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Neurofibromatosis (von Recklinghausen’s disease)

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Autosomal dominant neurocutaneous disorder, with complete penetrance.

NF1 has 100% penetrance and 80% variable degree of expression.

NF1 is one of the most common genetic syndromes which affects all racial in ethnic groups.

NF1 is the most prevalent neurocutaneous syndrome and accounts for about 90% of all cases of neurofibromatosis.

Most patients present before eight years of age.

Late onset has rarely been described, and there is no gender or racial predilection.

 

There are three types.

 

NF type 1  is the most common occurs in one in 3000 persons.

 

NF type 1 patients may have bone deformities and about 50% of learning difficulties.

 

NF1 features include cafe au lait spots and neurofibromas on or under the skin, freckling of the armpits or groin.

NF1 prevalence of one in 2000-1 in 5000 persons.

NF1 gene is located on chromosome 17q11.2 and generates the intracellular protein neurofibromin.

About 50% of individuals have a spontaneous mutation of the NF1 gene due to the large size of the gene.

 

 

 

NF 1 patients are at increased risk for central and peripheral nervous system tumors.

 

Plexiform neurofibromas are benign peripheral nerve sheath tumors that usually develop in early childhood.

 

Plexiform neurofibromas can cause pain, disfigurement, neurologic dysfunction, compression of vital structures, and malignant transformation.

 

Surgical resection is a standard approach to management of plexiform neurofibromas, if feasible.

Neurofibromin, a Ras GTPase-activating protein, which has a role in tumor suppression.

Disease is known as segmental NF1if it’s clinical features of confined to a single area of the body.

Neurofibromin is a tumor suppressor catalyzing inactivator of the proto-oncogene P21-ras, a protein that plays a role in mitogenic intracellular signaling pathways.

Neurofibromin activates GTPase, promoting the hydroxylases of active ras-GTP to inactive ras-GDP.

Neurofibromin reduction or loss of function leads to activation of ras signal transduction pathway, which regulates signaling pathways, including mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase B (PI3K), protein kinase B (PKB), and mammalian target of rapamycin (mTOR) kinase.

Results when gene mutations produce neurofibromin, leading to over expression of P21-ras.

Neurofibromin is expressed mainly in Schwann cells, astrocytes, oligodendrocyte, leukocytes, and the Adrenal medulla.

Inactivation of the gene, either by allelic loss or mutation, results in reduced neurofibromin production or function, leading to uncontrolled cell growth or tumor formation.

Neurofibromatosis results from a loss of function mutation in the NF1 gene localized to chromosome band 17q11.2 and comprised of 60 exons and 350 kb of genomic DNA.

More than 500 different NF1 mutations have been identified.

Approximately 30-50% of cases involve de novo germ line mutations, indicating that the absence of a positive family history does not exclude the possibility of the diagnosis.

Estimated incidence 1:2500-3000, and prevalence 1:4000-5000.

Skin lesions and Lisch nodules in the iris are most characteristic of NF1.

Clinical manifestations include pigment manifestations, axillary or inguinal freckling, iris hamartomas (Lisch nodules), osseous dysphasia, optic gliomas and increased risk of developing benign and malignant tumors.

NF1 diagnosis requires 6 or more café au lait macules larger than 5 mm in prepubertal patients and larger than 15 mm in postpubertal individuals, 2 or more fibromas of any type or 1 plexiform neurofibromin, 3 freckling in the axillary or inguinal regions, 4 optic glioma, 5 or more Lisch nodules, osseous lesions such a sphenoid dysplasia or thinning of the long bone cortex with or without pseudoarthrosis and a first relative with neurofibromatosis above.

NF1 associated with pseudoarthrosis, congenital glaucoma, sphenoid wing dysplasia, compression injuries from plexiform neurofibromas, mediastinum tumors, embryonic tumors in childhood, optic pathways gliomas.

NF1 has a typically benign clinical course, but malignancies associated with the process are the most common cause of death and reduce average life expectancy by 10-to 15 years.

Patients with NF1 at increased risk of benign and malignant tumors, with a 2.7 fold increasing cancer risk and a cumulative risk of 20% among affected persons greater than 50 years of age.

Patients with NF-1 have at least a 150-fold increased risk of GIST compared with the general population.

Most NF-1–associated with GISTs are clinically indolent, with favorable histologic parameters.

Incidence of malignancy in NF1 patients ranges between 4-52%.

Malignant tumors occur more frequently in NF1 pateints less than 39 years of age as compared to patients over the age of 40.

NF1 patients are heterozygous for an NF1 mutation, having one normal and one mutated copy of the NF1 gene.

Loss of heterozygosity, that is mutation, in the normal copy of the NF1 gene is a prerequisite for the development of malignancies in these patients.

Malignant peripheral nerve sheath tumors are the most common malignant tumors in NF1 patients.

Other malignant tumors associated with NF1 include rhabdomyosarcoma, gastrointestinal tumors, neuroectodermal tumors, pheochromocytoma, and breast cancer.

The incidence of malignant peripheral nerve sheath tumors estimated to be 2-5% with a cumulative lifetime risk as high as 10%.

NF1 patients with malignant peripheral nerve sheath tumors usually present in the 2nd and 3rd decades, nearly a decade earlier than patients without this genetic change.

Prospective information from 448 patients with NF1 a cumulative risk of malignancy was 20% by age 50, with no statistical increase after that (Friedman).

Plexiform neurofibromas may underlie café au lait spots in neurofibromatosis type 1 (NF1).

Cafe Au Lait spots have a predilection for the trunk and extremities.

The scalp face palms and soles are usually spared.

 

Potential consequences including blindness, deafness, disfigurement, bone abnormalities, disabling pain, and learning disabilities.

The number and location of Cafe Au Lait spots have no relationship to the number and location of future neurofibromas.

Neurofibromas are the benign peripheral nerve sheath tumors composed of an extracellular matrix and a heterogeneous mixture of Schwann cells and fibroblasts.

Cutaneous neurofibromas often appear during puberty or pregnancy, and increase in size and number with age.

Cutaneous neurofibromas are found in almost all adults with NF1.

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Somatic alteration of the NF1 gene, as opposed to germline mutations, is associated with sporadic malignancies to include small cell lung cancer, adenocarcinoma of the colorectum, or ovarian cancer, and myelodysplastic syndrome, and anaplastic astrocytoma.

Cancer death is the most common cause for patients with NF1 mutation and results in a 10-to 15 year decreased life expectancy.

Large fibrous lesions of the subcutaneous tissues may cause significant disfigurement.

Neurofibromatosis type2 (NF2), central neurofibromatosis, associated with neuromas.

Acoustic neuromas (vestibular schwannomas) are benign tumors composed of neoplastic Schwann cells arising form the eighth cranial nerve are the hall mark of neurofibromatosis type 2.

NF2 may also have café au lait spots.

 

NF2 tumor’s  suppressor gene control cell growth through different cyclical signaling pathways including MEK, mTOR, ERbB2, Stc, Rac1.

Characterized by bilateral vestibular schwanomas.

NF2 more likely diagnosed in middle aged individuals than NF1 which is usually diagnosed in children.

The gene responsible for NF2 is chromosome 2.

NF2 incidence 1 in 40,000 in the U.S.

A variety of cancers are associated with this disease and include: neurofibromas, gliomas, optic gliomas, soft tissue sarcomas, breast cancer, lung cancer, small intestine cancer, colorectal cancer, thyroid cancer, pharyngeal cancer, ovarian cancer, melanoma and biliary cancer, with a combined incidence of 24-36%.

 

NF2 type tumors involved bilateral vestibular schwannomas, and hearing loss and occurs in one in 25,000-30,000 persons.

 

Vestibular schwannoma growth causes progressive hearing loss.

 

No effective treatment exists for vestibular schwannomas that recur or continue to grow despite surgery and/or radiation.

 

The third type of NF is schwannomato sis  characterized by painful schwannomas usually on the spinal or peripheral nerves.

 

No cure for NF presently exist.

 

The mTOR inhibitor sirolimus in patients  with NF1 associated plexiform neurofibromas prolonged time to progression compared to placebo 15.4 months versus 11.9, respectively, but did not shrink tumors.

 

Selumetinib approved for NF1 plexiform neurofibromas specifically for children three years of age and older with inoperable progressive plexiform neurofibromas.

 

Most children with neurofibromatosis type 1 and inoperable plexiform neurofibromas have durable tumor shrinkage and clinical benefit from selumetonib.

 

MEK inhibitors show efficacy.

The MEK inhibitor selumentinib had a 70% partial response rate in inoperable plexiform neurofibromas.

 

Bevicizumab  can slow the growth of vestibular schwannomas  in patients  with NF2.

 

 

 

 

 

 

 

 

 

 

 

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