Genetic evaluation of von Hippel–Lindau disease for early diagnosis and improved prognosis

von Hippel-Lindau disease (VHL) is a rare autosomal-dominant disorder in which affected individuals develop tumors in a number of locations. It occurs at a frequency of one per 36,000 population. Metastatic renal cell carcinoma (RCC) remains the leading cause of mortality in patients with clear cell RCC arising from mutations in the VHL tumor suppressor. RCC is the presenting feature in only 10% of VHL patients. VHL patients can present with a number of other renal lesions, such as hemangiomas and benign adenomas, in addition to simple cysts and RCC. We have investigated VHL gene mutations in familial RCC. The study cohort consisted of four patients with synchronous VHL and RCC and 31 kindreds. Analysis of the chromosomes was performed by the Moorehead method. Although none of the kindreds investigated had clinical evidence of VHL disease, 22 were found to have a VHL gene mutation consisting of deletions on the short arm of chromosomes 3, 17, and 19. Detailed clinical examination of the 22 kindreds with a VHL mutation revealed cerebellar hemangioblastoma (three kindreds), meningioma (two) and renal cell carcinoma (five). No VHL gene mutation was detected in nine kindreds. The prevalence of VHL gene mutations was 70.9% in the familial RCC kindreds. As a result of this study, the kindreds of patients with synchronous VHL and RCC have undergone molecular genetic testing and should be investigated for associated disorders.     

Role of SDHAF2 and SDHD in von Hippel–Lindau Associated Pheochromocytomas

Background

Pheochromocytomas (PCCs) develop from the adrenal medulla and are often part of a hereditary syndrome such as von Hippel–Lindau (VHL) syndrome. In VHL, only about 30 % of patients with a VHL missense mutation develop PCCs. Thus, additional genetic events leading to formation of such tumors in patients with VHL syndrome are sought. SDHAF2 (previously termed SDH5) and SDHD are both located on chromosome 11q and are required for the function of mitochondrial complex II. While SDHAF2 has been shown to be mutated in patients with paragangliomas (PGLs), SDHD mutations have been found both in patients with PCCs and in patients with PGLs.

Materials and methods

Because loss of 11q is a common event in VHL-associated PCCs, we aimed to investigate whether SDHAF2 and SDHD are targets. In the present study, 41 VHL-associated PCCs were screened for mutations and loss of heterozygosity (LOH) in SDHAF2 or SDHD. Promoter methylation, as well as mRNA expression of SDHAF2 and SDHD, was studied. In addition, immunohistochemistry (IHC) of SDHB, known to be a universal marker for loss of any part the SDH complex, was conducted.

Results and conclusions

LOH was found in more than 50 % of the VHL-associated PCCs, and was correlated with a significant decrease (p < 0.05) in both SDHAF2 and SDHD mRNA expression, which may be suggestive of a pathogenic role. However, while SDHB protein expression as determined by IHC in a small cohort of tumors was lower in PCCs than in the surrounding adrenal cortex, there was no obvious correlation with LOH or the level of SDHAF2/SDHD mRNA expression. In addition, the lack of mutations and promoter methylation in the investigated samples indicates that other events on chromosome 11 might be involved in the development of PCCs in association with VHL syndrome.     

Hereditary renal cell carcinoma associated with von Hippel–Lindau disease: a description of a Nova Scotia cohort

Background

von Hippel–Lindau (VHL) disease is an autosomal dominant condition characterized by the development of benign and malignant tumours, including cases of renal cell carcinoma (RCC). Early detection of RCC through routine surveillance can lead to decreased morbidity and mortality. Data on the number of patients in Nova Scotia (NS) who have VHL disease, disease manifestations and the frequency and mode of the surveillance have not previously been collected or reported. This project was designed to obtain that information.

Methods

The number and management of patients with VHL disease was determined by multiple sources: the Maritime Medical Genetics Service, patient charts, and pathology, radiology and laboratory data. The actual surveillance being performed was compared with that recommended in the literature.

Results

Twenty-one patients from 11 families in NS were identified. Manifestations included cases of RCC (31.6%), central nervous system (CNS) hemangioblastoma (73.7%), retinal hemangioma (47.4%), renal cyst (47.4%) and pheochromocytoma (10.5%). Of the 6 patients with RCC, 4 had bilateral tumours, 2 required kidney transplants and 1 developed metastatic disease. Routine surveillance was being done for the CNS in 62.5% of patients, retina in 47.4%, abdomen in 43.8% and urine catecholamines in only 10.5%. Only 1 of the 6 patients who developed RCC was undergoing routine abdominal imaging. Surveillance investigations were ordered by a number of different specialists.

Conclusion

Patients with VHL disease in NS have a number of manifestations associated with their disease, including RCC, in a similar frequency to that reported in the literature. The surveillance of these patients is suboptimal in frequency and coordination. von Hippel–Lindau disease is a complex condition that requires a coordinated approach to care to ensure proper surveillance and treatment. Our study highlights current deficiencies and offers an enormous opportunity for improvement.     

Re-evaluation of the role of the human endolymphatic sac in Menière's disease

The role of endolymphatic sac (ES) dysfunction in the etiopathogenesis of Meniere's disease has remained controversial since the early 1900s. The first reports of the ultrastructural (transmission electron microscopy, TEM) pathology of the human ES in Meniere's disease have been published only in the last decade. These studies have been based on biopsies of the extraosseous (intradural) ES and in no cases has the TEM appearance of the intraosseous ES been described. Likewise the control material used has been from biopsies of extraosseous ES taken from patients with acoustic schwannomas. To date, no reports have compared the ultrastructure of the intrasosseous ES from normal control patients to patients with Meniere's disease. Since the intraosseous ES is believed to be the most active portion of the entire ES, studies were made of the ultrastructure of ten normal interosseous human ESs fixed immediately after death and obtained at autopsy (control material). Fourteen patients undergoing translabyrinthine (TL) neurotologic procedures (10, TL resection of acoustic schwannoma; 4, TL eighth cranial nerve section for Meniere's disease) had the entire vestibular aqueduct, containing the endolymphatic duct and the intraosseous ES, removed and processed for TEM. The roles of the epithelium, subepithelial space, and vasculature were morphologically studied to evaluate possible ES pathology in Meniere's disease and in patients with acoustic schwannoma. Wide anatomic variation in the distribution and density of the subepithelial connective tissue was observed in all groups. There was no difference in the TEM appearance of the intraosseous ES from normal controls and patients with eighth nerve schwannoma, nor was there any difference in the ES collagen deposition in patients with Meniere's disease. The ESs from two patients with Meniere's disease showed evidence of abnormal glycoprotein metabolism; one with possible hypersecretion and one with possible alteration of degradation of resorbed glycoprotein. The results of this preliminary study suggest that "perisaccular fibrosis" of the intraosseous ES was not a pathologic feature in these four cases of Meniere's disease and that alteration of ES glycoprotein secretion/resorption may be of etiopathologic significance.     

Pancreatic Lesions in von Hippel–Lindau Disease? A Systematic Review and Meta-synthesis of the Literature

Background

von Hippel?CLindau (vHL) disease is a rare condition that leads to characteristic lesions within many different body systems. Pancreatic manifestations of vHL cover a wide spectrum of pathologies, and thus, accurate characterization and management is critical.

Methods

A comprehensive and systematic text word and MeSH search of the medical literature was performed to identify studies where information regarding the prevalence, clinical characteristics, and management recommendations could be extracted.

Results

Eleven studies were identified but 2 studies utilized the same data set. Of the 10 remaining studies, a total of 1,442 patients with vHL were available for analysis. Four hundred and twenty patients were examined for any type of pancreatic lesion, 362 for simple cysts or serous cystadenomas (SCAs), and 1,442 for neuroendocrine tumors (NETs). Of the 420 assessed for any pancreatic manifestation of vHL, 252 (60%) had a pancreatic lesion identified. Simple cysts that present as the sole manifestation of pancreatic disease were common and found in 169 of 362 (47%) patients. These are usually asymptomatic and do not normally require intervention. SCAs were reported in 39 of 362 (11%) patients and followed a similar benign course; resection is acceptable in symptomatic patients. NETs were identified in 211 of 1,442 (15%) patients, and 27 of 1,442 (2%) lesions behaved malignantly. Management of NETs depends on size, doubling time, and underlying genetics. Renal cell carcinoma is a characteristic in vHL, but there were no cases of pancreatic metastases identified from the included studies. Adenocarcinomas of the pancreas are not pathogenically linked to vHL.

Conclusions

This review highlights the wide spectrum and high prevalence of pancreatic lesions in vHL. Simple cysts and SCAs are benign, but NETs require careful observation due to their malignant potential.     

Von Hippel–Lindau disease manifesting disseminated leptomeningeal hemangioblastomatosis: surgery or medication?

We report the case of a 46-year-old man with von Hippel-Lindau (VHL) disease, manifesting disseminated leptomeningeal hemangioblastomatosis. The patient initially presented with a solitary hemangioblastoma in the right cerebellum. Later, he was diagnosed with VHL disease and underwent several surgical procedures in the following 14 years. But the prognosis was poor. Recently, the hemangioblastomatosis disseminated along leptomeninges involving both brain and spine. We aim to analyze the possible reason for the leptomeninges dissemination, discuss the imaging characteristics of this rare disease with ominous manifestation and propose the optimal strategy for treatment. We think the optimal treatment strategy should be surgical biopsy and surgical decompression. A long-term follow-up is inevitable. Antiangiogenic medication might be the hope for remission of this disease.     

Association of Type O Blood with Pancreatic Neuroendocrine Tumors in Von Hippel–Lindau Syndrome

Background

ABO blood type antigens are expressed not only on human red blood cells, but also throughout the gastrointestinal tract and in normal pancreatic tissue. Previous studies have identified an association between ABO blood type and various malignancies. We analyzed the association of ABO blood type with pancreatic neuroendocrine tumors (PNETs) in a high-risk cohort of patients with Von Hippel?CLindau (VHL) syndrome.

Methods

A retrospective review was performed of 798 patients with VHL syndrome. Blood type was confirmed for 181 patients. Fisher??s exact test and Mehta??s modification to Fisher??s exact test were used to test for an association between ABO blood type and manifestations of VHL syndrome.

Results

We found a strong trend for association between O blood type and pancreatic disease manifestation in patients with VHL syndrome (P?=?0.047). More importantly, there was a significant association of O blood type with solid pancreatic lesions consistent with PNETs (P?=?0.0084). Patients with solid pancreatic lesions who met criteria for surgical resection at the National Institutes of Health also had a higher rate of O blood type than those who did not require surgery (P?=?0.051).

Conclusions

Our findings suggest an association between O blood type and pancreatic manifestation of disease in patients with VHL syndrome, especially for PNETs. Screening and surveillance approaches for pancreatic lesions in patients with VHL syndrome should also consider patient blood type. The possibility of A, B, H misexpression in PNETs should also be explored to determine whether the serologic association with disease translates into a relationship with tissue pathology.     

Metastasis of Clear-Cell Renal Carcinoma to Cerebellar Hemangioblastoma in von Hippel Lindau Disease: Rare or not Investigated?

Summary. A new case of metastatic hypernephroma to cerebellar hemangioblastoma is described in a patient affected by von Hippel-Lindau disease. To our knowledge this is the third reported case of metastasis of renal carcinoma to intracranial hemangioblastoma associated with Von Hippel-Lindau disease. The real frequency of this pathological entity and its management are not well defined.     

Laparoscopic management of a complicated case of Wilkie’s syndrome: A case report

IntroductionSuperior mesenteric artery (SMA) syndrome also known as Wilkie’s syndrome is a rare condition caused by the entrapment of the third part of the duodenum between the aorta and the SMA. The incidence of Wilkie’s syndrome range between 0.013% and 0.3%. The normal angle between the aorta and SMA has been described to range between 38° and 65°, whereas in Wilkie’s syndrome this angle is reduced to less than 20° causing gastric outlet obstruction.Case presentationWe report a case of a previously diagnosed 43 year-old male with SMA syndrome, whom had been conservatively managed for 5-years for recurrent admissions with symptoms of gastric outlet obstruction. During his last admission, CT abdomen demonstrated gastric pneumatosis and portal venous gas requiring urgent surgical intervention. Duodenojejunostomy was successfully performed using laparoscopic technique.DiscussionSMA syndrome is thought to occur secondary to the rapid and excessive weight loss leading to the reduction of the mesenteric fat around the aorta and SMA, thereby reducing the normal angle between the two arteries. Conservative medical management is usually the first line of treatment in uncomplicated cases. Surgical management is usually reserved only after failed conservative management or complicated cases, at which time either an open or laparoscopic surgical approach is undertaking.ConclusionSurgical intervention is the mainstay in complicated cases of SMA syndrome and in refractory cases to conservative management. Advantages of laparoscopic approach over open surgery include rapid recovery time, reduced post-operative pain and shorter hospital stay.     

Conservative management of posterior interosseous neuropathy in an elite baseball pitcher’s return to play: a case report and review of the literature

This report documents retrospectively a case of Posterior Interosseous Neuropathy (PIN) occurring in an elite baseball pitcher experiencing a deep ache in the radial aspect of the forearm and altered sensation in the dorsum of the hand on the throwing arm during his pitching motion. The initial clinical goal was to control for inflammation to the nerve and muscle with active rest, microcurrent therapy, low-level laser therapy, and cessation of throwing. Minimizing mechanosensitivity at the common extensor region of the right elbow and PIN, was achieved by employing the use of myofascial release and augmented soft tissue mobilization techniques. Neurodynamic mobilization technique was also administered to improve neural function. Implementation of a sport specific protocol for the purposes of maintaining throwing mechanics and overall conditioning was utilized. Successful resolution of symptomatology and return to pre-injury status was achieved in 5 weeks. A review of literature and an evidence-based discussion for the differential diagnoses, clinical examination, diagnosis, management and rehabilitation of PIN is presented.     

Epidemiology of testicular tumors in Slovakia (1993–1997): Preliminary report

Worldwide increase of the incidence of testicular tumors was also reflected in the increasing number of these malignancies in the Slovak Republic. Lack of the accurate information about the occurrence of testicular tumors in Slovakia has helped to create a new multicentric retrospective study based on occurrence, histology, risk factors, diagnosis and treatment of this malignancy in Slovakia. The analysed study group consists of 1010 patients with testicular cancer, diagnosed from the beginning of 1993 to the end of 1997. Identification and histological data about the patients were obtained from the heads of departments of urology in Slovakia. In this study considerable differences were found between information obtained from departments of urology and information published by the National Cancer Register of the Slovak Republic. Ascertained information is higher than the one published by the National Cancer Register from the last five officially concluded years.     

Behçet's disease: a case report

While Beh?et's disease is an uncommon presentation to a podiatric clinical setting, it is nonetheless a fascinating and poorly understood disease as demonstrated by the current and historical research available about the topic. Much debate remains about the disease cause, course and treatment goals. Only through further research into the specific components of this multisystem disease will medicine be more fully able to address the needs of the patient. This discussion should offer the podiatric physician an overview of the disease as well as available treatment options.     

The first successful heart–lung transplantation in Japan: report of a case

Although legislation regarding organ transplantation from brain-dead donors in Japan was approved in 1997, no heart–lung transplantation procedures were performed for some time. Herein, we report the first case of successful heart–lung transplantation in Japan. The recipient was a 35-year-old man with Eisenmenger syndrome, caused by a double outlet right ventricle, who had been suffering hemoptysis and continued NYHA class 3–4 symptoms for 66 months since being registered on the waiting list. He underwent heart–lung transplantation from a 30-year-old donor. The organ ischemic time was 247 min, the postoperative course was uneventful, and the patient was discharged 66 days after the transplant surgery.     

Massive hemorrhage in a patient with intestinal Behçet's disease: report of a case

Major gastrointestinal bleeding is a rare manifestation of intestinal Behçet's disease. We report herein the case of a 64-year-old man with intestinal Behçet's disease complicated by myelodysplastic syndrome who suffered massive hemorrhage. Colonoscopy demonstrated ulceration of the entire colon from the cecum to the rectum, characterized by punched-out ulcers. Angiography demonstrated apparent extravasation of contrast material in the terminal ileum, and embolization was not successful. Continued and massive bleeding necessitated surgical resection of the involved segment of ileum; however, massive bleeding recurred. Re-endoscopy showed oozing hemorrhage from the multiple colon ulcerations. Intra-arterial prednisolone injection therapy was given, following which the melena gradually subsided and completely stopped within a few days.     

Traumatic correction of Linburg–Comstock anomaly: a case report

Linburg–Comstock anomaly describes an anatomical variant of flexor tendons of the hand. Flexor pollicis longus (FPL) sends a connecting tendon to flexor digitorum profundus (FDP), causing simultaneous flexion at the distal interphalangeal joint (DIPJ) of the index finger when the interphalangeal joint (IPJ) of the thumb is flexed. Epidemiological studies have revealed a unilateral prevalence as high as 31% of individuals; however, the condition rarely causes symptoms. The anomaly can present with a restrictive flexor tenosynovitis, requiring explorative surgery to confirm the diagnosis and disconnection of the anomalous tendon slip to relieve symptoms. We describe the case of a rock climber who suffered a forced extension injury to the DIPJ of the right index finger, resulting in traumatic rupture of his anomalous FPL–FDP connecting tendon. This is the first reported case of rupture of a Linburg–Comstock anomaly. Through rupture of this anomalous tendon, the patient can be viewed as having corrected his aberrant tendon to conform with the more prevalent anatomical configuration and function. We identified the rupture using dynamic ultrasound of the wrist; to our knowledge, this technique has not been described previously in the literature. We recommend the use of this imaging modality to confirm diagnosis, thus avoiding explorative surgery.     

Kienböck's disease in a 14-year-old gymnast: a case report

Kienb?ck's disease is rare in children and there are few reports and therapeutic recommendations in the literature about this condition. We report a case of a 14-year-old female gymnast for whom nonsurgical treatment was followed by complete healing within 12 months. Repeated computed tomography scans provided a sequential coronal, sagittal, and transverse illustration of the progressive healing of the lunate.