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Neurofibromatosis is an inherited disorder and is divided into two types. NF 1 is characterized by multiple neurofibromas, acoustic nerve schwannomas, gliomas of the optic nerve, meningiomas, pigmented nodules of the iris, and hyperpigmented spots on the skin (cafe au lait spots). It is associated with a gene on chromosome 17. With time, the neurofibromas may become malignant neurofibrosarcomas. NF 2 is sometimes called central neurofibromatosis. It is caused by a gene on chromosome 22. Bilateral schwannomas of the acoustic nerve and multiple meningiomas are characteristic.


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Usefulness of screening investigations in neurofibromatosis type 1. A study of 152 patients.

Wolkenstein P, Freche B, Zeller J, Revuz J.

Department of Dermatology, Hopital Henri-Mondor, Creteil, France.

Arch Dermatol 1996 Nov;132(11):1333-6 Abstract quote

OBJECTIVE: To evaluate the usefulness of screening investigations in patients with neurofibromatosis type 1 (NF1).

DESIGN: Clinical and screening data were retrospectively collected from a case series of patients with NF1. Screening investigations included an opthalmologic consultation, chest x-ray film, abdominal ultrasonography, cerebral imaging, and analysis of urinary catecholamine levels. Clinical features and complications of patients with NF1 were compared with those of the Neurofibromatoses Institute Clinical Research Program and of the Southeast Wales study patients.

SETTING: Ambulatory care in a referral center.

PATIENTS: Between 1988 and 1992, 152 patients classified as having NF1 according to the criteria of the National Institutes of Health Consensus Development Conference Statement were studied.

MAIN OUTCOME MEASURE: Complications requiring therapeutic action detected using screening investigations vs clinical examination.

RESULTS: Systemic chest x-ray films were taken of 134 patients, and intrathoracic nodules thought to be neurofibromas were discovered in 2 patients. Ninety-three asymptomatic patients had cerebral imaging performed, which showed optic pathway glioma in 12 patients. Abdominal ultrasonography was performed on 62 asymptomatic patients, results of which showed internal neurofibromas in 4 patients. In 2 of these patients, abdominal surgery was performed. Eighty-three patients without hypertension had 24-hour urinary specific catecholamine levels analyzed, which were within the normal range. Clinical features and complications were not different from other large clinical studies. Nearly 400 systematic investigations were performed without clinical orientation, detecting 21 abnormalities. In only 2 cases, these discoveries led to therapeutic action. On the other hand, 22 complications requiring treatment were detected by clinical examination.

CONCLUSION: Clinical follow-up seems to be more beneficial than systematic investigations in patients with NF1.

Type 1 neurofibromatosis: a descriptive analysis of the disorder in 1,728 patients.

Friedman JM, Birch PH.

Department of Medical Genetics, University of British Columbia, Vancouver, Canada

Am J Med Genet 1997 May 16;70(2):138-43 Abstract quote

Type 1 Neurofibromatosis, NF1, is a common genetic disorder with variable clinical manifestations. Although NF1 often is only of cosmetic concern, serious and even lethal complications may occur. It is not possible to predict which symptoms will develop in any affected individual. The NNFF International Database is a multicentre collaborative system for collecting information about this condition.

At the time of this analysis, complete clinical information was available on 1,479 probands and 249 of their affected relatives with NF1. On average, the age at diagnosis of NF1 was 8 years younger in the probands than in the affected relatives (P<.01). Many of the manifestations of NF1 were more frequent in the probands than in their affected relatives. The age-specific prevalence of most manifestations of NF1 increases with age. Despite biases inherent in a convenience sample from specialist clinics, the frequencies of many of the serious manifestations of NF1 are similar to those of two smaller population-based studies. The frequencies in this study are likely representative of patients seen at specialized clinics.

NF1 gene and neurofibromatosis 1.

Rasmussen SA, Friedman JM.

Centers for Disease Control and Prevention, Division of Birth Defects and Developmental Disabilities, Atlanta, GA 30341, USA.

Am J Epidemiol 2000 Jan 1;151(1):33-40 Abstract quote

Neurofibromatosis 1 (NF1), also known as von Recklinghausen disease, is an autosomal dominant condition caused by mutations of the NF1 gene, which is located at chromosome 17q11.2. NF1 is believed to be completely penetrant, but substantial variability in expression of features occurs. Diagnosis of NF1 is based on established clinical criteria.

The presentation of many of the clinical features is age dependent. The average life expectancy of patients with NF1 is probably reduced by 10-15 years, and malignancy is the most common cause of death. The prevalence of clinically diagnosed NF1 ranges from 1/2,000 to 1/5,000 in most population-based studies. A wide variety of NF1 mutations has been found in patients with NF1, but no frequently recurring mutation has been identified. Most studies have not found an obvious relation between particular NF1 mutations and the resulting clinical manifestations. The variability of the NF1 phenotype, even in individuals with the same NF1 gene mutation, suggests that other factors are involved in determining the clinical manifestations, but the nature of these factors has not yet been determined.

Laboratory testing for NF1 mutations is difficult. A protein truncation test is commercially available, but its sensitivity, specificity, and predictive value have not been established. No general, population-based molecular studies of NF1 mutations have been performed. At this time, it appears that the benefits of population-based screening for clinical features of NF1 would not outweigh the costs of screening.


A genetic study of type 2 neurofibromatosis in the United Kingdom. I. Prevalence, mutation rate, fitness, and confirmation of maternal transmission effect on severity.

Evans DG, Huson SM, Donnai D, Neary W, Blair V, Teare D, Newton V, Strachan T, Ramsden R, Harris R.

Department of Medical Genetics, St Mary's Hospital, Manchester.

J Med Genet 1992 Dec;29(12):841-6 Abstract quote

A clinical and genetic study of type 2 neurofibromatosis (NF2) has been carried out in the United Kingdom. Virtually complete ascertainment of cases in the north-west of England was achieved and suggests a population incidence of 1 in 33,000 to 40,000.

In the UK as a whole, 150 cases have been identified and been used to study the clinical and genetic features of NF2. The autosomal dominant inheritance of NF2 was confirmed, 49% of cases were assessed as representing new mutations, and the mutation rate was estimated to be 6.5 x 10(-6). Evidence to support a maternal gene effect was found in that age at onset was 18.17 years in 36 maternally inherited cases and 24.5 in 20 paternally inherited cases (p = 0.027). The preponderance of maternally inherited cases was also significant (p = 0.03). Data are presented which suggest that there are two types of NF2, one with later onset and bilateral vestibular schwannomas as the only usual feature, and the other with earlier onset and multiple other tumours. A considerable number of cases did not fall easily into one or other group and other factors such as maternal effect on severity and anticipation need to be considered.

A genetic study of type 2 neurofibromatosis in the United Kingdom. II. Guidelines for genetic counselling.

Evans DG, Huson SM, Donnai D, Neary W, Blair V, Newton V, Strachan T, Harris R.

Department of Medical Genetics, St Mary's Hospital, Manchester.

J Med Genet 1992 Dec;29(12):847-52 Abstract quote

The major defining features, age at onset of symptoms, and survival in 150 patients with type 2 neurofibromatosis (NF2) have been studied.

The mean age at onset was 21.57 years (n = 110) and no cases presented after 55 years of age. Patients presented with symptoms attributable to vestibular schwannomas (acoustic neuroma), cranial meningiomas, and spinal tumours. In 97 cases studied personally by the authors, skin and eye examination were found to be useful to detect early signs of the condition. Examination of the skin is likely to assist in early diagnosis in at least 10% of cases and examination of the eye for a lens opacity or cataract in at least as many again. There are marked interfamilial differences in disease severity and tumour susceptibility. Vestibular schwannomas are not fully penetrant, but the condition is usually expressed in another way. Alteration to the current diagnostic criteria is advocated to cover the lack of provision for new mutations.

A screening protocol is proposed and the effect of disease heterogeneity on management is discussed.

Neurofibromatosis 2 (NF2): clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity.

Parry DM, Eldridge R, Kaiser-Kupfer MI, Bouzas EA, Pikus A, Patronas N.

Clinical Epidemiology Branch, National Cancer Institute, Bethesda, Maryland 20892.

Am J Med Genet 1994 Oct 1;52(4):450-61 Abstract quote

To determine the spectrum of manifestations in neurofibromatosis 2 (NF2) and to assess possible heterogeneity, we evaluated 63 affected individuals from 32 families.

Work-up included skin and neurologic examinations, audiometry, a complete ophthalmology examination with slit-lamp biomicroscopy of the lens and fundus, and gadolinium-enhanced MRI of the brain and, in some, of the spine. Mean age-at-onset in 58 individuals was 20.3 years; initial symptoms resulted from vestibular schwannomas (44.4%), other CNS tumors (22.2%), skin tumors (12.7%), and ocular manifestations including cataracts and retinal hamartomas (12.7%). Five asymptomatic individuals were diagnosed through screening. Vestibular schwannomas were documented in 62 individuals (98.4%); other findings included cataracts (81.0%), skin tumors (67.7%), spinal tumors (67.4%), and meningiomas (49.2%). Usually, clinical manifestations and course were similar within families but differed among families. To assess possible heterogeneity, we assigned affected individuals to three proposed subtypes (representing mild, intermediate, and severe NF2) based on age-at-onset, presence or absence of CNS tumors other than vestibular schwannomas, and presence or absence of retinal hamartomas. Comparisons among the three subtypes for many clinical parameters demonstrated that patients in the mild subtype differed from those in the other two subtypes for most parameters, but that none of the parameters distinguished patients in the intermediate subtype from those in the severe subtype.

Thus, there are likely two rather than three subtypes of NF2. Classification of patients to subtype may aid in counseling about long-term prognosis and in formulating individualized guidelines for medical surveillance.



Ampullary Adenocarcinoma in Neurofibromatosis Type 1. Case Report and Literature Review

Renato Costi, M.D., Pietro Caruana, M.D., Leopoldo Sarli, M.D., Vincenzo Violi, M.D., Luigi Roncoroni, M.D. and Cesare Bordi, M.D.

Department of Surgery (RC, LS, VV, LR), Institute of General Surgery, and Department of Pathology (PC, CB), Section of Anatomic Pathology, University of Parma School of Medicine, Parma, Italy

Mod Pathol 2001;14:1169-1174 Abstract quote

Periampullary tumors in patients affected by Neurofibromatosis Type 1 (NF-1) are usually carcinoids or stromal tumors and, rarely, adenocarcinomas.

We report a case of an adenocarcinoma of the ampulla of Vater in a 54-year-old woman with NF-1 admitted to the hospital with jaundice and undergoing pancreato-duodenectomy. Histologically, the resected specimen showed an adenocarcinoma of the ampulla as being a part of a complex atypical epithelial proliferation extended from the papilla to the mucosa of the duodenum and distal choledochus, islet-cell adenomatosis of the pancreas and multiple gastric, duodenal, jejunal stromal tumors.

The ampullary and periampullary adenocarcinomas in NF-1 patients have peculiar features, suggesting a widespread predisposition to cancer development in periampullary tissues and requiring widely demolitive surgery. Moreover, they occur at a younger age than those occurring in non-NF-1 patients, may be associated with additional periampullary epithelial tumors, are often operable and may present long survival.


Epidermodysplasia verruciformis associated with neurofibromatosis type 1: coincidental association or model for understanding the underlying mechanism of the disease?

Alpsoy E, Ciftcioglu MA, Keser I, De Villiers EM, Zouboulis CC.

Department of Dermatology, Akdeniz University School of Medicine, 07070 Antalya, Turkey.

Br J Dermatol 2002 Mar;146(3):503-7 Abstract quote

We describe a 25-year-old man with epidermodysplasia verruciformis (EV) associated with neurofibromatosis type 1 (NF1).

The lesions, persisting for more than 15 years, consisted of widespread planar warts on the backs of the hands and wrists, and reddish-brown macules on the trunk, neck and face. During the last 5 years, our patient developed several epithelial tumours, namely solar keratoses, plaques of Bowen's disease and squamous cell carcinomas (SCCs). He also presented with NF1 lesions with neurofibromas, cafe-au-lait macules, axillary freckling and Lisch nodules. He had left tibial bowing.

Polymerase chain reaction analysis of the skin lesions demonstrated the presence of human papillomavirus (HPV) 15 in a flat wart, HPV 20 in a plaque of Bowen's disease, and HPV 15 and HPV 20 in an SCC lesion. Both EV and NF1 show an inherited predisposition to malignancy but the molecular mechanism underlying tumour development is not fully understood.

The appearance of both diseases in our patient may be a coincidental association but may also contribute to the identification of loci for susceptibility to NF1 and EV on chromosome 17.


Malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1: a clinicopathologic and molecular study of 17 patients.

Leroy K, Dumas V, Martin-Garcia N, Falzone MC, Voisin MC, Wechsler J, Revuz J, Creange A, Levy E, Lantieri L, Zeller J, Wolkenstein P.

Department of Dermatology, Henri-Mondor Hospital, F-94010 Creteil CEDEX, France.

Arch Dermatol 2001 Jul;137(7):908-13 Abstract quote

OBJECTIVE: To identify potential prognostic factors and criteria for early detection of malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1 (NF1).

DESIGN: Retrospective study of malignant peripheral nerve sheath tumors in a cohort of 395 patients with NF1 followed up between October 1, 1988, and January 1, 1999; review of the clinical and histological characteristics of treatment and course; and analysis of p53 mutations and overexpression in tumors.

SETTING: Teaching hospital referral neurofibromatosis center for adults.

PATIENTS: Seventeen patients with NF1 (9 males and 8 females). Mean +/- SD patient age at diagnosis was 32 +/- 14 years.

MAIN OUTCOME MEASURES: (1) Clinical symptoms, (2) comparison of p53 mutations and overexpression in benign vs malignant tumors; and (3) median survival.

RESULTS: Twelve patients had high-grade tumors. All tumors except 1 developed on preexisting nodular or plexiform neurofibromas. Pain and enlarging mass were the first and predominant signs. None of the benign tumors displayed significant p53 staining or p53 mutations. Six of 12 malignant tumors significantly overexpressed p53, and 4 of 6 harbored p53 missense mutations. Median survival was 18 months overall, 53 months in peripheral locations, and 21 months in axial locations.

CONCLUSIONS: Malignant peripheral nerve sheath tumors are highly aggressive in NF1. They mostly arise from plexiform or nodular neurofibromas. Investigations and deep biopsy of painful and enlarging nodular or plexiform neurofibromas should be considered in patients with NF1. Late appearance of p53 mutations and overexpression precludes their use as predictive markers of malignant transformation.

Melanocytic nevi are associated with neurofibromas in neurofibromatosis, type I, but not sporadic neurofibromas. A study of 226 cases*.

Ball NJ, Kho GT.

Departments of Pathology and Medicine (Dermatology), The University of British Columbia, Vancouver General Hospital, Vancouver, British Columbia, Canada.

J Cutan Pathol. 2005 Sep;32(8):523-32. Abstract quote  

Background: Neurofibromatosis, type 1, is associated with cutaneous melanin pigmentation, but an association with ordinary melanocytic nevi has not been described.

Methods: This retrospective case-control study was designed to see if neurofibromas in patients with neurofibromatosis, type 1 (NF-1) differ from sporadic neurofibromas (SN) in their incidence of associated melanocytic nevi and other histologic features. Slides from 114 NF-1 were compared with 112 SN and 300 intradermal melanocytic nevi (IDN).

Results: Small lentiginous melanocytic nevi were identified over 13 NF-1 (11%) but no SN (P = 0.0002). Compared with other NF-1, NF-1 with nevi were more frequently associated with melanocytic hyperplasia, giant melanosomes and diffuse neurofibroma (P < 0.03). Compared with SN, NF-1 were also more frequently associated with melanocytic hyperplasia, lentigo simplex-like changes, diffuse neurofibroma and plexiform neurofibroma (P < 0.001). Sebaceous hyperplasia (14%), dermal elastosis (9%), lipomatous change (8%), epithelial cysts (4%) and keratin granulomas or folliculitis (3%) were not significantly different in prevalence between NF-1, SN and the control group of IDN.

Conclusions: This study suggests that there is a difference in the potential for melanocytic proliferation in NF-1 compared with SN. NF-1, SN and IDN are associated with a similar range of incidental histologic changes.



An analysis of variation in expression of neurofibromatosis (NF) type 1 (NF1): evidence for modifying genes.

Easton DF, Ponder MA, Huson SM, Ponder BA.

Department of Pathology, University of Cambridge, England.

Am J Hum Genet 1993 Aug;53(2):305-13 Abstract quote

Neurofibromatosis (NF) type 1 (NF1) is notable for its variable expression.

To determine whether variation in expression has an inherited component, we examined 175 individuals in 48 NF families, including six MZ twin pairs. Three quantitative traits were scored--number of cafe-au-lait patches, number of cutaneous neurofibromas, and head circumference; and five binary traits were scored--the presence or absence of plexiform neurofibromas, optic gliomas, scoliosis, epilepsy, and referral for remedial education. For cafe-au-lait patches and neurofibromas, correlation was highest between MZ twins, less high between first-degree relatives, and lower still between more distant relatives. The high correlation between MZ twins suggests a strong genetic component in variation of expression, but the low correlation between distant relatives suggests that the type of mutation at the NF1 locus itself plays only a minor role. All of the five binary traits, with the exception of plexiform neurofibromas, also showed significant familial clustering. The familial effects for these traits were consistent with polygenic effects, but there were insufficient data to rule out other models, including a significant effect of different NF1 mutations. There was no evidence of any association between the different traits in affected individuals.

We conclude that the phenotypic expression of NF1 is to a large extent determined by the genotype at other "modifying" loci and that these modifying genes are trait specific.

Neurofibromatosis type 1: pathology, clinical features and molecular genetics.

von Deimling A, Krone W, Menon AG.

Department of Neuropathology, University of Bonn Medical Center, Germany

Brain Pathol 1995 Apr;5(2):153-62 Abstract quote

Neurofibromatosis type 1 (NF1) or von Recklinghausen neurofibomatosis, is a common heritable neurocutaneous disorder. This disorder appears to affect all races, with a prevalence estimated to be 1 in 3000. Approximately half of all cases of NF1 represent new mutations. The characteristics of NF1, which include cafe-au-lait spots, neurofibromas, Lisch nodules, optic glioma, osseous lesions, macrocephaly, short stature and mental retardation suggest that the genetic lesion affects the proper development of multiple organ systems.

Within the past few years, the gene causing NF1 has been identified and the protein encoded by this gene, neurofibromin, has been the subject of detailed investigation. The NF1 gene spans over 350 kb of genomic DNA and encodes a protein product of 2818 amino acids. Neurofibromin is expressed in many different tissues. It is now known that one role of neurofibromin is as a GTPase activating protein (GAP), very likely in the same pathway of signal transduction as ras. Absence of neurofibromin in mice homozygously mutant for the NF1 gene results in profound developmental abnormalities. In mice that are heterozygous for NF1, an accelerated onset of tumor formation is observed.

Combined with studies of tumors from NF1 patients showing homozygous deletions in the NF1 gene, these data suggest a role for NF1 as a "tumor suppressor". Evidence suggesting other roles played by neurofibromin, in control of proliferation in some situations and differentiation in others, is gradually bringing the previously hazy picture of this genetic disorder into sharper focus.

Chromosome 17 loss-of-heterozygosity studies in benign and malignant tumors in neurofibromatosis type 1.

Rasmussen SA, Overman J, Thomson SA, Colman SD, Abernathy CR, Trimpert RE, Moose R, Virdi G, Roux K, Bauer M, Rojiani AM, Maria BL, Muir D, Wallace MR.

Department of Pediatrics, Division of Genetics, University of Florida College of Medicine, Gainesville, Florida, USA.

Genes Chromosomes Cancer 2000 Aug;28(4):425-31 Abstract quote

Neurofibromatosis type 1 (NF1) is a common autosomal dominant condition characterized by benign tumor (neurofibroma) growth and increased risk of malignancy. Dermal neurofibromas, arising from superficial nerves, are primarily of cosmetic significance, whereas plexiform neurofibromas, typically larger and associated with deeply placed nerves, extend into contiguous tissues and may cause serious functional impairment. Malignant peripheral nerve sheath tumors (MPNSTs) seem to arise from plexiform neurofibromas. The NF1 gene, on chromosome segment 17q11.2, encodes a protein that has tumor suppressor function. Loss of heterozygosity (LOH) for NF1 has been reported in some neurofibromas and NF1 malignancies, but plexiform tumors have been poorly represented. Also, the studies did not always employ the same markers, preventing simple comparison of the frequency and extent of LOH among different tumor types.

Our chromosome 17 LOH analysis in a cohort of three tumor types was positive for NF1 allele loss in 2/15 (13%) dermal neurofibromas, 4/10 (40%) plexiform neurofibromas, and 3/5 (60%) MPNSTs. Although the region of loss varied, the p arm (including TP53) was lost only in malignant tumors. The losses in the plexiform tumors all included sequences distal to NF1. No subtle TP53 mutations were found in any tumors. This study also reports the identification of both NF1 "hits" in plexiform tumors, further supporting the tumor suppressor role of the NF1 gene in this tumor type.

Molecular characterization and gene content of breakpoint boundaries in patients with neurofibromatosis type 1 with 17q11.2 microdeletions.

Jenne DE, Tinschert S, Reimann H, Lasinger W, Thiel G, Hameister H, Kehrer-Sawatzki H.

Max-Planck-Institute of Neurobiology, Department of Neuroimmunology, Martinsried, Germany.

Am J Hum Genet 2001 Sep;69(3):516-27 Abstract quote

Homologous recombination between poorly characterized regions flanking the NF1 locus causes the constitutional loss of approximately 1.5 Mb from 17q11.2 covering > or =11 genes in 5%-20% of patients with neurofibromatosis type 1 (NF1).

To elucidate the extent of microheterogeneity at the deletion boundaries, we used single-copy DNA fragments from the extreme ends of the deleted segment to perform FISH on metaphase chromosomes from eight patients with NF1 who had large deletions. In six patients, these probes were deleted, suggesting that breakage and fusions occurred within the adjacent highly homologous sequences. Reexamination of the deleted region revealed two novel functional genes FLJ12735 (AK022797) and KIAA0653-related (WI-12393 and AJ314647), the latter of which is located closest to the distal boundary and is partially duplicated. We defined the complete reading frames for these genes and two expressed-sequence tag (EST) clusters that were reported elsewhere and are associated with the markers SHGC-2390 and WI-9521. Hybrid cell lines carrying only the deleted chromosome 17 were generated from two patients and used to identify the fusion sequences by junction-specific PCRs. The proximal breakpoints were found between positions 125279 and 125479 in one patient and within 4 kb of position 143000 on BAC R-271K11 (AC005562) in three patients, and the distal breakpoints were found at the precise homologous position on R-640N20 (AC023278). The interstitial 17q11.2 microdeletion arises from unequal crossover between two highly homologous WI-12393-derived 60-kb duplicons separated by approximately 1.5 Mb.

Since patients with the NF1 large-deletion syndrome have a significantly increased risk of neurofibroma development and mental retardation, hemizygosity for genes from the deleted region around the neurofibromin locus (CYTOR4, FLJ12735, FLJ22729, HSA272195 (centaurin-alpha2), NF1, OMGP, EVI2A, EVI2B, WI-9521, HSA272196, HCA66, KIAA0160, and WI-12393) may contribute to the severe phenotype of these patients.

Somatic NF1 mutational spectrum in benign neurofibromas: mRNA splice defects are common among point mutations.

Serra E, Ars E, Ravella A, Sanchez A, Puig S, Rosenbaum T, Estivill X, Lazaro C.

Centre de Genetica Medica i Molecular--IRO, Hospital Duran i Reynals, Barcelona, Spain.

Hum Genet 2001 May;108(5):416-29 Abstract quote

Neurofibromas, benign tumors that originate from the peripheral nerve sheath, are a hallmark of neurofibromatosis type 1 (NF1). Although loss of heterozygosity (LOH) is a common phenomenon in this neoplasia, it only accounts for part of the somatic NF1 mutations found. Somatic point mutations or the presence of "two hits" in the NF1 gene have only been reported for a few neurofibromas. The large size of the NF1 gene together with the multicellular composition of these tumors has greatly hampered their molecular characterization.

Here, we present the somatic NF1 mutational analysis of the whole set of neurofibromas studied by our group and consisting in 126 tumors derived from 32 NF1 patients. We report the identification of 45 independent somatic NF1 mutations, 20 of which are reported for the first time. Different types of point mutations together with LOH affecting the NF1 gene and its surrounding region or extending along the 17q arm have been found. Among point mutations, those affecting the correct splicing of the NF1 gene are common, coinciding with results reported on germline NF1 mutations. In most cases, we have been able to confirm that both copies of the NF1 gene are inactivated.

We have also found that both somatic and germline mutations can be expressed at the RNA level in the neoplastic cells. Furthermore, we have observed that the study of more than one tumor derived from the same patient is useful for the identification of the germline mutation. Finally, we have noticed that the culture of neurofibromas and their fibroblast clearance facilitates LOH detection in cases in which it is difficult to determine.

Mutations affecting mRNA splicing are the most common molecular defects in patients with neurofibromatosis type 1.

Ars E, Serra E, Garcia J, Kruyer H, Gaona A, Lazaro C, Estivill X.

Medical and Molecular Genetics Center-IRO, Hospital Duran i Reynals, Avia. Castelldefels, Km 2.7, L'Hospitalet de Llobregat, 08907 Barcelona, Spain.

Hum Mol Genet 2000 Jan 22;9(2):237-47 Abstract quote

Neurofibromatosis type 1 (NF1) is one of the most common inherited disorders in humans and is caused by mutations in the NF1 gene. To date, the majority of the reported NF1 mutations are predicted to result in protein truncation, but very few studies have correlated the causative NF1 mutation with its effect at the mRNA level.

We have applied a whole NF1 cDNA screening methodology to the study of 80 unrelated NF1 patients and have identified 44 different mutations, 32 being novel, in 52 of these patients. Mutations were detected in 87% of the familial cases, but in 51% of the sporadic ones. At least 15 of the 80 NF1 patients (19%) had recurrent mutations. The study shows that in 50% of the patients in whom the mutations were identified, these resulted in splicing alterations. Most of the splicing mutations did not involve the conserved AG/GT dinucleotides of the splice sites. One frameshift, two nonsense and two missense mutations were also responsible for alterations in mRNA splicing. The location and type of mutation within the NF1 gene, and its putative effect at the protein level, do not indicate any relationship to any specific clinical feature of NF1.

The high proportion of aberrant spliced transcripts detected in NF1 patients stresses the importance of studying mutations at both the genomic and RNA level. It is possible that part of the clinical variability in NF1 could be due to mutations affecting mRNA splicing, which is the most common molecular defect in NF1.


Genetic aberrations in sporadic and neurofibromatosis 2 (NF2)-associated schwannomas studied by comparative genomic hybridization (CGH).

Antinheimo J, Sallinen SL, Sallinen P, Haapasalo H, Helin H, Horelli-Kuitunen N, Wessman M, Sainio M, Jaaskelainen J, Carpen O.

Department of Neurosurgery, University of Helsinki, Finland.

Acta Neurochir (Wien) 2000;142(10):1099-104; Abstract quote

BACKGROUND: Schwannomas occur sporadically or in association with neurofibromatosis 2 (NF2), an autosomal dominant disorder, which predisposes to multiple schwannomas, meningiomas and spinal ependymomas, with bilateral vestibular schwannomas as the classic hallmark. As NF2 and sporadic schwannomas differ in some respect in their clinical and biological behavior we evaluated whether there are any differences in the distribution of genetic aberrations between NF2 and sporadic schwannomas. Our interest was also to verify whether secondary genetic alterations besides the loss of 22q could be detected in schwannomas.

METHODS: We investigated DNA copy number changes in 25 schwannomas (12 NF2 and 13 sporadic schwannomas) using the comparative genomic hybridization (CGH) technique. Some chromosomal regions were further studied by LOH or FISH analysis.

FINDINGS: CGH detected genomic abnormalities in 15 of 25 schwannomas (60%). The most common alteration was loss on 22q, found in 32% (8/25) of schwannomas. No consistent changes were detected in other chromosomal regions. The overall number of genetic aberrations was similar in NF2 and in sporadic schwannomas.

INTERPRETATION: Our results support the present view that loss of chromosome 22q harboring the NF2 gene plays a universal role in the pathogenesis of schwannomas without consistent involvement of other chromosomal regions.

Analysis of the human neurofibromatosis type 2 gene promoter and its expression.

Welling DB, Akhmametyeva EM, Daniels RL, Lasak JM, Zhu L, Miles-Markley BA, Chang LS.

Department of Otolaryngology, Ohio State University and Children's Hospital, USA.

Otolaryngol Head Neck Surg 2000 Oct;123(4):413-8 Abstract quote

OBJECTIVE: It is hypothesized that transcriptional regulation plays an important role for neurofibromatosis type 2 (NF2) expression in Schwann cells and other cell types. The objective of this study is the isolation and characterization of the transcriptional regulatory elements of the NF2 gene.

Study Design and Setting: A bacterial artificial chromosome library and a partial genomic DNA library were used to isolate the human NF2 gene; NF2 promoter-luciferase constructs were generated, and promoter activities were assayed. This study was carried out in a molecular biology laboratory.

RESULTS: A bacterial artificial chromosome clone with an approximately 100-kilobase insert containing nearly the entire human NF2 gene has been isolated. An additional 5' NF2 sequence has also been cloned. Transient transfection experiments demonstrate strong promoter activity from the NF2 5' flanking DNA.

CONCLUSIONS: The NF2 gene is approximately 100 kilobases long. Both positive and negative regulatory elements are present in NF2 5' flanking regions.

SIGNIFICANCE: Better understanding of the NF2 gene and its regulation will improve molecular diagnostics and ultimately treatment of patients with NF2.

The parental origin of new mutations in neurofibromatosis 2.

Kluwe L, Mautner V, Parry DM, Jacoby LB, Baser M, Gusella J, Davis K, Stavrou D, MacCollin M.

Department of Neurosurgery, University Hospital Eppendorf, Hamburg, Germany.

Neurogenetics 2000 Sep;3(1):17-24 Abstract quote

Neurofibromatosis 2 (NF2) is an autosomal dominant disorder characterized by schwannomas and meningiomas that develop after inactivation of both copies of the NF2 gene. Approximately half of all patients with NF2 have unaffected parents and the disease results from new mutations at the NF2 locus. Loss of heterozygosity (LOH) in tumor specimens due to deletions covering the normal NF2 allele can be used to infer the haplotypes surrounding underlying mutations and determine the allelic origin of new mutations.

We studied 71 sporadic NF2 patients using both LOH and pedigree analysis and compared the parental origin of the new mutation with the underlying molecular change. In the 45 informative individuals, 31 mutations (69%) were of paternal and 14 (31%) were of maternal origin (P=0.016). Comparison with corresponding constitutional mutations revealed no correlation between parental origin and the type or location of the mutations. However, in 4 of 6 patients with somatic mosaicism the NF2 mutation was of maternal origin.

A slight parent of origin effect on severity of disease was found. Further clinical and molecular studies are needed to determine the basis of these unexpected observations.


Neurofibromin and NF1 Gene Analysis in Composite Pheochromocytoma and Tumors Associated with von Recklinghausen's Disease.

Kimura N, Watanabe T, Fukase M, Wakita A, Noshiro T, Kimura I.

Department of Pathology and Laboratory Medicine (NK), Tohoku Rosai Hospital, Sendai.

Mod Pathol 2002 Mar;15(3):183-8 Abstract quote

Composite tumor of pheochromocytoma and neuroblastoma, or ganglioneuroma, or ganglioneuroblastoma (composite pheochromocytoma), also known as mixed neuroendocrine and neural tumor, are sometimes combined with neurofibromatosis type 1 (NF1).

To better understand the relationship between NF1 and composite pheochromocytoma, an immunohistochemical study using anti-neuro-fibromin that is an NF1 gene product and DNA sequence of NF1 Exon 31 were carried out in five cases of composite pheochromocytoma and in various tumors from five patients with NF1. Neurofibromin was not expressed in Schwann cells and sustentacular cells of composite pheochromocytomas and was very weakly or negatively expressed in neurofibroma of NF1 patients. However, it was strongly expressed in ganglionic cells and pheochromocytoma cells of the composite pheochromocytomas and also in mucosal ganglioneuromas, a gangliocytic paraganglioma, and in pheochromocytomas from the patients with NF1.

Although there was no mutation in NF1 Exon 31, it could not be ruled out that there were mutations in other sites of the NF1 gene. Neurofibromin insufficiency may induce abnormal proliferation of Schwann cells in composite pheochromocytomas as well as in neurofibromatosis.


Peripheral Nerve Sheath Tumors from Patients with Neurofibromatosis Type 1 Do Not Have the Chromosomal Translocation t(X;18).

Liew MA, Coffin CM, Fletcher JA, Hang MT, Tanito K, Niimura M, Viskochil D.

Department of Pediatrics, Division of Medical Genetics, University of Utah, 50 North Medical Drive, Salt Lake City, UT 84132, USA.

Pediatr Dev Pathol 2002 Mar-Apr;5(2):165-9 Abstract quote

Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder that is caused by a mutation in the NF1 gene. Hallmark characteristics include dermal neurofibromas, cafe-au-lait spots, and learning disabilities. In approximately 25% of NF1 cases, plexiform neurofibromas, or peripheral nerve sheath tumors (PNSTs) that involve large segments of nerve sheath and nerve root, can form, of which a small percentage become malignant (MPNST). Most MPNSTs are composed of spindled neoplastic cells, and they can resemble other spindle-cell sarcomas, including leiomyosarcoma and monophasic synovial sarcoma. Histological diagnosis of MPNST is not always straightforward, and various immunohistochemical and molecular adjuncts can be critical in establishing a correct diagnosis.

One example of genetic testing is the assay for the t(X;18) chromosomal translocation, which has been found to be common in synovial sarcomas. The aim of this study was to determine whether MPNSTs contain the t(X;18) chromosomal translocation. To detect the t(X;18) translocation product, SYT-SSX, total RNA was extracted from frozen archival tumors (15 dermal neurofibromas, 4 plexiform neurofibromas, and 7 MPNSTs) using Trizol. The RNA was then subjected to reverse-transcriptase polymerase chain reaction (RT-PCR) to specifically amplify SYT-SSX.

None of the dermal neurofibromas, plexiform neurofibromas, or MPNSTs analyzed were positive for SYT-SSX mRNA. The results indicate that the t(X;18) translocation is absent in neurofibromas and is not a marker for MPNST in patients with NF1.



A genetic study of neurofibromatosis type 1 (NF1) in south-western Ontario. II. A PCR based approach to molecular and prenatal diagnosis using linkage.

Rodenhiser DI, Ainsworth PJ, Coulter-Mackie MB, Singh SM, Jung JH.

Molecular Medical Genetics Program, Children's Hospital of Western Ontario, London, Canada.

J Med Genet 1993 May;30(5):363-8 Abstract quote

Neurofibromatosis type 1 (NF1) is a common, autosomal dominant genetic disorder with a variety of highly variable symptoms including cutaneous manifestations (such as cafe au lait spots), Lisch nodules, plexiform neurofibromas, skeletal abnormalities, an increased risk for malignancy, and the development of learning disabilities. The wide clinical variability of expression of the disease phenotype and high (spontaneous) mutation rate of the NF1 gene indicate that careful clinical examination of patients and family members is necessary to provide an accurate diagnosis of the disease. Since very few NF1 mutations have been identified, and with the apparent lack of a predominant mutation in this large, highly mutable gene, molecular diagnosis of NF1 will continue to be based on haplotypes using linkage analysis.

Here we report our experiences while providing a molecular diagnostic service for NF1 in the ethnically diverse region of south-western Ontario. Molecular diagnoses with at least one informative probe/enzyme combination are reported for 19 families including two families requesting prenatal diagnosis for NF1.

We have augmented the classical Southern based approach to linkage analysis with the use of PCR based assays for molecular linkage. Furthermore, criteria have been established in our laboratory for executing molecular linkage based on heterozygosity values, recombination fractions, and the use of intragenic probes/markers.

The Genoa experience of prenatal diagnosis in NF1.

Origone P, Bonioli E, Panucci E, Costabel S, Ajmar F, Coviello DA.

Department of Oncology, Biology and Genetics, University of Genoa, Italy.

Prenat Diagn 2000 Sep;20(9):719-24 Abstract quote

Type 1 neurofibromatosis (NF1) is an autosomal dominant disorder with an incidence of about 1 in 3500 live births. Symptoms are highly variable from a few cafe-au-lait spots and axillary freckling to plexiform neurofibromas, optic gliomas, pseudarthrosis, and malignancy. Since disease causing mutations are dispersed throughout the gene, prenatal diagnosis is usually performed in familial cases by linkage analysis and rarely by direct characterization of the mutation.

We have characterized 48 families and have performed four prenatal diagnoses. In three cases, the linkage analysis was carried out using informative markers. A direct approach using the protein truncation test (PTT) and sequencing was performed in one case in which a R1947X mutation was identified. The extreme variability of the phenotypic expression of the NF1 gene makes reproductive decisions in NF1 families very difficult, as molecular diagnosis cannot predict clinical expression of the disease.

The psychological management of the couple is therefore difficult. In two of the three examined families the reproductive choices were not influenced by the specific manifestations of the disease in that family.

Proton magnetic resonance spectroscopy of brain lesions in children with neurofibromatosis type 1.

Wilkinson ID, Griffiths PD, Wales JK.

Section of Academic Radiology, University of Sheffield, England, Sheffield, UK

Magn Reson Imaging 2001 Oct;19(8):1081-9 Abstract quote

Two of the recognized cranial MRI findings in children with neurofibromatosis type 1 (NF1) are neurofibromatosis bright objects (NBO) and brain glioma. Their differential diagnosis can be problematic.

This study aimed to determine the features of these abnormalities on short echo-time in-vivo proton magnetic resonance spectroscopy. Twenty children under the age of 16 with NF1 were studied. A single voxel, short echo-time technique (TE = 20 ms; TR = 5000 ms) was used to obtain proton spectra of typical NBO and any regions suggestive of atypical bright objects or tumor. Nine children without neurofibromatosis with no structural brain abnormality acted as aged-matched comparisons. A semi-quantitative analysis indicated significant increase in choline and myo-inisitol in tumors compared to typical NBO (p < 0.05) and compared to controls (p < 0.05); reduction in the levels of N-acetyl moieties in NBO compared to controls (p < 0.05); reduction in N-acetyl in tumors compared to controls (p < 0.001); and reduction in glutamate/glutamine in tumors compared to controls (p < 0.05).

This cross-sectional data suggests that proton spectroscopy can aid differentiating between NBO and brain (non-optic/hypothalamic) glioma. Typical NBO have different short echo-time spectroscopic appearances compared to normal brain.

Decreased bone mineral density in neurofibromatosis-1 patients with spinal deformities.

Illes T, Halmai V, de Jonge T, Dubousset J.

Department of Orthopaedics, Medical and Health Sciences Center, University of Pecs, Hungary.

Osteoporos Int 2001;12(10):823-7 Abstract quote

A cross-sectional study was carried out to obtain data on the bone mineral density status of a group of neurofibromatosis-1 patients with spinal deformities, and to search for possible accompanying changes in the bone mineral turnover.

Neurofibromatosis-1 is a heredofamiliar disorder that is associated with a variety of skeletal anomalies (mostly spinal deformities) in 10-50% of patients. Intraoperatively, a poor vertebral bone quality has been observed. Efforts have been made to identify factors preventing curve progression, to optimize operational planning and to explain the pathomechanism. As part of the preoperative evaluation, dual-energy X-ray absorptiometry was used to assess the bone mineral density of the lumbar spine in 12 patients with neurofibromatosis-1, supplemented by laboratory blood/urine investigations. A significant decrease in bone mineral density of the lumbar spine was measured. An inverse relation was suggested between the severity of scoliosis and the lumbar spine Z-scores. No pivotal alterations were identified in the laboratory measurements. The bony tissue abnormality observed intraoperatively in neurofibromatosis-1 patients may be described as a diminution of the axial bone mineral density. The biochemical parameters do not support the presence of hyperparathyroidism, renal disorders or other associated diseases influencing the bone mineral turnover.

The evaluation of bone mineral density in the course of the preoperative planning is proposed in neurofibromatosis-1; the exact background and the role of a possible osteoporosis in the prognosis remain to be elucidated.


The neuroimaging and clinical spectrum of neurofibromatosis 2.

Mautner VF, Lindenau M, Baser ME, Hazim W, Tatagiba M, Haase W, Samii M, Wais R, Pulst SM.

Department of Neurology, Allgemeines Krankenhaus Hamburg Ochsenzoll, Germany.

Neurosurgery 1996 May;38(5):880-5; discussion 885-6 Abstract quote

Neurofibromatosis 2 (NF2) is an autosomal dominant disease predisposing to multiple tumors of the central and peripheral nervous system. Bilateral vestibular schwannomas are the hallmark of the disease.

To define the clinical spectrum of the disease, we performed gadolinium-enhanced magnetic resonance imaging of the brain and spine as well as neurological, dermatological, and ocular examinations in 48 patients with NF2 diagnosed with the National Institutes of Health diagnostic criteria. Patients were ascertained from patient workshops and publications and from referral as a result of vestibular schwannoma surgery. Vestibular schwannomas were found in 46 patients (96%, 43 bilateral and 3 unilateral), spinal tumors were found in 43 (90%), posterior subcapsular cataracts were found in 30 (63%), meningiomas were found in 28 (58%), and trigeminal schwannomas were found in 14 (29%). The presenting symptoms included hearing loss or tinnitus in 15 patients (31%), multiple or nonspecific symptoms in 15 (31%), skin tumors in 12 (25%), and ocular symptoms in 6 (13%).

When the complete spine was imaged, spinal tumors were more common in patients with NF2 than has previously been reported. This is a noteworthy finding, because spinal tumors are a major cause of NF2 morbidity and mortality.

Neurofibromatosis type 2 diagnosed in the absence of vestibular schwannomas. A case report and guidelines for a screening protocol for children at risk.

Janse AJ, Tan WF, Majoie CB, Bijlsma EK.

Department of Paediatrics, Wilhelmina Children's Hospital, Utrecht, The Netherlands.

Eur J Pediatr 2001 Jul;160(7):439-43 Abstract quote

A 5-year-old girl presented with multiple tumours of the central nervous system. As on the first MRI scan bilateral vestibular schwannomas were not detected due to their small size, she initially did not meet the criteria for neurofibromatosis type 2 (NF2), although her clinical symptoms were highly suggestive for the diagnosis. Using molecular studies, a mutation in the NF2 gene was found confirming the clinical suspicion at an early age and indicating the value of molecular analysis. Follow-up MRI 3 years later demonstrated bilateral vestibular schwannomas more clearly, since they had increased in size.

CONCLUSION: In children, magnetic resonance imaging can be inconclusive for the diagnosis of neurofibromatosis type 2, since very small vestibular schwannomas may be missed. In these cases molecular studies may provide additional evidence for the diagnosis. We propose guidelines for a screening protocol for children at risk for having neurofibromatosis type 2.

High resolution deletion analysis of constitutional DNA from neurofibromatosis type 2 (NF2) patients using microarray-CGH.

Bruder CE, Hirvela C, Tapia-Paez I, Fransson I, Segraves R, Hamilton G, Zhang XX, Evans DG, Wallace AJ, Baser ME, Zucman-Rossi J, Hergersberg M, Boltshauser E, Papi L, Rouleau GA, Poptodorov G, Jordanova A, Rask-Andersen H, Kluwe L, Mautner V, Sainio M, Hung G, Mathiesen T, Moller C, Pulst SM, Harder H, Heiberg A, Honda M, Niimura M, Sahlen S, Blennow E, Albertson DG, Pinkel D, Dumanski JP.

Department of Molecular Medicine, CMM Building L8, Karolinska Hospital, SE-17176 Stockholm, Sweden.

Hum Mol Genet 2001 Feb 1;10(3):271-82 Abstract quote

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder whose hallmark is bilateral vestibular schwannoma. It displays a pronounced clinical heterogeneity with mild to severe forms. The NF2 tumor suppressor (merlin/schwannomin) has been cloned and extensively analyzed for mutations in patients with different clinical variants of the disease. Correlation between the type of the NF2 gene mutation and the patient phenotype has been suggested to exist. However, several independent studies have shown that a fraction of NF2 patients with various phenotypes have constitutional deletions that partly or entirely remove one copy of the NF2 gene.

The purpose of this study was to examine a 7 Mb interval in the vicinity of the NF2 gene in a large series of NF2 patients in order to determine the frequency and extent of deletions. A total of 116 NF2 patients were analyzed using high-resolution array-comparative genomic hybridization (CGH) on an array covering at least 90% of this region of 22q around the NF2 locus. Deletions, which remove one copy of the entire gene or are predicted to truncate the schwannomin protein, were detected in 8 severe, 10 moderate and 6 mild patients.

This result does not support the correlation between the type of mutation affecting the NF2 gene and the disease phenotype. This work also demonstrates the general usefulness of the array-CGH methodology for rapid and comprehensive detection of small (down to 40 kb) heterozygous and/or homozygous deletions occurring in constitutional or tumor-derived DNA.



Do NF1 gene deletions result in a characteristic phenotype?

Tonsgard JH, Yelavarthi KK, Cushner S, Short MP, Lindgren V.

Department of Pediatrics, University of Chicago, Illinois, USA.

Am J Med Genet 1997 Nov 28;73(1):80-6 Abstract quote

Neurofibromatosis-1 (NF1) is an autosomal dominant disorder with marked variability of expression. Analysis of the NF1 gene (NF1) has detected a variety of mutations without any clear correlation with phenotype. However, deletions which remove all of NF1 have been reported in a small number of patients who have minor facial abnormalities, mental retardation, learning disabilities, and early or excessive burden of cutaneous or plexiform neurofibromas.

The purpose of this study was to determine whether these phenotypic traits are associated with whole gene deletions. Out of 406 of our NF1 patients, 70 patients had manifestations previously associated with gene deletions. Thirty-five of these patients from 26 families were available for study. By fluorescence in situ hybridization (FISH) analysis, 4 were found to have deletions of the entire gene, including 2 sporadic cases, 1 familial case, and 1 case where family history could not be verified. In addition, the mother of the familial case was found to be mosaic for the deletion.

Our results suggest that although large NF1 deletions occur with relatively high frequency in patients with certain findings, the presence of a deletion cannot be predicted solely on the basis of clinical phenotype.

A clinical study of type 1 neurofibromatosis in north west England.

McGaughran JM, Harris DI, Donnai D, Teare D, MacLeod R, Westerbeek R, Kingston H, Super M, Harris R, Evans DG.

Department of Medical Genetics, St Mary's Hospital, Manchester, UK.

J Med Genet 1999 Mar;36(3):197-203 Abstract quote

A clinical study of patients on the North West Regional Genetic Register with neurofibromatosis type 1 (NF1) identified 523 affected cases from 304 families.

In those for whom relevant information was available, 86.7% (383 of 442) had more than six cafe au lait patches, 83.8% (310 of 370) had axillary freckling, 42.3% (151 of 357) had inguinal freckling, and 63% (157 of 249) had Lisch nodules. Cutaneous neurofibromas were present in 59.4% (217 of 365) and 45.5% (150 of 330) were noted to have subcutaneous tumours. Plexiform neurofibromas were present in 15.3% (80 of 523). A positive family history of NF1 was found in 71.2% (327 of 459) and 28.8% (132 of 459) of affected patients were considered to be the result of a new mutation. Learning difficulties of varying severity occurred in 62% (186 of 300). CNS tumours associated with NF1 were reported in 9.4% (49) of patients, optic gliomas occurring in 25 of these, 4.8% of patients. Some degree of scoliosis was reported for 11.7% (61), 1.9% (10) had pseudoarthrosis, 4.3% (23) had epilepsy, and 2.1% (11) had spinal neurofibromas. Actuarial analyses were carried out for both optic glioma and malignant nerve sheath tumours and the data are presented.

Associations of clinical features in neurofibromatosis 1 (NF1).

Szudek J, Birch P, Riccardi VM, Evans DG, Friedman JM.

Department of Medical Genetics, The University of British Columbia, Vancouver, British Columbia, Canada.

Genet Epidemiol 2000 Dec;19(4):429-39 Abstract quote

Neurofibromatosis 1 (NF1), an autosomal dominant disease, exhibits extreme clinical variability. This variability greatly increases the burden for affected families and impairs our ability to understand the pathogenesis of NF1.

Recognition of heterogeneity within a disease may provide important pathogenic insights, therefore we tested clinical data from three large sets of NF1 patients for evidence that certain common features are more likely to occur in some NF1 patients than in others. Clinical information on 4,402 patients with NF1 was obtained from three independent databases. We examined associations between pairs of clinical features in individual affected probands. We also examined associations between the occurrence of individual features in affected relatives. Associations were summarized as odds ratios with 95% confidence intervals. We found associations between several pairs of features in affected probands: intertriginous freckling and Lisch nodules, discrete neurofibromas and plexiform neurofibromas, discrete neurofibromas and Lisch nodules, plexiform neurofibromas and scoliosis, learning disability or mental retardation and seizures. We also found associations between the occurrence of Lisch nodules, macrocephaly, short stature, and learning disability or mental retardation as individual features in parents and children with NF1.

Our observations suggest that, contrary to established belief, some NF1 patients are more likely than others to develop particular manifestations of the disease. Genetic factors appear to determine the development of particular phenotypic features.

Use of the national institutes of health criteria for diagnosis of neurofibromatosis 1 in children.

DeBella K, Szudek J, Friedman JM.

Department of Medical Genetics, University of British Columbia, Vancouver, Canada.

Pediatrics 2000 Mar;105(3 Pt 1):608-14 Abstract quote

OBJECTIVE: The National Institutes of Health (NIH) Diagnostic Criteria for neurofibromatosis 1 (NF1) are very useful clinically, but some individuals who are later shown to have NF1 cannot be diagnosed in early childhood using these criteria. The aim of this study is to determine the value of the NIH Diagnostic Criteria for NF1 in early childhood, to determine the age at which diagnosis can confidently be made, and to clarify the age at onset of the cardinal clinical features used in the NIH Diagnostic Criteria.

METHODS: We studied 1893 NF1 patients under 21 years old from the National Neurofibromatosis Foundation International Database to determine the age at which the features included in the NIH Diagnostic Criteria appear.

RESULTS: Approximately 46% of sporadic NF1 cases fail to meet the NIH Diagnostic Criteria by 1 year of age. Nearly all (97%; 95% confidence interval: 94-98) NF1 patients meet the criteria for diagnosis by 8 years old, and all do so by 20 years old. The usual order of appearance of the clinical features listed as NIH criteria is cafe-au-lait macules, axillary freckling, Lisch nodules, and neurofibromas. Symptomatic optic glioma is usually diagnosed by 3 years old, and characteristic osseous lesions are usually apparent within the first year of life.

CONCLUSION: The diagnosis of NF1 cannot always be made in young children using the NIH Diagnostic Criteria. Modification of these criteria may be necessary for children under 8 years old.

Spinal Neurofibromatosis without Cafe-au-Lait Macules in Two Families with Null Mutations of the NF1 Gene.

Kaufmann D, Muller R, Bartelt B, Wolf M, Kunzi-Rapp K, Hanemann CO, Fahsold R, Hein C, Vogel W, Assum G.

Departments of Human Genetics, University of Ulm, Ulm, Germany.

Am J Hum Genet 2001 Dec;69(6):1395-400 Abstract quote

Spinal neurofibromatosis (SNF) is considered to be an alternative form of neurofibromatosis, showing multiple spinal tumors and cafe-au-lait macules. Involvement of the neurofibromatosis type 1 (NF1) locus has been demonstrated, by linkage analysis, for three families with SNF. In one of them, a cosegregating frameshift mutation in exon 46 of the NF1 gene was identified.

In the present study, we report four individuals from two families who carry NF1 null mutations that would be expected to cause NF1. Three patients have multiple spinal tumors and no cafe-au-lait macules, and the fourth has no clinical signs of NF1. In the first family, a missense mutation (Leu2067Pro) in NF1 exon 33 was found, and, in the second, a splice-site mutation (IVS31-5A-->G) enlarging exon 32 by 4 bp at the 5' end was found. The latter mutation has also been observed in an unrelated patient with classical NF1. Both NF1 mutations cause a reduction in neurofibromin of approximately 50%, with no truncated protein present in the cells.

This demonstrates that typical NF1 null mutations can result in a phenotype that is distinct from classical NF1, showing only a small spectrum of the NF1 symptoms, such as multiple spinal tumors, but not completely fitting the current clinical criteria for SNF. We speculate that this phenotype is caused by an unknown modifying gene that compensates for some, but not all, of the effects caused by neurofibromin deficiency.

Is the distribution of dermal neurofibromas in neurofibromatosis type 1 (NF1) related to the pattern of the skin surface temperature?

Kaufmann D, Tinschert S, Algermissen B.

Abteilung Humangenetik, Universitat Ulm, Albert-Einstein-Allee 11, D 89070 Ulm, Germany.

Eur J Dermatol 2001 Nov-Dec;11(6):521-5 Abstract quote

The formation of dermal neurofibromas is a hallmark of the neurofibromatosis type 1 (NF1). A total loss of the NF1 gene product by stochastic events inactivating the wild type allele in Schwann cells should precede the development of neurofibromas. Dermal neurofibromas tend to be located mainly on the surface of the trunk and not in the body periphery. This distribution partly resembles the density of sensitive nerve endings in the epidermis.

Our hypothesis is that a better correlation concerns the pattern of normal body surface temperature. According to our clinical observations we assume that in skin areas with higher temperatures the number of visible dermal neurofibromas is higher than in colder areas such as the arms/legs or nose. It is known that differences in temperature are able to determine differentiation.

We suggest that the regulation of skin temperature is also involved in the formation of NF1 dermal neurofibromas and is related to the intrafamilial variability in NF1.


Vestibular schwannomas in children.

Pothula VB, Lesser T, Mallucci C, May P, Foy P.

Departments of Otolaryngology and Neurosurgery, University Hospital Aintree, Liverpool, England, U.K.

Otol Neurotol 2001 Nov;22(6):903-7 Abstract quote

OBJECTIVE: This article highlights the clinical presentation and management issues of unilateral vestibular schwannomas in children. We demonstrate how the presentation differs from neurofibromatosis type 2 (NF2) and from adult unilateral vestibular schwannomas.

STUDY DESIGN: This article is composed of a series of three cases and a literature review.

SETTING: The study was performed at a university hospital (tertiary referral center).

PATIENTS: Three children, aged 9, 11, and 13 years, with histologically confirmed vestibular schwannomas were studied. All children under 16 years of age in the world literature with unilateral vestibular schwannomas were reviewed.

INTERVENTION: Analysis of presentation and surgical management of these three children and those children reported in the literature.

MAIN OUTCOME MEASURE: Pattern of presentation relative to children with NF2 and people with adult unilateral vestibular schwannomas.

RESULTS: Two patients had multiple cranial nerve weakness and recurrence, and one patient had successful removal of the tumor with preservation of all functions of the cranial nerves, including the facial nerve.

CONCLUSION: Vestibular schwannomas in children are very uncommon. It is likely that it is the first manifestation of NF2, but it may also be a variant of sporadic vestibular schwannomas. A presentation of three cases and a review of 36 other cases in the literature demonstrates how the presentation is different from adult sporadic vestibular schwannomas and NF2 because it lacks primary audiological symptoms. The study also provides evidence of non-NF2 vestibular schwannomas presenting in children and suggests that it is likely that these are a variant of unilateral sporadic vestibular schwannomas. The search for the features of NF2 in these cases remains mandatory.


The clinical and diagnostic implications of mosaicism in the neurofibromatoses.

Ruggieri M, Huson SM.

Institute of Bioimaging and Pathology of the Central Nervous System, National Research Council, Catania, Italy.

Neurology 2001 Jun 12;56(11):1433-43 Abstract quote

Neurofibromatosis type 1 and type 2 both occur in mosaic forms. Mosaicism results from somatic mutations. Early somatic mutations cause generalized disease, clinically indistinguishable from nonmosaic forms. Later somatic mutation gives rise to localized disease often described as segmental. In individuals with mosaic or localized manifestations of neurofibromatosis type 1 (segmental neurofibromatosis type 1), disease features are limited to the affected area, which varies from a narrow strip to one quadrant and occasionally to one half of the body. Distribution is usually unilateral but can be bilateral, either in a symmetric or asymmetrical arrangement.

Patients with localized neurofibromatosis type 2 have disease-related tumors localized to one part of the nervous system; for example a unilateral vestibular schwannoma with ipsilateral meningiomas or multiple schwannomas in one part of the peripheral nervous system.

The recognition of mosaic phenotypes is important. Individuals with the mosaic form, even with a generalized phenotype, are less likely to have severe disease. They also have lower offspring recurrence risk than individuals with the nonmosaic form. The mosaic forms of neurofibromatosis provide a good example of the effects of somatic mutation. It is increasingly recognized that mild and unusual forms of many dominantly inherited disorders are caused by the same mechanism.



Multinucleate giant cells in neurofibromas: a clue to the diagnosis of neurofibromatosis.

Taungjaruwinai WM, Goldberg LJ.

Department of Dermatology, Boston University School of Medicine, MA, USA.

J Cutan Pathol. 2009 Nov;36(11):1164-7. Abstract quote

BACKGROUND: A 54-year-old African-American male patient underwent removal of several cutaneous neurofibromas. Histopathologic examination revealed a nonencapsulated, haphazardly arranged proliferation of slender spindle cells in a myxoid stroma consistent with neurofibroma. Interestingly, each specimen exhibited numerous, large, multinucleate giant cells with nuclei arranged in a wreath-like or linear pattern. Immunoperoxidase staining revealed these cells to be negative with S-100 and CD-34. It was subsequently learned that this patient has neurofibromatosis type 1 (NF1).

METHODS: A retrospective review of all lesions coded as neurofibroma from our institution between 1 June 2006 and 28 August 2006 was performed.

RESULTS: Biopsies of 53 cutaneous neurofibromas from 51 patients were reviewed. In these, multinucleate giant cells were present in only three (5.7%), all in patients with single lesions.

CONCLUSIONS: Although the incidence of floret-like giant cells in neurofibromas of patients with NF1 is unknown, our findings suggest that the presence of these cells might be a clue to the presence of NF1.


Special stains S100 positive





Medical management of neurofibromatosis 1: a cross-sectional study of 383 patients.

Drappier JC, Khosrotehrani K, Zeller J, Revuz J, Wolkenstein P.

Department of Dermatology, Henri-Mondor Hospital, AP-HP, Paris XII University, Creteil, France.
J Am Acad Dermatol. 2003 Sep;49(3):440-4. Abstract quote  

BACKGROUND: The morbidity and mortality caused by neurofibromatosis 1 are a result of complications that may involve any of the body systems. Two models of management have been proposed for the detection of various complications in specialized neurofibromatosis clinics: investigation protocols (including extensive imaging and analysis of 24-hour urinary catecholamine levels); or clinical follow-up without imaging.

OBJECTIVE: Our purpose was to validate the strategy of clinical follow-up (without routine imaging and 24-hour urinary catecholamine levels).

METHODS: We retrospectively compared the number of treated complications during 2 successive periods from our database: screening investigations from November 1988 to June 1995 and clinical examination from July 1995 to June 2000.

RESULTS: The number of treated complications during the 2 periods was not statistically different (27/166 vs 28/217; Fisher's exact test, P =.39).

CONCLUSION: Screening investigations added little to clinical follow-up. Indeed, routine clinical examination can easily identify complications that require treatment in adult patients with neurofibromatosis 1.

Clinical risk factors for mortality in patients with neurofibromatosis 1: a cohort study of 378 patients.

Khosrotehrani K, Bastuji-Garin S, Zeller J, Revuz J, Wolkenstein P.

Department of Dermatology, Hopital Henri-Mondor, F-94010 Creteil CEDEX, France.

Arch Dermatol 2003 Feb;139(2):187-91 Abstract quote

OBJECTIVE: To identify the main clinical features associated with mortality in patients with neurofibromatosis 1.

DESIGN: Cohort study.

SETTING: Referral center for neurofibromatosis.

PATIENTS: Three hundred seventy-eight patients with neurofibromatosis 1 who had more than 1 year of follow-up in the center.

MAIN OUTCOME MEASURES: Mortality. Clinical features, especially dermatological, were evaluated as potential factors associated with mortality.

RESULTS: Factors associated independently with mortality were the presence of subcutaneous neurofibromas (odds ratio, 10.8; 95% confidence interval, 2.1-56.7; P<.001), the absence of cutaneous neurofibromas (odds ratio, 5.3; 95% confidence interval, 1.2-25.0; P =.03), and facial asymmetry (odds ratio, 11.4; 95% confidence interval, 2.6-50.2; P<.01).

CONCLUSIONS: Some features that can be found by a routine clinical examination are associated with mortality in patients with neurofibromatosis 1. Clinical follow-up should be focused on patients with subcutaneous neurofibromas and/or the absence of cutaneous neurofibromas and/or facial asymmetry.

Quality-of-Life Impairment in Neurofibromatosis Type 1 A Cross-sectional Study of 128 Cases

Pierre Wolkenstein, MD, PhD; Jacques Zeller, MD; Jean Revuz, MD; Emmanuel Ecosse, PhD; Alain Leplège, MD, PhD

Arch Dermatol. 2001;137:1421-1425 Abstract quote

Neurofibromatosis type 1 affects quality of life (QoL) through association with severe complications, impact on cosmetic features, and uncertainty of the effects of the disorder.

To evaluate the impact of the severity and visibility of neurofibromatosis type 1 on QoL.

Monocenter, cross-sectional study.

One French academic dermatological and neurofibromatoses clinic.

A total of 128 adult patients with neurofibromatosis type 1.

Main Outcome Measures
Evaluation of severity and visibility using, respectively, the Riccardi and Ablon scales. Evaluation of skin disease–specific and general QoL using, respectively, Skindex-France and SF-36 (Short Form 36 health survey) profiles controlled for sex, age, severity, and visibility.

In a multiple regression model controlling for sex, age, and visibility, visibility remained independently associated with the alteration of 3 aspects of the skin disease–specific QoL (Skindex-France): emotions, physical symptoms, and functioning (P = .03, P = .009, and P = .002, respectively). Patients with more severe neurofibromatosis reported more effects on the following domains of their general health QoL (SF-36): physical function, bodily pain, general health perception, and vitality (P = .006, P = .03, P = .01, and P = .04, respectively).

Neurofibromatosis type 1 has a significant impact on QoL through alteration of health and appearance. The consequences of visibility and severity from the viewpoint of patients can be evaluated using Skindex and the SF-36, respectively.

A prospective 10 year follow up study of patients with neurofibromatosis type 1.

Cnossen MH, de Goede-Bolder A, van den Broek KM, Waasdorp CM, Oranje AP, Stroink H, Simonsz HJ, van den Ouweland AM, Halley DJ, Niermeijer MF.

Department of Paediatrics, University Hospital Sophia/Dijkzigt, Rotterdam, Netherlands.

Arch Dis Child 1998 May;78(5):408-12 Abstract quote

OBJECTIVE: To establish the prevalence and incidence of symptoms and complications in children with neurofibromatosis type 1 (NF1) and to assess possible risk factors for the development of complications.

DESIGN: A 10 year prospective multidisciplinary follow up study.

PATIENTS: One hundred and fifty children diagnosed with NF1 according to criteria set by the National Institutes of Health.

RESULTS: In 62 of 150 children (41.3%) complications were present, including 42 (28.0%) children with one complication, 18 (12.0%) with two complications, and two (1.3%) with three complications (mean (SD) duration of follow up 4.9 (3.8) years). Ninety five of the 150 children presented without complications (follow up, 340.8 person-years). The incidence of complications was 2.4/100 person-years in this group. An association was found between behavioural problems and the presence of complications.

CONCLUSION: This is the largest single centre case series of NF1 affected children followed until 18 years of age. Children with NF1, including those initially presenting without complications, should have regular clinical examinations.


Stereotactic radiosurgery and fractionated stereotactic radiotherapy for the treatment of acoustic schwannomas: comparative observations of 125 patients treated at one institution.

Andrews DW, Suarez O, Goldman HW, Downes MB, Bednarz G, Corn BW, Werner-Wasik M, Rosenstock J, Curran WJ Jr.

Department of Neurosurgery, Thomas Jefferson University Hospital-Wills Neurosensory Institute, Philadelphia, PA 19107, USA.

Int J Radiat Oncol Biol Phys 2001 Aug 1;50(5):1265-78 Abstract quote

BACKGROUND: Stereotactic radiosurgery (SRS) and, more recently, fractionated stereotactic radiotherapy (SRT) have been recognized as noninvasive alternatives to surgery for the treatment of acoustic schwannomas. We review our experience of acoustic tumor treatments at one institution using a gamma knife for SRS and the first commercial world installation of a dedicated linac for SRT.

METHODS: Patients were treated with SRS on the gamma knife or SRT on the linac from October 1994 through August 2000. Gamma knife technique involved a fixed-frame multiple shot/high conformality single treatment, whereas linac technique involved daily conventional fraction treatments involving a relocatable frame, fewer isocenters, and high conformality established by noncoplanar arc beam shaping and differential beam weighting.

RESULTS: Sixty-nine patients were treated on the gamma knife, and 56 patients were treated on the linac, with 1 NF-2 patient common to both units. Three patients were lost to follow-up, and in the remaining 122 patients, mean follow-up was 119 +/- 67 weeks for SRS patients and 115 +/- 96 weeks for SRT patients. Tumor control rates were high (> or =97%) for sporadic tumors in both groups but lower for NF-2 tumors in the SRT group. Cranial nerve morbidities were comparably low in both groups, with the exception of functional hearing preservation, which was 2.5-fold higher in patients who received conventional fraction SRT.

CONCLUSION: SRS and SRT represent comparable noninvasive treatments for acoustic schwannomas in both sporadic and NF-2 patient groups. At 1-year follow-up, a significantly higher rate of serviceable hearing preservation was achieved in SRT sporadic tumor patients and may therefore be preferable to alternatives including surgery, SRS, or possibly observation in patients with serviceable hearing.

Management of vestibular schwannomas (acoustic neuromas): auditory and facial nerve function after resection of 120 vestibular schwannomas in patients with neurofibromatosis 2.

Samii M, Matthies C, Tatagiba M.

Department of Neurosurgery, Nordstadt Hospital, Hannover, Germany.

Neurosurgery 1997 Apr;40(4):696-705 Abstract quote

OBJECTIVE: Vestibular schwannomas (VSs) affect young patients with Neurofibromatosis 2 (NF-2) and cause very serious problems for hearing, facial expression, and brain stem function. Our objective was to determine a therapy concept for the right timing and indication of neurosurgical therapy.

METHODS: In 1000 consecutive VS resections, 120 tumors in 82 patients with NF-2 were surgically treated by the same surgeon (MS) at the Department of Neurosurgery at Nordstadt Hospital from 1978 to 1993. The mean age of the patients was 27.5 years. Sixty tumors were surgically treated in 41 male patients, and 60 tumors were surgically treated in 41 female patients. Bilateral tumor resection was performed in 38 patients (76 operations, after previous partial surgery in 15 cases elsewhere), and unilateral operations were performed in 44 patients, 5 of whom had undergone ipsi- or contralateral surgery that was performed elsewhere. The operative and clinical findings are evaluated and compared with the data of patients without NF-2.

RESULTS: In 105 cases, complete tumor resections were achieved. In 15 cases, deliberate subtotal resections were performed. These were for brain stem decompression in 4 cases and for hearing preservation in the last hearing ear in 11 cases, with successful preservation in 8 of the 11. Pre- and postoperative hearing rates were higher in male than in female patients (70% in male versus 65% in female patients before surgery and 40.5 versus 31%, respectively, after surgery). Hearing was preserved in 29 of 81 ears (36%). The rate of preservation was 24% in cases of large tumors and 57% in cases of small tumors (<30 mm). Twenty-one of 82 patients (26%) were bilaterally deaf before surgery. Twenty-five patients had uni- or bilateral hearing after surgery (i.e., 41 % of those with preoperative hearing or 30.5% of the whole group). Anatomic facial nerve preservation was achieved in 85%. The facial nerve was reconstructed intracranially at the cerebellopontine angle by sural grafting in 17 cases and by hypoglossal-facial reanimation in 5. Two deaths occurred 1 and 3 months postsurgically as a result of malignant tumor growth with brain stem dysfunction and respiratory problems. In summary, for patients with NF-2, the presentation ages are lower, tumor progression is faster, the chances of anatomic and functional nerve preservation are lower, the chances of good outcomes are best when surgery is performed early and when there is good preoperative hearing function, and the danger of sudden hearing loss is higher. The chances and danger often differ from side to side among individual patients.

CONCLUSION: The indication and the timing of tumor resections are in some respects different from normal VS handling and are dependent on the tumor extension and related necessity of brain stem decompression and on the auditory function. As an optimal goal, completeness of resection with functional cochlear nerve preservation is formulated, and as an acceptable compromise, subtotal microsurgical resection with functional cochlear nerve preservation in the last hearing ear is suggested.

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