Picture Quiz: Distinctive skin signs

A 48 year old man presented to the accident and emergency department with syncope and was admitted for further investigation. He had the signs shown in figures 1 and 2, which are well recognised clinical features of an inherited disorder.

Photo of patient's back

Close up of patient's back

Questions

(1) What are the lesions shown in figure 1?

(2) What is the lesion shown in figure 2?

(3) What is this condition called?

(4) What is the inheritance pattern?

Answers

(1) Neurofibromas (tumours arising from the Schwann cells and fibroblasts of the myelinated nerve sheath).

(2) Cafe-au-lait patch.

(3) Von Recklinghausens's neurofibromatosis.

(4) Autosomal dominant.

The condition neurofibromatosis encompasses at least two distinct diseases, neurofibromatosis type 1 (von Recklinghausen's neurofibromatosis) and neurofibromatosis type 2. The patient was diagnosed with neurofibromatosis type 2 on clinical grounds; his syncopal episode was incidental and unrelated.

Neurofibromatosis type 1

Neurofibromatosis type 1 was first described by RW Smith in 1849 and later in 1892 by Friedreich D von Recklinghausen. It is now recognised as the most common genetic disorder affecting the nervous system.

The overall incidence in the UK is estimated to be between 1 in 3000 to 1 in 4000. The condition shows an autosomal dominant pattern of inheritance and has almost 100% penetrance, yet the severity of the disorder varies greatly within a family. Half of cases, though, have no family history and represent de novo mutations.

The genetic basis for the development of the disease is the inactivation of the NF1 gene, located on chromosome 17; its main role is to act as a tumor suppressor gene. The inactivation of the gene leads to loss of functions and the development of the clinical manifestations.

Clinical features

In 1987 the US National Institutes of Health (NIH) developed a consensus statement setting out the criteria for a diagnosis of neurofibromatosis type 1.These criteria are still in use today-namely, at least two of the following:

1. Six or more cafe-au-lait spots
2. Multiple axillary or inguinal freckling
3. At least one plexiform neurofibroma (a neurofibroma that spreads in the subcutaneous or deeper tissues) or two neurofibromas of any type
4. Optic nerve or chiasmatic glioma
5. Two or more Lisch iris nodules
6. Bony dysplasia (thinning of long bone cortex with or without pseudoarthrosis, dysplasia of the sphenoid bone
7. First degree relative with neurofibromatosis type 1.

The most well recognised clinical feature of type 1 neurofibromatosis is the neurofibroma, which can be one of three histologically distinct types:

1. Benign neurofibromas within the dermis
2. Nodular neurofibromas within peripheral nerves, which may grow vast
3. Plexiform neurofibromas, which are usually congenital and may infiltrate the nerve and surrounding tissues.

Nodular and plexiform neurofibromas have malignant potential in 2-16% of patients.

Complications and associated features

1. Increased risk of malignancy: neurofibrosarcoma, astrocytoma, pheochromocytoma, rhabdomyosarcoma, intestinal tumors, and chronic myeloid leukaemia
2. Learning disability in 40-60% of children
3. Macrocephaly
4. Seizures in about 5% of cases
5. Absence of the greater sphenoidal wing with absence of the posterior orbital wall, leading to pulsating exophthalmus
6. Hypertension in about 6% of cases
7. Scoliosis or kyphoscoliosis in about 2% of cases
8. Short stature.

Treatment

Neurofibromatosis type 1 currently has no cure, so management is reserved for people with symptoms. Tumours can be surgically removed to relieve symptoms or for cosmetic reasons. Shunting procedures are occasionally needed to relieve obstructions caused by the tumours. Genetic counselling and prenatal diagnosis are possible by mutation analysis.

Neurofibromatosis type 2

Neurofibromatosis type 2 was once thought to be a variant of neurofibromatosis type 1 because patients often have neurofibromas and cafe-au-lait spots. Although the inheritance pattern is autosomal dominant, type 2 is much less common than type 1 and usually much more serious. The incidence of neurofibromatosis type 2 is in the region of 1/25,000 to 1/40,000. Up to half of cases are thought to arise through sporadic gene mutations.

The condition arises as a result of a mutation in the NF2 gene located on chromosome 22, which like the NF1 gene acts as a tumor suppressor.

Clinical features

1. Bilateral eighth-nerve schwannomas shown by computed tomography or magnetic resonance imaging; or
2. Unilateral eighth-nerve tumour and a first degree relative with NF2; or
3. Two of the following: cutaneous neurofibroma, meningioma, glioma, schwannoma, presenile posterior cataract, a first degree relative with NF2.

In most cases symptoms exist for many years before diagnosis. Progressive hearing loss develops in 90% of patients with neurofibromatosis type 2.

Complications and associated features

1. Progressive bilateral or unilateral hearing loss
2. Tinnitus, vertigo, headache, ataxia
3. Compression of cranial nerve seven, leading to facial palsy
4. Schwannomas on fifth, ninth, tenth, twelfth cranial nerve
5. Tumours of the cauda equina
6. Meningiomas
7. Ependymomas (glial cell tumour arising from ependymal cells within the central nervous system).

Treatment

Surgery to remove eighth-nerve tumours is the only treatment. Genetic counselling is important. All children at risk should have annual neurological examinations after puberty but can be excluded from risk by genetic testing for a known family mutation.

Further reading

Reynolds R, et al. Von Recklinghausen's neurofibromatosis: neurofibromatosis type 1. Lancet 2003;361:1552-4.

Bradley W, et al. Neurology in clinical practice. 2nd ed. London: Butterworth-Heinemann, 1996.

Lakkis M, Tennekoon G. Neurofibromatosis type 1. J Neurosci Res 2000;62:755-63.

Competing interests: None declared.

Provenance and peer review: Not commissioned, externally peer reviewed.

1 Sharif S, Ferner R, Birch J, Gattamaneni R, Gillespie J, Evans DGR. Second primary tumours in neurofibromatosis 1 (NF1) patients treated for optic glioma: substantial risks post radiotherapy. J Clin Oncol 2006;16:2570-5.

2 Evans DGR, Moran A, King A, Saeed S, Gurusinghe N, Ramsden R. Incidence of vestibular schwannoma and neurofibromatosis 2 in the north west of England over a 10 year period: higher incidence than previously thought. Otol Neurotol 2005;26:93-7.

3 Ferner RE, Huson S, Thomas N, Moss C, Willshaw H, Evans DG, et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1 (NF1). J Med Genet 2007;44:81-8.

4 Evans DGR, Baser ME, O'Reilly B, Rowe J, Gleeson M, Saeed S, et al. Management of the patient and family with neurofibromatosis 2: a consensus conference statement. Br J Neurosurg 2005;19:5-12.

Menelaos Philippou, pre-registration house officer, Manchester Royal Infirmary, Manchester M13 9WL
Katie Clifford, pre-registration house officer, Royal Oldham Hospital, Oldham OL12PN
Steven Derbyshire, emergency medicine consultant
Email: mphilippou@doctors.org.uk


Student BMJ 2007;15:427-470 ISSN 0966-6494 | December

       

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