Neurofibromatosis-1 (NF-1) or Von Recklinghausen disease is one of the inheritable neurocutaneous disorders manifested by developmental changes in the nervous system, bones, and skin. It is an autosomal dominant disorder. Moreover, it is the most common amongst all the hamartoma neoplastic syndromes such as tuberous sclerosis, Gardner, Cowden syndromes.
NF-1 is an autosomally dominant inheritable disorder. The gene for NF-1 is located on chromosome 17, and it encodes a gene product named neurofibromin. This protein is widely expressed in a variety of tissues, and it functions as a tumor suppressor gene by downregulating the RAS gene product. The mutation or deletion of this NF-1 gene results in this disease and the resultant proliferation of multiple neurofibromas and other tumors. Being an attention-deficit (AD) disorder with 100% penetrance, it affects all the generations of affected individuals with no skip generations.
NF-1 is an autosomal-dominant genetic disorder that affects all the offspring of an affected individual. The incidence of NF-1 is 1 in 2600 to 3000 individuals with no predilection for male or female genders. Among these cases, 50% are familial while the rest of the cases are sporadic. The sporadic mutations typically occur in paternally derived chromosomes. The risk of these sporadic mutations increases with increasing paternal age. The incidence of the so-called segmental NF-1, a form that predominantly has skin manifestations only, is 1 in 36,000 to 40,000 individuals.
Neurofibromas affecting the skin stem from peripheral nerves and their supporting structures, including neurilemmal cells. The fibroblasts in these neurofibromas are derived from factor XIIIa connective tissue cells which are HLA-DR-positive in peripheral nerves. Cafe-au-lait spots sometimes contain giant pigment granules found in epidermal cells and melanocytes.
Histopathology of various lesions commonly seen in NF-1 is discussed below:
The course of NF-1 varies considerably in various patients, but the majority have a benign course of the disease without developing major complications. In fact, diagnosis is usually made in middle-age or later in life. The variability in presentation appears to be at least partially genetically determined and is unrelated to the unaffected allele. Patients with NF-1 may present with the following:
The diagnosis of NF-1 is mainly clinical, based upon agreed clinical criteria which require two or more of the following conditions to be fulfilled:
The outlook for patients with NF-1 is guarded and depends on the severity of the disease, presence of malignancy, and extent of the deformity. Those with mild disease can have a reasonable life expectancy, but those with moderate to severe disease have a poor quality of life.
The patient and parents should be aware of the prognosis and the possible complications that can develop. Genetic counseling should be offered prior to conception.
All genetic disorders are rare, and they are thought to be associated with extreme worrisome for the families. The main aim is to ensure proper diagnosis of the disease and genetic counseling of the affected families to prevent their children from the disease.
The presentation of patients with NF-1 is extremely variable and because the disorder affects many organs, it is best managed by an interprofessional team including nurse practitioners. While the disorder is benign, it is vital that healthcare workers closely monitor patients because many organ systems are involved. To improve patient outcomes, it is important to remember that a few patients may develop neurological tumors. Other malignancies reported to have associated with the disease are Wilms tumor, rhabdomyosarcoma, leukemia, retinoblastoma, and malignant melanoma. A thorough exam and serial imaging studies are the only way to identify the presence of these lesions.
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