Trasplante de médula ósea haploidéntico en un paciente pediátrico con síndrome de Wiskott-Aldrich. A propósito de un caso / Haploidentical bone marrow transplantation in a pediatric patient with Wiskott-Aldrich syndrome. A case report

El síndrome de Wiskott-Aldrich es un error innato de la inmunidad de herencia ligada al cromosoma X, producido por variantes en el gen que codifica la proteína del síndrome de Wiskott-Aldrich (WASp). Reportamos el caso clínico de un paciente de 18 meses con diagnóstico de Wiskott-Aldrich que no presentaba donante antígeno leucocitario humano (HLA) idéntico y recibió un trasplante de células progenitoras hematopoyéticas (TCPH) con donante familiar haploidéntico. La profilaxis para enfermedad de injerto contra huésped incluyó ciclofosfamida (PT-Cy). El quimerismo del día +30 fue 100 % del donante y la evaluación postrasplante de la expresión de la proteína WAS fue normal. Actualmente, a 32 meses del trasplante, presenta reconstitución hematológica e inmunológica y quimerismo completo sin evidencia de enfermedad injerto contra huésped. El TCPH haploidéntico con PT-Cy se mostró factible y seguro en este caso de síndrome de WiskottAldrich en el que no se disponía de un donante HLA idéntico.

Wiskott-Aldrich syndrome (WAS) is an X-linked genetic disorder caused by mutations in the gene that encodes the Wiskott-Aldrich syndrome protein (WASp). Here, we report the clinical case of an 18-month-old boy diagnosed with Wiskott-Aldrich syndrome, who did not have an HLA-matched related or unrelated donor and was treated successfully with a hematopoietic stem cell transplant (HSCT) from a haploidentical family donor. Graft-versus-host disease (GvHD) prophylaxis included post-transplant cyclophosphamide (PT-Cy). At day +30, the peripheral blood-nucleated cell chimerism was 100% and the WAS protein had a normal expression. Currently, at month 32 post-transplant, the patient has hematological and immune reconstitution and complete donor chimerism without evidence of GvHD. HSCT with PT-Cy was a feasible and safe option for this patient with WAS, in which an HLA matched donor was not available.

Estudo de células T regulatórias em camundongos deficientes em WASP / T Cell study regulatory in mice disabled in wasp

A Síndrome de Wiskott-Aldrich (WAS) é uma imunodeficiência associada a infecçõesrecorrentes, câncer e autoimunidade. Ela é causada por mutações no gene que codifica amolécula WASP (“Wiskott-Aldrich syndrome protein”), envolvida na reorganização docitoesqueleto de actina em células de origem hematopoiética. Camundongos deficientes emWasp (WKO) apresentam migração leucocitária e proliferação linfocitária deficientes, edesenvolvem colite. Esse processo inflamatório está associado a eventos deimunodesregulação importantes, como participação exacerbada de células Th2 e diminuiçãode células T regulatórias (Treg) no timo e baço desses animais. Assim, esse trabalho visacaracterizar as células Treg tímicas e avaliar os mecanismos potencialmente relacionados àdiminuição dessas células no timo de camundongos WKO. Nas análises de CD25 e CD122,importantes para a diferenciação de células Treg, observamos uma diminuição na expressãode CD25 na população de células CD4+CD8-Foxp3+, além de uma diminuição no númeropercentual dessa população. As células Treg tímicas de animais WKO apresentaram níveisnormais de CD122 e de moléculas de ativação, mas mostraram uma diminuição na expressãoda molécula funcional CD39, responsável pela hidrólise tecidual de ATP. Saliente-se aindaque estudos sobre a morte celular ex-vivo, a transmigração in vitro mediada por S1P e alocalização intratímica de células Treg não revelaram diferenças significativas na comparaçãoentre animais WKO e seus controles. De forma interessante, precursores tímicos de célulasTreg CD4+CD8-CD25+Foxp3-também se apresentaram diminuídos em WKO, assim como ascélulas Treg Helios...

The Wiskott-Aldrich syndrome (WAS) is an immunodeficiency associated with recurrentinfections, malignancies and autoimmunity. It is caused by mutations in the gene encodingWASP (Wiskott-Aldrich syndrome protein), a molecule involved in the actin cytoskeletonrearrangements in hematopoietic cells. Wasp deficient mice (WKO) show impaired leukocytemigration and lymphocyte proliferation, and also develop colitis. This inflammatory processis associated with important immunodysregulation events, such as exacerbated participationof Th2 cells and decreased numbers of regulatory T cells (Treg) in the thymus and spleen ofthese animals. Thus, this study aims to characterize the thymic Treg cells and evaluate thepotential mechanisms involved in the decreased number of these cells in the thymus of WKOmice. In the analysis of CD25 and CD122, important molecules for the differentiation of Tregcells, we observed a decreased expression of CD25 in the CD4+CD8-Foxp3+ cells, and adecrease in the percentage number of this population. WKO Treg cells showed normal levelsof CD122 and activation molecules, but present a decreased expression of the functionalmarker CD39, molecule responsible for ATP hydrolysis in the tissues. Also, it is important topoint out that studies about ex vivo cell death, S1P-mediated in vitro transmigration andintratymic localization of Treg cells revealed no significant differences between WKOanimals and their controls. Interestingly, both CD4+CD8-CD25+Foxp3- Treg precursors andHelios+ Treg cells are reduced in WKO thymus. More over, we also observed an importantincrease in the basal expression of pSTAT-5 in Treg cells of WKO mice and their precursors.Altogether, our results indicate an important role of Wasp in thymic Treg cell development,and point to the necessity of further studies on the mechanisms involved in the generation ofTreg cells in WKO mice...

A Familial Case of Wiskott-Aldrich Syndrome with a Hotspot Mutation in Exon 2 of the WAS Gene

The Wiskott-Aldrich syndrome (WAS) is a severe X-linked disorder characterized classically by thrombocytopenia, immunodeficiency, and eczema. The phenotype observed in this syndrome is caused by mutation in the WAS gene. Peripheral blood DNAs were isolated from an 18-month-old boy with WAS and his mother, maternal uncle, and maternal grandmother. Genetic analysis for the detection of a mutation of WAS gene was performed by polymerase chain reaction-single strand conformational polymorphism analysis (PCR-SSCP) and direct sequencing of the PCR product. In PCR-SSCP, the patient and his maternal uncle had an abnormal shift band, which was not found in normal controls, and his mother and maternal grandmother showed heterozygous bands. In direct sequencing analysis, the patient with WAS had CGC-->CAC point mutation in exon 2 that resulted in an amino acid change in codon 86 (Arg86His). The present study identified a gene mutation responsible for WAS at a mutation hotspot of the WAS gene in a Korean family.

Successful allogeneic peripheral blood stem cell transplantation in Wiskott-Aldrich Syndrome Patients: first report in Thailand.

Wiskott-Aldrich syndrome (WAS), an X-linked recessive disorder, is characterized by primary progressive T cell immunodeficiency, impaired antipolysaccharide antibody production, eczema, and thrombocytopenia. Stem cell transplantation is the only curative therapy. To evaluate the use of allogeneic peripheral stem cell transplantation (PBSCT) in this group of patients, we performed allogeneic PBSCT in two WAS patients (3 and 12 years old). The conditioning regimen consisted of busulfan 4 mg/kg/day for 4 days, and cyclophosphamide 50 mg/kg/day for 4 days. Graft-versus-host disease prophylaxis was consistent with cyclosporin A and methotrexate. Peripheral blood stem cells were collected from their brother donors (6 and 16 years old) by continuous flow leukapheresis after mobilization with granulocyte-colony-stimulating factor at a dose of 7.5 microg/kg/day for 5 days. Both recipients achieved neutrophils engraftment on days 11 and 12. The first patient achieved platelets engraftment on day 30. The second patient did not have platelet count below 20.0 x 10(9)/l during PBSCT procedure. Both did not develop acute or chronic graft-versus-host disease. At present, they are healthy after PBSCT. The follow up time after transplantation is 1,170 days and 269 days, respectively. Allogeneic PBSCT is economically feasible for WAS. The cost of PBSCT in Thailand is 20 to 30% less than bone marrow and cord blood stem cell transplantation. The cost of the transplant procedure for each patient in Thailand is US $ 12,000. This study is the first report of a successful stem cell transplantation in WAS patients in Thailand.

The usefulness of X-linked polymorphic loci as gene markers to track X allele and chimerism in a post-allogeneic peripheral blood stem cell transplant patient with Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome (WAS), an X-linked recessive disorder, is characterized by progressive T-cell immunodeficiency. Laboratory findings generally demonstrate reduced response to T-cell mitogens, markedly decreased serum concentration of IgM, and thrombocytopenia with small platelet volume. Allogeneic HLA-matched sibling bone marrow transplantation (BMT) can correct this disorder. We report the usefulness of X-linked polymorphic loci to detect X-allele gene tracking among WAS siblings and chimerism between a pre- and post-allogeneic matched sibling peripheral blood stem cell transplantation (PBSCT). A 3 1/2 year old boy with clinical and laboratory findings consistent with WAS underwent allogeneic matched sibling PBSCT. We used BclI restriction fragment length polymorphism (RFLP) of intron 18 of factor VII gene and MseI RFLP of the 5' flanking region of factor IX gene to detect X-allele gene tracking among siblings and family members and chimerism in patients between pre-and post-allogeneic matched sibling PBSCT. We were able to demonstrate that determination of BclI and MseI RFLP can be employed to recognize the difference in X-allele genes between the recipient and donor for allogeneic matched sibling PBSCT. The authors also were able to demonstrate that these polymorphic loci can detect full chimerism of donor hematopoietic cells in recipient blood after allogeneic PBSCT. This finding was correlated with improvement of post-PBSCT clinical and laboratory findings. BclI and MseI RFLP associated with X-chromosome can effectively track X-allele, detect carrier state, and demonstrate the different X-allele among male siblings, and chimerism of hematopoietic cells between donors and recipients in a setting of allogeneic matched sibling BMT or PBSCT for X-linked hereditary diseases such as Wiskott-Aldrich syndrome.

Síndrome de Wiskott Aldrich / The Wiskott-Aldrich syndrome

Introducción. El síndrome de Wiskott-Aldrich es un padecimiento recesivo ligado al cromosoma X, caracterizado por la triada de eccema, trombocitopenia e inmunodeficiencia variable, generalmente letal por la tendencia a infecciones graves. Caso clínico. Se describe el caso de lactante masculino de seis meses de edad quien manifestó inicialmente eccema a los 20 días de vida y cinco meses después se hicieron aparentes infecciones y petequias corroborándose trombocitopenia. Conclusiones. Tener presente esta posibilidad en el paciente varón con eccema, trombositopenia y tendencia a infecciones ya que se tiene la opción terepéutica del transplante de médula ósea