Neurofibromatosis-1 (NF-1) or Von Recklinghausen's 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 tumor suppressor gene by downregulating 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 which 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:
Neurofibroma: These are well-circumscribed spindle cell proliferation, but they rarely are encapsulated. They have a mucinous background and many mast cells. Spindle cells have a wavy appearance. As neurofibromas result from a proliferation of all supporting elements of neural fibers, so they may have Schwann cells, perineural cells, and blood vessels as well. Axons stains show the random distribution of individual axons in neurofibroma.
Plexiform neurofibroma: They are thought to be the pathognomonic sign of the disease. Histologically, they show numerous elongated encapsulated neurofibromas, often mixed with diffuse neurofibroma that involves the dermis and subcutaneous fat.
Cafe-au-lait spots: Histologically, these macules show hyperpigmentation of stratum basalis and giant melanosis has also been demonstrated.
History and Physical
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:
Cafe-au-lait macules: Sharply defined light brown patches that vary in size from 0.5 cm to 50 cm, the majority are ten cm or less in size. They are the first feature of the disease and appear in all children affected with the disease. They increase in size and number during the first decade of life.
Neurofibromas: These are soft iliac-pink tumors, mostly sessile and dome-shaped while some are pedunculated. Mostly found on trunk and limbs ranging from few millimeters to several centimeters in diameter. In females, they are prominent on areola of the breast. The plexiform neuroma is a diffuse elongated neuroma along the course of the nerve, frequently trigeminal and cervical nerves are involved, and they usually present during the first two years of life. On palpation, they have a characteristic "bag of worms" sensation.
Freckling: Axillary freckling in patients is usually pathognomonic for NF-1, and it is known as Crow's sign. It is present in around 70% of the individuals and appears later than cafe-au-lait spots. Freckling may also be present in other intertriginous areas like the groin.
Lisch-nodules: They appear as dome-shaped lesions around the iris on slit-lamp-examination. They are present in over 90% of the affected individuals and are also known as pigmented iris hamartomas. They are usually asymptomatic but used as an aid to confirm the diagnosis.
Oral lesions: Papillomatous neurofibromas of the hard palate, tongue, etc. are present in only 5% to 10% of cases.
Skeletal abnormalities: Kyphoscoliosis occur in 2% of the affected individuals, and high-level lesions may lead to respiratory difficulties. Pseudoarthrosis of tibia or radius occurs in about 1% of the cases. Sphenoid wing dysplasia is a characteristic abnormality in NF-1.
Malignancies: Neurological tumors consist of optic nerve glioma, astrocytoma, and schwannomas. Intracranial tumors can cause seizures. Other malignancies reported to have associated with the disease are Wilms tumor, rhabdomyosarcoma, leukemia, retinoblastoma, and malignant melanoma.
The diagnosis of NF-1 is mainly clinical based upon an agreed clinical criteria which require two or more of the following conditions to be fulfilled:
Cafe-au-let spots:; six or more with the greatest dimension of 5-15mm.
Neurofibromas: two or more of any type or one plexiform neurofibroma
Freckling: axillary or inguinal
Lisch nodules: two or more
Bony lesions: sphenoid dysplasia and others
Family history: a first-degree relative with the disease.
Treatment / Management
There is no definitive treatment for NF-1 as being a genetic disorder and having multiple manifestations. Treatment is mainly symptomatic for various NF-1 manifestations, for example:
Carbon dioxide laser is used to excise most disfiguring neurofibromas, but hypertrophic or atrophic scars may result from the treatment.
Surgery is indicated when patients present with pain and increase in the size of a tumor.
Seizures or epilepsy should thoroughly be investigated as neurosurgical intervention is sometimes very beneficial for the patient.
Follow-up at every 12 months to assess different complications of the disease.
All infants are screened with cranial MRI to look for neurological abnormalities.
Genetic counseling is very important in the disease management. Informing the patients about the different complications of the disease is very important. And it should be made very clear to the patients regarding their children that 50% are likely to be affected and the disease may be severe. First-degree relatives who have no disease manifestations are unlikely to carry the gene, and the risk for their offspring is small but not absent.
Pearls and Other Issues
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.