Leonóra Méhes

New and recurrent gain-of-function STAT1 mutations in patients with chronic mucocutaneous candidiasis from Eastern and Central Europe

Background Chronic mucocutaneous candidiasis disease (CMCD) may result from various inborn errors of interleukin (IL)-17-mediated immunity. Twelve of the 13 causal mutations described to date affect the coiled-coil domain (CCD) of STAT1. Several mutations, including R274W in particular, are recurrent, but the underlying mechanism is unclear. Objective To investigate and describe nine patients with CMCD in Eastern and Central Europe, to assess the biochemical impact of STAT1 mutations, to determine cytokines in supernatants of Candida-exposed blood cells, to determine IL-17-producing T cell subsets and to determine STAT1 haplotypes in a family with the c.820C>T (R274W) mutation. Results The novel c.537C>A (N179K) STAT1 mutation was gain-of-function (GOF) for γ-activated factor (GAF)-dependent cellular responses. In a Russian patient, the cause of CMCD was the newly identified c.854 A>G (Q285R) STAT1 mutation, which was also GOF for GAF-dependent responses. The c.1154C>T (T385M) mutation affecting the DNA-binding domain (DBD) resulted in a gain of STAT1 phosphorylation in a Ukrainian patient. Impaired Candida-induced IL-17A and IL-22 secretion by leucocytes and lower levels of intracellular IL-17 and IL-22 production by T cells were found in several patients. Haplotype studies indicated that the c.820C>T (R274W) mutation was recurrent due to a hotspot rather than a founder effect. Severe clinical phenotypes, including intracranial aneurysm, are presented. Conclusions The c.537C>A and c.854A>G mutations affecting the CCD and the c.1154C>T mutation affecting the DBD of STAT1 are GOF. The c.820C>T mutation of STAT1 in patients with CMCD is recurrent due to a hotspot. Patients carrying GOF mutations of STAT1 may develop multiple intracranial aneurysms by hitherto unknown mechanisms.

Herpes in STAT1 gain-of-function mutation

Department of Infectious and Paediatric Immunology, Medical and Health Science Centre, University of Debrecen, Debrecen, Hungary (B Toth PhD, L Mehes MD, S Tasko, Prof L Marodi MD); Department of Dermatology, Heim Pal Children’s Hospital, Budapest, Hungary (Z Szalai MD); 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary (Prof Z Tulassay MD); St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA (S Cypowyj PhD, Prof J-L Casanova MD); and Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Necker Medical School, INSERM U980 and University Paris Descartes, Paris, France (Prof J-L Casanova MD, A Puel PhD)

Herpes in STAT1 deficiency

Department of Infectious and Paediatric Immunology, Medical and Health Science Centre, University of Debrecen, Debrecen, Hungary (B Toth PhD, L Mehes MD, S Tasko, Prof L Marodi MD); Department of Dermatology, Heim Pal Children’s Hospital, Budapest, Hungary (Z Szalai MD); 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary (Prof Z Tulassay MD); St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, USA (S Cypowyj PhD, Prof J-L Casanova MD); and Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Necker Medical School, INSERM U980 and University Paris Descartes, Paris, France (Prof J-L Casanova MD, A Puel PhD)

Phagocytosis and intracellular killing of heterogeneous vancomycin-intermediate Staphylococcus aureus strains.

Risk factors for invasive infections by heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) may involve resistance to opsonophagocytosis and bacterial killing. hVISA strains typically have a thickened cell wall with altered peptidoglycan cross-linking. To determine whether hVISA may be endowed with an increased resistance to phagocytosis, this study assessed the characteristics of uptake and killing by granulocytes of three hVISA strains. All isolates were analysed by multilocus sequence typing and staphylococcal chromosome cassette mec typing. One of the strains belonged to the Hungarian meticillin-resistant S. aureus (MRSA) clone ST239-MRSA-III and the other two to the New York/Japan MRSA clone ST5-MRSA-II. In the presence of 10 % normal serum, the extent of phagocytosis and killing by blood granulocytes was equivalent for hVISA, MRSA and meticillin-sensitive S. aureus (MSSA) strains. Using granulocytes and serum from one patient who survived hVISA infection, the rate of phagocytosis and killing was also found to be comparable to that by control cells in the presence of 10 % serum. However, phagocytosis and killing of hVISA and MRSA (ATCC 25923) strains by normal granulocytes was markedly decreased in the presence of low concentrations (1 and 2.5 %) of serum from the patient who survived hVISA infection compared with that found with normal human serum. These data suggest that hVISA and MRSA isolates may be more resistant to opsonophagocytosis and bacterial killing than MSSA isolates, at least in some cases.

Effective PAD (bortezomib, doxorubicine, dexamethasone) treatment of a patient with plasma cell leukaemia developed after autologous stem cell transplantation

A plazmasejtes leukemia a myeloma multiplex ritka es agressziv megjelenesi formaja. Kezelese megoldatlan, es kulonosen a szekunder plazmasejtes leukemiak eseten varhato gyors progresszio. A szekunder formaban ugyanis tobbnyire intenziv kemoterapiaban reszesult myelomas betegekben terminalisan kovetkezik be a leukemias transzformacio, mig a primer esetekben mar a diagnozis idejen kimutathatok a plazmasejtes leukemia tunetei. A szerzők nem szekretoros myeloma multiplex miatt periferias autolog őssejttranszplantacion atesett plazmasejtes leukemias beteguk kezeleset ismertetik. A bortezomib (proteaszomagatlo), a doxorubicin es a dexamethason kombinacioja (PAD-protokoll) komplett remissziot es kilenc honapos tulelest eredmenyezett. A tobbnyire betegismerteteseken alapulo irodalmi adatok szerint a PAD-protokoll, sajat tapasztalatunkhoz hasonloan, plazmasejtes leukemiaban is hatekony es jol toleralhato. Autolog es/vagy allogen transzplantacioval kombinalva a betegek tulelesenek tovabbi javulasa varhato. after autologous stem cell transplantation. The most agressive and rare manifestation of multiple myeloma is plasma cell leukaemia (PCL). While secondary form of PCL represents those heavily pretreated cases when leukaemic transformation developes terminally after intensive chemotherapy in patients with multiple myeloma, primary cases are characterized by leukaemic symptoms present at diagnosis. The secondary form has a rapid progression. The management of PCL is still unsolved. The authors present a case of a patient with non-secretory multiple myeloma who had developed plasma cell leukaemia after peripheral stem cell transplantation. PAD (bortezomib, doxorubicine, dexamethasone) treatment resulted in complete remission and 9-month survival of the patient. Previous case reports in the literature and our experience have revealed PAD protocol to be well tolerated and effective in PCL. Combination of PAD treatment with autologous and/or allogenic stem cell transplantation might further improve patients’ outcome.

Chromosomal aberrations and CD38 expression in two siblings with B-cell chronic lymphocytic leukemia: A report of two siblings

In this study our purpose was to define chromosomal aberrations and CD38 expression in male siblings 69 and 66-years-old with B-cell chronic lymphocytic leukemia (B-CLL). Cells from peripheral blood were analysed by comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH). The alteration detectable by CGH was the over-representation of the Y chromosome in both samples. Interphase FISH were performed using locus (13q14 and 17p53) and centromere (chromosome 12, 17 and Y) specific DNA probes. One brother (patient 1, 69 years of age) showed deletion of the 13q14 region, this alteration was associated with low CD38 expression, both predicting a favourable prognosis. However, the younger patients (patient 2, 66 years of age) cells expressed CD38 in high percent, which is considered as an indicator of poor prognosis, and deletion of the 13q14 was not seen. Other, relatively frequent chromosomal alterations including trisomy 12 and deletion of 17p53 were not present in any of the samples. The cytogenetic findings and the CD38 expression are in concordance with the clinico-pathological data of the siblings. Thus, we found the variability of these parameters described in B-CLL even in the familial form of the disease.

The pathophysiology, clinical signs and therapy of urate nephropathy

Tumor lysis syndrome is an oncologic emergency that is characterized by severe electrolyte abnormalities. The syndrome occurs in patients with lymphoproliferative malignancies, most often after chemotherapy, but also spontaneously. The pathophysiology involves tumor cell lysis resulting in the release of potassium, phosphate and uric acid. The deposition of uric acid and calcium phosphate crystals in the renal tubules may lead to acute renal failure. The treatment consists in hydration, correction of the acidosis and hyperkalemia, use of allopurinol and recombinant urate oxidase (rasburicase) for preventing urate nephropathy and haemodialysis. The authors report a case of a patient with acute myeloid leukemia, who developed severe tumor lysis syndrome after chemotherapy.

Az urát-nephropathia patofiziológiája, klinikuma és kezelése

Tumor lysis syndrome is an oncologic emergency that is characterized by severe electrolyte abnormalities. The syndrome occurs in patients with lymphoproliferative malignancies, most often after chemotherapy, but also spontaneously. The pathophysiology involves tumor cell lysis resulting in the release of potassium, phosphate and uric acid. The deposition of uric acid and calcium phosphate crystals in the renal tubules may lead to acute renal failure. The treatment consists in hydration, correction of the acidosis and hyperkalemia, use of allopurinol and recombinant urate oxidase (rasburicase) for preventing urate nephropathy and haemodialysis. The authors report a case of a patient with acute myeloid leukemia, who developed severe tumor lysis syndrome after chemotherapy.

Krónikus lymphoid leukaemia transzformációja myelodysplasticus szindrómába: betegismertetés és az irodalom áttekintése

Chronic lymphocytic leukaemia (CLL) may transform to either malignant lymphoid disorder or increase the occurrence of solid neoplasms. However myeloid malignancies seldom develop. We report a case of a patient who has remained untreated for CLL and developed myelodysplastic syndrome (refracter anemia with ringed sideroblasts) six years after the diagnosis of CLL. Development of myelodysplastic syndrome resulted in concurrent attenuation of CLL. Discussion of the pathogenesis of myeloid disorders occurring with CLL and review of the literature are also presented.

Krónikus lymphoid leukaemia transzformációja myelodysplasticus szindrómába: betegismertetés és az irodalom áttekintése@@@Transformation of chronic lymphocytic leukemia to myelodysplastic syndrome: case presentation and review of the literature

Chronic lymphocytic leukaemia (CLL) may transform to either malignant lymphoid disorder or increase the occurrence of solid neoplasms. However myeloid malignancies seldom develop. We report a case of a patient who has remained untreated for CLL and developed myelodysplastic syndrome (refracter anemia with ringed sideroblasts) six years after the diagnosis of CLL. Development of myelodysplastic syndrome resulted in concurrent attenuation of CLL. Discussion of the pathogenesis of myeloid disorders occurring with CLL and review of the literature are also presented.