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.

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.

Ophthalmologic manifestations of type B Niemann-Pick diseases.

Type B Niemann-Pick Disease (NPB) is a rare lysosomal storage disease resulting from diminished activity or deficiency of sphingomyelinase and is characterized by multi-system involvement with visceromegaly. Rare ocular involvement (the Macula Halo Syndrome) has been reported. Eight patients (ages 4-36) with NPB underwent complete ophthalmologic evaluations. All patients had periorbital fullness, a hitherto unreported clinical feature. Two patients had a classic Macula Halo Syndrome. One patient developed peri-macular granular deposits forming an incomplete Macula Halo over 5 years. Another patient had macular granular deposits and developed deterioration of central vision and abnormal visual evoked potentials. Ophthalmologic involvement in NPB is more common than previously described. Complete ophthalmologic evaluation is recommended in all patients suspected to have NPB.

Genetic flanking markers refine diagnostic criteria and provide insights into the genetics of Von Hippel Lindau disease.

Von Hippel Lindau disease (VHL) is a hereditary syndrome, associated with tumors and cysts in multiple organ systems, whose expression and age of onset are highly variable. The availability of a genetic test for the early and reliable detection of individuals carrying the defective gene would be beneficial for VHL patients and their relatives, since many of the manifestations of VHL can be successfully treated if detected in their early stages, while the complications of undetected disease can be devastating. We have previously shown that the VHL gene maps to chromosome 3p. To provide genetic markers for the development of a reliable diagnostic test, and to further narrow and eventually clone the VHL defect, we have generated DNA markers for chromosome 3p. With these markers, we have performed a multipoint genetic linkage analysis in 28 VHL pedigrees, comprising 470 individuals, 164 of whom were affected with VHL. Here we report the identification of tightly linked markers, including flanking markers that bracket the VHL gene to a small region on chromosome 3p25-p26. This finding has several major implications. While visceral cysts of the kidney, pancreas, and epididymis are commonly found in VHL and are considered diagnostic criteria for this disorder, they also occur in the general population. The presence of cysts, unaccompanied by other more typical lesions such as retinal and cerebellar hemangioblastoma, may therefore represent a major diagnostic problem, leading to errors in the assessment of disease status. The application of flanking markers for the VHL gene for presymptomatic diagnostic testing confirms that epididymal cysts are indeed not suitable as a diagnostic criterion in this disorder. Pheochromocytomas occur nonuniformly in VHL families and may also be associated with other hereditary tumor syndromes; our genetic studies imply that the phenotype in VHL families with and without pheochromocytomas is caused by defects within the same gene. The absence or presence of this tumor type is therefore due to the pleiotropic expression of a single gene rather than to the existence of several different genes for VHL. The region on chromosome 3p13-p14 known to contain several chromosomal translocation breakpoints in families with "pure familial renal cell carcinoma" is quite proximal to the VHL locus in 3p25-p26 we have identified. Chromosome 3p may therefore contain two loci for renal cell carcinoma: one gene (or genes) in 3p13-p14 and the VHL gene in 3p25-p26, whose aberration is also associated with other typical manifestations of VHL. Since renal cell carcinoma, pheochromocytoma, and visceral cysts can occur sporadically even in young people and may also be associated with other tumor syndromes, the availability of flanking markers for the VHL gene will be useful in identifying VHL gene carriers, particularly among those individuals at risk in whom these are the only manifestations of disease. The isolation and characterization of the VHL gene, based on the identification of flanking markers, will have important implications for diagnosis and treatment of patients with VHL, as well as for a much larger number of individuals having the sporadic counterparts of VHL-associated tumor types.

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.

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.

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.

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.

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.

von Hippel-Lindau disease: radiologic screening for visceral manifestations.

The visceral manifestations of von Hippel-Lindau (VHL) disease can cause significant morbidity and mortality. The authors prospectively screened 37 persons from a single kindred. Twenty-five subjects underwent abdominal ultrasound (US), contrast material-enhanced abdominal computed tomography (CT), and nonenhanced abdominal magnetic resonance (MR) imaging. Eight subjects younger than 16 years of age underwent abdominal US and MR imaging only. Scrotal US was employed in 25 male patients. Eleven subjects had renal cysts or tumors. Contrast-enhanced CT depicted renal abnormalities in 10 of these subjects, US in seven, and MR imaging in nine. Among 12 subjects with pancreatic cysts or tumors, CT showed pancreatic abnormalities in all 12, US in nine, and MR imaging in nine. Three subjects (mean age, 34.5 years) had renal tumors, and three had pancreatic masses. Scrotal US revealed epididymal cystadenomas in seven subjects; two of these tumors were surgically verified. A combination of contrast-enhanced CT and scrotal US in male patients appears to be the best way to screen for visceral manifestations of VHL disease.

Radiologic screening for von Hippel-Lindau disease: the role of Gd-DTPA enhanced MR imaging of the CNS.

Thirty-seven members of a family with von Hippel-Lindau disease (VHL) were prospectively screen for CNS hemangioblastomas; 10 family members were previously known to have VHL. Radiographic studies included noncontrast magnetic resonance (MR) imaging of the head (all patients) and spine (34 patients) and contrast-enhanced CT (CCT) of the head (all adult patients). Eleven patients had Gd-DTPA enhanced MR (CMR) of the head and 10 patients had CMR of the spine. Sixteen patients had radiographic evidence of CNS hemangioblastomas and all but six patients were symptomatic. Using comparable studies, CMR of the head demonstrated more lesions than the other modalities (31, 22, and 19 for CMR, MR, and CCT, respectively). Furthermore, CMR better separated tumor from edema, as well as cystic from solid components. Contrast enhanced MR was superior to noncontrast MR of the spine in lesion detection (31 vs. 4; p less than 0.001). Noncontrast MR was particularly limited in four patients with syringomyelia. We conclude that postcontrast MR of the head and spine is the best currently available means of detecting hemangioblastomas associated with VHL.

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.

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.

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.

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.

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.

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.