Uniform Clinical Picture Research Articles

Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome

AbstractWe report here 7 new mutations in the ADAMTS13 gene responsible for Upshaw-Schulman syndrome (USS), a catastrophic phenotype of congenital thrombotic thrombocytopenic purpura, by analyzing 5 Japanese families. There were 3 mutations that occurred at exon-intron boundaries: 414+1G>A at intron 4, 686+1G>A at intron 6, and 1244+2T>G at intron 10 (numbered from the A of the initiation Met codon), and we confirmed that 2 of these mutations produced aberrantly spliced messenger RNAs (mRNAs). The remaining 4 mutations were missense mutations: R193W, I673F, C908Y, and R1123C. In expression experiments using HeLa cells, all mutants showed no or a marginal secretion of ADAMTS13. Taken together with the findings in our recent report we determined the responsible mutations in a total of 7 Japanese patients with USS with a uniform clinical picture of severe neonatal hyperbilirubinemia, and in their family members, based on ADAMTS13 gene analysis. Of these patients, 2 were homozygotes and 5 were compound heterozygotes. The parents of one homozygote were related (cousins), while those of the other were not. Molecular models of the metalloprotease, fifth domain of thrombospondin 1 (Tsp1-5), and Tsp1-8 domains of ADAMTS13 suggest that the missense mutations could cause structural defects in the mutants.

Deceptively bland cutaneous angiosarcoma on the nose mimicking hemangioma-A clinicopathologic and immunohistochemical analysis.

We investigated 2 cases of deceptively bland cutaneous angiosarcoma (AS), which showed a uniform clinical presentation with a rapidly growing tumor on the nose. It remains unclear whether this was a primary cutaneous manifestation or a metastasis. Both tumors initially presented a high histologic overlap with a benign vascular tumor. The diagnosis was primarily based on the rapidly progressing clinical course and on the results of the staging procedures. Immunohistochemical stains were performed for cytokeratin (AE1/AE3 and MNF116), CD31, ERG, CD34 (HPCA1/my10), D2-40/podoplanin, LYVE-1, Ki67, PHH3, αSMA (1A4), MYC, FOS-B, CAMTA-1, TFE-3, WT1, nestin, VEGFR-2(KDR), VEGFR-3(FLT4), HHV8. MYC amplification was also investigated by fluorescence in situ hybridization. The tumor cells were negative for MYC and revealed no D2-40/podoplanin expression. SMA-positive pericytes formed rims around the vessel. The proliferative activity (Ki-67) was elevated, in one case only in a later stage. Cutaneous ASs can be rather bland and may easily be mistaken for benign vascular tumors. Both cases presented a uniform clinical picture, which implied a malignant vascular tumor. In contrast, the cytomorphology of the endothelial cells and the immunohistochemical profile were not suspicious. We worked out subtle histological criteria, which should allow an early detection of such tumors.

Clinical features and genetic background of the periodic Fever syndrome with aphthous stomatitis, pharyngitis, and adenitis: a single center longitudinal study of 81 patients.

PFAPA syndrome is the most common autoinflammatory disorder in childhood with unknown etiology. The aim of our study was clinical evaluation of PFAPA patients from a single tertiary care center and to determine whether variations of AIM2, MEFV, NLRP3, and MVK genes are involved in PFAPA pathogenesis. Clinical and laboratory data of consecutive patients with PFAPA syndrome followed up at the University Children's Hospital, Ljubljana, were collected from 2008 to 2014. All four genes were PCR amplified and directly sequenced. Eighty-one patients fulfilled criteria for PFAPA syndrome, 50 (63%) boys and 31 (37%) girls, with mean age at disease onset of 2.1 ± 1.5 years. Adenitis, pharyngitis, and aphthae were present in 94%, 98%, and 56%, respectively. Family history of recurrent fevers in childhood was positive in 78%. Nineteen variants were found in 17/62 (27%) patients, 4 different variants in NLRP3 gene in 13 patients, and 6 different variants in MEFV gene in 5 patients, and 2 patients had 2 different variants. No variants of clinical significance were found in MVK and AIM2 genes. Our data suggest that PFAPA could be the result of multiple low-penetrant variants in different genes in combination with epigenetic and environmental factors leading to uniform clinical picture.

Autosomal recessive non-progressive ataxia with an early childhood debut.

The case histories and clinical studies are given of 7 consanguineous patients, 4 adults and 3 children, with a rather uniform clinical picture of nonprogressive cerebellar ataxia manifesting in early childhood. Most patients have in addition slight spastic signs, short stature and normal intelligence. There are no signs of other organ pathology, biochemical aberrations, endocrine- or immunopathology. CT-scan and PEG show cerebellar atrophy. The pedigree analysis indicates an autosomal recessive mode of inheritance. The condition falls between the ataxic syndromes in the cerebral palsy range and the heredo-ataxias. Until now, no similar disorders seems to have been described.

Functional Significance and Clinical Phenotype of Nontruncating Mismatch Repair Variants of

Germline mutations in mismatch repair genes are associated with hereditary nonpolyposis colorectal cancer. A significant proportion of mutations are nontruncating and associated with a variability of clinical phenotype and microsatellite instability and with occasional presence of residual protein in tumor tissue that suggests impaired functional activity but not total lack of mismatch repair. To address pathogenic significance and mechanism of pathogenicity, we studied the functionality of 31 nontruncating MLH1 mutations found in clinically characterized colorectal cancer families and 3 other variations listed in a mutation database. Mutations constructed by site-directed mutagenesis were studied for protein expression/stability, subcellular localization, protein-protein interaction, and repair efficiency. The genetic and biochemical data were correlated with clinical data. Finally, comparative sequence analysis was performed to assess the value of sequence homology as a tool for predicting functional results. Altogether, 22 mutations were pathogenic in more than one assay, 2 variants were impaired in one assay, and 10 variants acted like wild-type protein. Twenty of 34 mutations affected the quantity of MLH1 protein, whereas only 15 mainly amino-terminal mutations were defective in an in vitro repair assay. Comparative sequence analysis correctly predicted functional studies for 82% of variants. Pathogenic nontruncating alterations in MLH1 may interfere with different biochemical mechanisms but generally more than one. The severe biochemical defects are mirrored by phenotypic characteristics such as early age at onset and high microsatellite instability, whereas variants with no or mild defects in functionality are associated with variable clinical phenotypes.

Treatment of anorexia nervosa in adults

It essential to match the treatment for anorexia nervosa to the needs of the individual. This requires a careful assessment of risk and resources. A risk assessment of anorexia nervosa includes consideration of several dimensions: physical health, clinical features, capacity, motivation and social factors. The outcome of anorexia nervosa; in terms of recovery and mortality rates is improved if the illness is short in duration i.e. early interventions are to be recommended. However because the onset is in early adolescence in most cases those presenting to adult services have had the illness for over 3 years and so the prognosis is less good. Severe weight loss is dangerous in the short term and leads to an adverse long-term outcome. Specialized treatments are more acceptable, efficacious and cost effective in anorexia nervosa than non-specialised treatment. Anorexia nervosa has a relatively uniform clinical picture: onset age 15, median duration 6 years. Early intervention services need to be focused on 16–21 year olds. The services for adult cases include the poor prognostic group and therefore will need a higher level of resources with a greater proportion of more intensive interventions. 20–30% have a chronic course with both physical and psychological morbidity. Approximately 30% of adult cases can be expected to have a good outcome after a year of treatment.

Hyperargininemia due to liver arginase deficiency

The urea cycle is a series of six reactions necessary to rid the body of the nitrogen generated by the metabolism, primarily of amino acids, from the diet or released as the result of endogenous protein catabolism. Arginase is the sixth and final enzyme of this cycle. Arginase catalyzes the conversion of arginine to urea and ornithine, the latter recycled to continue the cycle. Hyperargininemia due to arginase deficiency is inherited in an autosomal recessive manner and gene for arginase, designated AI, has been cloned. Unlike the other urea cycle enzymes, a second gene encoding arginase, with similar structural properties and enzyme characteristics, exists and has been named Arginase II (AII). Comprehensive histories and physical examinations confirm a strikingly uniform clinical picture and one notably different from patients with other urea cycle disorders. This condition rarely presents in the neonatal period and first symptoms typically present in children between 2 and 4 years of age. First symptoms are often neurologically based. If untreated, symptoms are progressive with a gradual loss of developmental milestones. With adherence to a dietary and drug regimen, a favorable outcome can be expected, with cessation of further neurological deterioration and in some instances, of improvement. This article summarizes the clinical course of selected patients who represent the full spectrum of presentations of arginase deficiency. In addition to the clinical characterization of this disorder; the biochemical, enzymatic, and molecular evidence of disease is summarized. Treatment and prenatal diagnosis are also discussed.

Recurrent nasopharyngeal carcinoma presenting as diffuse dermal lymphatic infiltration in the neck: three case reports.

Any malignancy has the propensity to metastasize to skin. The frequency of skin metastases vary in different tumors and occur in about 0.7% to 10% of all patients diagnosed with cancer. It is rare in nasopharyngeal carcinoma. Three cases of relapsed nasopharyngeal carcinoma with diffuse dermal involvement were described. Their clinical presentation, results of investigations, and response to treatment were reviewed. Literature review of similar forms of presentation was done by means of a MEDLINE search. At the time of dermal relapse, all three patients had a uniform clinical picture of facial, periorbital, and lip swelling associated with stridor and dysphagia. Histologic findings showed dermal infiltrates of malignant cells, and CT scan showed diffuse infiltration of the subcutaneous tissue. Despite chemotherapy, the clinical course was relentless. This report describes a presentation of disease that is underdiagnosed and heightens awareness of oncologists to this form of recurrence in nasopharyngeal carcinoma.

Transient global amnesia and functional retrograde amnesia: contrasting examples of episodic memory loss.

We studied 11 patients with transient global amnesia (TGA) and ten patients with functional retrograde amnesia (FRA). Patients with TGA had a uniform clinical picture: a severe, relatively isolated amnesic syndrome that started suddenly, persisted for 4-12 h, and then gradually improved to essentially normal over the next 12-24 h. During the episode, the patients had severe anterograde amnesia for verbal and non-verbal material and retrograde amnesia that typically covered at least two decades. Thirty hours to 42 days after the episode, the patients had recovered completely and performed normally on tests of anterograde and retrograde amnesia. By contrast, patients with FRA had a sudden onset of memory problems that were characterized by severe retrograde amnesia without associated anterograde amnesia and with a clinical presentation that otherwise varied considerably. The episodes persisted from several weeks to more than two years, and some of the patients had not recovered at the time of our last contact with them. The uniform clinical picture of TGA and the variable clinical picture of FRA presumably reflect their respective neurologic ('organic') and psychogenic ('non-organic') aetiologies.

Therapie der dilatativen Kardiomyopathie mit rekombinantem humanem Wachstumshormon (Therapy of dilated cardiomyopathy with human recombinant growth hormone)

Dilated cardiomyopathy is a disease of the myocardium which is characterized by predominant enlargement of the left ventricle, decreased systolic function, and reduced myocardial wall thickness. The reduction in the number and function of myocardial fibers induces hypertrophy and leads to interstitial fibrosis. Ventricular dilatation and reduced wall thickness contributes to a further increase of the already elevated myocardial wall stress and triggers the continuous decrease of myocardial function. The initial myocyte injury by different and mostly unknown causes leads to progressive myocyte damage resulting in a similar uniform clinical picture independent from the initial myocellular derangement. One of the common pathways may be an inadequate response of the heart to human growth hormone (GH). Several studies support this hypothesis: GH deficiency results in a significant reduction of ventricular wall thickness and myocardial function, and GH-substitution is able to normalize the depressed left ventricular function. In addition, Sacca et al. reported in an uncontrolled study that GH-therapy reduced left ventricular wall stress by 40% in 7 patients with dilated cardiomyopathy. There was a parallel increase of the ejection fraction from 34% to 47%. This improvement was accompanied by a decrease of the functional classification of heart failure from NYHA 2.7 to 1.6. This therapeutic approach to alter the myocyte function directly by growth factors may open a new therapeutic concept in dilated cardiomyopathy. If double blind, randomized studies confirm the results of Sacca's study, a new era of therapeutic options may be available for the treatment of dilated cardiomyopathy.

Identical mutations and phenotypic variation.

The relationship between pathogenetic mutations and disease phenotype is becoming increasingly complex. Well-delineated clinical entities can be genetically heterogeneous, and mutations in a particular gene may result in fundamental clinical differences. Genetic heterogeneity includes mutations at different gene loci or allelic mutations within a single gene, resulting in a similar phenotype. However, one and the same mutation is expected to be associated with a uniform clinical picture. In the present article, evidence is presented that this is not necessarily the case, and examples of identical mutations resulting in highly variable combinations of clinical features are discussed. Although the number of examples of this puzzling phenomenon is rapidly increasing, the underlying mechanisms are as yet poorly understood. In some cases, interacting genetic alterations can be held responsible for the phenotypic heterogeneity; in others, epigenetic phenomena provide a plausible explanation. These and other mechanisms under discussion are considered here. The Mendelian concept of monofactorial disease causation appears to be increasingly untenable for a growing number of developmental errors.

Psychological aspects of ″environmental illness,” ″multiple chemical sensitivity,” and building-related illness

Psychological aspects of ″environmental illness,” ″multiple chemical sensitivity,” and building-related illness

Psychological aspects of “environmental illness,” “multiple chemical sensitivity,” and building-related illness

Psychological aspects of “environmental illness,” “multiple chemical sensitivity,” and building-related illness

Inhaled particles and respiratory disease

Inhaled particles and respiratory disease

Computed Tomography and Histologic Results in the Early Stages of Endotoxin-Injured Pig Lungs as a Model for Adult Respiratory Distress Syndrome

To determine early radiographic changes in diffuse alveolar injury, the authors correlated computed tomography (CT) and histopathology in pigs with recurrent endotoxinemia. Five pigs received recurrent endotoxin over a 17-hour period. Three pigs received physiologic saline and served as controls. Hemodynamic and blood-gas data were analyzed. CT was performed immediately before killing the animals. The lungs were cut into 5-mm-thick slices in the same axis as the CT scans and were investigated by light and electron microscopy. Hemodynamic data, blood-gas analysis, and morphologic changes closely simulated the clinical situation of septic shock in the five pigs that had received endotoxin. Results of histologic examination depicted changes similar to those associated with adult respiratory distress syndrome (ARDS). CT clearly demonstrated both interstitial, and to a minor degree, intra-alveolar lesions in the endotoxin-injected group, which correlated well with dilated lymph vessels, thickened interstitium, and areas of dystelectasis on histologic examination. Although there was a rather uniform clinical picture, CT and histologic findings showed different degrees of involvement. CT clearly depicts changes in endotoxin-injured pig lungs in an early clinical state, which are similar to changes associated with ARDS on histologic examination.

Epidemic polyarthritis in Australia, 1980-1981.

Information concerning their clinical illness was obtained by self-administered questionnaire from 528 patients who suffered from epidemic polyarthritis in Australia during 1980 and 1981. The clear and uniform clinical picture which has emerged from this study should facilitate the diagnosis of this disease. The illness begins suddenly with the onset of acute aching in the muscles and joints, followed by a maculopapular rash in between 40% and 78% of patients, and extensive polyarthritis. This affects chiefly the ankles, fingers, knees and wrists, usually serially, but no joint is spared. Estimates of incubation time suggest that it ranges from three to 21 days (mean, nine days). Women, especially housewives, are the group most frequently affected. Exposure to mosquitoes is an important predisposing factor; the implications of this for prevention and future research are considered. The mechanism of the survival of the virus in nature remains poorly understood.

Serotonin and noradrenaline uptake inhibitors in the treatment of depression--relationship to 5-HIAA in spinal fluid.

Evidence is accumulating that endogenous depression, in spite of its relatively uniform clinical picture, may have different pathophysiological correlates, and that these may predict the outcome of treatment. The distribution of the serotonin (5‐HT) metabolite, 5‐hydroxyindoleacetic acid (5‐HIAA) in the spinal fluid (CSF) from depressed patients has repeatedly been shown to be bimodal, provided that sufficiently sensitive biochemical methods (mass fragmentography) are used for the analysis.A study of nortriptyline revealed a poor antidepressant effect of this typical noradrenaline (NA) uptake blocker in patients with low pretreatment CSF 5‐HIAA. Chlorimipramine (CI), which is a potent 5‐HT uptake blocker in vitro and in animals was therefore given to depressed patients. The serotonin effects were borne out by a profound decrease in CSF 5‐HIAA. This effect, which is presumably mediated by feed‐back inhibition of 5‐HT synthesis was correlated to the plasma concentration of CI, but only up to a certain plasma level. Above this, there was little effect on 5‐HIAA, suggesting that high concentrations of CI may block 5‐HT receptors. The concentration of the NA metabolite, 4‐hydroxy‐3‐methoxyphenyl glycol (HMPG) in CSF decreased in proportion to the demethyl metabolite (DMCI) concentration in plasma. DMCI is a potent NA uptake blocker in vitro. Patients with low pretreatment CSF 5‐HIAA reacted equally well to treatment with CI as those with high levels, but only in the latter group was there a correlation to plasma levels (between DMCI and antidepressant effect). The antidepressant effect was also correlated to HMPG reduction in CSF, suggesting that these patients recover in proportion to drug effect on NA

Acquired Aphasia in Childhood with Seizure Disorder: A Heterogeneous Syndrome

The authors report six children with acquired aphasia of unknown etiology. The clinical picture was clearly different from that seen in the usual childhood aphasias and resemble other cases initially reported as "syndrome of acquired aphasia with convulsive disorder". All had associated paroxysmal EEG abnormalities, and 5 have had clinical seizures. The language disorder has improved or remained stationary and no other neurological signs have developed. Our review of the literature and the study of our personal cases show no uniform clinical picture in these children. Three different clinical patterns seem to emerge. The first group show rapid onset and recovery of aphasia, frequent fluctuations in the severity of the language deficit typical of so-called epileptic aphasia. These children appear to have a better prognosis. The second group show worsening of the aphasic deficit after repeated seizures or episodes of aphasia. In the third group progressive deficit in language comprehension (auditory agnosia) with a variable degree of recovery and rare or no clinical seizures. The possible significance of the EEG abnormalities has been discussed and the importance of the aphasia on general behavior and the problems of differential diagnosis have been stressed.

Psychotherapy in eating disorders.

This paper emphasizes that neither obesity nor severe malnutrition represents a uniform clinical psychiatric picture. The therapist must always pay attention to and integrate the various factors involved in eating disorders such as the underlying personality problems, resolution of the interactional conflicts within the family and correction of the abnormal nutritional states. The similarities and differences of both obesity and anorexic states are described. Primary or typical anorexia nervosa is differentiated from the atypical kinds. The importance of early developmental factors of how the child differentiates inner and outer stimuli, the appropriate or inappropriate responses to these and the manner in which these early experiences later affect somatic, social and psychological self concepts are discussed. Various parameters and modalities of treatment are described based on the author's long-term experiences with a large number of patients.

Polyunsaturated fatty acid lipidosis infantile form of so-called neuronal ceroidlipofuscinosis.

ABSTRACT. Hagberg, B., Haltia, M., Sourander, P., Svennerholm, L. and Eeg‐Olofsson, O. (Departments of Paediatrics II, Pathology I and Neurochemistry, University of Gothenburg, Sweden, and Pathology II, University of Helsinki, Finland). Poly‐unsaturated fatty acid lipidosb—an infantile form of so‐called neuronal ceroidlipo‐fuscinosis. Acta Paediatr Scand, 63:753, 1974.—Clinical, histological and ultrastructural findings in three children of Finnish origin and with a severe progressive encephalopathy are reported. The main symptoms were rapid developmental regression from about one year of age, loss of speech, severe visual failure and pronounced secondary microcephaly. A decerebrated state was reached within 1–3 years. Laboratory tests revealed a successively decreasing CSF τ‐fraction. The fatty acid composition of Serum lecithin showed an increased amount of arachidonic acid in the early stage of the disease, a pattern consistent with the biochemical changes in the brain.The morphological characteristics consisted of extreme cerebral and cerebellar atrophy, massive neuronal destruction associated with a pronounced macrophage and astrocytic reaction, and strongly PAS‐reacting and autofluorescent granular deposits in the cytoplasm of the remaining cells. Electron microscopy revealed cytoplasmic osmiophilic deposits in the form of aggregates of globules with a uniform and finely granular ultra‐structure.The condition was considered to be a nosological entity with a uniform clinical picture and characteristic ultrastructural changes in the brain. The evidence produced suggests that the disease described is identical with a progressive heredodegenerative disorder, known to have been diagnosed during recent years in more than 50 Finnish infants and small children and earlier described under the name of infantile type of so‐called neuronal ceroidlipifuscinosis.