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© Borgis - Postępy Nauk Medycznych 11, s. 866-869
*Stanisław Zajączek
Neurofibromatosis type II (NF2)
Nerwiakowłókniakowatość typu II (NF2)
International Hereditary Cancer Center, Genetics and Pathology Unit, Cytogenetics Unit, Department of Pathology, Pomeranian Medical University, Szczecin
Head of the Genetics and Pathology Unit: prof. dr hab. med. Jan Lubiński Head of the Cytogenetics Unit: prof. dr. hab. Stanisław Zajączek Streszczenie
NF2 jest rzadką chorobą autosomalnie dominującą, ze złym rokowaniem, wynikającą z mutacji genu merliny. Gen zlokalizowany jest w chromosomie 22q12.2. Merlina jest białkiem, uczestniczącym w szlaku sygnałowym onkogenu RAS. Ryzyko przekazania choroby potomstwu wynosi 50% a penetracja sięga 100%. Zmiany skórne są zbliżone do obserwowanych w NF1 lecz słabiej espresjonowane. Mimo podobnej nazwy i objawów NF2 jest chorobą całkowicie odmienną od NF1. Charakteryzuje się ona obustronnie synchronicznie lub metachronicznie pojawiającymi się guzami typu schwannoma n. słuchowego ale także o innych lokalizacjach w obrębie układu nerwowego. Niemal zawsze rozwijają się one przed 30 r.ż. Pierwszymi objawami mogą być: motoneuropatia i zaćma. Plamy café-au-lait występują zwykle w liczbie mniejszej niż 6 i są mniejsze, aniżeli w NF1. Również zmiany oczne mają inny charakter i powodują tylko dyskretne objawy. Wczesne objawy są wywołane przez guzy przedsionkowe i mogą się ograniczać do dyskretnych, asymetrycznych, postępujących deficytów słuchu. Guzy znacznych rozmiarów mogą pozostawać nierozpoznane. Około połowa przypadków ma charakter rodzinny, pozostałe wynikają z mutacji de novo. 20-30% przypadków sporadycznych ma charakter mozaikowy. Rozpoznanie, podobnie jak w NF1 ustalane jest w oparciu o objawy kliniczne i kryteria NIH. Diagnostyka mutacji jest możliwa a jej efektywność w ostatnich latach znacznie wzrosła; możliwa jest także diagnostyka prenatalna. Przedstawiono zasady poradnictwa genetycznego i opieki medycznej w rodzinach z NF2. Słowa kluczowe: neurofibromatosis II, schwannoma n. słuchowego, opieka i poradnictwo rodzinne
Summary
NF2 is a rare autosomal dominant disorder, with poor prognosis, due to merlin gene mutations. The gene was localized to chromosome 22q12.2. Merlin is a protein probably involved in oncogene RAS signaling pathway. Risk of inheritance is ~50%. The penetrance reaches up to almost 100%. Skin lesions are similar to those observed in NF1 but usually of lower expression. Despite the similar name and some clinical signs NF2 is completely different from NF1. NF2 is characterized by the high risk of bilateral vestibular schwannomas and other tumors of nerve tissue. Almost all affected people develop tumors by the age of 30. VS tumors develop bilaterally either synchronically or metachronically. Motoneuropathy and cataracts may be the first signs and occur, in some cases, in childhood. Café-au-lait spots hardly ever reach the number of six which is typical for NF1. They are smaller and never associated with pigmented skin lesions. Eye lesions are different compare to NF1 and cause only subtle vision defects Early symptoms are usually caused by VS. Generally it takes many years to develop a clinically noticeable progressive, asymmetric hearing deficit. Even huge VS may be not diagnosed. About 50% of the cases are familial, the rest occur due to de novo mutations. 25-30% of non-familial cases are mosaic for an NF2 mutation. Large submicroscopic deletions are present in 10-15% of families. Clinical diagnosis can be made, similar to NF1, by employing NIH clinical consensus criteria. Mutation scanning is used and in recent years its effectiveness grows. Prenatal diagnosis is also possible. The chapter presents the principles of the genetic counseling and medical care for families with NF2. Key words: neurofibromatosis 2, merlin, vestibular schwannoma, medical care and genetic counseling
NF2 has an autosomal dominant pattern of inheritance. The penetrance reaches up to almost 100%. Skin lesions are similar to those observed in NF1 but usually of lower expression. However, NF2 is a completely distinct disease, caused by merlin gene mutations at chromosome 22q12. NF2 is a rare occurrence. In Europe it is diagnosed with the frequency of 1:200,000. Those numbers seem to be underestimated and the true prevalence in live newborns is estimated to be 1:25-45,000. In half of cases the disease is a result of a de novo germinal mutation (1, 5, 7, 8).
THE DIAGNOSIS AND THE CLINICAL COURSE OF THE DISEASE
There are three groups of symptoms characteristic for NF2:
1. Tumors; typically vestibular schwannomas
2. Skin lesions: café-au-lait (CAL) spots, sometimes nodules; its number and size are generally smaller compared to NF1.
3. Eye lesions such as cataracts, clouding of the lens, pigmented lesions and hamartomas of the retina
The most common tumors is NF2, previously referred to as acoustic neurinomas, are now denoted vestibular schwannomas (VS) according to NIH Consensus Conference of Acoustic Neuroma in 1992 (9). The clinical features and the frequency of NF2 are presented in table 1.
Table 1. Major symptoms of NF2 and their frequency (%).
The diagnostic criteria of NF2, (a modification of NIH Consensus for easier use) are the following:
1) Bilateral VS histologically confirmed or seen with gadolinium-enhanced MRI.
2) A first-degree relative with NF2 diagnosed.
a) The unilateral VS in the patient.
b) The presence of at least two of the following: meningioma, glioma, schwannoma, subcapsular lens clouding, brain calcifications.
3) The unilateral VS and the presence of at least two of the following lesions: meningioma, glioma, schwannoma, subcapsular lens clouding, brain calcifications.
4) Two or more meningiomata and the presence of at least one of the following: glioma, schwannoma, subcapsular lens clouding, brain calcifications.
VS tumors develop bilaterally either synchronically or metachronically in 85-95% of cases. When asynchronous tumors appear at a mean interval of 7.5 years (~20 years of patient age) tinnitus, vertigo, and gradual, subtle hearing loss are uncharacteristic early symptoms of VS (2, 3,7).
Schwannomas with localization other than the hearing organ are also observed with the frequency of 75-90%. They can develop in the brainstem as well. Only 26% are symptomatic at diagnosis. X-rays and an intraoperative examinations are not able to distinguish them from neurofibromas of the spinal cord that appear in NF1. The diagnosis can be settled based on histopatological examination (7).
Café-au-lait spots hardly ever reach the number of six which is typical for NF1. They are smaller and never associated with pigmented skin lesions in the armpit region.
Peripheral nerve tumors have the following clinical presentation (2, 7):
– skin nodules (NF2 plaques); present in half of all patients, well circumscribed, elevated lesions of rough surface, smaller than 2 cm, typically hair in the lesion.
– NF1-like nodules; present in about 40% of patients.
Peripheral nerve lesions are always structurally schwannomas.
Eye lesions such as subcapsular lens clouding, various types of cataract, retinal pigment epithelium hypertrophy, and retinal hamartomas cause only subtle vision defects scarcely reported by patients (2, 3, 7).
First detectable symptoms of NF2 are usually identified at the age of 20 (2-52 years). The diagnosis in expert institutions is established at an average age of 27-28 years. However, 10% of patients might have been diagnosed at the age of 10 years when the disease was asymptomatic (3, 7).
Early symptoms are usually caused by VS. Generally it takes many years to develop a clinically noticeable hearing deficit. Even huge VS may be asymptomatic. Surgical intervention usually leads to hearing loss. It makes such treatment difficult to recommend (7).
Heterogeneity of the symptoms in NF2 is common. Nevertheless, there are two typical forms of NF2:
– Moderate (Gardner, 1, A type); the onset (about 25 years old) of symptoms associated predominantly with VS, poor development of other types of tumors and skin lesions;
– Severe (Wishart, 2, B type); the onset of symptoms before the age of 25 years, VS development in half of patients, frequent, huge, multifocal tumors in different locations, rapid progression, frequently fatal before puberty (1, 2, 7, 10).
Eventually, the disease becomes incurable and the prognosis is fatal. The average survival of a patient from expert British institutions is 15 years. Average life expectancy is 36 years (3).
MOLECULAR DIAGNOSIS OF NF2
The NF2 gene of the known sequence is located in chromosome 22. It comprises 16 constitutively spliced exons and one alternatively spliced exon. As a result of the alternative splicing the gene encodes at least 2 forms of merlin (protein). These forms have different tissue expression. The NF2 gene sequence is homologous with the gene family referred to as protein 4.1. They, and the merlin, accordingly, intermediate between the external environment and the cellular cytoskeleton.
The mutation type of schwannoma tumors, especially the loss of heterozygosity of constitutive mutations, classifies the NF2 gene into the suppressor group. Long sequence or all gene losses or stop mutations are usually observed. They cause merlin molecule shortening and inactivation. Mild phenotypes of Gardner 1A type are observed in merlin carboxyl terminus mutation carriers. Severe phenotypes of Wishart 2B type are generally observed in stop mutation carriers where the protein is significantly shortened or in long deletion carriers (2, 3).
From a practical point of view, diagnosis is established after the application of all available methods. It is reached in 90% of patients with familial history and in ~70% of patients without such history but who meet the diagnostic criteria.
Patients with long deletions in the NF2 gene form a large group of NF2 patients. High-resolution cytogenetic analyses or FISH may be used to detect such deletions. They appear in a form of aberrations as inversion/deletion, ring, translocation/deletion, etc in chromosome 22. MLPA and/or sequencing serve for smaller deletion and point toward a mutation diagnosis. Mosaic form of a constitutive mutation is relatively common. Probably, it reaches up to 30% of all patients. Leukocyte DNA analysis in such patients show no constitutive mutation. It can be found in tumor tissue DNA or some peripheral tissues. It especially concerns patients with hereditary isolated NF2 (1). Those patients may be difficult to diagnose, due to slow progression and unilateral disease.
The NF2 gene is shorter than the NF1 gene. That factor, amongst others, makes NF2 gene analysis faster and cheaper. Thus, the introduction of NF2 gene analysis into routine diagnostic procedures is realistic. It applies to sequencing and family diagnosis with the use of intra-gene and extra-gene linked markers. Molecular analysis plays a significant role in the identification of carriers among still asymptomatic members of a susceptible family. However, such procedure is doubtful from an ethical and psychological point of view (2, 3).
Frequently used screening techniques, such as SSCP and DGGE, make detecting ~30-65% of actually existing point mutations possible. Most of them are truncating C>T transitions, producing stop codons and a non-functional protein. Missense mutations with completely altered products are rarely detected. Such mutations and, surprisingly, large deletions, lead to no protein production (!) and cause a relatively mild expression and clinical course. Splice site mutations are related to a greater variety of phenotypes. Patients with mutations localized in exons 9-15 and more pronouced expressions of other localizations suffer from a milder course of the disease. Generally, missense mutation disease has a better outcome, compared with nonsense mutations and frameshifts (4).
The real number of huge rearrangements (deletions, duplications, inversions etc.) may currently be only estimated. Recent introduction of MLPA techniques allows for detection in ~15% constitutive cases. The most common are deletions of the promoter, whole gene, intron and exon 1. Some, probably 1/3-1/2 of cases of large-scale alterations, may also be detected by FISH (4).
Frequency of various mutation types differ between familial, sporadic, mosaic and somatic mutations.
Whole gene analysis with detection of large-scale alterations is a gold standard test of molecular diagnostics. In a significant number of families, after mutation has been detected in the proband, linkage analysis may be performed. It is shorter and less cost-consuming (Evans).
A considerable group of patients, probably 15-30% of the cases are mosaic (2, 4). The percentage of abnormal cells and the number of cell lines depend on the time of mutation after conception. Genetic counseling in such cases is troublesome, if ever possible. The basic question is the existence of a mutation in the germline cells of the proband. Mosaic cases frequently demonstrate a milder phenotype, negative findings of peripheral blood DNA screening and, rarely, unilateral expression of the symptoms (4).
DIFFERENTIATION AND SIMILAR DISORDERS (1)
a) NF1:Similarity of some phenotypes, flexibility of the diagnostic criteria, and almost the same historical names may easily lead to wrong diagnosis.
b) Unilateral vestibular schwannoma:It is relatively frequent tumor among the general population. It does not show a constitutive association with NF2. However, the appropriate follow-up is important. Only about 6% of such patients are mosaic form carriers of NF2. The remainder is free from risk. It applies especially to the patients with the onset coming after the age of 55 years. On the other hand, the diagnosis of NF2 is particularly probable, if a unilateral, isolated tumor develops before 30 years of age.
c) Schwannomatosis:This means a development of multiple schwannomas, with the vestibular system being spared. Schwannomas grow intracranially in spinal roots and in peripheral organs. Malignant transformation is seldom. The locus responsible is located on chromosome 22 but it is different from the merlin gene.
d) Meningiomatosis:Multiple meningiomata usually develop after the age of 25-30 years and preserve the vestibular system. The genetic conditioning is different from NF2, but still unknown. Nevertheless, even a single meningioma in a child should be considered as a harbinger of NF2.
PATIENT AND AFFECTED FAMILY CARE (1, 3, 6, 7, 10)
The NF2-oriented diagnosis comprises dermatological, ophthalmologic, neurological, and ENT examinations and an objective hearing test. Formal screenings of family members may be performed earlier but it is obligatory in all first-degree family members at ten years. However, some signs such as vision defects and intracranial meningiomata may be present earlier. Gadolinium-enhanced MRI scans of the brain and the spinal cord are essential, even if the diagnosis is uncertain. The MRI has to be repeated when new symptoms develop. The diagnostic procedures presented above also apply to all first-degree relatives of the patient. In the presence of a tumor, the brainstem electrical response audiometry and gadolinium-enhanced MRI should be performed annually. Spinal tumors may be detected in ~60-80% of the patients, but only 30% of them require surgical treatment. Spinal MRI has to be repeated every 3 years if new symptoms occur.
Molecular analysis of the NF2 gene, if accessible, may verify the diagnosis. However, a diagnosis has to be established even if a molecular analysis is impossible (3, 9). It can be polemic to inform carriers about a mutation during asymptomatic childhood. It seems to be reasonable only if it affects the patient's future life plans such as education and their choice of profession. However, even in such circumstances the risk of negative psychological effects requires extremely delicate patient management (1).
Because of the development of subclinical eye lesions in the majority of mutation carrying children, expert institutions recommend begining the ophthalmologic screening at the age of 10 (2). Objective hearing tests are also recommended to all members of the family. The test records have to be archived for future progression evaluation. They will serve as a valuable reference point.
Surgical treatment of the tumors, especially VS, should be administered only in centers with neurosurgery and ENT wards which are experienced in VS treatment. VS in NF2, in contrary to isolated schwannomas, are frequently multifocal. and more lobular. Due to frequent complications of surgery (facial nerve damage), the risk of surgery and radiotherapy has to be considered. Brainstem and cochlear implants are some of the choices, even though hearing loss is a frequent side effect of the therapy (2). Many patients die early, between 20-30 years of age. (Evans). Piśmiennictwo
1. Evans DG, Huson SM, Neary W: A Genetic Study of Type 2 Neurofibromatosis. II. Guideliness for Genetical Counselling. J Med Genet 1992; 29: 847-52.
2. Evans DG, Huson SM, Neary W: A Clinical Study of Type 2 Neurofibromatosis. Quart J Med 1992; 304: 603-18.
3. Evans DG, Sainio M, Baser ME: Neurofibromatosis type 2. J Med Genet 2000; 37, 12: 897-904.
4. Evans DGE, Wallace A: NF2: Mutations and Menagement of Disease. In Neurofibromatoses, Kofmann D. (ed.) Monogr. In Hum Genet 2008; 16: 154-166, Basel, Karger.
5. Gusella J: Neurofibromatosis at the Millenium, The National Neurofibromatosis Foundation Millenium Lecture 2000; http://www.nf.org
6. Gutmann DH, Consensus Group: The Diagnostic Evaluation and Multidisciplinary Menagement of Neurofibromatosis 1 and Neurofibromatosis 2, J Am Med Assoc 1997; 278: 51-7.
7. Huson SM, Korf B: Phakomatoses: [In:] Emery's and Rimoin's Principles and Practice of Medical Genetics, Churchill-Livingstone, London 2002; 3: 3162-202.
8. Narod SA, Parry DM, Parboosingh J et al.: Neurofibromatosis Type 2 Appears to be a Genetically Heterogenous Disease. Am J Hum Genet 1992; 51: 486-96.
9. National Institutes of Health Consensus Development Conference Statement: Acoustic Neuroma. Neurofibromatosis Res Newsl 1992; 8: 1-7.
10. Riccardi VM: Neurofibromatosis: Phenotype, Natural History and Pathogenesis, 2nd Ed J Hopkins Univ Press, Baltimore 1986.
otrzymano/received: 2010-10-01 zaakceptowano/accepted: 2010-10-29 Adres/address: *Stanisław Zajączek Międzynarodowe Centrum Nowotworów Dziedzicznych Zakład Genetyki i Patomorfologii i Samodzielna Pracownia Cytogenetyki Katedry Patologii Pomorski Uniwersytet Medyczny ul. Połabska 4, 70-115 Szczecin tel.: (91) 466-15-32 e-mail: blue1945@o2.pl Artykuł Neurofibromatosis type II (NF2) w Czytelni Medycznej Borgis. |
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