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DISORDERS ASSOCIATED WITH DEFECTS IN PROTEINS THAT REGULATE CELL GROWTH

Normal growth and differentiation of cells is regulated by two classes of genes: proto-oncogenes and tumor-suppressor genes, whose products promote or restrain cell growth ( Chapter 7 ). It

is now well established that mutations in these two classes of genes are important in the pathogenesis of tumors. In the vast majority of cases, cancer-causing mutations affect somatic cells

and hence are not passed in the germ line. In approximately 5% of all cancers, however, mutations transmitted through the germ line contribute to the development of cancer. Most familial

cancers are inherited in an autosomal dominant fashion, but a few recessive disorders have also been described. This subject is discussed in greater detail in Chapter 7 . Here we provide an

example of two common familial neoplasms.

Neurofibromatosis: Types 1 and 2

Neurofibromatoses comprise two autosomal dominant disorders, affecting approximately 100,000 people in the United States. They are referred to as neurofibromatosis type 1 (previously

called von Recklinghausen disease) and neurofibromatosis type 2 (previously called acoustic neurofibromatosis). Although there is some overlap in clinical features, these two entities are

genetically distinct.[41]

Neurofibromatosis type 1 is a relatively common disorder, with a frequency of almost 1 in 3000. Although approximately 50% of the patients have a definite family history consistent

with autosomal dominant transmission, the remainder appear to represent new mutations. In familial cases, the expressivity of the disorder is extremely variable, but the penetrance is 100%.

Neurofibromatosis type 1 has three major features: (1) multiple neural tumors (neurofibromas) dispersed anywhere on or in the body; (2) numerous pigmented skin lesions, some of which are

café au lait spots; and (3) pigmented iris hamartomas, also called Lisch nodules. A bewildering assortment of other abnormalities (cited later) may accompany these cardinal manifestations.

Morphology.

The neurofibromas arise within or are attached to nerve trunks anywhere in the skin, including the palms and soles, as well as in every conceivable internal site, including the cranial nerves.

Three types of neurofibromas are found in individuals with neurofibromatosis type 1: cutaneous, subcutaneous, and plexiform. Cutaneous, or dermal, neurofibromas are soft, sessile, or

pedunculated lesions that vary in number from a few to many hundreds. Subcutaneous neurofibromasgrow just beneath the skin; they are firm, round masses that are often painful. The

cutaneous and subcutaneous neurofibromas may be less than 1 cm in diameter; moderate-sized pedunculated lesions; or huge, multilobar pendulous masses, 20 cm or more in greatest

diameter. The third variant, referred to as plexiform neurofibroma, diffusely involves subcutaneous tissue and contains numerous tortuous, thickened nerves; the overlying skin is frequently

hyperpigmented. These may grow to massive proportions, causing striking enlargement of a limb or some other body part. Similar tumors may occur internally, and in general the deeply



situated lesions tend to be large. Microscopically, neurofibromas reveal proliferation of all the elements in the peripheral nerve, including neurites, Schwann cells, and fibroblasts. Typically,

these components are dispersed in a loose, disorderly pattern, often in a loose, myxoid stroma. Elongated, serpentine Schwann cells predominate, with their slender, spindle-shaped nuclei.

The loose and disorderly architecture helps differentiate these neural tumors from schwannomas. The latter, composed entirely of Schwann cells, virtually never undergo malignant

transformation, whereas plexiform neurofibromas become malignant in about 5% of patients with neurofibromatosis type 1.[42] Malignant transformation is most common in the large

plexiform tumors attached to major nerve trunks of the neck or extremities. The superficial lesions, despite their size, rarely become malignant.

The cutaneous pigmentations, the second major component of this syndrome, are present in more than 90% of patients. Most commonly, they appear as light brown café au laitmacules, with

generally smooth borders, often located over nerve trunks. They are usually round to ovoid, with their long axes parallel to the underlying cutaneous nerve. Although normal individuals may

have a few café au lait spots, it is a clinical maxim that when six or more spots greater than 1.5 cm in diameter are present in an adult, the patient is likely to have neurofibromatosis type 1.

Lisch nodules(pigmented hamartomas in the iris) are present in more than 94% of patients age 6 years or older. They do not produce any symptoms but are helpful in establishing the

diagnosis.

A wide range of associated abnormalities has been reported in these patients. Perhaps most common (seen in 30% to 50% of patients) are skeletal lesions, which take a variety of forms,

including (1) erosive defects owing to contiguity of neurofibromas to bone, (2) scoliosis, (3) intraosseous cystic lesions, (4) subperiosteal bone cysts, and (5) pseudoarthrosis of the tibia.

Patients with neurofibromatosis type 1 have a twofold to fourfold greater risk of developing other tumors, especially Wilms tumors, rhabdomyosarcomas, meningiomas, optic gliomas, and

pheochromocytomas. Affected children are at increased risk of developing chronic myeloid leukemia.

Although some patients with this condition have normal intelligence quotients (IQs), there is an unmistakable tendency for reduced intelligence. When neurofibromas arise within the

gastrointestinal tract, intestinal obstruction or gastrointestinal bleeding may occur. Narrowing of a renal artery by a tumor may induce hypertension. Owing to variable expression of the gene,

the range of clinical presentations is almost limitless, but ultimately the diagnosis rests on the concurrence of multiple café au lait spots and multiple skin tumors. The neurofibromatosis type

1 (NF-1) gene has been mapped to chromosome 17q11.2. It encodes a protein called neurofibromin, which down-regulates the function of the p21Ras oncoprotein (see section on oncogenes,

Chapter 7 ). NF-1 therefore belongs to the family of tumor-suppressor genes.

Neurofibromatosis type 2 is an autosomal dominant disorder in which patients develop a range of tumors, most commonly bilateral acoustic schwannomas and multiple meningiomas.

Gliomas, typically ependymomas of the spinal cord, also occur in these patients. Many individuals with neurofibromatosis type 2 also have non-neoplastic lesions, which include nodular

ingrowth of Schwann cells into the spinal cord (schwannosis), meningioangiomatosis (a proliferation of meningeal cells and blood vessels that grows into the brain), and glial hamartia

(microscopic nodular collections of glial cells at abnormal locations, often in the superficial and deep layers of the cerebral cortex). Café au lait spots are present, but Lisch nodules in the iris

are not found. This disorder is much less common than neurofibromatosis type 1, having a frequency of 1 in 40,000 to 50,000.

The NF-2 gene, located on chromosome 22q12, is also a tumor-suppressor gene. As further discussed in Chapter 7 , the product of the NF-2 gene, called merlin, shows structural similarity to

the ezrin, radixin, moesin (ERM) family of proteins. These cytoskeletal proteins interact with actin on the one hand and membrane proteins on the cell surface on the other hand. It is thought

that merlin regulates contact inhibition and proliferation of Schwann cells.[43]


Date: 2016-04-22; view: 619


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