Neurofibromatosis

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70 Neurofibromatosis

Instruction

Examine this patient.

Salient features

History

• Presents in childhood with cutaneous features including café-au-lait spots, axillary freckles and neurofibromas

• Obtain history of learning disabilities (about half the patients with neurofibroma 1 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 to 500 times the normal risk (N Engl J Med 1997;336:1713–20).

Examination

• Multiple neurofibroma and café-au-lait spots (brown macules, >2.5 cm diameter and >5 lesions)

• Examine the axilla for freckles

• Check visual acuity and fundus for optic glioma (Fig. 70.1)

• Hearing and corneal sensation for acoustic neuroma

• The iris for Lisch nodules (often apparent only by slit-lamp examination). The incidence of Lisch nodules in type 1 increases with age (at the age of 5 years only 22% have Lisch nodules, whereas at the age of 20 years 100% have them). Therefore, older individuals who do not have Lisch nodules are unlikely to have type 1 neurofibromatosis (Fig. 70.2)

• The spine for kyphoscoliosis

• Tell the examiner that you would like to check the BP (for renal artery stenosis or phaeochromocytoma).

image

Fig. 70.1 Typical combined hamartoma of retina. Note typical juxtapapillary and epipapillary location of lesion.

(With permission from Yanoff, Duker 2008.)

image image

Fig. 70.2 Neurofibromatosis type 1. Slit-lamp examination (B) is essential for differentiation of Lisch nodules (iris hamartoma) from iris freckles. Iris freckles are flat and have a lace-work structure; Lisch nodules are raised, round, fluffy, and light brown.

(Courtesy Lucian Szmyd, with permission from Habif 2009.)

Remember the triad for neurofibromatosis—neurofibroma, café-au-lait spots and Lisch nodules—allows identification of virtually all patients with neurofibromatosis type 1.

Diagnosis

This patient has multiple café-au-lait spots and neurofibromas (lesion) caused by von Recklinghausen’s disease (aetiology), which are cosmetically disfiguring (functional status).

Advanced-level questions

What are the criteria for neurofibromatosis type 1 (von Recklinghausen’s disease)?

Neurofibromatosis type 1 may be diagnosed when two or more of the following are present:

• Six or more café-au-lait spots, the greatest diameter of which is >5 mm in prepubertal patients and >15 mm in postpubertal patients

• Two or more neurofibromas or one plexiform neurofibroma. Plexiform neurofibroma is considered by some to be a defining lesion of neurofibroma 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 Engl J Med 1988;318:685).

Note: Blockade of vascular endothelial growth factor (VGEF) with bevacizumab improves hearing in some patients (not all) with neurofibromatosis type 2 and has been associated with a reduction in the volume of most growing vestibular schwannomas (N Engl J Med 2009;361:358–67).

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. Therefore, older patients who do not have Lisch nodules are also unlikely to have neurofibromatosis 1. They are an important tool in establishing the diagnosis of neurofibromatosis type 1 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 neuritis, 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 a 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 pseudoarthrosis of the tibia

• Intellectual disability

• Aqueductal stenosis

• Epilepsy

• Sarcomatous change.

Is phaeochromocytoma common in this condition?

In neurofibromatosis type 1, phaeochromocytoma is relatively rare (<5%). Because of this, routine screening for the tumour is not generally recommended. Genetic testing in members of an affected family is possible. Phaeochromocytomas in affected individuals usually produce both epinephrine and norepinephrine.

What do you know about the inheritance of the two types?

Both are autosomal dominant syndromes, type 1 being carried on chromosome 17q11.2 and type 2 on chromosome 22 (Science1987;236:110, Nature 1993;363:515). The gene for neurofibromatosis type 1 encodes a protein called neurofibromin (GTPase-activating protein), which downregulates the function of the p21 Ras oncoprotein (Neuron 1993;10:335). Learning disabilities have been ascribed to abnormal brain development resulting from deficiency in neurofibromin signalling (Nature 2000;403:895–8). The gene for type 2 neurofibromatosis (locus is 22q11) also encodes a tumour suppressor protein (merlin or schwannomin), which 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.

What is the risk of a further child being affected in a family?

If one parent is affected then there is a 50% chance that another child will be affected, whereas when neither parent is affected then the risk of another child being affected is no more than the standard risk in the normal population.

The first case reports of probable neurofibromatosis appeared in the 16th century.

The first review of this condition was published in 1849 by Robert W Smith, Professor of Surgery in Dublin, who suggested that the tumours originated from connective tissue surrounding small nerves.

Friedreich Daniel von Recklinghausen (1833–1910) was Professor of Pathology successively at Könisberg, Wüurzburg and Strasbourg. He also described another disease, arthritis deformans neoplastica, to which his name is attached. Von Recklinghausen in 1882 was the first to recognize that the characteristic tumours arise from nervous tissue. He described in the report of his second case: ‘His [a 47-year-old male] most striking abnormality consisted of innumerable tumours, running close to a thousand altogether, in the outer skin layer. …The patient could only report that he had had them as long as he could remember …and that they had increased markedly after his fifteenth year …my interest turned understandably to the externally palpable peripheral nerve trunks. …I was soon able clearly to recognise thickenings of these in their gross distribution’ (Lancet 2003; 361:1552–4).

The elephant man, John Merrick, is commonly believed to have suffered from neurofibromatosis, but according to Wallace (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 Waardenburg in 1918 but he did not appreciate the association with neurofibromatosis.

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