NEUROFIBROMATOSES

These are genetic disorders involving the skin and/or the nervous system. There are at least two types i.e. Neurofibromatosis Type I, and Neurofibromatosis Type II. The physical characteristics are often present at birth and become more apparent with age.
 

NEUROFIBROMASIS TYPE I (NFI)
 This is one of the most common genetic disorders. It affects approximately 1 in 3000-4000 people. Neurofibromatosis Type I, also called von Recklinghausen’s disease, is more common than Neurofibromatosis Type II, occurring in 85% of cases.

CLINICAL MANIFESTATIONS
There are café au lait spots distributed any where on the body except the eye brows, scalp, palms and soles. They vary in shape and size, ranging from 10 to 30 millimeters in diameter with well-defined, sharp and smooth edges; and are often darker than the surrounding normal skin. There is focal or generalized hyperpigmentation of the skin. Freckling of the skin occurs usually later in childhood and adulthood, where ever there is skin-to-skin contact, most frequently in the armpit and groin areas. They may also occur all over the entire body in some cases. Premature aging appearance of the face often occurs with laxity of the skin.

Individuals with the disease develop benign tumors originating from the nerve sheaths. They are called neurofibromas. They may grow as tags on, or nodules in the skin, or even as masses deep in the body. They usually vary in number and size; are few in childhood but tend to become more numerous around puberty in both male and female, and during pregnancy. They occur in the areola of 80% or more of adult women with the disease.

Four types of these neurofibromas have been described, viz:

Cutaneous Neurofibromas develop in the skin, and are moveable with the skin. They are soft, flesh-colored; range from several millimeters to many centimeters in size, but do not cause pain. They may appear as early as 4 to 5 years of age, but are seen more frequently at 8 to 12 years of age; occurring in about 10% of cases. They are associated with skin itch, and are cosmetically unpleasant.

Subcutaneous Neurofibromas are firm, rubbery and usually painful tumors which develop deep in the skin. They may be small, or quite large; and are seen in about 20% of cases. They may cause serious functional problems.

Nodular Plexiform Neurofibromas are usually tumors of large clusters of tangled masses of nerve tissue under the skin. They may be felt as firm, usually tender masses along the course of the nerves on which they develop. If present in the spinal vertebrae, may cause disfigurement, and even cause the collapse of the vertebrae. Compression of the spinal cord may lead to severe neurologic incapacitation; and involvement of major nerves may cause severe, intractable pain.

Diffuse Plexiform Neurofibromas are similarly tumors which develop from clusters of tangled masses of nerve tissues. They usually spreads diffusely into nerves, they are highly vascular, may involve all skin layers, the surrounding tissues, replace sections of muscles, erode bones, and may even spread to internal organs. They may look small on the outside but may be quite extensive inside. They are often associated with hyperpigmentation of the overlying skin, covered with excessive hair growth; rapid growth progression with pain and neurologic disability; and the tendency to progress into malignancy.

Internal organ involvement may lead to constipation, obstruction and bleeding.

NEUROFIBROMATOSIS TYPE II (NFII)
 This is much less common than Type I, and has an estimated occurrence of 1 in 50,000 people.

CLINICAL MANIFESTATIONS
 The symptoms of Neurofibromatosis Type II begin usually in individuals in their 20,s or 30,s; but may start before they reach their tenth year of age or as late as their 60,s or 70,s. The first symptom may be loss of hearing, accompanied by intermittent ringing in the ears, facial weakness and unsteadiness.

Several slow-growing tumors develop in several parts of the nervous system, with mild, intermediate or severe manifestations. Café au lait spots are fewer in number and are less pigmented; and there is no freckling of the skin. There are superficial, raised papules in and under the skin. They have rough, often pigmented surface covered with excess hair. Tumors develop on nerves outside the central nervous system, most frequently on the palm of the hands and also on the sides of the nose, and cause the involved nerves to become thickened and palpable. Tumors often occur along side the spinal nerve roots and are the major cause of the morbidity and spinal cord dysfunction. Although several tumors may develop in the brain and the spinal cord, malignancies are uncommon with Neurofibromatosis Type II.

DIAGNOSIS
 Although there are some diagnostic laboratory tests, they are reserved at present, primarily for suspected cases and family members of patients with the disease. The basic diagnostic criteria for both Neurofibromatosis Type I and Neurofibromatosis Type II are based on clinical and physical observation. CAT scan or MRI can be used to detect the presence and the extent of tumors in the brain and in the spinal cord.

Neurofibromatosis Type I (NFI)
 “The presence of two or more of the following meet the diagnostic criteria:

Neurofibromatosis Type II (NFII)
 The diagnosis is made by the presence of any one of the following criteria, which are highly technical and may not be readily understandable to non-medical individuals:
1. The presence of tumors of both the eighth cranial (auditory) nerves shown by CAT scan or MRI; or
2. A first-degree relative with NFII, and either:
The presence of tumor on one of the eighth cranial (auditory) nerve, or
Two of the following: Neurofibroma, Meningioma, Glioma, Schwannoma, Opacity of the lens of the eye.”


 COMPLICATIONS of NEUROFIBROMATOSES
There is a broad spectrum of complications. They include stenosis of the arteries to the kidneys, erosion of bones, congenital bowing of the tibia, bone cysts, spinal deformities, blockage of spinal fluid circulation in the brain with an enlarged head, short stature, tumors in various areas of the nervous system, circulatory impairment resulting in high risk for frequent infections in the extremities, mobility limitations, protrusion and bobbing of the eyeballs, hypertension, endocrine disturbance, vascular headaches, mental retardation and learning disabilities, hearing impairment, droopy eyelids which may lead to visual impairment, loss of vision; and the possibility of malignant progression.

MANAGEMENT
 The numerous complications of Neurofibromatosis involving several organ systems usually lead to the involvement of a number of sub-specialists. Symptomatic disease in childhood is usually an indication of poor prognosis. Early diagnosis before the development of central nervous system tumors will allow for genetic counseling and family planning.

There are no specific curative treatment for the disease. Surgical excision of the tumors is merely palliative, but necessary, when the tumors are associated with rapid growth, excessive size, compression of critical nearby structures, progressive symptoms; and become intractable. It may also be necessary for skeletal overgrowth of the jaw or fingers. Plastic surgery is needed, if necessary, for improvement of cosmetic appearance or disfigurement.

Multiple surgical interventions should be expected, because of the progressive and recurrent nature of the tumors.

Radiation therapy may be used as primary treatment of tumors associated with the orbit; or as an addition to surgical treatment of some benign and malignant tumors in the central nervous system.

The management of plexiform neurofibromas with extension into the spinal cord is a particularly very difficult task because of the following reasons:

The required spinal surgery is associated with a high risk of progressive humpback
deformity.

In 1993 a group of researchers investigated local immune system response in neurofibromatosis type I and type II. The group concluded that the presence of chronic inflammation, immunologic interdependency, and the immune system reactions against non-self warrants subsequent studies and favors the employment of immunomodulatory treatment. {Minerva Med 1993 Feb; 84(1-2): 23-31}

In 1996 the group investigated tumor suppressor genes, immunology and local manifestation of neurofibromatosis phenotypes. They stated that severe pathogenic stimuli may affect predisposed cells and pre-existing damaged genes to an uncontrollable state that overcomes the body’s defences. They concluded with the following statement: “Hope for future therapy lies in the development of drugs that can either mimic the immune system or the proteins encoded by the oncosuppressor genes.” {Panminerva Med 1996 Sept: 38(3): 157-63}