Neurofibromatosis

There are two main types of neurofibromatosis. Type 1 is also known as Von Recklinghausen's disease.

This is a genetic disorder causing lesions in the skin, nervous system and skeleton.

• Type 1 is the commoner form and caused by a defect in the gene producing neurofibromin, a protein that is believed to suppress tumour formation. Effects of the defect are highly variable between sufferers and can appear at any age. There is even significant variation within families. The mutation is on chromosome 17 at gene map locus 17q11.2, 2p22-p21.
• Type 2 is a central form with CNS tumours rather than skin lesions. There are multiple inherited schwannomas that are typically bilateral vestibular tumours but also meningiomas and ependymomas. It may be considered to be a type of schwannomatosis rather than neurofibromatosis. There is a mutation of that gene for neurofibromin-2. The mutation is on the chromosome 22 at gene map 22q12.2.

There are several other rarer types including type 3 (NF3), type 4 (NF4) and Neurofibromatosis Noonan Syndrome (NFNS), not to be confused with Noonan Syndrome.

Both types are inherited as autosomal dominants but in both types there is no family history in about half. They are presumably new mutations.

• The incidence of type 1 is given as 1 in 3,000 population but may be slightly higher because of failure to diagnose milder cases.
• The incidence of type 2 is given as 1 in 33,000-40,000 population.¹

As expected of an autosomal dominant, the sex ratio is equal. It appears to be commoner in white races.

There are diagnostic criteria for NF1 that require at least 2 of 7 criteria. Some of these do not appear until later childhood or adolescence, and so confirmation of the diagnosis may be delayed.

• At least 6 café au lait spots or hyperpigmented macules. They must be at least 5mm wide in children younger than 10 years and 15 mm in adults.
• Axillary or inguinal freckles.
• Two or more typical neurofibromas or 1 plexiform neurofibroma.
• Optic nerve glioma.
• Two or more iris hamartomas. They are called Lisch nodules and are seen by slit-lamp examination.
• Sphenoid dysplasia or typical long-bone abnormalities such as arthrosis.
• Having a first-degree relative with NF1.

At least 1 of the following 3 are required for diagnosis of NF2:

• Bilateral 8th nerve masses on MRI.
• First-degree relative with NF2 for a unilateral eighth nerve mass.
• First-degree relative with NF2 for an individual with at least 2 of the following:
  • Meningioma
  • Glioma
  • Schwannoma
  • Juvenile cataract

Severe, intractable hypertension can be caused by either a phaeochromocytoma or fibromuscular hyperplasia of the renal artery.

Dermal Features

• Café au lait spots are the first findings in NF1. They may be present at birth or may appear with time. They usually increase in size and number during childhood.
• Axillary or inguinal freckles are rare at birth but appear throughout childhood and adolescence.
• Urticaria pigmentosa may be seen in a small subset of infants. It is a collection of mast cells within the dermis.

Neurofibromas

• They may be in the skin or subcutaneous tissues. Deep lesions may require palpation for detection but cutaneous lesions may appear initially as small papules on the trunk, extremities, scalp, or face.
• They are rare in young children but develop with time in older children, adolescents, and adults.
• There may be an increase in numbers and a growth of existing lesions at puberty or in pregnancy.
• Sudden rapid growth may suggest malignancy.
• Plexiform neurofibromas are more diffuse growths that can be locally invasive and quite deep. There may be bony erosion and pain. They may also be accompanied by hyperpigmentation or hypertrichosis over the lesions.²
• In NF2, sensori-motor polyneuropathy may be seen and there may identifiable tumours along the relevant peripheral nerves.

Ocular Problems

• Tumours of the optic nerve occur in children of less than 5 years and may not be clinically apparent.
• The commonest presentation is asymmetrical visual field defects. Optic nerve gliomas occasionally start to cause symptoms in older children or even adults. They can also undergo spontaneous regression.
• Subtle peripheral field defects, colour defects, optic nerve pallor, or proptosis may occur with an optic glioma, even without problems of visual acuity.
• Lisch nodules are usually only seen by slit lamp. Occasionally they can be visible via the ophthalmoscope.
• Patchy choroidal abnormalities and corkscrew retinal vessels are sometimes seen in patients with NF1.
• In NF2, posterior subcapsular or juvenile cataracts can precede CNS symptoms. These cataracts may progress over time, impairing visual acuity. Some have retinal hamartomas or epiretinal membranes that are not always significant to vision.

Skeletal Problems

• Sphenoid dysplasia usually causes no problem but can cause herniation through the bony defect. Patients with plexiform neurofibroma of the eyelid or temporal region often have ipsilateral sphenoid dysplasia.
• Congenital pseudarthrosis may be apparent at birth. Bowing of the tibia is the commonest presentation. Thinning and angulation of long bones with prominence of the anterior tibia and progressive deformity can occur throughout early childhood. Bowing of the forearm is less common.
• The thoracic cage may be asymmetrical with flaring or prominence of the inferior ribs. It affects some children with NF1 but rarely requires surgical correction.
• Scoliosis may occur with or without kyphosis. This may become evident in childhood or adolescence and adolescent girls are affected rather more often than boys. If it starts before 10 years, scoliosis has a poor prognosis and is likely to be rapidly progressive. Scoliosis detected in adolescence should be followed, but is less likely to require orthopaedic intervention.
• Head circumference should be recorded in the first 3 years of life. A slightly fast rate of growth is common but it should only cause concern if growth is very fast.

Tests for hearing and vestibular function are important in NF2.

Plain X-ray

• Dural ectasia is often seen on x-rays of the vertebral column. It may suggest future progressive scoliosis.
• X-rays are required if there is:
  • Possible modeling defects of the long bones or ribs
  • Concern that a bony lesion may be adjacent to a plexiform neurofibroma.
  • Scoliosis
  • Bone pain

Scans

CT or MRI scanning may be required.

• There is some difference of opinion about the value of baseline scans, including scans of the head. Even detection of an asymptomatic optic nerve glioma does not necessitate intervention.
• MRI is preferred for diagnostic head imaging. Bright areas representing hamartomas are seen more often in children with learning disabilities and fine motor impairment.
• Consider CT or MRI scans to check ventricular size if head circumference in an infant is increasing rapidly. Hydrocephalus is rare in NF1.
• MRI can evaluate the optic nerves or optic chiasm. It is indicated for optic nerve pallor, visual changes, proptosis, or precocious puberty.
• Consider MRI scans of the head if headaches increase in frequency or intensity over time. Brain tumours are more common in NF2 than NF1.
• MRI can also be useful to evaluate mediastinal masses, spinal cord tumours, deep plexiform neurofibromas, abdominal and pelvic lesions and neurofibromas of the brachial or sacral plexus.

Electrophysiology

• If seizures occur, EEG is required in assessment.
• Myelography is occasionally helpful to clarify the extent of a spinal cord tumour but generally, MRI alone is enough.
• Visual evoked potentials (VEP) may be helpful in detecting optic nerve gliomas or assessing tumour progression with optic pathway tumours.

Slit Lamp Examination

This usually requires the expertise of an ophthalmologist.

• Slit-lamp examination may provide essential diagnostic information in older children and adults who present with only 1 clinical criterion such as multiple café au lait spots.
• The frequency of Lisch nodules increases with age. They are seen in more than 95% with NF1 who are older than 10 years.
• Slit-lamp examination is valuable to decide if the parents of an affected child carry the NF1 mutation, even in the absence of any other features of the disease.

Genetic Testing

At present, genetic testing is of limited value.³

• Type 1 tends to present in childhood or adolescence whilst type 2 usually presents in adults under 40 years, and mostly in the 20s.
• Around 45% of type 2 present with hearing problems such as deafness and tinnitus with or without loss of balance or facial weakness due to vestibular schwannomas.
• Café au lait spots are the usual, early feature of NF1 but there are rarely more than 6 spots in NF2. It rarely shows axillary or inguinal freckles.
• Multiple subcutaneous lesions can be indistinguishable between the two.
• Posterior subcapsular lenticular opacities, even in childhood, would be suggestive of NF2, whereas Lisch nodules would be diagnostic of NF1.

Care is largely a matter of monitoring progress and intervening as appropriate if tumours produce pressure symptoms or suggest malignant change.

• Follow up is usually twice a year until 5 and then annually.
• Annual eye examinations, especially before the 5th birthday, are essential for early detection of optic nerve lesions. Optic nerve gliomas may appear in older children and young adults and so annual examinations should continue indefinitely.
• Check the skin for new neurofibromas and progression of existing ones.
• Plexiform neurofibromas may be locally invasive. Determine the extent of involvement and any evidence of bony erosion or nerve entrapment.
• Check for skeletal involvement, including scoliosis, hemihypertrophy, and long-bone modeling defects.
• Check blood pressure at every visit and take prompt action if there is hypertension.
• Ask about the child's neurodevelopment, to note any learning disabilities and take early action. Children and adolescents are more likely to suffer attention deficit hyperactivity disorder(ADHD).

There are no specific drugs for the disorder, although they may be needed for secondary problems such as hypertension, epilepsy or ADHD.

Neurofibromas

• Neurofibromas that press on vital structures, obstruct vision, or grow rapidly need urgent attention.
• Plexiform neurofibromas can be difficult. They often recur after resection because there are residual cell rests deep in soft tissues.
• Neurofibromas on the scalp, along the hairline, or around the waist where clothes rub can cause irritation and discomfort and are worthy of removal.
• In NF2, there has been some success with cochlear implants for bilateral acoustic neuroma.⁴

Spinal cord tumours

• Prompt attention is required if neurological symptoms appear. Resection of spinal cord tumours is quite difficult but may be necessary to prevent progressive paraplegia or quadriplegia.
• For some patients, surgical intervention may not cure but it provides valuable palliation.

Orthopaedic Surgery

• Rapidly progressive scoliosis or severe bony defects need urgent attention.
• Early referral for scoliosis gives the best results.
• Long bone defects can require amputation but mode bracing and casting techniques have reduced the need.

Vascular Surgery

• Percutaneous transluminal renal artery angioplasty (PTRAA) may be effective in treating some renal artery stenosis due to fibromuscular dysplasia.
• Others may require surgical repair and anastomosis of the renal artery.

Most of the complications, but not all, have been mentioned above.

• Locally invasive plexiform neurofibromas.
• Dumbbell spinal cord neurofibromas or neurofibromas of the brachial or sacral plexus.
• Optic nerve gliomas, especially in children younger than 5 years.
• Scoliosis, which is especially aggressive in children below 10 years.
• Bony modeling defects may lead to pseudarthrosis, thoracic cage asymmetry, or pathological fractures.
• Hypertension due to pheochromocytoma or renal vascular stenosis secondary to fibromuscular dysplasia.
• Increased risk for brain tumours, leukemia, and other malignancies of neural crest origin, including neurofibrosarcomas.⁵ Brain tumours are rather more common in NF2.
• Occasionally, peripheral nerve sheath tumours undergo malignant change in NF1 but not NF2. The risk of malignant change is usually rated as quite low but a study from Manchester suggested that the lifetime risk for an individual with NF1 is 8 to 13% with a mean age of diagnosis of 26 and a 5 years survival rate of 21%.⁶ This is a serious cause for concern.
• Precocious puberty occurs in about 3% and is associated with tumours of the optic chiasma.⁷
• Learning disabilities, attention deficit disorder, ADHD, or, rarely, mental retardation. Figures cited for the incidence of ADHD in NF1 are often around 40%.⁸
• Children with NF1 often have difficulties forming friendships and developing social skills.⁹

• Type 1 in particular, is so varied in its manifestation, that it is difficult to predict outcome as it can vary enormously, even within families.
• Most people with NF1 lead relatively long and healthy lives, but it does reduce life expectancy by around 15 years. The major complications are hypertension and malignancy.¹⁰
• Early detection and prompt attention to complications may reduce overall morbidity and mortality.
• If an individual who is at risk of inheriting NF1 has reached 10 years old with no features, he is probably free of the disease.