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H P Neumann

Publications and source records attributed to H P Neumann.

At least 73 records · Page 4Linked to original sources
PubMed1995

Retinal vascular hamartoma in von Hippel-Lindau disease.

OBJECTIVE: To diagnose von Hippel-Lindau disease at an early stage in the presence of atypical retinal lesions. DESIGN: Case series. METHODS: In an 11-year interdisciplinary clinical follow-up study of von Hippel-Lindau disease, 52 patients with retinal angiomas were investigated. RESULTS: Besides retinal angiomas, in five patients with von Hippel-Lindau disease or in the close relatives of such patients, unusual retinal vascular hamartomas other than retinal angiomas were detected. Retinal hamartomas are characterized by small, moss fiber-like, relatively flat vascular lesions with smooth and occasionally irregular margins and without enlarged afferent and efferent vessels. They are located within the superficial retina, usually adjacent to a retinal vein. In addition to typical peripheral retinal angiomas, a 28-year-old man with a pheochromocytoma had a treelike hamartoma. In another family, a brother and sister both had circumscribed red hamartomas with irregular outlines close to the retinal vessels. On fluorescein angiography, the early arterial filling of the hamartomas in two of these patients was striking. CONCLUSION: It is prudent to be aware of these unusual vascular retinal changes in von Hippel-Lindau disease. They may occur in isolation without additional retinal angiomas (as in four of our patients) but may suggest the presence of von Hippel-Lindau disease.

Adolescent↗
PubMed1995

Mutation of the RET protooncogene in sporadic medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) occurs sporadically or as part of the inherited cancer syndrome multiple endocrine neoplasia (MEN) type 2. In MEN 2A, germline missense mutations are found in one of five cysteine codons within exons 10 and 11 in the extracellular domain of the RET protooncogene. In MEN 2B, germline mutations occur in codon 918 (exon 16) within the catalytic core of the tyrosine kinase domain. To determine if RET mutations similar to those in MEN 2A and 2B play a role in the pathogenesis of sporadic MTC, we analysed 71 sporadic tumours comprising 68 primary tumours and three cell lines, for mutations in RET exons 10, 11, and 16. We found that 23% of sporadic MTC had RET codon 918 mutations, while only 3% had exon 10 mutations, and none had mutations in exon 11. We found no exon 16 mutations in MTC from 14 MEN 2A cases. Thus, exon 10 and 11 mutations, commonly found in familial MTC and MEN 2A, rarely occur in sporadic MTC; somatic mutation of RET codon 918 appears to play a role in the tumourigenesis of a significant minority of sporadic MTC but not MEN 2A tumours. In addition to their biological interest, these findings may have some clinical application in determining whether a patient presenting with isolated MTC is truly sporadic or is part of an inherited cancer syndrome.

Carcinoma, Medullary↗
PubMed1995

Loss of heterozygosity in the tuberous sclerosis (TSC2) region of chromosome band 16p13 occurs in sporadic as well as TSC-associated renal angiomyolipomas.

Angiomyolipomas (AMLs) are renal tumors that occur both sporadically and in association with tuberous sclerosis (TSC). TSC is an autosomal dominant disorder characterized by hamartomatous lesions in multiple organs. Two TSC loci are recognized: TSC1 on 9q34 and TSC2 on 16p13. Loss of heterozygosity (LOH) at the TSC1 and TSC2 loci in lesions from TSC patients has recently been reported. Lesions that are not associated with TSC have not been previously examined for LOH at the TSC loci. We analyzed 29 renal angiomyolipomas from patients without a history of TSC. Three tumors demonstrated LOH on 16p13. This is the first report indicating that mutations in TSC2 occur in tumors of patients who do not have TSC. We also found LOH on 16p13 in 5 of 8 TSC-associated AMLs. Two of these tumors were from a single patient and demonstrated different regions of LOH. These findings support the hypothesis that the TSC2 gene functions as a tumor suppressor.

Adult↗
PubMed1995

Von Hippel-Lindau (VHL) disease with pheochromocytoma in the Black Forest region of Germany: evidence for a founder effect.

We identified a germline missense mutation at nucleotide 505 (T to C) of the VHL tumor suppressor gene in 14, apparently unrelated, VHL type 2A families from the Black Forest region of Germany. This mutation was previously identified in two VHL 2A families living in Pennsylvania (USA). All affected individuals in the 16 families shared the same VHL haplotype indicating a founder effect. This missense mutation at codon 169 (Tyr to His) would probably cause an alteration in the structure of the putative VHL protein. The association of this distinct mutation with the pheochromocytoma phenotype in VHL may help to elucidate the genetic mechanism of carcinogenesis in this multi tumor cancer syndrome.

Adrenal Gland Neoplasms↗
PubMed1995

Low frequency of germline mutations in the RET proto-oncogene in patients with apparently sporadic medullary thyroid carcinoma.

BACKGROUND AND OBJECTIVES: Medullary thyroid carcinoma (MTC) occurs both sporadically and in the autosomal dominantly inherited multiple endocrine neoplasia (MEN) type 2 syndromes. The distinction between true sporadic MTC and a new mutation familial case is important for future clinical management of both the patient and family. The susceptibility gene for MEN 2 is the RET proto-oncogene. Systematic analysis for germline mutations of the RET proto-oncogene was performed in a series of 67 patients with apparently sporadic MTC to determine whether they were true sporadic cases or unsuspected de novo MEN 2 cases. DESIGN AND PATIENTS: Sixty-seven unselected patients with sporadic MTC were randomly ascertained from clinic patients from four centres. The diagnosis of MTC was confirmed by histopathology. Germline DNA was extracted from peripheral blood leucocytes or from paraffin-embedded tissue and subsequently used for polymerase chain reaction amplification. MEASUREMENTS: Polymerase chain reaction based RET mutation analysis was performed by direct double-stranded cycle sequencing of exons 10, 11, 13 and 16, within which the majority of MEN2 mutations have been shown to occur. RESULTS: In this series, there was one proven case of germline mutation in RET codon 620, which previously has been shown to be responsible for MEN 2, thus indicating heritable disease. No germline mutation in codon 918, typical of MEN 2B, was found. CONCLUSIONS: A figure of 1.5% germline mutations in 67 apparently sporadic MTC is lower than the incidence of familial disease reported in previous series involving clinical and biochemical screening. The presence of a germline mutation in the RET proto-oncogene in a patient with MTC indicates heritable disease. The absence of germline RET exon 10, 11, 13 or 16 mutation appears to rule out MEN 2A to a high probability, although the presence of a familial form of MTC other than classical MEN 2A cannot be excluded conclusively.

Adolescent↗
PubMed1995

Von Hippel-Lindau syndrome.

After a decade of intensive clinical and molecular genetic efforts the von Hippel-Lindau (VHL) gene was cloned in 1993. The open reading frame encodes the putative protein of 284 amino acids. A large number of different mutations have been identified so far, including single base mutations, deletions, rearrangements and more complex mutations. So far, in about 75% of the VHL families germline mutations were detected. Geno-phenotypic comparison has revealed specific mutations with distinct manifestation patterns. Not all of the 6 classical lesions (hemangioblastoma of the CNS, retinal angiomatosis, pancreatic cysts, renal cysts and carcinoma, pheochromocytoma and epididymal cystadenoma) are present in VHL families. Pedigrees with pheochromocytoma but without renal cancer in general have point mutations. These recent results provide insight in the pathogenesis of a multiorgan cancer susceptibility tumor suppressor gene and allow determination of carrier status.

Brain↗
PubMed1995

Tuberous sclerosis complex with end-stage renal failure.

Renal angiomyolipoma is common in the tuberous sclerosis complex (TSC), the classic features of which are facial angiofibroma, seizures, and mental retardation. We report a family with three affected members demonstrating the wide spectrum of TSC-associated lesions ranging from asymptomatic findings to life-threatening complications. The predominant symptoms of the index patient were hypertension and mild renal insufficiency at age 48, resulting in end-stage renal failure at age 63 due to giant bilateral angiomyolipoma of the kidneys. The two TSC-affected siblings had died years previously, one from pulmonary lymphangioleiomyomatosis and the other during an epileptic state; the latter had situs inversus totalis as another remarkable finding. The diagnosis of TSC may be overlooked if CNS symptoms are absent and if cutaneous lesions are masked by cosmetic procedures, as occurred in the index case. Chronic renal failure due to angiomyolipoma is not widely known to clinical nephrologists, but develops in approximately 15% of TSC patients. Displacement of functional renal parenchyma by abnormal tissue appears to be the major pathogenetic mechanism leading to end-stage renal failure. Angiomyolipomas can be diagnosed from this characteristic sonographic pattern and the demonstration of fatty tissue in CT or MRI. Multiple renal cysts are also common in TSC. Therefore TSC should be considered in the differential diagnosis of polycystic kidney disease.

Angiomyolipoma↗
PubMed1994

False-positive diagnosis of a pheochromocytoma with I-123 metaiodobenzylguanidine.

The rare case of a false-positive scintiscan with I-123 labelled metaiodobenzylguanidine (MIBG) in a patient with suspected pheochromocytoma is reported. Focal accumulation of the tracer in the upper right abdomen, primarily thought to represent a right-sided pheochromocytoma, was subsequently proven to be caused by an ampullary renal pelvis. In cases of unexplained MIBG accumulation the possibility of prolonged retention of the tracer, because of an abnormality of the renal pelvis, should be considered and excluded by ultrasound.

3-Iodobenzylguanidine↗
PubMed1994

Germ-line mutations in the von Hippel-Lindau tumor-suppressor gene are similar to somatic von Hippel-Lindau aberrations in sporadic renal cell carcinoma.

von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome predisposing to multifocal bilateral renal cell carcinomas (RCCs), pheochromocytomas, and pancreatic tumors, as well as angiomas and hemangioblastomas of the CNS. A candidate gene for VHL was recently identified, which led to the isolation of a partial cDNA clone with extended open reading frame, without significant homology to known genes or obvious functional motifs, except for an acidic pentamer repeat domain. To further characterize the functional domains of the VHL gene and assess its involvement in hereditary and nonhereditary tumors, we performed mutation analyses and studied its expression in normal and tumor tissue. We identified germline mutations in 39% of VHL disease families. Moreover, 33% of sporadic RCCs and all (6/6) sporadic RCC cell lines analyzed showed mutations within the VHL gene. Both germ-line and somatic mutations included deletions, insertions, splice-site mutations, and missense and nonsense mutations, all of which clustered at the 3' end of the corresponding partial VHL cDNA open reading frame, including an alternatively spliced exon 123 nt in length, suggesting functionally important domains encoded by the VHL gene in this region. Over 180 sporadic tumors of other types have shown no detectable base changes within the presumed coding sequence of the VHL gene to date. We conclude that the gene causing VHL has an important and specific role in the etiology of sporadic RCCs, acts as a recessive tumor-suppressor gene, and appears to encode important functional domains within the 3' end of the known open reading frame.

Adult↗
PubMed1993

Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease.

BACKGROUND: Pheochromocytoma is a feature of two disorders with an autosomal dominant pattern of inheritance--multiple endocrine neoplasia type 2 (MEN-2) (with medullary thyroid carcinoma and hyperparathyroidism) and von Hippel-Lindau disease (with angioma of the retina, hemangioblastoma of the central nervous system, renal-cell carcinoma, pancreatic cysts, and epididymal cystadenoma). The frequency of these syndromes in patients with pheochromocytoma is not known. METHODS: In an unselected group of patients with pheochromocytoma, we performed pentagastrin tests, parathyroid hormone assays, computed tomography (CT) or magnetic resonance imaging (MRI) of the brain, ophthalmoscopy, CT imaging of the abdomen, and ultrasonography of the testes. We also screened members of families with MEN-2 or von Hippel-Lindau disease for pheochromocytoma by measuring plasma and urine catecholamines and plasma chromogranin A and by performing abdominal ultrasonography, CT and MRI, and metaiodobenzylguanidine scintigraphy. RESULTS: Nineteen of 82 unselected patients with pheochromocytomas (23 percent) were carriers of familial disorders; 19 percent had von Hippel-Lindau disease and 4 percent had MEN-2. Prospectively, in 36 of 79 subjects at risk for pheochromocytoma (46 percent), 42 unsuspected pheochromocytomas were found. Overall, there were 130 patients with 185 pheochromocytomas; 43 had von Hippel-Lindau disease, 24 had MEN-2, and 63 had sporadic tumors. The patients with familial and those with sporadic pheochromocytomas differed in mean age at diagnosis (32 vs. 46 years, P < 0.001), multifocal localization (55 vs. 8 percent, P < 0.001), and cancer (0 vs. 11 percent, P = 0.005); but not in the frequency of extraadrenal tumors (24 vs. 16 percent). Thirty-eight percent of carriers of von Hippel-Lindau disease and 24 percent of carriers of MEN-2 had pheochromocytoma as the only manifestation of their syndrome. CONCLUSIONS: All patients with pheochromocytomas should be screened for MEN-2 and von Hippel-Lindau disease to avert further morbidity and mortality in the patients and their families. All patients in families with MEN-2 or von Hippel-Lindau disease should be screened for pheochromocytoma, even if they are asymptomatic.

Adolescent↗