Neurofibromatosis and Tuberous Sclerosis

Question 1

Neurofibromatosis

Answer 1

There are two types of neurofibromatosis, NF1 and NF2. Both are inherited in an autosomal dominant fashion

NF1 is also known as von Recklinghausen’s syndrome. It is caused by a gene mutation on chromosome 17 (Neurofibromatosis has 17 characters) which encodes neurofibromin and affects around 1 in 4,000

Café-au-lait spots (>= 6, 15 mm in diameter)
Axillary/groin freckles
Peripheral neurofibromas
Iris hamatomas (Lisch nodules) in > 90%
Scoliosis
Phaeochromocytoma's

NF2 is caused by gene mutation on chromosome 22 (NF2 all the 2s) and affects around 1 in 100,000

Bilateral acoustic neuromas
Multiple intracranial schwannomas, mengiomas and ependymomas

Neurofibromatosis patients can develop HTN for 3 main reasons:

1) Co-existant essential HTN
2) Phaeochromocytoma
3) Renal Vascular Stenosis 2dry to Fibromuscular dysplasia

Question 2

Neurofibromatosis - Example Question

Answer 2

A 24-year-old woman is referred urgently to neurology for lower limb weakness. This has been getting gradually worse over the past 4 weeks and she is now experiencing problems walking.

She also complains of bilateral tinnitus which has been present for the past 3 months. This is associated with episodes of vertigo.

On examination both lower limbs have reduced power (3/5), with increased tone and hyperreflexia. The patient has one 1cm tan lesion on his torso but no other skin lesions are noted.

A MRI of his spine is requested:

SEE PASSMED MRI NF2

What is the most likely diagnosis?

	Multiple sclerosis
	> Neurofibromatosis
	Von Hippel-Lindau disease
	Tuberous sclerosis
	Ataxia telangiectasia

This patient had neurofibromatosis type 2 (NF2). The MRI shows multiple tumours of the spinal cord in the context of the syndrome of multiple intracranial schwannomas, mengiomas and ependymomas.

Patients with NF2, in contrast to type 1, often have few skin changes. This patient had tinnitus due to the presence of bilateral acoustic neuromas.

Question 3

Neurofibromatosis Diagnosis

Answer 3

Diagnostic Criteria NF1:

The NIH consensus development group published some criteria to aid diagnosis of neurofibromatosis type 1 in 1988, as neurocutaneous disorders can be difficult to distinguish.

It is important to note that these criteria focus on cafe au lait macule size in adults and children.

A child with 6 or more cafe au lait macules larger than 0.5 cm would fit one of the criteria but they would need to be 1.5 cm or larger in an adult.

Other criteria include:

• axillary freckling
• 2 or more cutaneous/subcutaneous neurofibromas or one plexiform neurofibroma, optic pathway glioma, bony dysplasia
• 2 or more Lisch nodules
• or a 1st-degree relative with neurofibromatosis type 1. At least two of these criteria are required to reach clinical diagnosis.

Diagnostic criteria for NF2 are:

Bilateral vestibular schwannomas

A first degree relative with NF2 AND
Unilateral vestibular schwannoma OR
Any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities

Unilateral vestibular schwannoma AND
Any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities

Multiple meningiomas AND
Unilateral vestibular schwannoma OR
Any two of: schwannoma, glioma, neurofibroma, cataract

Question 4

Tuberous Sclerosis

Answer 4

Genetic condition of autosomal dominant inheritance

Neuro and Cutaneous Features

Neuro Features:

• Developmental Delay
• Epilepsy (Infantile, partial)
• Intellectual Impairment

Cutaneous Features:

• Depigmented ‘ash leaf’ spots > fluorescent under UV light
• Roughened skin over lumbar spine = SHAGREEN PATCHES
• Adenoma sebaceum = angiofibromas over nose in butterfly distribution
• Fibromata beneath nails = Sublingual fibromata
• Can also have cafe au lait spots

ALSO:

• Retinal haemorrhages (white areas on retina)
• Rhabdomyomas of the heart
• Gliomatous changes can occur in brain lesions
• Polycystic kidneys and renal angiomyolipomata
• Lymphangioleiomyomatosis - multiple lung cysts

DIFFERENTIAL = Neurofibromatosis

Question 5

NF vs TS

Answer 5

BOTH:

• Neurocutaneous Fx
• Autosomal dominant
• Ocular Haemtomas (however NF has IRIS haemartomas = LISCH nodules, TS has RETINAL Haemartomas = Phakomata)
• Both have Cafe Au Lait Spots (NF more so)

Neurofibromatosis:

• Axiallary/Groin Freckles
• Phaeochromoctyoma
• NF2 = Acoustic neuromas and other CNS tumours
• IRIS haemartomas (Lisch nodules)

Tuberous Sclerosis:

• Ash leaf spots
• Adenoma Sebaceum
• Shagreen patches
• Subungal Fibromata
• Epilepsy
• Developmental Delay
• RETINAL Haemartomas

Question 6

TS Respiratory Cx - Example Question

Answer 6

A 39-year-old woman with known tuberous sclerosis is referred to the respiratory clinic after developing progressive dyspnoea. Her GP had requested a chest x-ray which showed significant changes.

SEE PASSMED CT LAM

What complication has developed?

	Metastatic angiomyolipoma
	> Lymphangioleiomyomatosis
	Lung rhabdomyomas
	Lung angiofibromas
	Subependymal giant cell astrocytoma

The CT demonstrate innumerable small regular lung cysts diffusely distributed throughout the lungs, the typical appearance of lymphangioleiomyomatosis (LAM). This disorder may occur alone on in association with tuberous sclerosis.