von Recklinghausen's disease and its pathogenesis

von Recklinghausen's disease was first described in 1882. Formerly, it was considered a single disease, but is now known to be two distinct disease, neurofibromatosis 1 (NF 1, peripheral form of neurofibromatosis) and neurofibromatosis 2 (NF 2, bilateral acoustic neurofibromatosis). Neurofibromatosis is inherited as an autosomal dominant with a high rate of penetrance. NF 1 gene is located in the pericentromeric region of chromosome 17. NF 2 gene is localized to chromosome 22. Clinically, there are some characteristic signs and symptoms. The typical NF 1 patient has café-au-lait spots, melanin pigmentation and palpable neurofibromas, while NF 2 has its onset with the development of tinnitus or hearing loss, due to the presence of bilateral acoustic neuroma.     

Intestinal leiomyosarcoma and gastroparesis associated with von Recklinghausen's disease

BACKGROUND: The major histocompatibility complexes, MHC class I and II, are found only sparsely or not at all in the retina. Since the eye is immunoprivileged, we decided to investigate how the MHC class I and II antigens were influenced by a retinal transplant and whether this could be correlated to rejection of the transplant. METHODS: Fetal neural retinas of Sprague-Dawley (SD) rats were implanted in the subretinal space of adult Lewis and SD rats. After 5 weeks the retinas and the transplants were evaluated with antibodies against MHC class I and II antigens as well as microglia. RESULTS: In the syngeneic transplants no upregulation of MHC class I antigen was seen and no MHC class II-positive cells could be detected. In the allogeneic transplants, on the other hand, there was marked upregulation of MHC class I antigen. Numerous MHC class II antigen-positive cells were seen in the subretinal transplant but also in the host retina. CONCLUSION: Allogeneic retinal transplants seem to grow and thrive just as well as syngeneic transplants, but in the former there is considerable upregulation of MHC expression. Our interpretation of these results is that the allogeneic transplants are recognized as nonself, but that there is also something that modifies this reaction of the immune system at this level, preventing the rejection that would normally ensue.     

Giant retroperitoneal hematoma in a patient with von Recklinghausen's disease]

A 51-year-old male of von Recklinghausen's disease presented with huge retroperitoneal hematoma caused by spontaneous arterial rupture. He died of uncontrollable hemorrhage during the operation. Gross appearance of aorta, renal artery, celiac artery, pulmonary artery and lumbar artery were extremely fragile, and there was a complete rupture between aorta and lumbar artery. On the microscopic examination, significant medial dysplasia were demonstrated in these arteries. Arterial stenosis is well-known vascular complication in von Recklinghausen's disease. Spontaneous rupture of major artery, however, has been extremely uncommon. This is the 26th case reported in the world literature, and 21th case in the Japanese literature.     

Spontaneous haemothorax associated with von Recklinghausen's disease: review of occurrence in Japan

The case history is presented of a 61 year old man with von Recklinghausen's disease who developed a spontaneous haemothorax. In spite of being asymptomatic for five days after drainage, he died as a result of fatal sudden re-bleeding. The post mortem examination showed dissection and rupture of the left subclavian artery. Microscopically, disarrangement of smooth muscle and decrease of elastic fibre was observed in the ruptured artery. Haemothorax in patients with von Recklinghausen's disease may require thoracotomy, even if the condition of the patient appears to be stable.     

Bladder cancer associated with von Recklinghausen's disease: a case report

A 53-year-old man was admitted to our hospital with urinary frequency and miction pain. He had von Recklinghausen's disease with multiple café-au-lait spots and neurofibromatosis. Computed tomography scan and magnetic resonance imaging revealed an invasive bladder tumor 10 cm in diameter, and not metastasis. He was diagnosed as having a bladder tumor (T3a N0 M0 with von Recklinghausen's disease. After balloon occluded arterial infusion (BOAI) chemotherapy, total cystectomy was performed. Pathological diagnosis was transitional cell carcinoma, G3, pT3aN0M0. We reviewed and discussed 97 cases of carcinoma associated with von Recklinghausen's disease reported in the Japanese literature. Only 5 cases of bladder cancer have been reported, including the present case.     

Massive plexiform neurofibroma in the orbit in a child with von Recklinghausen's disease

We report a case of orbital plexiform neurofibroma presenting in a 10-year-old boy with von Recklinghausen's neurofibromatosis. The patient had shown a slow enlargement of exophthalmos of the right eye present since birth, together with multiple café au lait spots on the skin of the trunk. Magnetic resonance (MR) images revealed diffuse and irregular nodular involvement of the retrobulbar nerves within the muscle cone, which was confirmed at the surgery. The tumour extended into the ipsilateral cavernous sinus. We discuss the MR findings as pathognomonic signs of this rare orbital tumour, including its multinodular nature among dispersed intraconal fat tissue, location around the optic nerve, extension through the superior orbital fissure into the cavernous sinus and association with von Recklinghausen disease.     

Multiple small intestinal stromal tumors with skeinoid fibers in association with neurofibromatosis 1 (von Recklinghausen's disease)

A case of multiple small intestinal stromal tumors (SIST) with skeinoid fibers of the jejunum arising in a 50 year old male with neurofibromatosis 1 (NF-1) is reported. Seven small tumors of the jejunal wall were incidentally found and excised during an operation for abdominal and retroperitoneal neurofibromas. Histologically, the tumors were composed of uniform spindle-shaped cells with fascicular pattern, almost indistinguishable from the histology in leiomyoma. Periodic acid Schiff stain-positive hyaline globules were observed among the tumor cells. Ultrastructurally, these globules were stromal tangles of curvilinear, fluffy fibrils, consistent with skeinoid fibers. The electron-dense granules, possibly neuro-secretory granules, were found in the cytoplasm of the tumor cells. Immunohistochemically, the tumor cells were positive for vimentin, neuron specific enolase and CD34, but negative for muscle markers and S100 protein. The association of NF-1 and multiple SIST with skeinoid fibers may have clinical implications. The multiple occurrence of SIST with skeinoid fibers seems to be often cited as one of the gastrointestinal manifestations of NF-1. The possible site of origin of SIST with skeinoid fibers in NF-1 may be the enteric autonomic nerve plexus in the small intestinal wall.     

Ileus caused by Recklinghausen's disease of the jejunum

Obstruction of the jejunum diagnosed during operation in a female patient with an ileous state. The patient had a history of loss of body weight, intermittent abdominal spastic pain in the umbilical region, fatigue, vomiting, histologically evaluated as a jejunal manifestation of Recklinghausen's disease.     

Intercostal neurofibroma in a patient with von Recklinghausen's disease. Diagnostic utility of helical CT and nuclear magnetic resonance

A 44 year-old man with a type I Neurofibromatosis (NFI) and an intercostal mass is presented. By means of percutaneous fine needle aspiration punction under CT control, this tumor could be diagnosed of neurofibroma. It is important to remark not only the role of helical CT with anatomical reconstruction in the diagnosis of intercostal tumors, but also that intercostal location of neurofibromas has been rarely reported in the literature. Because of frequent association between NFI and neoplasms, it is always necessary to perform histological study of every new tumor that appears in the course of this entity.     

Correction of a dystrophic cervicothoracic spine deformity in Recklinghausen's disease

A case is presented of a 14-year-old boy with neurofibromatosis who had a 92 degrees dystrophic kyphosis (as measured on radiographs between C3 and C7) of the cervical spine. He was treated successfully by posterior stabilization and anterior fusion using a free vascularized fibula graft. This method appears to be an attractive alternative to an avascular fibula graft and avoids the risk of graft resorption (creeping substitution), weakening (fracture), or nonunion during the process of bony consolidation. It provides a stable and longstanding anterior strut, essential in the management of high grades of kyphosis. At 1-year followup the patient has no symptoms, is fully mobile, and shows radiographically complete incorporation of the graft with no loss of correction.     

Ras activation in astrocytomas and neurofibromas

Oncogenic mutations resulting in activated Ras Guanosine Triphosphate (GTP) are prevalent in 30% of all human cancers, but not primary nervous system tumors. Several growth factors/receptors are implicated in the pathogenesis of malignant astrocytomas including epidermal growth factor (EGFR) and platelet derived growth factor (PDGF-R) receptors, plus the highly potent and specific angiogenic vascular endothelial growth factor (VEGF). A significant proportion of these tumors also express a truncated EGFR, which is constitutively activated. Our work demonstrates that the mitogenic signals from both the normal PDGF-R and EGFR and the truncated EGFR activate Ras. Inhibition of Ras by genetic or pharmacological strategies leads to decreased astrocytoma tumorgenic growth in vitro and decreased expression of VEGF. This suggests that these agents may be potentially important as novel anti-proliferative and anti-angiogenic therapies for human malignant astrocytomas. In contrast to astrocytomas, where increased levels of activated Ras GTP results from transmitted signals from activated growth factor receptors, the loss of neurofibromin is postulated to lead to functional up-regulation of the Ras pathway in neurofibromatosis-1(NF-1). We have demonstrated that NF-1 neurofibromas and neurogenic sarcomas, compared to non-NF-1 Schwannomas, have markedly elevated levels of activated Ras GTP. Increased Ras GTP was associated with increased tumor vascularity in the NF-1 neurogenic sarcomas, perhaps related to increased VEGF secretion. The role of Ras inhibitors as potential therapy in this tumor is also under study.     

Alterations in glucose metabolism in patients with Alzheimer's disease

OBJECTIVE: To determine the alterations in glucose metabolism that occur in patients with Alzheimer's Disease (AD). DESIGN: Cross-sectional comparison of AD and healthy controls. SETTING: A University teaching hospital. PATIENTS: Healthy controls (n = 14, BMI: 24.9 +/- 0.5 kg/M2, age 73 +/- 1 years) and patients with AD (n = 12, BMI: 23.9 +/- 1.0 kg/M2, age 72 +/- 1 years). All controls and patients with AD had a normal history and physical examination, a negative family history of diabetes, and took no medications. MEASUREMENTS: All patients and controls underwent an assessment of their dietary intake and physical activity, a 3-hour oral glucose tolerance test (OGTT), and a 2-hour hyperglycemic glucose clamp study. RESULTS: Total caloric intake (AD: 27.1 +/- 1.3 kcal/kg/day; Control: 23.6 +/- 1.6 kcal/kg/day; P = ns) and intake of complex carbohydrates (AD: 5.9 +/- 0.4 kcal/kg/day; Control: 6.5 +/- 0.3 kcal/kg/day; P = ns) were not different between groups. Leisure time physical activity was greater in controls (AD: 2970 +/- 411 kcal/week; Control: 5229 +/- 864 kcal/week; P < 0.05). Patients with AD had higher fasting glucose (AD: 5.9 +/- 0.2 mmol/L; Control: 5.1 +/- 0.1 mmol/L; P < 0.01) and insulin (AD: 144 +/- 20 pmol/L; Control: 100 +/- 6 pmol/L; P < 0.05) values. In response to the OGTT, the area under the curve for glucose and insulin was similar in both groups. During the hyperglycemic clamp, steady-state glucose values were higher in the Alzheimer's patients (AD: 11.5 +/- 0.2 mmol/L; Control: 10.9 +/- 0.1 mmol/L, P < 0.01). First- and second-phase insulin responses were similar in each group. The insulin sensitivity index (units: mL/kg.min per pmol/L x 100), a measure of tissue sensitivity to insulin, was reduced in the patients with AD (AD: 0.59 +/- 0.06; Control: 0.79 +/- 0.07; P < 0.05). CONCLUSIONS: We conclude that early AD is characterized by alterations in peripheral glucose metabolism, which may relate, in part, to alterations in physical activity.     

von Hippel-Lindau disease

von Hippel-Lindau disease is a hereditary cancer syndrome characterized by the development of vascular tumors of the central nervous system and retina, clear cell renal carcinomas, pheochromocytomas, pancreatic islet cell tumors, endolymphatic sac tumors, and benign cysts affecting a variety of organs. VHL disease is caused by germline mutations of the von Hippel-Lindau tumor suppressor gene located on chromosome 3p25. Tumor development in this setting is due to inactivation or loss of the remaining wild-type allele in a susceptible cell. The highly vascular nature of VHL-associated neoplasms can be understood in light of the recent finding that the VHL gene product (pVHL) inhibits the accumulation of hypoxia-inducible mRNAs, such as the mRNA encoding vascular endothelial growth factor (VEGF), under normoxic conditions. This property of pVHL appears to be linked to its ability to bind to complexes containing elongin B, elongin C, and cullin 2 (Cul2). Elongin C and Cul2, based on their homology with Skp1 and Cdc53, respectively, are suspected of targeting certain proteins for covalent modification with ubiquitin and hence for degradation. One model, which remains to be tested, is that the binding of pVHL to elongins B/C and Cul2 affects the ubiquitination of RNA-binding proteins that regulate the stability of hypoxia-inducible mRNAs.     

Alterations of visual search strategy in Alzheimer's disease and aging.

Visual search, characterized by eye fixation patterns, was examined in 8 patients with Alzheimer's disease (AD), 8 cognitively intact, age-matched individuals, and 8 young control participants as they searched for a number among a nonlinear array of letters on a large computer screen. Among the 3 groups, target detection accuracy differed and detection time increased linearly. There were more fixations, and fixation duration was significantly longer in the AD patients than in the other 2 groups. These factors contributed to the lengthening of target detection time. This qualitative difference in the architecture of visual search between AD and aging may reflect a specific deficit in the disengagement of visual spatial attention, a prolongation of saccade initiation, or inefficiency in planning a search strategy. (PsycINFO Database Record (c) 2010 APA, all rights reserved)