Signs Of Neurofibromatosis Type Research Articles

A novel RAB39B mutation and concurrent de novo NF1 mutation in a boy with neurofibromatosis type 1, intellectual disability, and autism: a case report

BackgroundMutations in RAB39B at Xq28 causes a rare form of X-linked intellectual disability (ID) and Parkinson’s disease. Neurofibromatosis type 1 (NF1) is caused by heterozygous mutations in NF1 occurring de novo in about 50% of cases, usually due to paternal gonadal mutations. This case report describes clinical and genetic findings in a boy with the occurrence of two distinct causative mutations in NF1 and RAB39B explaining the observed phenotype.Case presentationHere we report a 7-year-old boy with multiple café-au-lait macules (CALMs) and freckling, severe macrocephaly, peculiar facial gestalt, severe ID with absent speech, epilepsy, autistic traits, self-harming, and aggressiveness. Proband is an only child born to a father aged 47. Parents did not present signs of NF1, while a maternal uncle showed severe ID, epilepsy, and tremors.By RNA analysis of NF1, we identified a de novo splicing variant (NM_000267.3:c.6579+2T>C) in proband, which explained NF1 clinical features but not the severe ID, behavioral problems, and aggressiveness. Family history suggested an X-linked condition and massively parallel sequencing of X-exome identified a novel RAB39B mutation (NM_171998.2:c.436_447del) in proband, his mother, and affected maternal uncle, subsequently validated by Sanger sequencing in these and other family members.ConclusionsThe case presented here highlights how concurrent genetic defects should be considered in NF1 patients when NF1 mutations cannot reasonably explain all the observed clinical features.

Comparison of characteristic features and local recurrence in syndromic versus non-syndromic multifocal non-ossifying fibroma

BackgroundMultiple non-ossifying fibromas (MNOF) could be presented with other extraskeletal anomalies (syndromic) or not (non-syndromic). In this study, we aimed to compare characteristic features and local recurrence between symptomatic syndromic and non-syndromic MNOFs. MethodsThirty-five patients with symptomatic MNOF were included in this study, comprised of 30 patients without the café-au-lait spot (non-syndromic) and five with café-au-lait spots plus other signs of neurofibromatosis type 1 (syndromic). Characteristic features of the patients and lesions were compared between syndromic and non-syndromic MNOFs. The lesions were treated with curettage and bone graft. The rate of local recurrences was also compared between the two groups of syndromic and non-syndromic MNOF. ResultsStudy population included 19 (54.3%) males and 16 (45.7%) females with the mean age of 7.63 ± 3.1 years (range 4–11). The mean follow-up of the patients was 65.6 ± 38.2 months (range 24–96). The lesion was bilateral in 13.3% of non-syndromic MNOFs and 80% of syndromic MNOFs. This difference was statistically significant (p = 0.01). After curettage and bone grafting, the lesion recurred in 6.7%of non-syndromic MNOFs and 60% of the syndromic MNOF. This difference was statistically significant, as well (p = 0.01). No other significant difference was found between syndromic and non-syndromic MNOFs. ConclusionsThe syndromic form of MNOF is much less prevalent and is associated with a higher rate of recurrence after surgical removal. Therefore, a more rigorous removal of the MNOF lesions might be necessary when presented in a syndromic context.

Tactile Corpuscle-like Bodies in Gastrointestinal-type Mucosa

Tactile corpuscle-like bodies (TCLB) are microscopic Schwannian structures that simulate the superficial mechanoreceptors of the peripheral nervous system (Wagner-Meissner corpuscles). They have been described nearly exclusively in peripheral nerve sheath tumors, namely diffuse neurofibromas, and schwannomas but also in cellular nevi. There are rare reports of these structures in the gastrointestinal tract (predominantly the lower tract), with the presumption that they are incidental reactive neural proliferations. We compiled 9 cases showing this rare phenomenon in gastrointestinal-type mucosa in nonsyndromic patients to further characterize its features. There were 6 men and 3 women (age range, 39 to 79 y, mean 56 y) with lesions involving esophagus/gastro-esophageal junction (n=7), sigmoid colon (n=1), and gastric heterotopia of the cricopharynx (n=1). Endoscopic examination was abnormal in 6 of the 7 cases (including changes consistent with Barrett esophagus and polypoid/nodular mucosa) and normal in 1 of 7 cases for which this information was available. The histologic features were similar in all cases, with unencapsulated clusters of lamellated and concentrically arranged spindle cells in the lamina propria. The foci of TCLB ranged in size from <0.1 to 1.5 mm in the greatest dimension. Abnormal histopathologic findings were identified in the background mucosa in 6 of 9 cases (including Barrett esophagus, active and inactive chronic gastritis, enterochromaffin-like cell hyperplasia, and gastric intestinal metaplasia). None of the patients showed signs of neurofibromatosis type 1, multiple endocrine neoplasia type 2B, Cowden syndrome, or other inherited syndrome. No morbidity related to TCLB was reported for the patients with available follow-up.

Giant liver hemangioma in patient with ileal gastrointestinal stromal tumor

Gastrointestinal stromal tumors are the most common mesenchymal neoplasms of the gastrointestinal tract. These tumors represent more than 80% of all mesenchymal tumors found in the gastrointestinal tract, though they account for only approximately 3% of all gastrointestinal malignancies. Literature offers case reports, which describe symptomatic gastrointestinal stromal tumors and they generally represent patients with larger tumors. We present the case of a small gastrointestinal stromal tumor in a 40-year-old man, with associated giant liver hemangioma and fever, and with history of abdominal discomfort and fever. Clinical examination revealed hepatosplenomegaly, palpable mass in the right lower abdomen, and signs of neurofibromatosis type 1 (Morbus von Recklinghausen). Computed tomography revealed a giant tumor in the right lobe of the liver. Magnetic resonance showed abscess in the hemangioma of the liver. An intestinal tumor was incidentally found and excised during surgical laparotomy. An intestinal gastrointestinal stromal tumor was revealed by histopathology and confirmed by immunohistochemistry. Although a multidisciplinary team proposed surgical removal of the liver tumor mass, the surgeons decided to follow up the patient because of a high risk of new intervention. According to the available data, this is a very rare case of small intestinal gastrointestinal stromal tumor, with symptoms of fever and giant abscess in the liver hemangioma.

Familial Lymphoproliferative Malignancies and Tandem Duplication of NF1 Gene

Background. Neurofibromatosis type 1 is a genetic disorder caused by loss-of-function mutations in a tumor suppressor gene (NF1) which codifies the protein neurofibromin. The frequent genetic alterations that modify neurofibromin function are deletions and insertions. Duplications are rare and phenotype in patients bearing duplication of NF1 gene is thought to be restricted to developmental abnormalities, with no reference to cancer susceptibility in these patients. We evaluated a patient who presented with few clinical signs of neurofibromatosis type 1 and a conspicuous personal and familiar history of different types of cancer, especially lymphoproliferative malignancies. The coding region of the NF-1 gene was analyzed by real-time polymerase chain reaction and direct sequencing. Multiplex ligation-dependent probe amplification was performed to detect the number of mutant copies. The NF1 gene analysis showed the following alterations: mosaic duplication of NF1, TRAF4, and MYO1D. Fluorescence in situ hybridization using probes (RP5-1002G3 and RP5-92689) flanking NF1 gene in 17q11.2 and CEP17 for 17q11.11.1 was performed. There were three signals (RP5-1002G3conRP5-92689) in the interphases analyzed and two signals (RP5-1002G3conRP5-92689) in 93% of cells. These findings show a tandem duplication of 17q11.2. Conclusion. The case suggests the possibility that NF1 gene duplication may be associated with a phenotype characterized by lymphoproliferative disorders.

Plexiform Neurofibroma of the Eye Region Occurring in Patients Without Neurofibromatosis Type 1

The purpose of the present study was to investigate the correlation between Plexiform Neurofibroma (PN) of the eye region and Neurofibromatosis type 1 (NF1). According to the textbooks of ophthalmology, PN and NF1 are very closely linked. Our clinical experience raised doubts about this, however. All biopsy reports from the Eye Pathology Institute, Copenhagen, for the 10-year period from 1999 to 2008 with PN as the histological diagnosis were identified. From the pathology referral forms, we determined whether the patients had had a history of NF1, and the medical records were reviewed for symptoms and signs of NF1. Patients with no known NF1 were invited for a clinical examination and a blood test for mutation analysis. 13 patients had been given the histological diagnosis of PN of the eye region during the 10-year period. Of these, 10 patients fulfilled the National Institute of Health (NIH) diagnostic criteria for NF1, but 3 patients had PN of the eye region as the only sign, and thus did not have NF1. In 2 of these patients, mutation analysis was performed on blood, and was negative. PN of the eye region is suggestive of NF1 but not pathognomonic of this disease.

Biallelic inactivation of NF1 in a sporadic plexiform neurofibroma

Plexiform neurofibromas are a major cause of morbidity in individuals with neurofibromatosis type 1 (NF1). Sporadically, these tumors appear as an isolated feature without other signs of NF1. A role for the NF1 gene in solitary plexiform neurofibromas has never been described. In this study, we report a 13-year-old boy who was diagnosed with a plexiform neurofibroma, without other NF1 diagnostic criteria. The tumor was partially resected and analyzed using different techniques: karyotyping, fluorescence in situ hybridization (FISH), and microarray comparative genomic hybridization (aCGH). Tumor Schwann cell culture and subsequent karyotyping showed a rearrangement involving chromosomes 1 and 17, namely an insertion of chromosomal bands 1p36-35 at 17q11.2. FISH demonstrated that the insertion interrupted the NF1 gene. In addition, a deletion was detected affecting the other NF1 allele. Whole-genome aCGH analysis of the resected tumor confirmed the presence of an 8.28 Mb deletion including the NF1 gene locus in ∼15-20% of tumor cells. We conclude that biallelic NF1 inactivation was at the origin of the isolated plexiform neurofibroma in this patient. The insertion is most likely the "first hit" and the large deletion the "second hit."

Spontaneous Remission of Primary Hyperparathyroidism in a Patient with Neurofibromatosis Type 1: Case Report

Neurofibromatosis type 1 (NF1) is an autosomal dominant multisystem disorder affecting approximately 1 in 3500 individuals. Patients with the disorder can develop carcinoid tumors, medullary thyroid carcinoma, pheochromocytoma and tumor of the hypothalamus. The association of NF1 with Primary Hyperparathyroidism (HPP) is very rare. We report a 56-year-old woman with NF1 who was referred to our service because of nephrolithiasis. Physical examination revealed the characteristic signs of NF1, and her laboratory calcium profile was compatible with HPP. The patient was referred for parathyroidectomy, but during the surgical work-up she underwent spontaneous remission of her HPP. This case is significant not only for the rarity of this presentation in NF1 patients, but also because of the spontaneous remission of HPP.

Pitfalls in molecular analysis for mismatch repair deficiency in a family with biallelic pms2 germline mutations

Heterozygous germline mutations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 cause Lynch syndrome. Biallelic mutations in the MMR genes are associated with a childhood cancer syndrome [constitutional mismatch repair deficiency (CMMR-D)]. This is predominantly characterized by hematological malignancies and tumors of the bowel and brain, often associated with signs of neurofibromatosis type 1 (NF1). Diagnostic strategies for selection of patients for MMR gene analysis include analysis of microsatellite instability (MSI) and immunohistochemical (IHC) analysis of MMR proteins in tumor tissue. We report the clinical characterization and molecular analyses of tumor specimens from a family with biallelic PMS2 germline mutations. This illustrates the pitfalls of present molecular screening strategies. Tumor tissues of five family members were analyzed for MSI and IHC. MSI was observed in only one of the analyzed tissues. However, IHC analysis of brain tumor tissue of the index patient and his sister showed absence of PMS2 expression, and germline mutation analyses showed biallelic mutations in PMS2: p.Ser46IIe and p.Pro246fs. The same heterozygous mutations were confirmed in the father and mother, respectively. These data support the conclusion that in case of a clinical phenotype of CMMR-D, it is advisable to routinely combine MSI analysis with IHC analysis for the expression of MMR proteins. With inconclusive or conflicting results, germline mutation analysis of the MMR genes should be considered after thorough counselling of the patients and/or their relatives.

Multiple, Unilateral Lisch Nodules in the Absence of Other Manifestations of Neurofibromatosis Type 1

Lisch nodules associated with Neurofibromatosis Type 1 (NF1) are usually multiple and bilateral in nature. Here, we report a 21-year-old healthy, Caucasian female who was diagnosed with multiple, unilateral Lisch nodules during routine eye examination. A thorough history and physical examination revealed no other signs of NF1. We diagnosed the rare occurrence of numerous, unilateral Lisch nodules in the absence of additional features of NF1 in our patient and provide a discussion concerning the differential diagnosis of Lisch nodules as well as the potential genetic explanation of this finding.

Optic Nerve Tumor in Tuberous Sclerosis Complex is not Responsive to Sirolimus

A 12-year-old girl with clinically established tuberous sclerosis complex, and without signs of neurofibromatosis type 1, developed a right retro-ocular optic nerve tumor. After rapid growth for 1 year after its discovery, the optic nerve tumor demonstrated modest progression. The patient received the mammalian target of rapamycin inhibitor, sirolimus, for recurrent subependymal giant cell brain tumors. Although her left ventricular subependymal giant cell tumor demonstrated a 49% reduction in volume, the optic nerve tumor did not respond, and even underwent slight (6%) growth during the 16-month treatment. The quality of this child's vision has remained normal in both eyes, and she is otherwise asymptomatic with regard to the optic nerve tumor.

Rhabdomyosarcoma in patients with constitutional mismatch-repair-deficiency syndrome

Background:Biallelic germline mutations in the mismatch repair genes MLH1, MSH2, MSH6 or PMS2 cause a recessive childhood cancer syndrome characterised by early-onset malignancies and signs reminiscent of neurofibromatosis type 1...

Homozygosity of MSH2 c.1906G→C germline mutation is associated with childhood colon cancer, astrocytoma and signs of Neurofibromatosis type I

Hereditary non-polyposis colorectal cancer is a cancer predisposition syndrome known to be caused by heterozygous germline mutations in DNA mismatch repair genes (MMR) most commonly hMLH1, hMSH2, hMSH6. Heterozygous mutations in one of these genes confer an increased risk, mainly for colon and endometrial cancer. Recently, several publications identified that biallelic mutations in the MMR genes are associated with a more severe phenotype, including childhood malignancies and signs of neurofibromatosis type I (NF1). We report on a non-consanguineous Ashkenazi Jewish family with two affected siblings with features of NF1, colon cancer and astrocytoma at age 13 and 14. Their mother developed endometrial cancer at age 54. Their father had leukoplakia of the vocal cords with a family history of pancreatic cancer. Molecular and pathology studies were done on the tumor tissue and on genomic DNA of family members. Tumor testing demonstrated a high degree of microsatellite instability (MSI analysis), expression of MLH1 and absence of expression of both MSH2 and MSH6 proteins. A biallelic c.1906G > C (p.A636P) mutation in the hMSH2 gene was detected in the blood of one affected child. Parental genetic testing showed that each parent was heterozygote for the mutation. The c.1906G > C mutation is a founder mutation in the Ashkenazi Jewish population. To our knowledge this is the first report of homozygosity for this founder mutation.

RNA-based mutation analysis identifies an unusual MSH6 splicing defect and circumvents PMS2 pseudogene interference

Heterozygous germline mutations in one of the mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 cause hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome, a dominantly inherited cancer susceptibility syndrome. Recent reports provide evidence for a novel recessively inherited cancer syndrome with constitutive MMR deficiency due to biallelic germline mutations in one of the MMR genes. MMR-deficiency (MMR-D) syndrome is characterized by childhood brain tumors, hematological and/or gastrointestinal malignancies, and signs of neurofibromatosis type 1 (NF1). We established an RNA-based mutation detection assay for the four MMR genes, since 1) a number of splicing defects may escape detection by the analysis of genomic DNA, and 2) DNA-based mutation detection in the PMS2 gene is severely hampered by the presence of multiple highly similar pseudogenes, including PMS2CL. Using this assay, which is based on direct cDNA sequencing of RT-PCR products, we investigated two families with children suspected to suffer from MMR-D syndrome. We identified a homozygous complex MSH6 splicing alteration in the index patients of the first family and a novel homozygous PMS2 mutation (c.182delA) in the index patient of the second family. Furthermore, we demonstrate, by the analysis of a PMS2/PMS2CL "hybrid" allele carrier, that RNA-based PMS2 testing effectively avoids the caveats of genomic DNA amplification approaches; i.e., pseudogene coamplification as well as allelic dropout, and will, thus, allow more sensitive mutation analysis in MMR deficiency and in HNPCC patients with PMS2 defects.

Homozygous PMS2 germline mutations in two families with early-onset haematological malignancy, brain tumours, HNPCC-associated tumours, and signs of neurofibromatosis type 1

Heterozygous germline mutations in mismatch repair (MMR) genes MLH1, PMS2, MSH2, and MSH6 cause Lynch syndrome. New studies have indicated that biallelic mutations lead to a distinctive syndrome, childhood cancer syndrome (CCS), with haematological malignancies and tumours of brain and bowel early in childhood, often associated with signs of neurofibromatosis type 1. We provide further evidence for CCS reporting on six children from two consanguineous families carrying homozygous PMS2 germline mutations. In family 1, all four children had the homozygous p.I590Xfs mutation. Two had a glioblastoma at the age of 6 years and one of them had three additional Lynch-syndrome associated tumours at 15. Another sibling suffered from a glioblastoma at age 9, and the fourth sibling had infantile myofibromatosis at 1. In family 2, two of four siblings were homozygous for the p.G271V mutation. One had two colorectal cancers diagnosed at ages 13 and 14, the other had a Non-Hodgkin's lymphoma and a colorectal cancer at ages 10 and 11, respectively. All children with malignancies had multiple café-au-lait spots. After reviewing published cases of biallelic MMR gene mutations, we provide a concise description of CCS, revealing similarities in age distribution with carriers of heterozygous MMR gene mutations.

Multiple Ipsilateral Lower Extremity Masses in a 46-year-old Man

Multiple Ipsilateral Lower Extremity Masses in a 46-year-old Man

Rapidly Growing Gingival Malignant Peripheral Nerve Sheath Tumour with Lung and Liver Metastases

Malignant peripheral nerve sheath tumour in the oral cavity is extremely rare. We report a case of malignant peripheral nerve sheath tumour on the maxillary gingiva without evidence of neurofibromatosis. A 54-year-old woman presented with a soft, non-tender mass without ulceration on her maxillary gingiva. The patient did not have signs of neurofibromatosis type 1. A partial maxillectomy with a wide resection margin was performed. Four months after presentation, local recurrence as well as lung and liver metastases were found.

A variable combination of features of Noonan syndrome and neurofibromatosis type I are caused by mutations in the NF1 gene

Signs of neurofibromatosis type 1 (NF1) and Noonan syndrome (NS), two distinct autosomal dominant disorders, occur together in patients reported as Watson syndrome (WS), neurofibromatosis-Noonan syndrome (NFNS), partial LEOPARD syndrome, NS with features of NF1, and NF1 with Noonan-like features. The molecular basis of these combined phenotypes was poorly understood and controversially discussed over several decades. Only recently, there is increasing evidence for WS and NFNS being allelic to NF1 in the majority of patients. In this study we describe seven novel patients from five unrelated families with variable phenotypes of the NF1-NS spectrum which were systematically analyzed for mutations in the disease-causing genes NF1 for NF1 and PTPN11 for NS. Heterozygous mutations or deletions of NF1 were identified in all patients, while no PTPN11 mutation was found. The NF1 mutation segregated with the phenotype in both familial cases. These results support the hypothesis that variable phenotypes of the NF1-NS spectrum represent variants of NF1 in the majority of cases. Constitutive deregulation of the Ras pathway either through activating mutations of PTPN11 or through haploinsufficiency of neurofibromin, which acts as a Ras-inactivating GTP-ase, is probably the common pathogenetic mechanism explaining the phenotypic overlap of NS and NF1.

Extraosseous schwannoma of the mental nerve clinically simulating intraosseous

We report a case of a benign neurilemmoma arising from the right mental nerve. Schwannomas are rare neurogenic tumours that originate from Schwann cells of the peripheral nervous system. Frequent locations are the head and neck region. Most of the tumours occur in the soft tissue whereas intraosseous schwannomas are rare. This case report deals with a young patient who was referred to our hospital with an unidentified fast-growing tumour located mainly in the premolar region of the right mandible. The tumour presented as an expansive, unilocular, well defined, radiolucent lesion on orthopantomography. No expansion of the mandibular canal could be seen. Computerized tomography scans of the mandible helped to identify the solid nature of the tumour. A biopsy was necessary to make the final diagnosis and the tumour was then excised surgically. Postoperative magnetic resonance imaging scans and a histological examination of the surgical specimen showed no signs of neurofibromatosis type 2.

Neurofibromatosis Type 1 in a Pediatric Population: Ste-Justine's Experience

To date, few pediatric series of neurofibromatosis type 1 (NF-1) have been described in the literature even though it is the most frequently encountered phakomatosis. We reviewed 987 charts of pediatric patients with a presumptive diagnosis of NF-1 who were evaluated at Ste-Justine hospital from January 1, 1991 to July 31, 2002. Patients who presented with two or more cardinal criteria were diagnosed with NF-1. Clinical and laboratory data were retrospectively collected, including: demographics, neuroimaging and presence or absence of associated symptoms or signs of NF-1. A total of 279 patients were diagnosed with NF-1. The mean age at diagnosis was 3.4 years. Ninety-nine percent of the patients had café au lait spots and 47% had a first degree relative with NF-1. Almost 60 percent (59.6%) of those seen by an ophthalmologist had Lisch nodules. Optic glioma was found in in 14.7%, cutaneous neurofibromas in 38.4%, plexiform neurofibromas in 24.7%, neurofibrosarcoma in 1.8%, learning disabilities in 39%, attention deficit disorder in 40.5%, osseous dysplasias in 7.2%, pseudoarthrosis in 3.6%, precocious puberty in 3.2% and short stature in 17.9%. Magnetic resonance, when performed, showed hyperintense T2 lesions in 87.1% of cases. The mean period of follow-up was 7.4 years. Neurofibromatosis type 1 is a multisystemic disorder associated with increased risk of malignancy. It can be diagnosed at a very young age and clinical follow-up is advised. To our knowledge, this is the largest single center study of NF-1 in a pediatric population.