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.

Clinical and genetic characteristics of 11 neonates with Wiskott-Aldrich syndrome / 中国新生儿科杂志

Objective:To study the clinical and genetic characteristics of Wiskott-Aldrich syndrome (WAS) in neonates.Methods:From January 2016 to August 2022, neonates with WAS admitted to the neonatal department of our hospital were studied.Their clinical features, laboratory findings, genetic characteristics and clinical outcomes were retrospectively analyzed.Results:A total of 11 neonates(all male) were included. The mothers of 3 neonates had thrombocytopenia during pregnancy. The presenting symptoms included isolated bloody stool (4 cases), jaundice (3 cases), bloody stool with petechiae, bloody stool with hematemesis, cough and fever(1 case each). Eczema appeared from 6 d to 3 months after birth and in 6 cases during the neonatal period. None of the 11 cases had serious infection during the neonatal period. 9 cases had infection from 8 d to 5 months and 2 cases had not been infected until the last follow-up. Genetic sequencing showed four frameshift variants(c.30dupC, c.205dupT, c.1340_1343dupC and c.673_674delA), four nonsense variants(c.37C>T, c.295C>T, c.889C>T and c.823G>T) and three missense variants(c.134C>T, c.397G>A and c.341T>C). Pedigree verification of variants found 10 cases were inherited from their mothers and 1 case was de novo variant.Conclusions:WAS is characterized by bloody stool and eczema in the neonatal period, mostly without serious infections and lacking specific manifestations. Genetic screening for early identification of unexplained thrombocytopenia in male newborns should be performed as early as possible.

Paciente con diagnóstico de Wiskott Aldrich y presencia de una nueva mutación

RESUMEN Introducción: El síndrome de Wiskott-Aldrich, es una inmunodeficiencia primaria, poco frecuente heredada de forma recesiva ligado al cromosoma X. Está asociado a fenotipos clínicos variables que se correlacionan con el tipo de mutación presente en la proteína del síndrome de Wiskott-Aldrich. Objetivo: Examinar el caso de un paciente con diagnóstico de Wiskott Aldrich y presencia de una mutación no descrita anteriormente. Presentación del caso: Paciente masculino cuya sintomatología se inició a los tres meses de edad, con infecciones respiratorias recurrentes, lesiones purpúricas hemorrágicas tipo equimosis, eccema y plaquetopenia. El diagnóstico se confirmó al año de inicio de los síntomas con la detección de una mutación no descrita anteriormente, ubicada en el codón 88 de la proteína del síndrome de Wiskott-Aldrich (p. Y88X; c.264C > G), asociada a una variante clásica. Conclusiones: La identificación temprana, diagnóstico y estratificación del fenotipo, es esencial para reducir los eventos desfavorables y complicaciones de la afección. El estudio genético es el medio de confirmación diagnóstica definitivo para el síndrome, lo que permite aplicar el protocolo terapéutico más adecuado para este tipo de inmunodeficiencia.

ABSTRACT Introduction: Wiskott Aldrich syndrome is a primary immunodeficiency, rarely inherited in a recessive way and linked to the X chromosome. It is associated with variable clinical phenotypes that correlate with the type of mutation present in the Wiskott Aldrich syndrome protein. Objective: Examine the case of a patient diagnosed with Wiskott Aldrich and presence of a mutation not described above. Case presentation: Male patient whose symptoms began at three months of age, with recurrent respiratory infections, purpuric hemorrhagic lesions such as ecchymosis, eczema and platelettopenia. The diagnosis was confirmed one year of after the symptoms onset with the detection of a mutation not previously described, located in codon 88 of the Wiskott Aldrich syndrome protein (p. Y88X; c.264C>G), associated with a classical variant. Conclusions: Early identification, diagnosis and stratification of the phenotype is essential to reduce unfavorable events and complications of the condition. The genetic study is the mean of definitive diagnostic confirmation for the syndrome, which allows to apply the most appropriate therapeutic protocol for this type of immunodeficiency.

Síndrome de Wiskott-Aldrich asociado a absceso de la glándula tiroides. Informe de caso / Wiskott-Aldrich syndrome associated with thyroid gland abscess. Case report

RESUMEN El Síndrome de Wiskott-Aldrich es una inmunodeficiencia hereditaria poco frecuente, acompañada de trombocitopenia. Así mismo, el absceso de tiroides se presenta raras veces, dados los niveles de iodo, irrigación linfática y lo encapsulado del órgano. El objetivo del presente trabajo es presentar el caso de un paciente con absceso de la glándula tiroides, que además era portador de Síndrome de Wiskott-Aldrich. De sexo masculino y 21 años de edad, fue atendido en el Hospital León Cuervo Rubio, de Pinar del Río. Una semana antes había sufrido un ántrax en la espalda, seguido del aumento de volumen del cuello y signos de compresión, aunque sin indicios de sepsis. Durante la intervención quirúrgica se encontró absceso de la glándula tiroides. El tratamiento oportuno del absceso de tiroides evita consecuencias fatales en enfermos inmunodeprimidos, como el paciente presentado.

ABSTRACT Wiskott-Aldrich Syndrome is a rare inherited immunodeficiency, accompanied by thrombocytopenia. In addition, thyroid abscess occurs rarely, given the levels of iodine, lymphatic irrigation and the encapsulation of the organ. The objective of this work is to present the case of a patient with an abscess of the thyroid gland, who was also a carrier of Wiskott-Aldrich syndrome. A 21 years old male was treated at the León Cuervo Rubio Hospital, in Pinar del Río. A week earlier, he had suffered a anthrax on his back, followed by swelling in his neck and signs of compression, but with no signs of sepsis. During the surgical intervention, an abscess of the thyroid gland was found. Timely treatment of thyroid abscess avoids fatal consequences in immunodeficient patients, such as the patient presented.

Síndrome de Guillain Barré e hidrocefalia en un lactante con Síndrome de Wiskott Aldrich / Guillain-Barré Syndrome and Hydrocephalus in an infant with Wiskott-Aldrich Syndrome

Resumen: Introducción: El Síndrome de Guillain-Barré (SGB) es raramente diagnosticado en lactantes menores de 1 año. Su asociación con el Síndrome de Wiskott Aldrich (SWA), es aún menos frecuente, y ha sido previa mente reportada sólo en dos pacientes a nuestro conocimiento. La hidrocefalia, es una complicación conocida, pero infrecuente del SGB. Objetivo: presentar el caso clínico de un lactante en el que se asocian las patologías de SGB, SWA e hidrocefalia. Caso Clínico: varon de 9 meses, portador de SWA hospitalizado en unidad de cuidados intensivos por hipotonía aguda y compromiso del estado gene ral. Evolucionó con parálisis fláccida, falla ventilatoria y arreflexia generalizada. Una punción lumbar mostró disociación albuminocitológica, y el estudio electrofisiológico mostró signos de polineuropatía desmielinizante severa. Se trató con inmunoglobulina, evolucionando en forma satisfactoria. Por bradicardia intermitente, se realizó tomografla axial computada cerebral (TAC), que mostró signos de una hidrocefalia aguda, manejada mediante válvula derivativa ventrículo peritoneal con favorable respuesta. En el largo plazo, se sometió a trasplante de médula ósea y debió ser reintervenido por complicaciones valvulares, sin embargo, su desarrollo psicomotor es normal sin secuelas neurológi cas evidentes hasta los 3 años. Conclusión: Presentamos el tercer caso de SGB en un paciente porta dor de SWA, destacando ser el primero de ellos en un lactante menor de 1 año. Adicionalmente, este niño presentó una hidrocefalia aguda como complicación del SGB. Consideramos relevante tener presente estas comorbilidades, debido a que su pronto diagnóstico y manejo oportuno, permiten una mejor recuperación neurológica y evitan complicaciones potencialmente letales.

Abstract: Introduction: Guillain-Barre Syndrome (GBS) is rarely diagnosed in the first year of life. The association of GBS with Wiskott-Aldrich syndrome (WAS) is even less frequent and has been previously reported in only two children to our knowledge. Hydrocephalus is a known but rare complication of GBS. Objective: To describe the case of an infant in which GBS, WAS and hydrocephalus appear clinically associated. Clinical Case: A nine-months-old male infant with a history of WAS was admitted to our ICU with acute hypotonia and poor general condition. He developed flaccid paralysis, absent deep tendon reflexes, and respiratory failure. A lumbar puncture showed albuminocytologic dissociation. GBS was suspected and an electromyography was performed, showing a demyelinating polyneuropathy. He was successfully treated with intravenous immunoglobulins. During hospitalization, he presented intermittent bradycardia, so a brain CT scan was performed, showing acute hydrocephalus which was managed through an external ventricular drain achieving favorable response. In the long term, the patient underwent bone marrow transplant and had to be reoperated due to valve-related complications. However, his psychomotor development is normal, with no obvious neurological sequelae. Conclusion: We present the third case of GBS in a patient with WAS, which is the first infant younger than one year. Additionally, he presented acute hydrocephalus as a complication of GBS. We suggest considering these three comorbidities since their early diagnosis and prompt management allow bet ter neurological recovery and avoid potentially lethal complications.

X-linked neutropenia caused by gain-of-function mutation in WAS gene: two cases report and literature review / 中华儿科杂志

Objective@#To investigate the clinical and genotypic manifestations of X-linked neutropenia caused by gain-of-function mutation in WAS gene.@*Methods@#The clinical history of two patients with X-linked neutropenia caused by gain-of-function mutation in WAS gene in Shenzhen Children′s Hospital were analyzed."X-linked neutropenia" and "WAS mutation" were used as key words to search related literatures published from January 2000 to December 2018 in CNKI,Wanfang, and Pubmed databases.@*Results@#The first case was male,1 year old, admitted for 1 year of neutropenia combined with 5 days of cough and 3 days of fever. Persistent neutropenia (0.1×109-0.3×109/L) was reported before admission and during hospitalization (0.4×109-0.5×109/L). The patient was treated with Ciprofloxacin, cefoperazone sulbactam and Vancomycin,and relieved from fever after 4 weeks of hospitalization,yet the neutropenia (0.1×109-0.6×109/L) continued after discharge. Variant in WAS gene (c.T869C (p.I290T) ) was identified, and the percentage of WAS protein on lymphocyte was 97.7%. The second case was male, 42 days old,admitted for fever and neutropenia (0.5×109/L). Similarly,he relieved from fever after 4 weeks of treatment with amoxicillin sulbactam,vancomysin,meropenem,rifampin and isoniacid,yet was discharged with continued neutropenia. Variant in WAS gene (c.T881C (p.I294T)) was identified and the percentage of WAS protein on lymphocyte was 92%. Published literature reported four variants,including I290T, L270P, S272P and I294T, as the pathogenic mutation of X-linked neutropenia in 18 patients from five families. Neutropenia (0.1×109-1.0×109/L) were reported in 15 patients,while normal neutrophil number was found in the rest. Recurrent infection,mainly pneumonia and otitis media,was the most common clinical manifestation.@*Conclusions@#Neutropenia is the prominent presentation in the patients with X-linked neutropenia caused by gain-of-function mutation in WAS gene, but it unnecessarily correlates with the clinical severity in terms of infection. Gene sequencing should be considered for the male patients with persistent neutropenia.

Outcome of Hematopoietic Stem Cell Transplantation in Wiskott-Aldrich Syndrome / 임상소아혈액종양

BACKGROUND: Wiskott-Aldrich syndrome (WAS) is a very rare disease and patients who do not receive timely treatment suffer from bleeding, infection, and malignancy. Hematopoietic stem cell transplantation (HSCT) has been recognized as an effective treatment, but the standard transplantation protocol has not been established. We report the outcomes of WAS patients who underwent HSCT in our institution. METHODS: We retrospectively studied patients who underwent HSCT at Seoul National University Children's Hospital from 2005 to 2018. Busulfan-based myeloablative conditioning regimen was used, and an intensive daily therapeutic drug monitoring (TDM) for busulfan dosing was started for effective myeloablation and to reduce toxicity since 2008. We collected and analyzed data regarding symptoms, engraftment, transplantation-related toxicities, and survival. RESULTS: Six WAS patients who received HSCT were evaluated. The median age of the patients at diagnosis was 5 years (range, 1–11). There were 2 matched unrelated donor bone marrow transplantations, 3 matched unrelated peripheral blood stem cell transplantations (PBSCT), and 1 haploidentical PBSCT. No patient experienced engraftment failure. Three patients developed grades II to IV acute graft-versus-host disease (GVHD). Two patients had veno-occlusive disease (VOD). Two patients died (due to VOD and acute GVHD). The 5-year overall survival was 66.7% with 8 years of median follow-up. Particularly, a patient who underwent haploidentical PBSCT using targeted busulfan is alive with a follow-up duration of 3 years after HSCT. CONCLUSION: In conclusion, WAS patients may be cured with HSCT with targeted busulfan-based myeloablative conditioning. But, long-term and multi-center studies are needed.

Wiskott-Aldrich syndrome related diseases / 中华实用儿科临床杂志

The Wiskott-Aldrich syndrome (WAS) related disorders,which include WAS,X-linked thrombocytopenia (XLT),and X-linked congenital neutropenia (XLN),are caused by WAS gene mutation and inherited in an X-linked recessive manner.The main clinical features of these disorders are eczema,thrombocytopenia and immunodeficiency.They can lead to severe complications,so early diagnosis and early treatment are necessary.In severe cases,allogeneic hematopoietic stem cell transplantation is required.

Wiskott-Aldrich syndrome without mean platelet volume reduction: a case report / 中华围产医学杂志

We reported a case of full-term male neonate who was diagnosed with Wiskott-Aldrich syndrome(WAS) characterized by eczema, persistent thrombocytopenia and gastrointestinal bleeding (hematochezia). Serial blood tests showed decreased platelet count without platelet volume reduction. Treatment with human immunoglobulin and platelet transfusion turned out to be ineffective. A heterozygous mutation (c.121c>T) in WA S gene was detected. Moreover, his mother also had heterozygous mutation at the corresponding loci and was confirmed as a carrier. WAS should be considered in neonates presenting with unexplained thrombocytopenia even without mean platelet volume reduction and obvious immune deficiency.

Síndrome de Wiskott-Aldrich com plaquetas de volume normal / Wiskott-Aldrich syndrome with normal-sized platelets

A Síndrome de Wiskott-Aldrich (WAS) é uma imunodeficiência congênita ligada ao cromossomo X, caracterizada por mutações no gene WAS, responsável pela proteína WASP. As principais manifestações clínicas são trombocitopenia com plaquetas de volume reduzido, eczema, infecções recorrentes e maior incidência de doenças autoimunes e neoplasias. Relatamos o caso de um paciente do sexo masculino com sintomas clássicos desta síndrome (eczema, trombocitopenia e infecções recorrentes), porém com plaquetas de volume normal. Existem poucos relatos desta síndrome em pacientes com plaquetas de volume normal, o que atrasou o encaminhamento do paciente ao imunologista, o qual foi tratado como portador de Síndrome de Evans e dermatite atópica até os quatro anos de idade. A confirmação diagnóstica foi por teste genético. O diagnóstico precoce possibilita profilaxia com antibioticoterapia e uso de imunoglobulina endovenosa, devido ao risco de infecções graves, e encaminhamento para transplante de células-tronco hematopoiéticas, que até o momento é o único tratamento curativo. A suspeita clínica deve existir em pacientes com trombocitopenia inexplicável, mesmo se as plaquetas tiverem o tamanho normal, associada às outras manifestações da doença.

Wiskott-Aldrich syndrome (WAS) is an X-linked congenital immunodeficiency characterized by mutations in the WAS gene of the WASP protein. The main clinical manifestations are thrombocytopenia with small-sized platelets, eczema, recurrent infections and a higher incidence of autoimmune diseases and cancer. We report the case of a male patient with classical symptoms of this syndrome (eczema, thrombocytopenia and recurrent infections), however presenting platelets with normal size. There are few reports of this syndrome in patients with normal-sized platelets, which delayed our patient's referral to the immunologist. The patient received treatment for Evans syndrome and atopic dermatitis until he was four years old. Confirmation of WAS diagnosis was made by genetic testing. Early diagnosis allows prophylactic treatment with antibiotics and the use of intravenous immunoglobulin due to the risk of serious infections, in addition to referral for hematopoietic stem cell transplantation, which is the only curative treatment available so far. WAS should be suspected when patients develop unexplained thrombocytopenia even with normal-sized platelets, especially in the presence of other manifestations.

Clinical feature and gene detection in one case of Wiskott-Aldrich syndrome / 临床儿科杂志

Objective To explore the characteristics of WAS gene mutation in Wiskott-Aldrich syndrome (WAS). Methods The clinical data of one infant with WAS were retrospectively analyzed. All exons and flanking sequences in WAS gene were detected by PCR. Results A 5-month-old boy, who has a history of eczema and recurrent infection, was hospitalized for thrombocytopenia. CD8+ and CD4+T cell were increased while CD19+B cell was normal. Bone marrow cytology suggested megakaryocyte mature hindrance. WAS gene detection found C.880 A?>?G (p.Ile294Val) mutation, but no mutations were found in parents. This site was a pathogenic mutation predicted by Polyphen 2 software and SIFT software. Besides, sequence conservation analysis of different species found it was a conservative site and structural prediction analysis revealed it may affect the normal protein structure. This site of mutation has not been reported before. Conclusions Gene detection can make early diagnosis of WAS and C.880 A?>?G (p.Ile294Val) is a new mutation.

Expression and significance of Rac1 and WAVE2 in glomerulus of high-fat diet induced C57BL/6J model mice / 天津医药

Objective To explore the expression and significance of Rac1 and WAVE2 protein in glomerulus of high- fat diet induced C57BL/6J model mice. Methods Thirty-two male C57BL/6J mice (3-week old) were randomly assigned into two groups(16 in each group). The control group was fed with basic diet (10%fat) for 4 weeks. The high-fat diet group was fed with high-fat diet (60%fat) for 4 weeks. The kidney morphological changes were examined by HE and PAS staining. The expressions of Rac1 and WAVE2 protein were examined by Western blot and immunohistochemistry analysis. Results HE and PAS results showed that there were glomeruli mesangial matrix hyperplasia and exudation in high-fat diet group compared with control group. The immunohistochemistry and Western blotting results showed that expressions of Rac 1 and WAVE2 in glomerulus were both increased in high-fat diet group compared with those of control group. Conclusion Rac1 and WAVE2 protein may be involved in glomerular injuries induced by high-fat diet.

Progress of diagnosis and treatment for Wiskott-Aldrich syndrome / 中华实用儿科临床杂志

Wiskott-Aldrich syndrome (WAS) is due to the mutation of the WAS gene on the X chromosome,which has both features of primary immunodeficiency disease (PID) and congenital hereditary hematopoietic disease.Although the clinical manifestations of classic WAS were more obvious,the related gene (WAS) and its protein product (WASP) have the value of diagnosis,but due to the low incidence,and there were significant differences in the severity of clinical symptoms of the patients,so WAS is easily misdiagnosed.This article through collecting and analyzing the recent years of research progress of literature data and the clinical reports,and combined with the author＇s previous experience in the diagnosis and treatment,to induct the main points of diagnosis and treatment for WAS.

Síndrome de Wiskott-Aldrich: Caso clínico / Wiskott-Aldrich syndrome: Case report

El síndrome de Wiskott-Aldrich es una inmunodeficiencia primaria; con una incidencia de 3,5 a 5,2 por cada millón de recién nacidos masculinos. Se caracteriza por tener un patrón de herencia recesiva ligada al cromosoma X. En estos pacientes; se ha descrito la tríada clásica de inmunodeficiencia; microtrombocitopenia y eczema. Presentamos un paciente de 5 años de edad; hispánico; con antecedentes de numerosas infecciones desde el primer año de vida. Actualmente; presenta desnutrición crónica; talla baja secundaria y retraso en el desarrollo del lenguaje. Se diagnosticó una mutación poco frecuente del gen asociado al síndrome de Wiskott-Aldrich.

The Wiskott-Aldrich syndrome is a rare X-linked recessive immunodeficiency, with an estimated incidence of 3.5 to 5.2 cases per million males. It is characterizedby immunodeficiency, microthrombocytopenia and eczema. We present a 5-year-old Hispanic male, with a medical history of numerous infectious diseases, compromised health, chronic malnutrition, language delay and failure to thrive. An infrequent mutation in the Wiskott-Aldrich syndrome gene was found.

Wiskott-Aldrich syndrome complicated with demyelinating disease of the central nervous system:report of one case and literature review / 中华神经科杂志

Objective To discuss the correlation of Wiskott-Aldrich syndrome (WAS) with autoimmune disease of the central nervous system and its possible pathogenesis by reporting one case of the disease and reviewing related literature.Methods One case of WAS complicated with demyelinating disease of the central nervous system was reported.The patient' s clinical symptoms,laboratory examinations (such as blood tests,immune function tests,etc) and imaging features were analyzed.The patient's blood DNA was extracted and performed gene testing.And related literature was reviewed.Results The patient showed typical clinical symptoms of WAS,including eczema,thrombocytopenia and immune deficiency,complicated with demyelinating disease of the central nervous system.The DNA testing showed C400G ＞ C p.(ALa134Pro) mutation,which is a missense mutation.The 134th amino acid in protein was changed from alanine to proline.The patient also showed the symptoms of demyelinating disease of the central nervous system,which drew our attention.This was the first report on WAS complicated with demyelinating disease of the central nervous system,which was perhaps caused by a gene mutation.Conclusions WAS complicated with demyelinating disease of the central nervous system is possibly resulted from the gene mutation,which leads to the expression disorder of WAS protein.And then non-red hematopoietic cells lead to signal transduction and cytoskeleton recombination disorders in response to environment stimulus,which produces lymphocytes immigration,signal transduction and immune synaps formation disorders.

Clinical characteristics and management of children with Wiskott-Aldrich syndrome / 中华实用儿科临床杂志

Objective To improve the early diagnosis of Wiskott-Aldrich syndrome (WAS),through summing up and analyzing the clinical characteristics of children with WAS.Methods The clinical and laboratory characteristics of 18 children with WAS,including the cases from Suzhou Jiulong Hospital,Shanghai Jiaotong University School of Medicine,and Tongji Hospital Affiliated to Tongji University,and the domestic reports in recent 6 years,were induced and analyzed.Results All patients were males;the average of incidence age was about 1.9 months and the average age at diagnosis was 10.8 months.All cases had the clinical characteristics of WAS including eczema,infection tendency and thrombocytopenia with small platelet size.Moreover,10/18 cases (55.56％) WAS patients progressed to severe cases (scores reached to 4 or 5 points)at diagnosis,and with the increase of age of the patients at diagnosis,the ratio of severe cases would be increased.The conventional immune function indexes showed no specific diagnostic value,and the typical clinical features and the WAS gene mutation detection were the key diagnostic basis.Seven cases used to be misdiagnosed as idiopathic thrombocytopenia,and received corticosteroids and intravenous immunoglobulin therapy.In a total of 18 cases,4 cases received allogeneic hematopoietic stem cell transplantation,of which,β cases were cured and 1 case died of transplantation-related interstitial pneumonia,while the remaining 14 cases are unknown for their with follow-up treatment and prognosis.Conclusions The typical clinical features and the WAS gene mutation detection were the key diagnostic basis.In order to improve the rate of early diagnosis and avoid misdiagnosis,it's a great need to improve the clinical understanding of WAS.

Molecular characterization of two Malaysian patients with Wiskott-Aldrich syndrome

The Wiskott-Aldrich Syndrome (WAS) is an X-linked immunodeficiency condition characterized by microthrombocytopenia, eczema and recurrent infections. It is caused by mutations in the Wiskott-Aldrich Syndrome protein (WASP) gene. We investigated two Malay boys who presented with congenital thrombocytopenia, eczema and recurrent infections. Here we report two cases of WASP mutation in Malaysia from two unrelated families. One had a novel missense mutation in exon 1 while the other had a nonsense mutation in exon 2. Both patients succumbed to diseaserelated complications. A differential diagnosis of WAS should be considered in any male child who present with early onset thrombocytopenia, especially when this is associated with eczema and recurrent infections.

Síndrome de Wiskott Aldrich. Presentación de un caso / Wiskott Aldrich Syndrome. Presentation of a Case

El síndrome de Wiskott Aldrich es una inmunodeficiencia primaria clasificada dentro del grupo de las bien definidas, se hereda con carácter recesivo ligado al X, el gen mutado codifica para una proteína citoplasmática presente en linfocitos y megacariocitos importante en la regulación de la polimerización de la actina y traducción de señales necesarias para la reorganización del citoesqueleto celular. Las manifestaciones clásicas están dadas por sangramientos, infecciones y eczemas; sus primeros síntomas pueden aparecer al nacimiento con hemorragia petequial, diarreas con sangre; mientras las infecciones y el eczema se desarrollan durante el primer año de edad, la otitis media es la infección que se presenta con mayor frecuencia. Desde el punto de vista inmunológico se caracteriza por tener niveles de inmunoglobulina M bajos, las inmunoglobulinas A y E son elevadas, mientras la inmunoglobulina G puede ser normal a lo que se une trombocitopenia. El diagnóstico de esta enfermedad se realizó en un niño de tres meses de edad, el cual permaneció ingresado por largo tiempo en cuidados intensivos y falleció a los dos años de edad por sepsis generalizada.

The Wiscott Aldrich Syndrome is a well-defined primary immunodeficiency X- linked recessive disorder, the mutated gene encodes a cytoplasmatic protein in lymphocytes and megakaryocytes which is important in actin polymerization and cytoskeletal reorganization .The classic manifestations involve bleeding, infections and eczema. The first symptoms may appear at birth with petechial hemorrhage, diarrhea with blood, while infections and eczema are present during the first year of age, otitis media is an infection that occurs more frequently. From the immunological point of view it is characterized by low levels immunoglobulin M, immunoglobulin A and E are high, while immunoglobulin G may be normal together with thrombocytopenia. This disorder was diagnosed in a three- year- month infant who was admitted at intensive care unit for a long period of time. The patient died when he was two years old due to generalized infection.

Clinical features, genotype and phenotype analysis and literature review of Wiskott-Aldrich syndrome / 中华实用儿科临床杂志

Objective To explore the clinical and genetic characteristics,protein expression of Wiskott-Aldrich syndrome (WAS).Methods 1.Clinical data of a Chinese sick boy patient who was treated in the First Affiliated Hospital of Guangxi Medical University was collected,and DNA samples were obtained from the patient and his mother,12 WAS gene exons were amplified by polymerase chain reaction (PCR) followed by direct sequencing,and then the protein expression was analyzed by Western blot.2.China National Knowledge Infrastructure (CNKI) was searched to identify the clinical data and clear genetic diagnosis of WAS literature from Jan.1991 to Oet.2013,combined with the case of WAS patient treated in this hospital,and a retrospective relationship analysis was made among WAS phenotype,genotype and protein phenotype in China.Results 1.The boy had a classical WAS phenotype,his clinical scores were 4.Sequencing revealed a nonsense mutation in exon 1,c.71C ＞ T (p.R13X).Western blot analysis revealed WASP-.The patient's mother was normal It's a de novo mutation in the patient.2.Other 53 cases of WAS patients had been reported,and they were all are male children,onset age from 1 day to 3 years.Forty-nine cases of typical WAS views,4 cases of X-linked thrombocytopenia (XLT).Immunological tests lack of specificity,mutant gene distribute in each exons except 4,5,6,9,12 and 1,3,6,7,8,9,11 introns.Protein detection was mostly negative.Conclusions Affected males who presented recurrent infections,persistent thrombocytopenia and eczema,should be considered to have the possibility of suffering from the WAS.Genetic diagnosis is the golden standard to diagnose the disease.And detection of protein expression can help define the relationship amone phenotype,genotype and protein phenotype.

Effect of oxidative stress on human Wiskott-Aldrich syndrome related protein 2 expression in placental trophoblasts in preeclampsia / 中华围产医学杂志

Objective To explore the effect of oxidative stress on human Wiskott-Aldrich syndrome related protein 2 (WAVE2) expression in placental trophoblasts in women with preeclampsia.Methods (1) Twenty women with preeclampsia and twenty-three normal term pregnant women,delivered from August 15,2011 to February 23,2012 in the First Affiliated Hospital of Chongqing Medical University,were recruited and divided into preeclampsia group and control group.Placenta samples were collected after cesarean section.The localization and distribution of WAVE2 in placenta was studied by immunohistochemistry.Quantitative real-time polymerase chain reaction and Western blot were employed to assay the WAVE2 mRNA and protein levels.Tissue homogenates was applied to determine the levels of reactive oxygen species (ROS).The correlation between ROS levels and WAVE2 was also analyzed.(2) An in vitro hypoxia/reoxygenation (H/R) model was utilized to simulate ischemia/reperfusion injury to placental trophoblasts.The HTR-8/ SVneo cells (immortalized human first trimester extravillous trophoblast cells) were pre-incubated overnight,after exposure to H/R or normoxic conditions for 48 hours.Flow cytometry was employed to analyze intracellular ROS level.Meanwhile,Transwell assay was utilized to analyze the invasion and migration of HTR-8/SVneo cells.The location and expression of WAVE2 in trophoblasts was evaluated by cell immunofluorescence and Western blot.Statistical differences between the two groups were evaluated by independent t-tests.Pearson's correlation coefficient test was used for correlation analysis.Results (1)Compared with the control group,preeclampsia group had significantly higher 24-hour proteinuria [(1.96±0.24) g vs (0.08±0.05) g,t=19.436,P＜0.05],systolic blood pressure [(154 ± 13) mm Hg vs (98 ±11) mm Hg,t=11.324,P＜0.05] and diastolic blood pressure [(105±14) mm Hgvs (69±8) mm Hg,t=9.612,P＜0.05].In addition,the placental weight and birth weight of infants in preeclampsia group were significantly reduced as compared to the control group [(432±53) g vs (536±67) g,(2446± 187) g vs (3207± 233) g,t=14.562 and 16.307,allP＜0.05)].The WAVE2 mRNA level (0.28±0.07 vs 1.01±0.02,t=12.747,P＜0.05) and the WAVE2 protein levels (0.63±0.08 vs 1.34±0.19,t=11.648,P＜0.05) were also significantly decreased in preeclampsia groups.The level of ROS in placenta in the preeclampsia group was significantly higher than in control group [(144.22 ± 12.32) nmol/(mg · prot) vs (75.17 ± 8.71) nmol/(mg · prot),t=20.467,P＜0.05].There was significant negative correlation between ROS level and WAVE2 protein expression in preeclamptic placenta (r =-0.726,P =0.000).(2) In vitro study showed that,the levels of ROS in normoxia group and H/R group was (82.9±5.8)％ and (155.6±8.1)％,(t=12.747,P＜0.05).Compared with normoxia condition,decreased cell invasion and migration were found in HTR-8/SVneo cells in H/R group [(51.9 ± 3.3)％ and (58.4 ±4.2)％ respectively,t=11.034 and 13.839,P＜0.05].Results from the cell immunofluorescence showed that WAVE2 protein located in the cytoplasm of HTR-8/SVneo cells,and the expression of WAVE2 protein was significant decreased in HTR-8/SVneo cells after exposure to H/R for 48 h (0.37±0.05 vs 0.76±0.06,t=8.631,P＜0.05).Conclusions Excessive oxidative stress in preeclamptic placentas was correlated with the decreased expression of WAVE2.H/R-induced oxidative stress could decrease WAVE2 expression,which may contribute to impaired trophoblast invasion and migration in preeclampsia.