Neurofibromatosis

Neurofibromatosis
Classification and external resources
Back of an elderly woman with neurofibromatosis
ICD-10	Q85.0
ICD-9	237.7
ICD-O:	9540/0
OMIM	162200 101000
eMedicine	derm/287
MeSH	D017253

Neurofibromatosis (commonly abbreviated NF; neurofibromatosis type 1 is also known as von Recklinghausen disease) is a genetically-inherited disorder in which the nerve tissue grows tumors (neurofibromas) that may be benign or may cause serious damage by compressing nerves and other tissues. The disorder affects all neural crest cells (Schwann cells, melanocytes and endoneurial fibroblasts). Cellular elements from these cell types proliferate excessively throughout the body, forming tumors; melanocytes also function abnormally in this disease, resulting in disordered skin pigmentation and "cafe-au-lait" spots. The tumors may cause bumps under the skin, colored spots, skeletal problems, pressure on spinal nerve roots, and other neurological problems.^[1][2]

Neurofibromatosis is an autosomal dominant disorder, which means only one copy of the affected gene is needed for the disorder to develop. Therefore, if only one parent has neurofibromatosis, his or her children have a 50% chance of developing the condition as well. The severity in affected individuals can vary, this may be due to variable expressivity. Approximately half of cases are due to de novo mutations and no other affected family members are seen. It affects males and females equally.

Classification

Neurofibromatosis type 1 (NF 1)

Plexiform neurofibroma on the neck of a patient; plexiform neurofibromas are a cause of morbidity in the affected individuals.

Patient with multiple small cutaneous neurofibromas and a 'café au lait spot' (bottom of photo, to the right of centre). A biopsy has been taken of one of the lesions.

Main article: Neurofibromatosis type I

Neurofibromatosis type 1 (also known as "von Recklinghausen disease"^[1]) is the most common form of NF, accounting for up to 90% of the cases. NF 1 has a disorder frequency of 1 in 4,000, making it more common than neurofibromatosis type 2, with a frequency of 1 in 45,000 people.^[3] It occurs following the mutation of neurofibromin on chromosome 17q11.2. 100,000 Americans have neurofibromatosis. Neurofibromin is a tumor suppressor gene whose function is to inhibit the p21 ras oncoprotein.^[3] In absence of this tumor suppressor's inhibitory control on the ras oncoprotein, cellular proliferation is erratic and uncontrolled, resulting in unbalanced cellular proliferation and tumor development. The diagnosis of NF1 is made if any two of the following seven criteria are met:

• Two or more neurofibromas on or under the skin, or one plexiform neurofibroma (a large cluster of tumors involving multiple nerves); neurofibromas are the subcutaneous bumps characteristic of the disease, and increase in number with age.
• Freckling of the groin or the axilla (arm pit).
• Café au lait spots (pigmented, light brown macules located on nerves, with smooth edged, "coast of California"^[4] birthmarks). Six or more measuring 5 mm in greatest diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals.
• Skeletal abnormalities, such as sphenoid dysplasia or thinning of the cortex of the long bones of the body (i.e. bones of the leg, potentially resulting in bowing of the legs)^[1]
• Lisch nodules (hamartomas of iris), freckling in the iris
• Tumors on the optic nerve, also known as an optic glioma
• Macrocephaly in 30-50% of the pediatric population without any hydrocephalus^[5]
• Epilepsy (seizures)
• Juvenile posterior lenticular opacity^[1]

NF 1 also increases the risk of tumor development, particularly, meningiomas, gliomas and pheochromocytomas.

Neurofibromatosis type 2 (NF 2)

Main article: Neurofibromatosis type II

Neurofibromatosis type 2 (also called "central neurofibromatosis"^[1]) is the result of mutation of the merlin (also known as "schwannomin"^[1]) in chromosome 22q12. It accounts for only 10% of all cases of NF, and its frequency is lower than NF1. It is also caused by a mutation in a tumor suppressor gene NF2 (whose gene product is schwannomin or merlin). The normal function of merlin is not well understood.^[3] The disorder manifests in the following fashion:

• bilateral acoustic neuromas (tumors of the vestibulocochlear nerve or cranial nerve 8 (CN VIII) also known as schwannoma), often leading to hearing loss. In fact, the hallmark of NF 2 is hearing loss due to acoustic neuromas around the age of twenty.
• The tumors may cause:
  • headaches
  • balance problems, and peripheral vertigo often due to schwannoma and involvement of the inner ear
  • facial weakness/paralysis due to involvement or compression of the facial nerve (cranial nerve 7 or CN VII)
  • patients with NF2 may also develop other brain tumors, as well as spinal tumors.
  • deafness and tinnitus

NF 2 increases the risk of meningiomas and ependymomas.^[3]

Schwannomatosis

Main article: Schwannomatosis

Schwannomatosis - mutation in both chromosomes 17 and 22

1. Multiple schwannomas occur.
2. The schwannomas develop on cranial, spinal and peripheral nerves.
3. Chronic pain, and sometimes numbness, tingling and weakness
4. About 1/3 of patients have segmental schwannomatosis, which means the schwannomas are limited to a single part of the body, such as an arm, a leg or the spine.
5. Unlike the other forms of NF, the schwannomas do not develop on vestibular nerves, and as a result, no loss of hearing is associated with schwannomatosis.
6. Patients with schwannomatosis do not have learning disabilities related to the disorder.

One must keep in mind, however, that neurofibromatosis can occur in or affect any of the organ systems, whether that entails simply compressing them (from tumor growth) or in fact altering the organs in some fundamental way. This disparity in the disorder is one of many factors that makes it difficult to diagnose, and eventually find a prognosis for.

Other variants

• Neurofibromatosis type 3
• Neurofibromatosis type 4
• Neurofibromatosis type 5

Related disorders

Neurofibromatosis is considered a member of the neurocutaneous syndromes (phakomatoses).^[2] In addition to the types of neurofibromatosis, the phakomatoses also include tuberous sclerosis, Sturge-Weber syndrome and von Hippel-Lindau disease. This grouping is an artifact of an earlier time in medicine, before the distinct genetic basis of each of these diseases was understood.

Signs and symptoms

Patients with neurofibromatosis can be affected in many different ways. Morbidity is often a result of plexiform neuromas, optic gliomas, or acoustic neuromas, but mortality can also be associated with malignant transformation of the neuromas, such as neurofibrosarcomas^[1] (often there is a malignant transformation in less than 3% of the cases of NF1^[3]). There is a high incidence of learning disabilities or cognitive deficit^[1][5] in patients with NF, particularly NF-1, however severe retardation is not part of the syndrome. Because of the tumor generating nature of the disorder and its involvement of the nervous system and also because of early onset macrocephaly in the pediatric population, there is often an increased chance of development of epilepsy in those affected. Neurofibromatosis also increases the risk of leukemia particularly in children; Children with NF-1 have 200 to 500 times the normal risk of developing leukemia compared to the general population.^[1] Since the tumors grow where there are nerves, they can also grow in areas that are visible, causing considerable social suffering for those affected. The tumors can also grow in places that can cause other medical issues that may require them to be removed for the patient's safety.^[6] Affected individuals may need multiple surgeries (such as reduction surgery, or Gamma knife surgery), depending on where the tumors are located. For instance, those affected with NF 2 might benefit from a surgical decompression of the vestibular tumors to prevent deafness.^[2]

Diagnosis

Prenatal testing

Embryo

For embryos produced via in vitro fertilisation, it is possible via preimplantation genetic diagnosis (PGD) to screen for NF-1.^[7]

"PGD has about 95-98% accuracy but requires that the partner with NF2 have a recognizeable genetic mutation, which is only the case for about 60% of people with a clinical diagnosis of NF2. Having the initial genetic testing to determine if the mutation is recognizeable takes approximately 6 months, and then preparing the probes for the PDG testing takes approximately another 6 months."^[8]

PGD can not be used to detect Schwannomatosis‎, because the gene for it has not yet been identified.^[9]

Fetus

Chorionic villus sampling or amniocentesis can be used:^[10]

• To detect Neurofibromatosis type I‎.
• To detect Neurofibromatosis type II‎ with 95% accuracy.
• Can not be used to detect Schwannomatosis‎, because the gene for it has not yet been identified.

Genetics

NF-1 and NF-2 may be inherited in an autosomal dominant fashion, as well as through random mutation.

Neurofibromatosis type 1 is caused by mutation on chromosome 17q11.2 , the gene product being neurofibromin (a regulator of the GTPase activating enzyme (GAP)).^[1][11] Neurofibromatosis type 2 is due to mutation on chromosome 22q, the gene product is merlin, a cytoskeletal protein.^[1]

Both NF-1 and NF-2 are autosomal dominant disorders, meaning only one copy of the mutated gene need be inherited to pass the disorder. A child of a parent with NF-1 or NF-2 and an unaffected parent will have a 50%-100% chance of inheriting the disorder, depending on whether the affected parent is heterozygous (Aa) or homozygous (AA) for the trait ("A" depicts the affected dominant allele, while "a" depics the recessive allele).

Complicating the question of heritability is the distinction between genotype and phenotype, that is, between the genetics and the actual manifestation of the disorder. In the case of NF1, no clear links between genotype and phenotype have been found, and the severity and the specific nature of the symptoms may vary widely among family members with the disorder. This is a good example of the phenomenon of variable expressivity: the differing severities of disease in different individuals with the same genotype.^[12] In the case of NF-2, however, manifestations are similar among family members; a strong genotype-phenotype correlation is believed to exist.^[12] Both NF-1 and NF-2 can also appear to be spontaneous de novo mutations, with no family history. These cases account for about one half of neurofibromatosis cases.^[12]

Similar to polydactyly, NF is also an autosomally dominant mutation, that is not prevalent in the society. Neurofibromatosis-1 is found in approximately 1 in 2,500-3,000^[3] live births (carrier incidence 0.0004, gene frequency 0.0002) and is more common than NF-2.

Pathophysiology

The gene affected in NF-1, is located on the long arm of the chromosome 17 (q11.2). It encodes for a protein called neurofibromin, otherwise known as a "tumor suppressor" protein. This protein is a negative regulator of the Ras kinase pathway (p21 oncoprotein).^[13] Neurofibromatosis alters or weakens this protein (due to deletion, missense mutation, or nonsense mutations,^[1]) allowing rapid, radical growth of cells all over the body, especially around the nervous system. The essential problem is the inability to inactivate GTP due to a defective GTP-ase (neurofibromin). This leads to the common symptoms for neurofibromatosis - clumpings of the tumors, called neurofibromas and schwannomas. Less is known about the NF-2 linked gene and its product, merlin. However, it is on the long arm of the chromosome 22q(11.1-13.1^[1]) and codes for the protein.

Treatment

Because there is no cure for the condition itself, the only therapy for patients with neurofibromatosis is a program of treatment by a team of specialists to manage symptoms or complications. Surgery may be needed when the tumors compress organs or other structures. Less than 10% of people with neurofibromatosis develop cancerous growths; in these cases, chemotherapy may be successful.^[14]

Although there is no cure for NF, the Neurofibromatosis Association is optimistic there will be an effective treatment within the next five to ten years. For families with NF, genetic screening and counselling is available.^[15]

The St. Louis Children's Hospital Neurofibromatosis Center maintains a comprehensive list of current NF research studies.

History

Neurofibromatosis (or von Recklinghausen disease^[2]) was first described in 1882 by the German pathologist, Friedrich Daniel von Recklinghausen. As a young scientist, Recklinghausen was the student of the then renowned Rudolf Virchow in Berlin. Recklinghausen was successful in generating some of the most descriptive medical observations of his time, making him the first person to describe and coin the term "hemachromatosis" (Hämochromatose, Tageblatt der Naturforschenden Versammlung). Recklinghausen is now known for his contributions to staining methods, and most importantly for his important paper on neurofibromatosis published in 1881, to honor Rudolf Virchow’s 25 year jubilee, in which he describes neurofibromatosis. Recognized as a distinguished histopathologist, and a great scientist to this date, he lends his name to the syndrome, which he himself elucidated.^[16]

Notable cases

In May 2011, a case was reported in the United Kingdom in which a 15-month-old child who turned out to have Neurofibromatosis type I was misdiagnosed as being abused under the assumption that the mother had Münchausen syndrome, because the child gained weight while in hospital and lost weight while at home.^[17] The child was placed in foster care for 6 months and then returned to his parents after he was correctly diagnosed.

In January 2008, 32-year-old Huang Chuncai of China underwent a second operation to remove another 4.5 kg (9.9 lb) of tumor from his face. A previous operation removed 15 kg (33 lb) from what was originally a 23 kg (55.7 lb) tumor.^[18][19]

In March 2007, the treatment of 30-year-old neurofibromatosis patient Pascal Coler of France ended after he had received what his doctors call the world's first successful full face transplant.^[20][21]

In November 2006, there was an hour-long documentary on the British television network Channel 4 about Facing the World, an organization that helps children with severe facial disfigurements in developing countries. One of the children featured on the documentary was Arianto, an Indonesian boy who suffered from a severe form of neurofibroma resulting in hemifacial giganticism.

Also in that year, another documentary on BBC2 (edge of life) featured a neurofibromatosis case. On that documentary was a young teenager, Amit Ghose, who had decided for himself to have corrective surgery at the age of 14. In this case, the neurofibroma occurred on the face, resulting in the loss of sight in one eye and having to have it removed. This was a case of NF-2, resulting in the disfigurement of the one side of the face, while leaving the other side completely normal.

Joseph Merrick, the Elephant Man, was once considered to have been affected with neurofibromatosis type I. However, it is possible Merrick suffered from the very rare Proteus syndrome. This, however, has given rise to the common misconception that neurofibromatosis and "Elephant Man disease" are one and the same.

Research Organizations

Foundations

Several national organizations provide support for those challenged by neurofibromatosis. Some include:

• Australia: Little Frog Foundation (a nonprofit organization working providing information and resources for families dealing with NF1, NF2, and tumour-related neurofibromatosis in Australia)
• Belgium: NF KONTAKT.be (a nonprofit organization providing information and resources for families, Schools and Health Care workers dealing with NF1, NF2, and tumour-related neurofibromatosis in Belgium and providing awareness and support of Neurofibromatosis in Europe)
• Canada: The Neurofibromatosis Association of Quebec
• France:
  • The Neurofibromatosis and Recklinghausen Association
  • Centre de Référence labellisé NEUROFIBROMATOSES
• United Kingdom: The Neuro Foundation
• United States:
  • The Children's Tumor Foundation (CTF) (a nonprofit organization working towards a cure for neurofibromatosis)
  • Neurofibromatosis Inc. (a nonprofit organization working towards neurofibromatosis patient support)
  • Neurofibromatosis Cafe (a nonprofit organization working providing patient education, awareness and support of Neurofibromatosis)

Academic Research and Clinical Centers

France

• At the Neurosurgery Clinic of the Hôpital Beaujon in Clichy, Hauts-de-Seine, and in collaboration with the Black Laboratory at Harvard University which focusses on meningioma research, Michel Kalamarides focusses on mouse modeling of NF2 meningioma.

United States

• California:
  • House Ear Institute in Los Angeles is a CTF NFPC focussing on NF2 schwannoma and meningioma.
  • The NF/Ras Pathway Clinic at UCSF Medical Center in San Francisco. This is a CTF NFPC focussing on NF1 myeloid leukemia.
• Florida:
  • The Wallace Lab and Muir Lab at the University of Florida in Gainesville, Florida focus on the molecular study of benign Schwann cell tumors and the development of new therapies for NF1.
  • The Neurofibromatosis Center at Miami Children's Hospital.
• Illinois: The Neurofibromatosis Program at University of Chicago Medical Center.
• Indiana: The Neurofibromatosis Clinic at Indiana University. This clinic has pioneered the use of Imatinib to treat neurofibromas.^[22]
• Maryland: The Johns Hopkins Comprehensive Neurofibromatosis Center at Johns Hopkins Hospital
• Massachusetts:
  • The Center for Neurofibromatosis and Allied Disorders at Harvard Medical School and Massachusetts General Hospital. This is a CTF NFPC focussing on NF2 schwannoma and meningioma.
  • Brigham and Women's Hospital at Harvard Medical School is a CTF NFPC focussing on NF1 malignant peripheral nerve sheath tumors.
  • The Center for Human Genetics at Boston University School of Medicine provides genetic testing laboratory service for Neurofibromatosis type I and Legius syndrome. Testing includes DNA sequencing and Multiplex ligation-dependent probe amplification.
• Missouri: The Neurofibromatosis Center at St. Louis Children's Hospital.^[23] This is a CTF NFPC focussing on NF1 optic pathway glioma. They maintain a comprehensive list of current NF research studies.
• New Jersey: The Neurofibromatosis Center of New Jersey and Institute of Genomic Medicine at University Hospital (Newark, New Jersey)
• New York:
  • The Neurofibromatosis Center at North Shore-LIJ Health System
  • The Neurofibromatosis Center at NYU Langone Medical Center (see also Department of Otolaryngology).
  • The Comprehensive Neurofibromatosis Clinic at NewYork–Presbyterian Hospital.
• Ohio: The Cincinnati Neurofibromatosis Center at Cincinnati Children's Hospital Medical Center. This is a CTF NFPC focussing on NF1 plexiform neurofibromas. The Ratner Lab focusses on interactions between glial cells and axons during nervous system development and how those interactions go awry to lead to NF1 and NF2 conditions.
• Pennsylvania: The Neurofibromatosis Program at Children's Hospital of Philadelphia
• Texas:
  • The Comprehensive Neurofibromatosis Clinic at University of Texas Southwestern Medical Center.
  • The Neurofibromatosis Clinic at Children's Medical Center (Dallas)

Drug Companies

The following drug companies are supporters of the Children's Tumor Foundation and are actively developing NF-related drugs:

• Avila Therapeutics
• Genentech
• Merck
• Novartis
• Pfizer

References

1. ^ ^{a b c d e f g h i j k l m} Raphael Rubin, David S. Strayer (2008 Baltimore). Rubin's Pathology: Clinicopathologic Foundation of Medicine (5 ed.). Wolters Kluwer Health: Lippincot Williams & Wilkins. pp. 201–3. ISBN 9780781795166. 
2. ^ ^{a b c d} Conrad Fischer, Farshad Bagheri, Rajpal Manchandani, Richard Pinsker, Sudheer Chauhan, Parenkumar Patel, Mohammad Maruf, Dhaval Satani, Kaushik Doshi, Ayaz Alwani, Naveen Pathak, Craigh Thurm, Mohammad Babury, Mahendra C. Patel, Arthur Shalanov, Samir Sarkar, Sabiha Raouf, Jebun Nahar, Prakashkumar Patel (2010). Master the Board USMLE Step 2 CK. KAPLAN Medical. p. 287. ISBN 9781607146537. 
3. ^ ^{a b c d e f} John Barone (2008). USMLE Step 1 Lecture Notes: Pathology. KAPLAN Inc. pp. 57. 
4. ^ William D James, Raj D Sheth, Nazanin Saedi (Jul 20, 2009). Cafe Au Lait Spots. eMedicine from WebMD. http://emedicine.medscape.com/article/911900-overview. Retrieved 13 December 2010. 
5. ^ ^{a b} Steen RG, Taylor JS, Langston JW, Glass JO, Brewer VR, Reddick WE, Mages R, Pivnick EK. (2001, May). "Prospective evaluation of the brain in asymptomatic children with neurofibromatosis type 1: relationship of macrocephaly to T1 relaxation changes and structural brain abnormalities". AJNR. American journal of neuroradiology (American Journal of Neuroradiology) 22 (5): 810–7. PMID 11337320. 
6. ^ Hayashi M, Chernov M, Tamura N, Yomo S, Ochiai T, Nagai M, Tamura M, Izawa M, Muragaki Y, Iseki H, Okada Y, Takakura K. (December 2010). "Gamma Knife surgery for abducent nerve schwannoma. Report of 4 cases". Journal of neurosurgery (Journal of Neurosurgery) 113: 136–43. doi:10.3171/2010.8.GKS10947. PMID 21121795. 
7. ^ "British couple successfully screens out genetic disorder using NHS-funded PGD" by Antony Blackburn-Starza, June 9, 2008, BioNews 461
8. ^ NF2 Planned Parenthood: Current prenatal testing options
9. ^ Schwannomatosis, by Susan Toomey MS, page 4
10. ^ "Are there any prenatal tests for the neurofibromatoses?"
11. ^ Fauci, et al. Harrison's Principles of Internal Medicine (Small textbook) (16 ed.). pp. 2453. 
12. ^ ^{a b c} Bruce R. Korf, Allan E. Rubenstein (2005). Neurofibromatosis: a handbook for patients, families, and health care professionals (2 ed.). Thieme. ISBN 9781588903013. 
13. ^ Feldkamp MM, Angelov L, Guha A (1999). Neurofibromatosis Type 1 Peripheral Nerve Tumors: Aberrant Activation of the Ras Pathway. 51. Surgical Neurology. pp. 211–218. 
14. ^ Janet M. Torpy, Alison E. Burke, MA, Richard M. Glass (2008). "JAMA patient page: Neurofibromatosis". JAMA: the Journal of the American Medical Association (JAMA (Journal of American Medical Association)) 300 (3): 352–352. doi:10.1001/jama.300.3.352. http://jama.ama-assn.org/content/300/3/352.full. 
15. ^ Trisha Macnair, Rob Hicks. "Neurofibromatosis". British Broadcasting Company (BBC) - MMX. http://www.bbc.co.uk/health/physical_health/conditions/neurofibroma1.shtml. Retrieved 13 December 2010. 
16. ^ Ole Daniel Enersen. "Friedrich Daniel von Recklinghausen". Who Named It?. http://www.whonamedit.com/doctor.cfm/1174.html. Retrieved 13 December 2010. 
17. ^ "Billingham mum speaks of joy as baby is returned to her", by Lindsay Bruce, May 10, 2011Evening Gazette (Teesside)
18. ^ Dan Childs. "50-Pound Face Tumor: One Man's Nightmare". ACB News. http://abcnews.go.com/Health/story?id=4116455&page=1. Retrieved 2008-01-23. 
19. ^ Radford, S. (2008-01-11). "Chinese man has surgery for 10 kg face tumour". The Daily Telegraph (London). http://www.telegraph.co.uk/news/main.jhtml?xml=/news/2008/01/09/whuang109.xml. Retrieved 2008-01-29. 
20. ^ Watt, Nick (2008-03-25). "World's First Full Face Transplant Hailed". abcnews.go.com. http://abcnews.go.com/Health/story?id=4511813&page=1. Retrieved 2008-03-25. 
21. ^ Franklin, Katie (2008-03-25). "Man has first full-face transplant". London: telegraph.co.uk. http://www.telegraph.co.uk/news/main.jhtml?xml=/news/2008/03/23/wface123.xml. Retrieved 2008-03-25. 
22. ^ "Gleevec Holds Potential As First Drug To Successfully Treat Neurofibromatosis, Scientists Report", Science Daily, October 31, 2008
23. ^ "Washington University Neurofibromatosis Center receives Department of Defense grant to participate in NF Clinical Trials Consortium", July 1, 2007, Press release