Neurofibromatosis type 1 overview

# Overview
Neurofibromatosis type I (NF-1), also known as von Recklinghausen syndrome, is a common inherited disease. Along with neurofibromatosis type II (a.k.a. MISME syndrome), tuberous sclerosis, Sturge-Weber, and Von Hippel-Lindau disease, NF1 is a member of the phakomatoses or neurocutaneous syndrome, all of which have both neurologic and dermatologic lesions. This grouping is historical and based on disease pathology rather than genetic diagnosis.

# Historical Perspective
Neurofibromatosis type 1 was fully described in1882 by German pathologyst Friedrich von Recklinghausen, for which the disorder was eponymously named after him (von Recklinghausen disease), although the recognition of individuals with this phenotype probably dates back from the Hellenistic era.

# Classification
There is no established system for the classification of neurofibromatosis type 1.

# Pathophysiology
Neurofibromatosis type 1 is an autosomal syndrome caused by a mutation in gene NF1 of chromosome 17, wich leads to a defective neurofibromin 1 protein. This mutation constitutes a phenotype with very pathognomonic features that are not always present; among them are the presence of Lisch nodules, neurofibromas, scoliosis, cognitive disabilities, vision disorders, multiple cafe au lait spots and epilepsy.

# Causes
Neurofibromatosis type 1 can be caused 50% of the time due to an autosomal dominant inherited pattern with the other 50% beign caused due to a de novo mutation on NF1 gene. To review risk factors for the development of neurofibromatosis type 1, click here.

# Differentiating Neurofibromatosis type 1 from Other Diseases
Neurofibromatosis type 1 should be differentiated from other genetic disorders who present with overlapping features, such as Von Hippel-Lindau syndrome, Carney complex, Li-Fraumeni syndrome, Gardner's syndrome, Multiple endocrine neoplasia type 2, Cowden syndrome, Acromegaly/gigantism, Pituitary adenoma, Hyperparathyroidism, Pheochromocytoma/paraganglioma, Adrenocortical carcinoma.

# Epidemiology and Demographics
Neurofibromatosis type 1 is the most common single gene disorder in humans, occurring in about 30 to 40 in 100,000 births worldwide.
The country with major prevalence of neurofibromatosis type 1 reported is Israel, while the one with the least reported in Denmark.
Older paternal age may increase the chances for de novo mutations in NF1 gene.
There is no race or gender predilection for neurofibromatosis type 1.

# Risk Factors
The biggest risk factor for acquiring neurofibromatosis type 1 is a family history of this disorder. Advanced paternal age increases the risk of an NF1 de novo mutation. There is no identified modifiable risk factor for acquiring neurofibromatosis type 1.

# Screening
Neurofibromatosis type 1 is acquiered 50% of the time by inheritance. Screening is made by taking a family history and a physical examination, and confirmed with genetic testing. Prenatal screening is controversial.

# Natural History, Complications, and Prognosis
Neurofibromatosis Type 1 manifestations vary widely among patients, from individuals with absent symptoms to rapidly progressive disorders. The most common complication of neurofibromatosis type 1 is disfigurement due to skin lesions. Prognosis will depend on the number of commorbidities, but it is usually moderately good. Life expectancy is usually reduced by 8-12 years, being malignant tumors the most common cause of death.

# Diagnosis

## Diagnostic Study of Choice
Neurofibromatosis type 1 is mainly diagnosed clinically. Neurofibromatosis type 1 is usually diagnosed early on in childhood. Genetic testing may be necessary in difficult cases.

## History and Symptoms
Neurofibromatosis type 1 manifestations vary widely among patients, from individuals with absent symptoms to rapidly progressive disorders. The most common complication of neurofibromatosis type 1 is disfigurement due to skin lesions Prognosis will depend on the number of commorbidities, but it is usually moderately good. Life expectancy is usually reduced by 8-12 years, being malignant tumors the most common cause of death.

## Physical Examination
Neurofibromatosis type 1 physical examination may vary widely among patients. The most common features are the presence of neurofibromas, plexiform neurofibromas, Lisch nodules, cafe au lait macules (CALM), delayed puberty features, and cognitive impairment. Neurofibromatosis type 1 may be diagnosed clinically with great specificity and sensitivity by the presence of 2 characteristic features on physical examination, although many children with the NF1 gene mutation may not meet the criteria at age 1, but will do so at 8 years old in 97% of the cases.

## Laboratory Findings
Metabolic and chemical laboratory studies usually appear normal in individuals with neurofibromatosis type 1. NF1 gene mutation can be diagnosed using linkage analysis and gene sequencing.

## Electrocardiogram
There are no characteristic ECG findings associated with neurofibromatosis type 1.

## X-ray
There are no typical x-ray findings associated with neurofibromatosis type 1, however, X-rays may be helpful in the diagnosis of other complications such as scoliosis, slender long bones, skeletal dysplasia, tibial pseudoarthrosis, and osteoporosis.

## Echocardiography and Ultrasound
There are no echocardiography/ultrasound findings associated with neurofibromatosis type 1.

## CT scan
There are no CT scan findings associated with neurofibromatosis type 1, however, a CT scan may be helpful in the diagnosis of complications. The use of routine screening brain CT scans in patients with neurofibromatosis type 1 is controversial.

## MRI
There are no CT scan findings associated with neurofibromatosis type 1, however, a MRI may be helpful in the diagnosis of complications. MRI is the preferred study method when studying the central nervous system (CNS). The use of routine screening brain MRI in patients with neurofibromatosis type 1 is controversial.

## Other Diagnostic Studies
There are no other diagnostic studies associated with neurofibromatosis type 1.

# Treatment

## Medical Therapy
There is no treatment for neurofibromatosis type 1; the mainstay of therapy is supportive care. Therapy for a patient with neurofibromatosis type 1 is aimed at decreasing symptoms and improving quality of life. At every age, different problems may develop, so a specific approach is necessary for the age and presentation of the individual. Supportive therapy for neurofibromatosis type 1 includes pain relief, psychotherapy, and antidepressants.

## Interventions
There are no recommended therapeutic interventions for the management of neurofibromatosis type 1.

## Surgery
Surgery is only used as a palliative, rather than curative therapy. Surgery can be helpful for the correction of some neurofibromatosis type 1 bone malformations and for removal of painful or disfiguring tumors.

## Primary Prevention
There are no established measures for the primary prevention of neurofibromatosis type 1.

## Secondary Prevention
Neurofibromatosis type 1 has a wide range of comorbidities, regular multidisciplinary follow-ups are mandatory. Annual mammogram and ophtalmologic examination should be made in patients with neurofibromatosis type 1. Neurocognitive evaluation and blood pressure measurements should be done regularly to record evolution and detect secondary causes of impairment.