[Gianotti-Crosti syndrome in an infant following immunization]. / Gianotti-Crosti-Syndrom nach Impfungen bei einem Kleinkind -- Fallbericht und Ubersicht der Literatur.

Gianotti-Crosti syndrome (GCS), first described by F. Gianotti in 1955, was originally reported to be associated with hepatitis B virus infection in children. The typical clinical picture allows diagnosis of GCS at first glance. The pathogenesis is still unknown. Besides HBV infection, a large number of infectious agents, mostly viruses, have been described as a trigger of GCS. Here we report the occurrence of GCS in an infant five days after the fourth immunization against poliomyelitis, DTPa, Hib, hepatitis B and Streptococcus pneumoniae. Our data and review of the literature suggest that GCS is rarely associated with immunizations, especially when performed with inactivated vaccines.

V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations.

Severe combined immunodeficiency (SCID) comprises a heterogeneous group of primary immunodeficiencies, a proportion of which are due to mutations in either of the 2 recombination activating genes (RAG)-1 and -2, which mediate the process of V(D)J recombination leading to the assembly of antigen receptor genes. It is reported here that the clinical and immunologic phenotypes of patients bearing mutations in RAGs are more diverse than previously thought and that this variability is related, in part, to the specific type of RAG mutation. By analyzing 44 such patients from 41 families, the following conclusions were reached: (1) null mutations on both alleles lead to the T-B-SCID phenotype; (2) patients manifesting classic Omenn syndrome (OS) have missense mutations on at least one allele and maintain partial V(D)J recombination activity, which accounts for the generation of residual, oligoclonal T-lymphocytes; (3) in a third group of patients, findings were only partially compatible with OS, and these patients, who also carried at least one missense mutation, may be considered to have atypical SCID/OS; (4) patients with engraftment of maternal T cells as a complication of a transplacental transfusion represented a fourth group, and these patients, who often presented with a clinical phenotype mimicking OS, may be observed regardless of the type of RAG gene mutation. Analysis of the RAG genes by direct sequencing is an effective way to provide accurate diagnosis of RAG-deficient as opposed to RAG-independent V(D)J recombination defects, a distinction that cannot be made based on clinical and immunologic phenotype alone.

Lack of association between childhood stroke after varicella and human leukocyte antigen (HLA)-B51.

Human leukocyte antigen (HLA)-B51 has been suggested as an immunogenetic marker for a genetic predisposition to vascular occlusion in response to an immunological stimulus. Varicella has been reported to be a possible risk factor for stroke. We performed DNA-based HLA typing in 11 young patients (mean age: 5.2 years) with unexplained ischaemic stroke. In eight of them varicella had occurred before their stroke. HLA-B51 was negative in all 11 patients and we did not find any significant accumulation of other HLA-subgroups. Our study does not support an association between susceptibility to stroke after varicella and HLA-B51.

Minimal change nephrotic syndrome: a possible complication of ehrlichiosis.

Ehrlichiae are rickettsial organisms recently shown to be human pathogens. Infections often cause fever, myalgia, and hematological abnormalities, and sometimes mild elevation in transaminases, creatinine, and urinary protein. We report a teenager with nephrotic syndrome from minimal change glomerulonephritis and serological evidence of ehrlichiosis. In the appropriate clinical setting, Ehrlichiae should be considered in the etiological assessment of patients with minimal change disease.

Decreases in CD5+ B lymphocytes in children with the DiGeorge anomaly.

The authors evaluated the lymphocyte subsets in eight children with the DiGeorge anomaly, compared with 48 age-matched control infants. Of particular interest was the finding that the percentage and number of CD5+ B lymphocytes were decreased in seven of the eight cases. This observation may provide insight into thymic function and the interaction of the B and T cell systems in some forms of congenital and acquired immunodeficiencies.

Investigation of the social status of paraplegic individuals after medical rehabilitation.

The social services of the German centres for spinal cord injuries compiled social data on 2000 recently injured paraplegics. The aim of the study was to determine whether and to what extent patients had been reintegrated to jobs after completion of physical rehabilitation treatment. A 31-point questionnaire surveyed all relevant data pertaining to the projected professional vita. The results for the medically rehabilitated population (n = 651) indicate that 45% returned to their previous job, school or college. Intensified use of computers and advanced academic backgrounds of afflicted individuals contribute to a higher chance for reintegration at a previous job. Our social statistics also include data on living conditions and social support. Household caretaking support is offered by family members in 73% of cases, while 5% permanently live in nursing homes.

Molecular and structural characterization of five novel mutations in the Bruton's tyrosine kinase gene from patients with X-linked agammaglobulinemia.

BACKGROUND: The Btk (Bruton's tyrosine kinase) gene has been shown to be mutated in the human immunodeficiency disease, XLA (X-linked agammaglobulinemia). Btk is a member of the Tec family of cytosolic protein tyrosine kinases with distinct functional domains PH, TH, SH3, SH2, and kinase. Mutations have been observed in each of the Btk subdomains in XLA. We have analyzed the Btk gene in six XLA patients from five unrelated families. MATERIALS AND METHODS: DNA was prepared from the patients peripheral blood. The Btk exons including the junctional sequences were analyzed by single-strand conformation polymorphism (SSCP) followed by direct nucleotide sequencing after PCR-amplification. For structural analysis, the missense mutations were introduced into three-dimensional models of the PH and kinase domains of Btk and the outcome was predicted based on the knowledge of the protein function. RESULTS: Five novel mutations and two novel polymorphisms, all of which resulted from single-base alterations, were identified. Three of the five mutations were in the PH domain and two were in the kinase domain of Btk. Three of these mutations were of the missense type, two of which altered the same codon in the PH domain; the third one was located in the kinase domain. The fourth mutation was a point deletion in the PH domain causing a frameshift followed by premature termination. The fifth mutation was a splice donor-site mutation within the kinase domain which could result in an exon skipping. In four of the five instances, mothers of the patients were shown to be obligate carriers. In one instance, a sibling sister was identified as a heterozygote establishing her as a carrier. CONCLUSIONS: Functional consequences of the mutations causing frameshifts and altered splicing can be inferred directly. Functional consequences of the missense mutations were interpreted by 3-dimensional structural modeling of Btk domains. It is proposed that the two PH domain mutations will interfere with membrane localization while the kinase domain mutation will interfere with the enzymatic function of Btk. This study provides further insight into the role of Btk in XLA.

Incomplete presentations in a series of 37 children with Kawasaki disease: the role of the pediatric ophthalmologist.

BACKGROUND: Kawasaki disease (KD) is an acute and sometimes fatal febrile vasculitis of childhood, the presenting signs of which include conjunctival vessel dilatation and iridocyclitis. Consultation with a pediatric ophthalmologist is helpful for early recognition of the disease, especially in identifying "incomplete" cases, ie, those which lack all of the classical, systemic signs. METHODS: After encountering a case of incomplete KD in which diagnosis was delayed, we reviewed the hospital records of 37 children with KD to establish how often the disease manifested "incompletely," and how often pediatricians consulted pediatric ophthalmologists to help in its early diagnosis. RESULTS: Forty-five percent of the children eventually diagnosed with KD lacked the complete diagnostic criteria of KD when admitted to the hospital, and diagnosis and treatment therefore were delayed. Coronary artery aneurysms, a complication that might have less serious consequences if treated earlier, developed in 24% of these patients. Although 67% presented to their pediatrician with bilateral conjunctival injection and/or iridocyclitis, pediatricians requested ophthalmologic consultation for only 5% of them. CONCLUSIONS: Our review of these cases indicates that the eye findings in KD could play a role in earlier diagnosis and treatment. Pediatric ophthalmologists and pediatricians should be more aware of their combined responsibilities for expedient recognition of KD.

Ragged red or ragged blue fibers.

Fibers called ragged red fibers are generally considered the morphological characteristic of mitochondrial encephalomyopathies. These fibers appear red in the modified Gomori trichrome (Tri) stain due to subsarcolemmal and interfibrillar increase in mitochondrial number and volume. Other accepted morphological abnormalities include partial cytochrome c oxidase deficiency and subsarcolemmal increase in succinate dehydrogenase and NADH tetrazolium reductase stain. We were interested to see which of these abnormalities would be the most specific for mitochondrial cytopathies such as Kearns-Sayre syndrome and chronic progressive external ophthalmoplegia. We analyzed five patients and found 74 fibers compatible with mitochondrial abnormalities as defined above. The modified Gomori Tri stain turned out to be the most specific and reliable technique.

Soropositividade para Doença de Chagas em pacientes com infecção pelo vírus da imunodeficiência humana (HIV) no Hospital Universitário Regional do Norte do Paraná (HURNP), Londrina, Paraná / Soropositivity to Chagas disease in patients with human immunodeficient virus infection attended at Hospital Universitário Regional do Norte do Paraná (HURNP), Londrina, Brazil

A reativação das formas indeterminadas e crônicas da Doença de Chagas (DC) tem sido associada com leucemias, linfomas, transplantes e infecção pelo vírus da imunodeficiência humana (HIV), segundo Rocha et al; Pitella; Uip et ai. Devido à disseminação da síndrome da imunodeficiência adquirida (SIDA) na América Latina, onde o DC continua sendo uma importante endemia, há um presente e crescente risco de co-infecção com o HIV e o Trypanossoma Cruzi, afirmam Amato e Neto et al. O objetivo deste trabalho é determinar a freqüência desta associação nos pacientes atendidos no HURNP, Londrina Paraná. Os resultados das reações sorológicas para DC (HAI, IFI, E ELISA) realizados em 181 soros randomicamente selecionados de pacientes com testes anti-HIV reagentes (Elisa e Western Blot) foram analisados. Entre eles, 4 (2,20%) mostraram resultados positivos em, pelo menos, duas reações sorológicas para DC; 4 (2,20%) somente na HAI; 2 (1,10% somente na IFI e 1 (0,55%) mostrou resultados duvidosos na HAI; 2 (1,10%) somente na IFI e 1 (0,55%) mostrou resultados duvidosos na HAI E IFI. O fato de que a migração tem levado a DC a novas regiões geográficas e de que a DC tem sido crescentemente diagnosticada em populações urbanas, onde há uma alta prevalência de infecção pelo HIV, segundo Rocha et al, reforça a importância de se considerar o T.cruzi outro importante patógeno oportunista associado com a SIDA, especialmente em regiões endêmicas para o T.cruzi.

A comparative analysis of cytoplasmic mu (C mu) expression in acute lymphoblastic leukemia by molecular and immunologic techniques. Identification of leukemia cases expressing C mu mRNA transcripts in the absence of detectable C mu proteins.

Among acute lymphoblastic leukemias derived from the B-cell lineage, the subset of cases expressing cytoplasmic mu heavy chain proteins (C mu) in the absence of surface immunoglobulin has been designated pre-B-cell acute lymphoblastic leukemia. This group, traditionally identified using immunologic smear techniques, has been associated with a poor prognosis in some series. In a comparative study, 25 cases of B-lineage acute lymphoblastic leukemia were analyzed for C mu expression using molecular and immunologic techniques. RNA derived from cryopreserved blast cells was hybridized in both Northern and slot-blot analyses using a probe (pBZ311) containing four exons of the human immunoglobulin heavy chain mu constant region gene. Expression of C mu proteins was assessed simultaneously by slide immunofluorescence and flow cytometric techniques in all samples. These studies were correlated with immunoglobulin heavy and light chain gene rearrangements, cell-surface immunophenotype, cytogenetics, and other clinicopathologic features. C mu mRNA transcripts were detected in 14 of 25 cases, whereas C mu proteins were detected in only 9 of these cases using flow cytometric techniques. Only four of these nine cases were positive by slide immunofluorescence techniques. These studies imply that molecular and flow cytometric techniques may be a more sensitive means to assess C mu expression. The identification of five cases that expressed C mu mRNA transcripts in the absence of detectable C mu proteins also suggests that molecular techniques may be valuable in identifying a unique subgroup of pre-B-cell acute lymphoblastic leukemia cases that contain C mu mRNA transcripts, but lack C mu proteins.

Human B-lymphocyte precursors do not express the N-myc gene.

N-myc expression has been reported in neuroblastoma, retinoblastoma and small cell lung carcinoma. Increased expression associated with gene amplification in neuroblastoma correlates with disease stage and prognosis. N-myc expression has been observed in diverse murine tissues during early stages of development with loss of expression in later stages. Abelson murine leukemia virus (A-MuLV)-transformed pre-B cells express N-myc, whereas mature B cells do not. To determine whether human B-lymphocyte precursors also have increased N-myc expression, we extracted DNA and RNA from representative cell lines, prepared Southern and Northern blots and examined them with the N-myc probe, pNB-1. RNA from the following B-cell developmental stages were examined. One null, 1 pre-pre-B, 3 pre-B (including pre-B-lymphoblastic leukemia, a poor prognostic category) and 5 mature B. Neuroblastoma cells and tissues served as positive controls; negative controls included human muscle, placenta, epithelial cell lines, monocytic, promyelocytic, and T-cell lines. N-myc expression was detected in neuroblastoma cells, but in none of the mature human B or B-lymphocyte precursor cells. Additional immunocytochemical studies performed for N-myc nuclear protein likewise failed to detect this gene product. We conclude that human pre-B cells, unlike murine B-cell precursors, do not express increased levels of N-myc RNA. Expression of this oncogene in human neoplastic B cells does not appear to correlate with developmental stage or prognostic group.

Prediction of persistent immunodeficiency in the DiGeorge anomaly.

To assess the natural history of the immune defect in DiGeorge anomaly, we reviewed serial immunologic studies in 18 patients. The diagnosis was made with criteria based on the concept of the DiGeorge anomaly as a field defect. Initial or early follow-up laboratory examination suggested moderate to normal T cell function in 14 patients. None of these patients have lost T cell capability; they have never had infections characteristic of T cell deficiency. Four patients had clinical and laboratory evidence of profound immunodeficiency. A decreased number of CD4+ cells (less than 400/microliters) and a decrease in phytohemagglutinin responsiveness (stimulation index less than 10) may be useful in discriminating patients with immunodeficiency; absolute lymphocyte count and immunoglobulin values were not informative. At the time of surgery, the thymus was not found in 11 of 14 patients; however, only two of these patients had immunodeficiency. Patients with a persistently low number of CD4+ cells and decreased phytohemagglutinin response are candidates for immunologic reconstitution.

Response of neoplasms of B cell lineage to the proliferative effects of B cell growth factor and the phorbol ester TPA.

Little information is available regarding the role of soluble growth factors in neoplastic B cell proliferation. The authors have measured B cell growth factor (BCGF)-induced proliferation in B lymphocytes isolated from 28 patients with malignancies representing different stages of B cell differentiation. The phorbol ester TPA (12-O-tetradecanoyl phorbol-13-acetate), a potent mitogen and inducer of BCGF receptor expression in normal B cells, was added in combination with BCGF to enhance the proliferative response. These results show that many neoplastic B cells are able to respond to BCGF (32%), particularly when combined with TPA (63%). The response was variable in frequency and magnitude within clinicopathologic groups; cells from patients with non-Hodgkin's lymphoma (NHL) were more refractory to stimulation than those from acute lymphocytic leukemia (ALL) and chronic lymphocytic leukemia (CLL). An attenuated response to BCGF plus TPA was observed in neoplastic cells with high rates of spontaneous DNA synthesis from all histologic categories. These observations suggest that some maximally stimulated cells appear incapable of responding to additional exogenous growth stimuli. Within apparently homogeneous clinicopathologic groups, distinct subgroups of B cell neoplasms can be defined by cellular responses to BCGF. The correlation of this biologic feature with the clinical behavior of the neoplasm requires additional study.

T4+ (helper phenotype) chronic lymphocytic leukemia: case report with liver failure and literature review.

T-cell lymphomas and leukemias are a heterogeneous group of neoplasms found in each anatomic compartment of the T system (marrow, thymus, and various peripheral tissues) and that have varying phenotypic expressions. Histopathologic features of the thymic and peripheral T neoplasms do not fit into a clearly defined pattern, and clinical expressions of T neoplasms are likewise variable. This report describes a 60-year-old man with "chronic" lymphocytic leukemia of T4+ (helper) phenotype. Rapid deterioration in liver function, presumably due to tumor infiltration, was unexpected and has not previously been reported. The unusual clinical and pathologic features are reviewed in the context of T-cell neoplasms, particularly T4+ processes.

Lymphoproliferative diseases in immunocompromised hosts: the role of Epstein-Barr virus.

Epstein-Barr virus (EBV) is a ubiquitous transforming virus of the herpes group showing tropism for B lymphocytes. Primary infection in normal hosts results in a transient lymphoproliferative disorder, acute infectious mononucleosis (IM), that is restricted by cytotoxic and suppressive lymphocytes. However, in the immunodeficient host, EBV-induced lymphoproliferation may behave in a biologically malignant fashion. Patients with primary immunodeficiencies and those with immune incompetence resulting from suppressive therapy in allograft transplantation or infection with human immunodeficiency virus (HIV) have EBV-related illness ranging from fulminant mononucleosis and invasive polyclonal B cell hyperplasia to monoclonal B cell malignancies. While the direct link between EBV and malignant B cell proliferation in these patients has not been elucidated, the association has been increasingly recognized with improved techniques of viral detection. Clinical management can be guided by the location and extent of tumor, histologic features, and clonality. Regional and node-based polyclonal proliferations may respond to prompt reduction of immunosuppressive therapy and efforts to interrupt the replicative cycle with antiviral agents. Systemic cytotoxic therapy often leads to further immunosuppression and should be reserved for patients with progressive disease, advanced visceral involvement, and monoclonal lymphoid malignancies.

Plasmacytic differentiation in follicular center cell (FCC) lymphomas.

Although follicular centers are the sites of production of plasma cell precursors, plasmacytic differentiation in follicular center cell (FCC) lymphomas is rarely seen, presumably because of a "block" in differentiation of the large noncleaved FCC. The authors reviewed a large number of these cases to determine the frequency of plasmacytic differentiation in FCC lymphomas. In one hundred ninety-eight, consecutive FCC lymphomas with a follicular pattern from a two-year period, 17 (9%) cases were found in which there were large numbers of plasma cells. Immunoperoxidase studies of paraffin-embedded sections (PIP) for cytoplasmic immunoglobulin showed polytypic marking in ten of these and a monotypic plasma cell population in seven. In this latter group, isotypically identical marking of the plasma cell and FCC populations could be demonstrated in three cases with immunoperoxidase (where the FCCs showed cytoplasmic marking) and in one case (of one tested) with surface typing studies. In addition, three patients had serum paraproteins identical to the plasma cell cytoplasmic immunoglobulins. These findings indicate that a small minority of FCC lymphomas contain sufficient plasma cells to be a diagnostic problem, and that in some of these cases, plasma cells are a differentiated component of the FCC lymphomas.