Examine this patient.



· Presents in childhood with cutaneous features including caf~-au-lait spots, axillary freckles and neurofibromas.

· Obtain history of learning disabilities (about half the patients with neurofibroma I are affected; Nature 2000; 403: 846-7).

· Childhood leukaemia. (The risk of malignant myeloid disorders, particularly juvenile myelomonocytic leukaemia and the

monosomy 7 syndrome, a childhood variant of myeloid dysplasia, is 200-500 times normal; N Engl J Med 1997; 336: 1713-20.)


· Multiple neurofibromas and caf~-au-lait spots (brown macules, >2.5 em diameter, and more than 5 lesions)

· Examine the axilla for freckles.

· Visual acuity and fundus for optic glioma.

· Hearing and corneal sensation for acoustic neuroma.

· The iris for Lisch nodules (often apparent only by slit-lamp examination) present in over 90% of patients.

· The spine for kyphoscoliosis.

· Tell the examiner that you would like to check the blood pressure (for renal artery stenosis or phaeochromocytoma).

Remember. The triad for neurofibromatosis - neurofibromas, cafd-au-lait spots and Lisch nodules - allows identification of virtually all

patients with neurofibromatosis type 1.


This patient has multiple cafe-au-lait spots and neurofibromas (lesion) due to yon Recklinghausen's disease (aetiology) which are

cosmetically disfiguring (functional status).


What are the criteria for neurofibromatosis type I (von Recklinghausen's disease)?

Neurofibromatosis type I may be diagnosed when two or more of the following are 'i


· Six or more caf6-au-lait spots, the greatest diameter of which is more than 5 mm in prepubertal patients and more than 15 mm

in postpubertal patients.

· Two or more neurofibromas or one plexiform neurofibroma. Plexiform neuro-fibroma is considered by some to be a defning

lesion of neurofibromatosis type 1.

· Freckling in the axilla or inguinal region (Crowe's sign).

· Optic glioma.

· Two or more Lisch nodules (iris hamartoma).

· A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex with or without pseudoarthroses.

· A parent, sibling or child with neurofibromatosis according to the above criteria.

What are the criteria for neurofibromatosis type 2?

· Bilateral eighth nerve palsy confirmed by CT or MRI.

· A parent, sibling or child with neurofibromatosis type 2 and either unilateral eighth nerve mass or any two of the following:

neurofibroma, meningioma, glioma, schwannoma or juvenile posterior subcapsular lenticular opacity (N Eng/ JMed 1988; 318:


What is the significance of the Lisch nodules?

Lisch nodules are melanocytic hamartomas that appear as well-defined, dome-shaped elevations projecting from the surface of the

iris and are clear to yellow and brown. The incidence increases with age: at the age of 5 years only 22% have Lisch nodules

whereas, at the age of 20 years, 100% have them. Older patients who do not have Lisch nodules are also, therefore, unlikely to

have neurofibromatosis 1. Lisch

nodules are an important tool in establishing the diagnosis of neurofibromatosis type I and in providing accurate genetic screening

(N Engl J Med 1991; 324: 1264).

What is the histology of the skin tumours?

The peripheral nerve tumours are of two types:

· Schwannomas: arise in cranial and spinal nerve roots and also in peripheral nerve trunks.

· Neurofibromas: composed of a proliferation of all elements of the peripheral nerve including nerve trunks, Schwann cells and

fibroblasts. In sensory nerve twigs they appear as subcutaneous nodules, while in peripheral nerve trunks they may appear as

a fusiform enlargement or a plexiform neurofibroma.

Is biopsy of the neurofibromas required to make a diagnosis?

No, as the diagnosis is usually evident on clinical grounds.

What are the associated abnormalities of neurofibroma?

· Lung cysts.

· Retinal hamartomas.

· Skeletal lesions: rib notching and other erosive bony defects, intraosseous cystic lesions, subperiosteal bony cysts, dysplasia of

the skull, bowed legs and pseudo-arthrosis of the tibia.

· Intellectual disability.

· Aqueductal stenosis.

· Epilepsy.

· Sarcomatous change.

What do you know about the inheritance of these two disorders?

Both are autosomal dominant syndromes, type I being carried on chromosome 17ql 1.2 and type 2 on chromosome 22 (Science

1987; 236:110; Nature 1993; 363: 515). The gene for neurofibromatosis type I encodes a protein called neurofibromin which

downregulates the function of the p21 ras oncoprotein (Neuron 1993; 10: 335). Learning disabilities have been ascribed to abnormal

brain development as a result of deficiency in neurofibromin signalling (Nature 2000; 403: 895-8). The gene for type 2

neurofibromatosis is also a tumour suppressor gene which encodes a protein that links integral membrane proteins of the

cytoskeleton. How this protein is involved in tumorigenesis is not clear. Family members at risk for type 2 neurofibromatosis should

be screened regularly with hearing tests and brainstem auditory evoked responses.

How would you manage these patients?

· Most are asymptomatic and require no treatment.

· Large plexiform neurofibromas should be usually left alone.

· Small neurofibromas can be removed if painful.

* Optic gliomas are treated with radiation.

When one child is affected with neurofibromatosis 1, what is the risk of another child being affected when one parent is

affected and when neither parent is affected?

If one parent is affected then there is a 50% chance that another child will be affected whereas when neither parent is affected the

risk of another child being affected is no more than the standard risk in the normal population.

Friedreich Daniel von Recklinghausen (1833-1910) was Professor of Pathology successively at Kbnigsberg, W0rzburg and Strasbourg. He also

described another disease, arthritis deformans neoplastica, to which his name is attached.

The elephant man, John Merrick, is commonly believed to have suffered from neurofibromatosis, but according to Science (1994; 264: 188) a rare

condition, Proteus syndrome, is the more likely diagnosis.

Professor Lisch first described the association of the Lisch nodule with neurofibromatosis in 1937 (Z Augenheilkd 1937; 93: 137-43). These nodules

were first described by Waardenbur9 in 1918 but he did not appreciate the association with neurofibromatosis.