RESUMEN
PURPOSE: We aimed to describe the clinical, immunological, and genetic features of patients with DOCK8 deficiency (DOCK8-Def) in a tertiary care center for children. METHODS: Retrospective chart review of patients' clinical, immunological, and genetic characteristics with DOCK8-Def. Genetic analysis was performed with targeted- or whole-exome sequencing; we also assessed DOCK8 protein expression and a lymphoproliferation assay and analyzed survival by the Kaplan-Meier method. RESULTS: We described 11 patients from 8 unrelated kindreds. The median age at symptoms' onset was 10 months (range 1-54 months). The median follow-up time was 53.4 months (4.8-118.8). All patients presented eczema and recurrent sinopulmonary and cutaneous infections. Besides those symptoms, the most frequent manifestations were bronchiectases (8/11), food allergies (6/11), and severe infections (6/11). Infrequent characteristics were detection of CMV in bronchial lavage, C. parvum-driven sclerosing cholangitis, Takayasu vasculitis, neurological syndromes, pulmonary tuberculosis, and lymphomatoid granulomatosis. CONCLUSION: DOCK8-Def has a broad spectrum of manifestations, including allergy, autoimmunity, inflammation, infection, and cancer. The hallmark of this inborn error of immunity is IEI-associated eczema with eosinophilia and increased IgE. Here, we report six new mutations causing human DOCK8 deficiency and symptoms previously unrecognized to occur in DOCK8-Def. Therefore, an early diagnosis of DOCK8-Def is essential to facilitate an adequate treatment such as HSCT.
Asunto(s)
Eccema , Hipersensibilidad , Síndrome de Job , Niño , Humanos , Lactante , Preescolar , Estudios Retrospectivos , Síndrome de Job/genética , Eccema/epidemiología , Eccema/genética , Mutación , Factores de Intercambio de Guanina Nucleótido/genéticaRESUMEN
Combinedimmunodeficiency (CID) due to DOCK8 deficiency is an inborn error of immunity (IBD) characterized by dysfunctional T and B lymphocytes; The spectrum of manifestations includes allergy, autoimmunity, inflammation, predisposition to cancer, and recurrent infections. DOCK8 deficiency can be distinguished from other CIDs or within the spectrum of hyper-IgE syndromes by exhibiting profound susceptibility to viral skin infections, associated skin cancers, and severe food allergies. The 9p24.3 subtelomeric locus where DOCK8 is located includes numerous repetitive sequence elements that predispose to the generation of large germline deletions and recombination-mediated somatic DNA repair. Residual production DOCK8 protein contributes to the variable phenotype of the disease. Severe viral skin infections and varicella-zoster virus (VZV)-associated vasculopathy, reflect an essential role of the DOCK8 protein, which is required to maintain lymphocyte integrity as cells migrate through the tissues. Loss of DOCK8 causes immune deficiencies through other mechanisms, including a cell survival defect. In addition, there are alterations in the response of dendritic cells, which explains susceptibility to virus infection and regulatory T lymphocytes that could help explain autoimmunity in patients. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment; it improves eczema, allergies, and susceptibility to infections.
Lainmunodeficiencia combinada (IDC) por deficiencia de DOCK8 es un error innato de la inmunidad, caracterizado por alteración en linfocitos T y B; el espectro de manifestaciones incluye alergia, autoinmunidad, inflamación, predisposición a cáncer e infecciones recurrentes. La deficiencia de DOCK8 se puede distinguir de otras IDC o dentro del espectro de síndromes de hiper-IgE porque presenta una profunda susceptibilidad a las infecciones virales de la piel, con cánceres de piel asociados y alergias alimentarias graves. El locus subtelomérico 9p24.3, donde se ubica DOCK8, incluye numerosos elementos repetitivos de secuencia que predisponen a la generación de grandes deleciones de la línea germinal, así como a la reparación del ADN somático, mediada por recombinación. La producción residual de la proteína DOCK8 contribuye al fenotipo variable de la enfermedad. Las infecciones virales graves de la piel y la vasculopatía asociada a virus de la varicela zóster (VVZ) reflejan una función importante de la proteína DOCK8, que normalmente se requiere para mantener la integridad de los linfocitos a medida que las células migran a través de tejidos. La pérdida de DOCK8 provoca deficiencias inmunitarias a través de otros mecanismos, incluido un defecto de supervivencia celular. Existen alteraciones en la respuesta de las células dendríticas, lo que explica la susceptibilidad a infección por virus, así como en los linfocitos T reguladores que podrían ayudar a explicar la autoinmunidad en los pacientes. El trasplante de células hematopoyéticas pluripotenciales es por el momento el único tratamiento curativo, mejora el eccema, la alergia y la susceptibilidad a infecciones.
Asunto(s)
Hipersensibilidad , Síndromes de Inmunodeficiencia , Síndrome de Job , Humanos , Síndrome de Job/complicaciones , Síndrome de Job/terapia , Síndrome de Job/genética , Inflamación , Linfocitos B , Factores de Intercambio de Guanina Nucleótido/genéticaRESUMEN
Autosomal recessive (AR) DOCK8 deficiency is a well-known actinopathy, a combined primary immune deficiency with impaired actin polymerization that results in altered cell mobility and immune synapse. DOCK8-deficient patients present early in life with eczema, viral cutaneous infections, chronic mucocutaneous candidiasis, bacterial pneumonia, and abscesses, together with eosinophilia, thrombocytosis, lymphopenia, and variable dysgammaglobulinemia that usually includes Hyper-IgE. In fact, before its genetic etiology was known, patients were described as having a form of Hyper-IgE syndrome, a name now deprecated in favor of genetic defects. We describe a school-age male patient with a clinical picture suggestive of DOCK8 deficiency, except for high serum IgE or a family history: early onset, failure to thrive, eczema, warts, condyloma, bronchiolitis, pneumonia, recurrent otitis media, bronchiectasis, candidiasis, leukocytosis, eosinophilia, high IgA, low IgG, and low CD4+ T cells. We were able to confirm the diagnosis through protein expression and whole-exome sequencing. We review the clinical, laboratory, and genetic features of 200 DOCK8-deficient patients; at least 4 other patients have had no elevated IgE, and about 40% do not have Hyper-IgE (above 1,000 IU/mL). Despite this, the constellation of signs, symptoms, and findings allow the suspicion of DOCK8 deficiency and other actinopathies.
RESUMEN
OBJECTIVES: To investigate effects and outcome of hematopoietic stem cell transplantation (HSCT) on sclerosing cholangitis, in pediatric patients with different primary immunodeficiencies (PIDs). STUDY DESIGN: From databases in 2 tertiary centers for immunodeficiencies and liver disease, we have identified children with PIDs and sclerosing cholangitis, who have paired clinical, radiologic, and histologic information before and after HSCT and studied their clinical progress and outcome. RESULTS: Seven of 13 children (53.8%) died at a median interval of 4 months (range, 3 months-5 years) after HSCT. However, 6 surviving children (46.2%) with different PIDs and less severe cholangiopathies showed an improvement in markers of liver injury within months of successful unrelated reduced intensity conditioning HSCT. The repeated native liver biopsy, performed in 4 patients at a median of 96 (range, 4-144) months post-HSCT, showed a considerable improvement. Biochemical markers of liver function in the survivors completely normalized after a median of 13 months (range, 2-48). All patients continue to have a mildly dilated extrahepatic biliary system on ultrasonography with no intrahepatic ductal changes on magnetic resonance cholangiography after a follow-up of median 18 years (range, 2-20). CONCLUSIONS: Effective HSCT has the potential to improve biochemical and histologic features of cholangiopathy in children with PIDs, presumably by clearance of chronic infection following establishment of immune competence. However, careful patient selection is critical as advanced liver injury is often associated with serious complications and mortality.
Asunto(s)
Causas de Muerte , Colangitis Esclerosante/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Enfermedades de Inmunodeficiencia Primaria/epidemiología , Enfermedades de Inmunodeficiencia Primaria/terapia , Factores de Edad , Biopsia con Aguja , Preescolar , Colangiopancreatografia Retrógrada Endoscópica/métodos , Colangitis Esclerosante/diagnóstico por imagen , Colangitis Esclerosante/epidemiología , Colangitis Esclerosante/patología , Enfermedad Crónica , Estudios de Cohortes , Bases de Datos Factuales , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Trasplante de Células Madre Hematopoyéticas/mortalidad , Hospitales Pediátricos , Humanos , Inmunohistoquímica , Lactante , Masculino , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Pronóstico , Estudios Retrospectivos , Medición de Riesgo , Índice de Severidad de la Enfermedad , Factores Sexuales , Análisis de Supervivencia , Resultado del Tratamiento , Reino UnidoRESUMEN
In the classification of primary immunodeficiencies, hyper-IgE syndrome, identified with OMIM code # 147060 in the Online Mendelian Inheritance in Man catalog, belongs to the group of syndromes associated with combined immunodeficiencies. It is characterized by elevated levels of IgE, eosinophilia, recurrent skin abscesses, pneumonia, lung parenchyma lesions, recurrent infections, rashes in newborns, eczema, sinusitis, otitis, and mucocutaneous candidiasis. Hyper-IgE syndrome can be transmitted by autosomal dominant or autosomal recessive modes of inheritance. Hyper-IgE syndrome in its dominant form includes non-immunological manifestations like characteristic facies, pathological dentition, scoliosis, bone disorders, and joint hyperextensibility. The reported cause of the dominant form is the loss of function of the signal transducer and activator of transcription 3 (STAT-3, with MIM # 102582). Mutations in dedicator of cytokines 8 (DOCK-8) is the most common cause of the autosomal recessive form of hyper-IgE syndrome.
En la Clasificación de las Inmunodeficiencias Primarias, el síndrome hiper-IgE, identificado con el código OMIM #147060 en el Catálogo Online Mendelian Inheritance in Man, pertenece al grupo de las inmunodeficiencias combinadas asociadas a síndromes. Se caracteriza por elevación de la concentración de IgE, eosinofilia, abscesos recurrentes en piel, neumonías, lesiones en parénquima pulmonar, infecciones recurrentes, erupciones en el recién nacido, eccema, sinusitis, otitis y candidiasis mucocutáneas. El síndrome hiper-IgE puede ser transmitido hereditariamente en forma autosómica dominante o autosómica recesiva. El síndrome hiper-IgE en su forma dominante incluye manifestaciones no inmunológicas como facies característica, dentición patológica, escoliosis, alteraciones óseas e hiperextensibilidad articular. La causa identificada en la forma dominante es la pérdida de la función del transductor de señales y activador de la transcripción 3 (STAT-3, MIM #102582). Las mutaciones en la proteína dedicada a la citocinesis 8 (DOCK-8) representan la mayoría de las causas de la forma autosómica recesiva del síndrome hiper-IgE.
Asunto(s)
Factores de Intercambio de Guanina Nucleótido/genética , Síndrome de Job/genética , Mutación , Factor de Transcripción STAT3/genética , Humanos , Síndromes de Inmunodeficiencia/clasificación , Síndrome de Job/clasificación , Síndrome de Job/complicacionesRESUMEN
Diferentes inmunodeficiencias primarias se caracterizan por niveles elevados de IgE e infecciones cutáneas de origen viral. Describimos el caso de un niño de 2 años y 8 meses de edad, con inmunodeficiencia combinada, dermatitis y molusco contagioso diseminado. El paciente presentaba niveles aumentados de IgE, eosinofilia y marcada linfopenia a predominio de TCD8. Se encontraron alteraciones en los ensayos funcionales por cultivo y en la respuesta a la vacunación. Resultados normales de la proteína ZAP-70, funcionalidad NK y niveles de HLA I, tendientes a verificar alteraciones cuantitativas y funcionales de las células citotóxicas, llevaron a la sospecha de deficiencia en el gen DOCK8. El resultado positivo del estudio molecular, junto con las características clínicas e inmunológicas del paciente, confirmaron el diagnóstico de esta nueva inmunodeficiencia, que, de acuerdo con nuestro conocimiento, sería el primer caso diagnosticado en un hospital pediátrico en nuestro país.
Different primary immunodeficiencies present increased levels of IgE and cutaneous infections of viral etiology. We report a case of a 2 y, 8 m old boy with combined immunodeficiency, dermatitis and disseminated molluscum contagiosum. The patient presented high titers of IgE, eosinophilia and pronounced TCD8 lymphopenia. Impaired proliferation assays and abnormal antibody response to vaccination were found. Normal results of ZAP-70 protein, NK function, and HLA I levels, to test quantitatives and functional defects of cytotoxic cells, lead us to suspect a mutation in DOCK8 gene. Positive result in molecular study together with clinical and immunology features in the patient confirmed the diagnosis of this new immunodeficiency, being to the authors Ì knowledge the first case recorded in a paediatric hospital in our country.