Specific genetic change in tumors associated with von Hippel-Lindau disease.

Previous reports showed that the loss of DNA sequences on the short arm of chromosome 3 (3p) is consistently found in sporadic renal cell carcinomas. To evaluate the significance of this genetic change, we looked for the loss of 3p alleles in hereditary renal cell carcinomas and other tumors from patients with von Hippel-Lindau disease. Specific loss of alleles from chromosome 3p was detected with polymorphic DNA markers in 11 renal cell carcinomas, one pheochromocytoma, two spinal hemangioblastomas and one cerebellar hemangioblastoma from von Hippel-Lindau patients. Multiple renal cell carcinomas in individuals with von Hippel-Lindau disease showed loss of the same chromosome 3p alleles, which demonstrated that the same chromosome was deleted in each tumor. Analysis of haplotypes indicated that the loss of chromosome 3p alleles was from the chromosome bearing the balancing, wild-type allele of the VHL gene. These results are consistent with the concept that the VHL gene is a recessive oncogene. Renal cell carcinoma, pheochromocytoma, and spinal and cerebellar hemangioblastomas develop in predisposed family members when somatic mutational events lead to loss of chromosome 3p sequences bearing the wild-type allele of the VHL gene.

Clinical and genetic analysis of progressive dystonia with diurnal variation.

We examined 17 patients with progressive dystonia with diurnal variation, a dominantly inherited, generalized dystonia that begins in childhood. Dystonia was typically least severe in the morning, increased as the day continued, and markedly improved with low doses of carbidopa-levodopa. We also studied the patient's parents, children, and siblings from seven families. We observed a spectrum of neurologic involvement, phenotypic variability among siblings, and incomplete genetic penetrance. Progression of motor impairment over several years, which reaches a plateau during late adolescence, is useful in distinguishing progressive dystonia with diurnal variation from cerebral palsy and degenerative disorders. It is important to recognize the subtle, as well the extreme, manifestations of progressive dystonia with diurnal variation because it is treatable. Genetic counseling must consider that mildly affected parents with little or no disability may have profoundly affected children. Appreciation of the phenotypic variability and degree of genetic penetrance will permit detailed genetic and biochemical analyses.

Carbamazepine in Fabry's disease: effective analgesia with dose-dependent exacerbation of autonomic dysfunction.

Seven patients with Fabry's disease and severe pain received carbamazepine (CMZ). Five of 7 patients had moderate to complete relief based upon self-assessment of pain levels. Preexisting autonomic dysfunction was exacerbated by CMZ in 2. Complications encountered were ileus, urinary retention, and gastrointestinal disturbance. Although CMZ was useful in treatment of pain, caution should be employed in this disease.

Central nervous system involvement in Von Hippel-Lindau disease.

Fifty individuals with Von Hippel-Lindau disease (VHL) were studied with gadolinium-enhanced magnetic resonance imaging (MRI) to determine the frequency and distribution of CNS lesions. The associated clinical features were also reviewed. Thirty-six (72%) of the 50 had 1 or more CNS tumors. The most frequently affected sites in the CNS excluding the retina were the cerebellum (52%), spinal cord (44%), and brainstem (18%). New regional predilections for the craniocervical junction and conus medullaris were demonstrated by this study. Forty-one percent of all VHL patients with CNS tumors were neurologically asymptomatic: cerebellar tumors (50%), spinal cord tumors (50%), and brainstem tumors (44%) were often without clinical signs or symptoms. Multiple lesions were common. The mean age of all VHL patients (34.5 years) was similar to the mean age of all CNS VHL patients (34.4 years), suggesting a lack of age association. CNS lesions commonly occurred in the 2nd decade of life. All patients at risk for VHL should be evaluated using gadolinium-enhanced MRI after 10 years of age, although ophthalmic examination should be initiated within the 1st 2 years of life. Enhanced MRI is particularly useful in the detection of CNS tumors in patients with the VHL gene.

Clinical, pathologic, and biochemical features of a cholesterol lipidosis accompanied by hyperlipidemia and xanthomas.

We describe the unique clinical and histopathologic features of a child with biochemical and immunocytochemical features of Niemann-Pick disease type C (NPC). Clinically, she was found to have multiple xanthomas of the upper aerodigestive tract with dysphagia and expressive language delay, splenomegaly, bony infarcts, and type IIb hyperlipidemia. Neurologic examination was otherwise normal. Microscopy revealed foam cells in her bone marrow, liver, tongue, tonsils, glottis, and in normal-appearing peritonsillar mucosa. Lipid analysis of a liver biopsy specimen showed a small increase in phospholipids, a twofold increase in sphingomyelin, a fivefold increase in cholesterol, and a marked (25-fold) increase in bis(monoacylglycerol) phosphate. Lysosomal acid hydrolase activities in cultured skin fibroblasts were nondiagnostic. Biochemical and immunocytochemical studies of cultured fibroblasts demonstrated lysosomal accumulation of unesterified LDL-derived cholesterol as well as delayed induction of homeostatic responses to endogenous cholesterol consistent with a diagnosis of NPC. Based upon these observations, we speculate that this patient could have a new phenotypic expression of NPC or represents a new cholesterol lipidosis biochemically resembling NPC. The chance occurrence of two separate lipid disorders seems less likely.

Clinical spectrum of Niemann-Pick disease type C.

Analysis of the neurologic symptomatology in 22 patients with Niemann-Pick disease type C revealed 3 phenotypes: (1) an early-onset, rapidly progressive form associated with severe hepatic dysfunction and psychomotor delay during infancy and later with supranuclear vertical gaze paresis, ataxia, marked spasticity, and dementia; (2) a delayed-onset, slowly progressive form heralded by the appearance, usually in early childhood, of mild intellectual impairment, supranuclear vertical gaze paresis, and ataxia, and later associated with dementia and, variably, seizures and extrapyramidal deficits; (3) a late-onset slowly progressive form distinguished from the 2nd pattern by later age of onset (adolescence or adulthood) and a much slower rate of progression. The existence of the 1st and 2nd phenotypes within the same sibship suggests that they are variant expressions of the same clinicopathologic disorder. Niemann-Pick disease type C should be considered not only in infants and children who present with organomegaly and a progressive neurodegenerative course, but also in adolescents and adults who have insidiously progressive neurologic dysfunction and only slight organomegaly. Associated with the disease is a marked deficiency in the ability of cultured fibroblasts to esterify exogenously supplied cholesterol. Assay of this deficiency is particularly useful for confirming the diagnosis in patients with atypical presentation.

Terminal transverse limb defects associated with familial cavernous angiomatosis.

Terminal transverse limb defects rarely are reported as familial. Multiple pathogenetic mechanisms, including vascular disruption, have been proposed to account for these defects. We report on a family followed over the past 6 years known to have familial cavernous angiomatosis in which 2 relatives have similar terminal transverse defects at the mid-forearm. Multiple relatives have had episodic bleeding from intracranial cavernous angiomas, a distinct finding in this disorder. Other findings in this family include retinal cavernous angiomas (2 patients), a high incidence of skin angiomas (12 patients), cavernous angiomas of the soft tissue (2 patients), and a hepatic angioma (one patient). One of the 2 individuals with the limb defect was evaluated extensively. Magnetic resonance imaging of the forearm with the terminal transverse defect using gadolinium-DTPA enhancement showed abrupt termination of all structures distal to the normal radial and ulnar heads. We propose that familial cavernous angiomatosis may be a new cause of vascular disruption resulting in terminal transverse limb defects.

Identifying genes determining trait differences in behavior and drug response: a comment on 'Quantitative trait loci and psychopharmacology'.

In Plomin, McClearn and Gora-Maslak's target article (see also Science 248: 183-188, 1990), reverse genetic approaches are emphasized for locating genes determining behavioral and pharmacogenetic traits. Furthermore, prospects for such an undertaking are presented pessimistically in that behavioral traits are asserted to be polygenic (due to the simultaneous action of variant alleles at multiple loci) and are conceptualized as being determined in large part by unshared environmental factors. We disagree with Plomin et al. in three major areas and argue the following:(1) Forward genetic approaches involving candidate locus analysis and detailed analysis of the phenotype are of primary importance for isolating genes for behavioral traits, as for other genetic traits.(2) Virtually all physiologic processes and metabolic pathways involve sets of genes, resulting in genetic heterogeneity (multiple genetic origins for a trait). However, polygenicity is approximately as unusual for behavioral traits as for other traits.(3) Heritability analyses underestimate the extent to which behavioral traits are amenable to genetic analysis and have been misinterpreted to overestimate the importance of environmental factors.

Niemann-Pick disease types C and D.

Patients grouped into categories termed type C Niemann-Pick disease and the Nova Scotia isolate called type D Niemann-Pick disease are characterized by mild to moderate hepatosplenomegaly, sea-blue histiocytes in the bone marrow, supranuclear gaze paresis in the vertical plane, slowly progressing ataxia, and mental deterioration. These signs are caused by abnormal intracellular cholesterol homeostasis. Cholesterol that enters cells from the circulation through the LDL receptor is not processed in a timely, normal manner by cells in parenchymal organs and the CNS. It therefore accumulates in toxic quantities as unesterified cholesterol causing cellular and tissue damage. Knowledge of the primary, consistent disturbance in cholesterol disposition has led to the development of tests to diagnose patients, identify heterozygotes, and assure the prenatal detection of these disorders. Therapeutic strategies include reduction of dietary cholesterol, apheresis techniques designed to reduce LDL cholesterol available to cells, and reduction of formation of LDL and increase of synthesis of HDL to lower cellular uptake of cholesterol and enhance egress of this lipid from intracellular storage sites. The development of procedures that block cholesterol formation but do not up-regulate LDL receptors on plasma cell membranes is considered to be highly important for the therapy of types C and D Niemann-Pick disease.

Papillary cystadenoma of the epididymis. A report of three cases with lectin histochemistry.

Papillary cystadenoma of the epididymis is an uncommon benign tumor associated with von Hippel-Lindau disease. Since metastatic renal cell carcinoma may be histologically similar to papillary cystadenoma, and both are associated with von Hippel-Lindau disease, differentiation between these two entities may be difficult. We performed lectin histochemistry studies on three papillary cystadenomas and compared the results with the staining observed in epididymal ducts, epididymal efferent ductules, and three renal cell carcinomas. Common positive staining was observed following incubation with soybean agglutinin in epididymal ducts and two of the three papillary cystadenomas, while the three renal cell carcinomas did not stain. When epididymal tumors histologically consistent with papillary cystadenoma fail to react with soybean agglutinin, thorough clinical evaluation for an occult renal cell carcinoma should be performed.

Brachial plexus neuropathy following high-dose cytarabine in acute monoblastic leukemia.

We describe brachial plexus neuropathy with high-dose cytarabine (Ara-C) therapy in a man who had acute monoblastic leukemia. Signs and symptoms of brachial plexus neuropathy appeared on two occasions within hours of exposure to high-dose Ara-C. Central nervous system complications have been described following systemic and intrathecal Ara-C. High-dose Ara-C has not been implicated previously as a cause of brachial plexus neuropathy.

Simple renal cysts, atypical renal cysts, and renal cell carcinoma in von Hippel-Lindau disease: a lectin and immunohistochemical study in six patients.

We compare the expression of four markers of renal tubular differentiation in six renal cell carcinomas, five atypical renal cysts, and five simple renal cysts from six patients with von Hippel-Lindau disease. Proximal tubular markers were expressed by five of six renal cell carcinomas, three of five atypical renal cysts, and zero of five simple renal cysts. Distal tubular markers were expressed by one of six renal cell carcinomas, five of five atypical renal cysts, and four of five simple renal cysts. One of the three atypical cysts which expressed distal tubular markers was associated with a renal cell carcinoma which also expressed distal tubular markers. Our findings suggest that simple renal cysts in von Hippel-Lindau disease arise more commonly from distal rather than proximal tubules, while atypical renal cysts show tubular origin similar to renal cell carcinomas.

Gadopentetate dimeglumine enhanced MRI in an anephric patient on dialysis.

Gadopentetate dimeglumine (Gd-DTPA) was injected into an anephric patient on maintenance haemodialysis. Sequential serum Gd levels before and after dialysis demonstrated incomplete removal of the administered dose. No clinical sequelae were observed. Gd-DTPA can be given to patients on dialysis, but like iodinated contrast media, may require more than one session for complete removal.

Windows and blinking: techniques for enhanced ocular computed tomographic imaging.

Computed tomography (CT) has become an important diagnostic modality in the evaluation of ocular and orbital disease. A weakness of CT, however, is its inability to show clearly intraocular lesions that do not contain calcium. These images can be improved by the careful selection of window width and window level and by the use of a technique known as "blinking." The use of these enhancement techniques is illustrated in two cases of leukocoria in children.

Niemann-pick variant disorders: comparison of errors of cellular cholesterol homeostasis in group D and group C fibroblasts.

Fluorescence microscopic examination of filipin-stained cultured skin fibroblasts derived from two brothers with group D Niemann-Pick disease revealed abnormal storage of low density lipoprotein (LDL)-derived cholesterol. LDL stimulation of intracellular cholesteryl ester synthesis was severely compromised in the Niemann-Pick D fibroblasts, as it also was in fibroblasts obtained from Niemann-Pick C patients. Cholesteryl ester synthesis was intermediately deficient in cells derived from an obligate group-D heterozygous carrier. Activity of acyl-CoA:cholesterol acyltransferase was within the normal range in cell-free extracts of both LDL-depleted and LDL-supplemented cultures of Niemann-Pick C and D fibroblasts. Incubation of Niemann-Pick D fibroblasts with LDL did not lead to as high a level of intracellular cholesterol accumulation as the excessive storage observed with Niemann-Pick C fibroblasts. These findings suggest that the Niemann-Pick variant disorders may represent a family of specific and possibly individual mutations that disrupt cellular cholesterol homeostasis.

Polyclonal B-cell lymphocytosis and hypergammaglobulinemia in patients with Gaucher disease.

Sera from 23 individuals with Gaucher disease (GD) were analyzed for hypergammaglobulinemia and oligoclonal and monoclonal gammopathies. Serum IgG level was elevated in 15/23 (65%) patients, and a diffuse hypergammaglobulinemia was present in 10/23 (43%) patients. An oligoclonal gammopathy was noted in six patients, and a monoclonal gammopathy in two. Lymphocyte subset analysis was also carried out in eight individuals with GD. Four of five individuals showed increased surface Ig-positive lymphocytes, while 7/7 were positive for either increased CD19- and/or CD20-positive lymphocytes. An eighth patient was found to have a B-cell leukemia. Statistical analysis of kappa and lambda histograms were suggestive of a monoclonal excess. However, restriction enzyme analysis of four individuals with GD and increased B cells failed to show any evidence of Ig gene rearrangements. Serum Ig abnormalities and perhaps B-cell lymphocytosis appear to be common in the GD patient population and are not associated with circulating monoclonal lymphocytes.

Cholesteryl ester storage disease: a patient with massive splenomegaly and splenic abscess.

Cholesteryl ester storage disease (CESD), a rare lysosomal storage disorder characterized by functional deficiency of acid lipase activity, classically features hepatomegaly in conjunction with lipid-laden macrophages containing excessive quantities of cholesteryl esters. We present a patient whose clinical course was complicated by massive, symptomatic splenomegaly, and an unsuspected splenic abscess. Computed tomographic and magnetic resonance imaging are correlated. Histologic, electron microscopic, and biochemical features are presented. To our knowledge, this is the first report of splenic abscess in CESD.