Neurofibromatosis Type 1 (Von Recklinghausen)


Article Author:
Abdullah Adil


Article Editor:
Achint Singh


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
6/3/2019 1:12:15 PM

Introduction

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[1]. Moreover, it is the most common amongst all the hamartoma neoplastic syndromes such as tuberous sclerosis, Gardner, Cowden syndromes.

Etiology

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[2]. 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.

Epidemiology

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

Pathophysiology

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

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[3][4]:

  • 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.

Evaluation

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[5]:

  • 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
  • Optic Gliomas
  • 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[1][6][7][8]. 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 an increase in the size of a tumor.
  • Seizures or epilepsy should thoroughly be investigated as a 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.[9][10][11]
  • Genetic counseling is very important in 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.

Enhancing Healthcare Team Outcomes

The presentation of patients with NF-1 is extremely variable and because the disorder affects many organs, it is best managed by a multidisciplinary 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.

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.[12]


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Neurofibromatosis Type 1 (Von Recklinghausen) - Questions

Take a quiz of the questions on this article.

Take Quiz
A teenager with a hereditary disorder is found to have the following lesions in his eye following a slit lamp exam (See image). He may have what disorder?

(Move Mouse on Image to Enlarge)
  • Image 7145 Not availableImage 7145 Not available
    Image courtesy S Bhimji MD
Attributed To: Image courtesy S Bhimji MD



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following statements about neurofibromatosis Type 1 is FALSE?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
An 13-year-old has a past medical history of recurrent bone fractures and optic gliomas. He now presents with a headache and projectile vomiting. What is the most likely diagnosis?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is not seen in von Recklinghausen disease?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 17-year-old boy has a past medical history of fractures and optic gliomas. He now presents with projectile vomiting and headache. What is the most likely diagnosis?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is not a criterion for diagnosing neurofibromatosis type 1 (NF1)?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following molecular abnormalities is associated with Von Recklinghausen neurofibromatosis?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
How is Neurofibromatosis type 1 is inherited?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is NOT a criterion for neurofibromatosis type 1?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is the most common intracranial tumor associated with neurofibromatosis type 1?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What chromosomal defect is associated with neurofibromatosis type 1?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A child was noticed to have multiple and large cafe au lait spots. What other diagnosis is likely in this patient?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following findings is not typical in patients with neurofibromatosis type 1?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
How many cafe-au-lait spots are needed to make a diagnosis of neurofibromatosis type 1?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is the appropriate treatment for neurofibromatosis type -1 with MRI findings at the left distal optic nerve having a high density with rapid intraorbital tumor growth?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
MRI of the brain shows two lesions, both hyperintense on T2WI. One involves the cerebellum extending into cerebral peduncles. The other involves an optic nerve. Which neurocutaneous syndrome is most likely present?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A patient's MRI reveals multiple non-enhancing, T2 hyperintense masses within the basal ganglia and dentate nuclei. What is the diagnosis?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following descriptions best matches findings of neurofibromatosis type 1?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A patient with cafe-au-lait spots is diagnosed with neurofibromatosis type 1. What other skin lesions may be present?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is NOT associated with neurofibromatosis type 1 (NF1)?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What is the most common phakomatosis?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 14 year old, previously healthy, female presents for a sports physical. She is entering the 8th grade and planning to play soccer. On exam, you incidentally notice 8 large cafe au lait spots. When you ask about them, the family states that both the patient's mother and the patient's maternal grandmother have "a lot more than that." What condition is probable?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Neurofibromatosis Type 1 (Von Recklinghausen) - References

References

Karaconji T,Whist E,Jamieson RV,Flaherty MP,Grigg JRB, Neurofibromatosis Type 1: Review and Update on Emerging Therapies. Asia-Pacific journal of ophthalmology (Philadelphia, Pa.). 2018 Nov 2;     [PubMed]
Williams VC,Lucas J,Babcock MA,Gutmann DH,Korf B,Maria BL, Neurofibromatosis type 1 revisited. Pediatrics. 2009 Jan;     [PubMed]
Friedman JM, Neurofibromatosis 1 1993;     [PubMed]
Gürsoy S,Erçal D, Genetic Evaluation of Common Neurocutaneous Syndromes. Pediatric neurology. 2018 Dec;     [PubMed]
Rosser T, Neurocutaneous Disorders. Continuum (Minneapolis, Minn.). 2018 Feb;     [PubMed]
Nemmi F,Cignetti F,Assaiante C,Maziero S,Audic F,Péran P,Chaix Y, Discriminating between neurofibromatosis-1 and typically developing children by means of multimodal MRI and multivariate analyses. Human brain mapping. 2019 May 11;     [PubMed]
Guerrini-Rousseau L,Suerink M,Grill J,Legius E,Wimmer K,Brugières L, Patients with High-Grade Gliomas and Café-au-Lait Macules: Is Neurofibromatosis Type 1 the Only Diagnosis? AJNR. American journal of neuroradiology. 2019 May 9;     [PubMed]
Micieli R,Salsberg JM, Visual Dermatology: Mosaic Generalized Neurofibromatosis 1. Journal of cutaneous medicine and surgery. 2019 May/Jun;     [PubMed]
Roth J,Ber R,Constantini S, Neurofibromatosis type 1 related hydrocephalus: treatment options and considerations. World neurosurgery. 2019 May 3;     [PubMed]
Armand ML,Taieb C,Bourgeois A,Bourlier M,Bennani M,Bodemer C,Wolkenstein P, Burden of adult neurofibromatosis 1: development and validation of a burden assessment tool. Orphanet journal of rare diseases. 2019 May 3;     [PubMed]
Bellampalli SS,Khanna R, Towards a neurobiological understanding of pain in neurofibromatosis type 1: mechanisms and implications for treatment. Pain. 2019 May;     [PubMed]
Taylor LA,Lewis VL Jr, Neurofibromatosis Type 1: Review of Cutaneous and Subcutaneous Tumor Treatment on Quality of Life. Plastic and reconstructive surgery. Global open. 2019 Jan;     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of PA-Hospital Medicine. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for PA-Hospital Medicine, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in PA-Hospital Medicine, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of PA-Hospital Medicine. When it is time for the PA-Hospital Medicine board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study PA-Hospital Medicine.