 2 neurofibromatosis (NF2)- characterised by schwannomas (tumour of nerve sheath): bilateral vestibular schwannomas, peripheral/ spinal schwannomas, mengingiomas, gliomas, cataracts.

Aetiology/ risk factors:

-Multiple mutations have been described in tumour suppressor genes NF1 and NF2.

NF1: autosomal dominant inheritance (gene locus 17q11.2)

mutation in NF1 gene which encodes neurofibromin

expression is variable, even within a family (i.e. to what extent the disease manifests)

NF2: autosomal dominant inheritance (gene locus 22q11)

mutation in NF2 gene which encodes merlin (or schwannomin- but merlin is way cooler)

50% are de novo (new mutation), with mosaicism in some (presence of 2 or more populations of cells with different genotypes in one individual)

Epidemiology:

equal sex ratio

no racial predilection

NF1: prevalence = 1 in 2,500

NF2: prevalence = 1 in 35,000

Symptoms:

NF1:

-skin lesions

-learning difficulties (in 40%)

-headaches

-disturbed vision (optic gliomas in ~ 15%)

-early puberty (may indicate lesions of pituitary from optic glioma involving the optic chiasm)

NF2:

-Bilateral vestibular Schwannomas- characteristic, symptomatic by ~ 20 years =

Tumours are benign but cause problems by pressing on local structures and increasing intracranial pressure. They may be absent in mosaic NF2.

-sensorineural hearing loss

-tinnitus

-vertigo

-balance problems

-headache

-facial pain or numbness

Signs:

NF1:

Café-au-lait spots: flat, coffee-coloured patches of skin see in first year of life, increasing in number and size with age. Adults have > 6, > 15mm across (> 5mm across pre-puberty).

Image result for cafe au lait spots

Freckling: typically in skin folds (armpit, groin), and usually present by age 10.

Image result for freckles neurofibromatosis

Dermal neurofibromas: small, violaceous (violet/pink) nodules, gelatinous texture, appear at puberty, may become papillomatous. May itch. Numbers increase with age.

Image result for Dermal neurofibromas

Nodular neurofibromas: arise from nerve trunks. Firm, clearly demarcated, can give rise to paraesthesia (pins and needles) if pressed.

Image result for Nodular neurofibromas:

Lisch nodules: tiny, harmless, regular brown/translucent mounds (hamartomas) on the iris 2mm diameter. Develop by 6yrs old in 90%.

Image result for lisch nodules

Spinal scoliosis

Image result for scoliosis neurofibromatosis

Short stature

Macrocephaly (big head)

NF2:

Café-au-lait spots- fewer than in NF1

Juvenile posterior subcapsular lenticular opacity = a form of cataract

Image result for Juvenile posterior subcapsular lenticular opacity neurofibromatosis

Occurs before other manifestations so useful for screening those at risk.

Investigations:

Ophthalmological assessment

Audiometry

MRI brain and spine- can show bilateral vestibular Schwannomas in NF2

Image result for mri bilateral vestibular schwannoma

 

Also look for meningiomas, and nerve root neurofibromas.

 

Skull x-ray- sphenoid dysplasia in NF1

Genetic testing- possible but difficult as the NF gene is very long

Management:

Education and genetic counselling. Surveillance for complications.

NF1:

-MDT approach: geneticist, neurologist, surgeon, physiotherapist, GP

-Monitor growth, neurodevelopmental, puberty and school progress, blood pressure, vision, hearing, skin lesions and scoliosis.

-If dermal neurofibromas are troublesome, excise them- but removing all lesions is unrealistic

-Treatment of scoliosis or bone deformities.

NF2:

-Hearing tests annually from puberty in affected families. MRI brain if abnormality detected.

-A clear scan at 30yrs (unless FHx of late onset), indicates that gene has not been inherited.

-Neurosurgical treatment of vestibular Schwannomas.

Complications:

NF1:

-local effects of neurofibromas:

-nerve root compression- weakness, pain, paraesthesia

-GI bleeds, obstruction

-bone-cystic lesions (e.g. sphenoid dysplasia) scoliosis, pseudoarthritis

-hypertension (6%) from renal artery stenosis or phaeochromocytoma

-stenosis of cerebral aqueduct by tumours = hydrocephalus

-plexiform neurofibromas- large, subcutaneous swellings

Image result for plexiform neurofibromas

-malignancy (5% patients)- optic glioma, sarcomatous change in a neurofibroma

-plexiform neurofibromas can undergo malignant transformation to malignant peripheral nerve sheath tumours (5-8% lifetime risk) = chronic pain, change in consistency or rapid growth

-slight increase in epilepsy risk

-carcinoid syndrome (rare)

NF2:

-vestibular Schwannoma surgery- hearing loss, facial palsy

-tender Schwannomas of cranial and peripheral nerves, and spinal nerve roots

-meningiomas (45% in NF2)

-glial tumours (less common)

Prognosis:

-Life expectancy appears to be shortened in NF1 (average by ~ 8 years).

Malignant peripheral nerve sheath tumour is an aggressive and potentially fatal malignancy (5-year event-free survival ~20%)

NF2- depends on many factors including age of symptom onset, which can range from 2-70 years.

Mean survival from diagnosis ~ 15 years (1992 study). Better with best practice.

References: Cheese & Onion, Rapid Medicine, Medscape

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