Histiocitosis de células de Langerhans. Avances en la patogenia y práctica clínica / Langerhans cell histiocytosis. Advances in pathogenesis and clinical practice

La histiocitosis de células de Langerhans (HCL) es un tipo de neoplasia hematológica de origen mieloide, que puede afectar a diferentes órganos o tejidos, con gran variabilidad en la presentación clínica y comportamiento biológico, por lo que puede simular diferentes enfermedades. Se recomienda realizar diversas pruebas clínicas, analíticas y de imagen, para determinar la extensión de la afectación, que puede ser única o multisistémica, y la presencia o no de disfunción en órganos de riesgo como sistema hematopoyético, hígado y bazo. El diagnóstico se debe confirmar mediante biopsia y estudio histológico. Los estudios moleculares han permitido identificar mutaciones en la vía MAPK, lo que han ampliado las opciones terapéuticas. El diagnóstico es complejo y existe controversia en el manejo de ciertos casos. Las recomendaciones terapéuticas dependen de la localización de las lesiones y de la extensión de la afectación. Los estudios colaborativos internacionales han demostrado la efectividad de terapias prolongadas combinadas como vinblastina y prednisona en formas graves o multisistémicas y destaca el papel beneficioso de fármacos antiinflamatorios como indometacina y de otras combinaciones de citostáticos. La HCL representa un buen ejemplo de la importancia de la medicina de precisión y del beneficio de la identificación de dianas moleculares, comunes a diferentes neoplasias, para desarrollar nuevas terapias dirigidas. Los inhibidores de la vía MAPK representan una alternativa terapéutica en casos refractarios y en las formas neurodegenerativas de la HCL. Los estudios moleculares pueden contribuir en el pronóstico, el tratamiento y el seguimiento, especialmente en las formas graves. (AU)

Langerhans cell histiocytosis (LCH) is a type of myeloid neoplasia that can affect different organs or tissues and exhibits substantial variability in its clinical presentation and biological behaviour, so it may mimic different diseases. Performance of different clinical assessments and laboratory and imaging tests is recommended to determine the extent of involvement, which may be of a single location or multisystemic, and the presence or absence of dysfunction in risk organs, such as the haematopoietic system, liver and spleen. The diagnosis must be confirmed by histological examination of a biopsy sample. Molecular tests have identified mutations in the mitogen-activated protein kinase (MAPK) pathway, which has expanded treatment options. The diagnosis is complex and there is controversy regarding the management of certain cases. Treatment recommendations depend on the location of the lesions and the extent of involvement. International collaborative studies have demonstrated the effectiveness of prolonged combination therapies such as vinblastine and prednisone in severe or multisystemic forms, and anti-inflammatory drugs such as indomethacin and other cytostatic combinations have proven beneficial. LCH is a good example of the importance of precision medicine and the benefit of identifying molecular targets, common to different neoplasms, to develop new therapies. MAPK pathway inhibitors offer an alternative treatment option in refractory cases and neurodegenerative forms of LCH. Molecular testing can contribute to the prognosis, treatment and follow-up of LCH, especially in severe forms of disease. (AU)

Cytokine profile and brain biopsy in a case of childhood-onset central nervous system vasculitis in Noonan syndrome-like disorder due to a novel CBL variant.

The authors describe a 5-year-old girl who developed a Noonan syndrome-like disorder as a result of the CBL c.1194C>G/p.His398Gln variant, including headache, papilledema, intracranial hypertension, hyperproteinorrhachia, leucorrhachia, and brain inflammation and vasculitis with CD3 positive lymphocyte infiltration. The patient responded partially to corticosteroids, acetazolamide, and ventriculoperitoneal valve placement. The serum cytokine profile revealed persistently elevated levels of IL-1 RA, IL-2R alpha, IL-6, IL-18, MCP-1, and MCP-3. Cyclophosphamide was used as a bridge to allogeneic hematopoietic stem cell transplantation in this case.

Trombocitopenia inmune primaria: experiencia de una consulta especializada / Primary immune thrombocytopenia: Experience of a specialised clinic

INTRODUCCIÓN: La trombocitopenia inmune primaria (PTI) es poco frecuente en la infancia, pero es la causa más habitual de trombocitopenia. Se han intentado establecer factores de riesgo para predecir su evolución, con el objetivo de poder optimizar su manejo, que se ha modificado en los últimos años, debido, entre otros factores, a una atención más especializada. MATERIAL Y MÉTODOS: Estudio retrospectivo, observacional y analítico de los pacientes con PTI, en un periodo de 3 años, en una consulta especializada en Hematología Pediátrica. RESULTADOS: Desde el punto de vista epidemiológico, clínico y analítico, las características de esta serie son similares a las de otros grupos. La mayoría de los pacientes (23/31; 74,2%) presentaron una PTI de duración menor de 12 meses, sin complicaciones graves relacionadas con la enfermedad ni con el tratamiento. Se establecieron como factores de riesgo relacionados con una evolución tórpida (supervivencia libre de eventos [SLE] menor), sin alcanzar la significación estadística, el sexo femenino, la edad mayor de 10 años, la leucopenia, la ausencia de trombocitopenia grave inicial y la atención no especializada. La ausencia de antecedente de infección se relacionó significativamente con una SLE menor. CONCLUSIONES: Los factores de riesgo de evolución tórpida de PTI epidemiológicos y analíticos de este estudio coinciden con los descritos en la literatura. Presentaron una SLE menor los pacientes tratados antes del inicio de la atención especializada. Estos datos parecen apoyar la recomendación actual de que las enfermedades poco frecuentes, como esta, se controlen en unidades especializadas

INTRODUCTION: Although primary immune thrombocytopenia (ITP) is rare in childhood, it is the most frequent cause of thrombocytopenia. There have been attempts to establish risk factors to predict the progression of the disease in order to optimise its management, which has changed in recent years due to, among other reasons, specialised care. MATERIAL AND METHODS: A retrospective, observational and analytical study was conducted on patients diagnosed with ITP over a 3-year period in a Paediatric Haematology specialist clinic. RESULTS: From the epidemiological, clinical and analytical point of view, the characteristics of this group are similar to others. Most of the patients (23/31, 74.2%) had ITP for less than 12 months, with there being no serious complications related to the disease or the treatment received. It was established that risk factors were related to being slowly evolving (lower event-free survival (EFS)) with no statistical significance, female gender, age over 10 years, leukopenia absence of initial severe thrombocytopenia, and non-specialised care. The absence of a history of infection was significantly related to a lower EFS. CONCLUSIONS: The epidemiological and analytical risk factors for a slowly evolving ITP are the same that described in the literature. Patients treated before the beginning of specialised care also had a lower EFS. These data seem to support the current recommendation that rare diseases should be managed in specialised units

[Primary immune thrombocytopenia: Experience of a specialised clinic]. / Trombocitopenia inmune primaria: experiencia de una consulta especializada.

INTRODUCTION: Although primary immune thrombocytopenia (ITP) is rare in childhood, it is the most frequent cause of thrombocytopenia. There have been attempts to establish risk factors to predict the progression of the disease in order to optimise its management, which has changed in recent years due to, among other reasons, specialised care. MATERIAL AND METHODS: A retrospective, observational and analytical study was conducted on patients diagnosed with ITP over a 3-year period in a Paediatric Haematology specialist clinic. RESULTS: From the epidemiological, clinical and analytical point of view, the characteristics of this group are similar to others. Most of the patients (23/31, 74.2%) had ITP for less than 12 months, with there being no serious complications related to the disease or the treatment received. It was established that risk factors were related to being slowly evolving (lower event-free survival (EFS)) with no statistical significance, female gender, age over 10 years, leukopenia absence of initial severe thrombocytopenia, and non-specialised care. The absence of a history of infection was significantly related to a lower EFS. CONCLUSIONS: The epidemiological and analytical risk factors for a slowly evolving ITP are the same that described in the literature. Patients treated before the beginning of specialised care also had a lower EFS. These data seem to support the current recommendation that rare diseases should be managed in specialised units.

Extreme Phenotypes With Identical Mutations: Two Patients With Same Non-sense NHEJ1 Homozygous Mutation.

Cernunnos/XLF deficiency is a rare primary immunodeficiency classified within the DNA repair defects. Patients present with severe growth retardation, microcephaly, lymphopenia and increased cellular sensitivity to ionizing radiation. Here, we describe two unrelated cases with the same non-sense mutation in the NHEJ1 gene showing significant differences in clinical presentation and immunological profile but a similar DNA repair defect.

Histiocitosis de células de Langerhans / Langerhans cell histiocytosis

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Infecciones por Serratia, ¿debemos pensar en mmunodeficienaas primarias? / Serratia infections, should we think about primary immunodeficiencies?

La enfermedad granulomatosa crónica es una inmunodeficiencia primaria, con una incidencia de 1/200 000-250 000recién nacidos vivos. Afecta, principalmente, a varones; la mayoría de las mutaciones son ligadas al cromosoma X y las formas autosómicas recesivas ocurren, con más frecuencia, en comunidades con mayor número de matrimonios consanguíneos. Se caracteriza por sensibilidad a infecciones recurrentes y graves, bacterianas y fúngicas, con formación de granulomas, debido a la incapacidad de los fagocitos para generar compuestos reactivos de oxígeno, necesarios para la muerte intracelular de microorganismos fagocitados. Se presentan tres casos de enfermedad granulomatosa crónica en los que se aisló Serratia marcescens y, tras una anamnesis minuciosa y obtener resultados de pruebas de funcionalidad de neutrófilos, se llegó a un diagnóstico molecular de la enfermedad. La enfermedad granulomatosa crónica puede manifestarse de formas muy variadas, por lo que el alto índice de sospecha y una buena anamnesis son fundamentales para alcanzar un diagnóstico.

Chronic granulomatous disease (CGD) is a primary immunodeficiency with an incidence of 1/200,000-250,000 live births. CGD affects mainly male patients, most of the mutations being X-linked, and autosomal recessive forms occur more frequently in communities with greater numbers of consanguineous marriages. CGD is characterized by sensitivity to recurrent and severe bacterial and fungal infections, with formation of granulomas due to the inability of phagocytes to generate reactive oxygen compounds, necessary for the intracellular death of phagocytic microorganisms. We report three cases of CGD in which Serratia marcescens was isolated, and after detailed anamnesis and performance of neutrophil function tests, a molecular diagnosis of the disease was reached. CGD can be manifested in a wide variety of ways, so that high suspicion and a meticulous anamnesis are essential to reach a diagnosis.

[Serratia infections, should we think about primary immunodeficiencies?] / Infecciones por serratia, ¿debemos pensar en inmunodeficiencias primarias?

Chronic granulomatous disease (CGD) is a primary immunodeficiency with an incidence of 1/200,000-250,000 live births. CGD affects mainly male patients, most of the mutations being X-linked, and autosomal recessive forms occur more frequently in communities with greater numbers of consanguineous marriages. CGD is characterized by sensitivity to recurrent and severe bacterial and fungal infections, with formation of granulomas due to the inability of phagocytes to generate reactive oxygen compounds, necessary for the intracellular death of phagocytic microorganisms. We report three cases of CGD in which Serratia marcescens was isolated, and after detailed anamnesis and performance of neutrophil function tests, a molecular diagnosis of the disease was reached. CGD can be manifested in a wide variety of ways, so that high suspicion and a meticulous anamnesis are essential to reach a diagnosis.

La enfermedad granulomatosa crónica es una inmunodeficiencia primaria, con una incidencia de 1/200 000-250 000 recién nacidos vivos. Afecta, principalmente, a varones; la mayoría de las mutaciones son ligadas al cromosoma X y las formas autosómicas recesivas ocurren, con más frecuencia, en comunidades con mayor número de matrimonios consanguíneos. Se caracteriza por sensibilidad a infecciones recurrentes y graves, bacterianas y fúngicas, con formación de granulomas, debido a la incapacidad de los fagocitos para generar compuestos reactivos de oxígeno, necesarios para la muerte intracelular de microorganismos fagocitados. Se presentan tres casos de enfermedad granulomatosa crónica en los que se aisló Serratia marcescens y, tras una anamnesis minuciosa y obtener resultados de pruebas de funcionalidad de neutrófilos, se llegó a un diagnóstico molecular de la enfermedad. La enfermedad granulomatosa crónica puede manifestarse de formas muy variadas, por lo que el alto índice de sospecha y una buena anamnesis son fundamentales para alcanzar un diagnóstico.

Anemia arregenerativa en el lactante: 2 casos de smdrome de Pearson / A regenerative anemia in infants: 2 cases of Pearson's syndrome

La anemia es frecuente en lactantes, y, aunque su causa, habitualmente, es banal, debe establecerse un diagnóstico etiológico adecuado. Cuando la anemia es arregenerativa, puede deberse a aplasia medular, síndrome mielodisplásico, infiltración medular o déficits de factores hematopoyéticos. Otra posible causa es el síndrome de Pearson, una rara enfermedad mitocondrial que se presenta con anemia asociada a otras citopenias, insuficiencia pancreática, acidosis láctica y gran variabilidad en su presentación clínica condicionada por la heteroplasmia. Es característico encontrar en el aspirado/biopsia de médula ósea vacuolización de los precursores de serie roja y sideroblastos en anillo. El diagnóstico de certeza se establece mediante el estudio genético del ácido desoxirribonucleico mitocondrial con Southern blot (amplificación completa de ácido desoxirribonucleico mitocondrial mediante reacción en cadena de la polimerasa-largo), que obtiene deleción del 70%-80% de 4977 pb (DNAm 8343-13459). No existe tratamiento curativo y las medidas son de soporte. Es frecuente el fallecimiento en los primeros años de vida. Se presentan dos casos de lactantes con síndrome de Pearson.

Anemia is very common in infants. Although its causes are usually not severe and treatable, proper etiologic diagnosis should be established. When anemia is non-regenerative, it can be caused by aplastic anemia, myelodysplastic syndrome, bone marrow infiltration or hematopoietic factors deficiencies. Another possible cause is Pearson's syndrome, a rare mitochondrial disease that causes non-regenerative anemia associated with other cytopenias, pancreatic insufficiency, lactic acidosis and great variability in clinical presentation conditioned by heteroplasmy. It is characteristic to find in bone marrow studies variable vacuolization in erythroblastic progenitors and ring sideroblasts. The diagnosis is established by genetic study of mitochondrial deoxyribonucleic acid performed by Southern blot analysis (complete mitochondrial deoxyribonucleic acid amplification by polymerase chain reaction -long), obtaining 70-80% deletion of 4977 bp (NMD 8343-13459). There is no curative therapy and support treatment is the only available nowadays. Death is frequent in early years of life. Two cases of infants with Pearson syndrome are presented.

[A regenerative anemia in infants: 2 cases of Pearson´s syndrome]. / Anemia arregenerativa en el lactante: 2 casos de síndrome de Pearson.

Anemia is very common in infants. Although its causes are usually not severe and treatable, proper etiologic diagnosis should be established. When anemia is non-regenerative, it can be caused by aplastic anemia, myelodysplastic syndrome, bone marrow infiltration or hematopoietic factors deficiencies. Another possible cause is Pearson's syndrome, a rare mitochondrial disease that causes non-regenerative anemia associated with other cytopenias, pancreatic insufficiency, lactic acidosis and great variability in clinical presentation conditioned by heteroplasmy. It is characteristic to find in bone marrow studies variable vacuolization in erythroblastic progenitors and ring sideroblasts. The diagnosis is established by genetic study of mitochondrial deoxyribonucleic acid performed by Southern blot analysis (complete mitochondrial deoxyribonucleic acid amplification by polymerase chain reaction -long), obtaining 70-80% deletion of 4977 bp (NMD 8343-13459). There is no curative therapy and support treatment is the only available nowadays. Death is frequent in early years of life.

La anemia es frecuente en lactantes, y, aunque su causa, habitualmente, es banal, debe establecerse un diagnóstico etiológico adecuado. Cuando la anemia es arregenerativa, puede deberse a aplasia medular, síndrome mielodisplásico, infiltración medular o déficits de factores hematopoyéticos. Otra posible causa es el síndrome de Pearson, una rara enfermedad mitocondrial que se presenta con anemia asociada a otras citopenias, insuficiencia pancreática, acidosis láctica y gran variabilidad en su presentación clínica condicionada por la heteroplasmia. Es característico encontrar en el aspirado/biopsia de médula ósea vacuolización de los precursores de serie roja y sideroblastos en anillo. El diagnóstico de certeza se establece mediante el estudio genético del ácido desoxirribonucleico mitocondrial con Southern blot (amplificación completa de ácido desoxirribonucleico mitocondrial mediante reacción en cadena de la polimerasa-largo), que obtiene deleción del 70%-80% de 4977 pb (DNAm 8343-13459). No existe tratamiento curativo y las medidas son de soporte. Es frecuente el fallecimiento en los primeros años de vida. Se presentan dos casos de lactantes con síndrome de Pearson

[Sepsis due to Pseudomona as a debut of a primary immunodeficiency in a child]. / Sepsis por Pseudomona como forma de debut de inmunodeficiencia primaria en un niño.

X-linked agammaglobulinemia is a primary humoral immunodeficiency. It is a recessive X-linked disorder characterized by low or absent circulating mature B cells, hypo/agammaglobulinemia and no humoral response to immunizations due to mutations along chromosome X. It is characterized by severe, recurrent and difficult treatment infections. It is diagnosed in the first 6 months of life in children; the only sign of alarm is the absent or decreased size of tonsils and lymph nodes, but it is not always present. The main cornerstones of treatment are immunoglobulin replacement therapy to maintain serum levels above 500-700 mg/dl and infection control; this allows these patients to do their day-to-day activities. We report a 2 year old boy with X-linked agammaglobulinemia, with no history of interest, who presented with P. aeruginosa sepsis. He had an excellent clinical improvement without further important infections after intravenous immunoglobulin replacement therapy.

La agammaglobulinemia ligada al X es una inmunodeficiencia humoral primaria, recesiva y ligada al cromosoma X, en la que existe una disminución marcada de linfocitos B maduros, hipo-/agammaglobulinemia y escasa respuesta humoral a las inmunizaciones, debido a mutaciones en el brazo largo del cromosoma X. Se caracteriza por infecciones graves, recurrentes y difíciles de tratar, que ocurren, generalmente, a partir de los 6 meses. El único signo de alarma, no siempre presente, es la ausencia o disminución del tamaño de las amígdalas y los ganglios linfáticos. El tratamiento de elección es el sustitutivo con inmunoglobulina G intravenosa para mantener niveles séricos por encima de 500-700 mg/dl y el control de las infecciones, lo que permite que estos pacientes hagan sus tareas habituales. Se presenta un niño de 2 años sin antecedentes personales ni familiares relevantes diagnosticado con agammaglobulinemia ligada al X tras una sepsis por P. aeruginosa. Tuvo una evolución clínica adecuada sin nuevos episodios infecciosos importantes tras el inicio del tratamiento sustitutivo con inmunoglobulina G intravenosa mensual.

Pancitopenia inducida por azatioprina: Casos clínicos / Azathioprine-induced pancytopenia: Case series

La azatioprina es un fármaco inmunosupresor que ha demostrado efectividad en el tratamiento de la enfermedad inflamatoria intestinal. Su metabolito, la 6-mercaptopurina, es metaboliza-do a través de la tiopurina metiltransferasa. Los pacientes con baja actividad enzimática pueden presentar mayores efectos secundarios. El más frecuente es la leucopenia. Más raramente, aparece mielotoxicidad en forma de pancitopenia. La monitori-zación de la actividad de la tiopurina metiltransferasa permite obtener un perfil individualizado de la actividad enzimática, pero no debe reemplazar la monitorización mediante la realización de hemogramas seriados. Ante un paciente con neutropenia grave y fiebre, debe iniciarse un tratamiento antibiótico empírico precoz para evitar infecciones graves y diseminadas. Se presentan dos casos con esta complicación.

Azathioprine is an immunosuppressive drug that has shown effectiveness in inflammatory bowel disease treatment. Its metabolite, 6-mercaptopurine, is metabolized through thiopurine methyltransferase. Patients with low enzyme activity may have more frequent and severe side effects. The most common is leukopenia, and rarely pancytopenia. The thiopurine methyltransferase activity monitoring shows an individualized profile of enzymatic activity but it should not replace monitoring by performing serial blood counts. In patients with fever and severe neutropenia, early empirical antibiotic treatment should be initiated to prevent severe and disseminated infection. Two patients with this condition are reported.

[Azathioprine-induced pancytopenia: case series]. / Pancitopenia inducida por azatioprina: casos clínicos.

Azathioprine is an immunosuppressive drug that has shown effectiveness in inflammatory bowel disease treatment. Its metabolite, 6-mercaptopurine, is metabolized through thiopurine methyltransferase. Patients with low enzyme activity may have more frequent and severe side effects. The most common is leukopenia, and rarely pancytopenia. The thiopurine methyltransferase activity monitoring shows an individualized profile of enzymatic activity but it should not replace monitoring by performing serial blood counts. In patients with fever and severe neutropenia, early empirical antibiotic treatment should be initiated to prevent severe and disseminated infection. Two patients with this condition are reported.

La azatioprina es un fármaco inmunosupresor que ha demostrado efectividad en el tratamiento de la enfermedad inflamatoria intestinal. Su metabolito, la 6-mercaptopurina, es metaboliza-do a través de la tiopurina metiltransferasa. Los pacientes con baja actividad enzimática pueden presentar mayores efectos secundarios. El más frecuente es la leucopenia. Más raramente, aparece mielotoxicidad en forma de pancitopenia. La monitori-zación de la actividad de la tiopurina metiltransferasa permite obtener un perfil individualizado de la actividad enzimática, pero no debe reemplazar la monitorización mediante la realización de hemogramas seriados. Ante un paciente con neutropenia grave y fiebre, debe iniciarse un tratamiento antibiótico empírico precoz para evitar infecciones graves y diseminadas. Se presentan dos casos con esta complicación.

Combination of a triple alpha-globin gene with beta-thalassemia in a gypsy family: importance of the genetic testing in the diagnosis and search for a donor for bone marrow transplantation for one of their children.

BACKGROUND: The simultaneous presence of a heterozygous ß-thalassemia with α-gene triplication may cause anything from a thalassemia trait to thalassemia intermedia of mild to moderate severity. CASE PRESENTATION: An 8-month-old ethnic Gypsy male infant with failure to thrive from birth, mild jaundice and splenomegaly. Clinical signs were compatible with severe microcytic anemia requiring bi-monthly blood transfusions. The ß-thalassemia gene analysis found homozygous mutation IVS-I-110 (G>A) (c.93-21G>A) in intron 1 of the hemoglobin beta globin gene and a non-pathogenic sequence variant (single nucleotide polimorfism (SNP) Rs1609812). In addition, the patient had α gene triplication (ααα(anti 3.7)/αα) caused by double heterozygosity for a 3.7 kb fragment that contained only the hemoglobin alpha globin gene-2 gene. This finding led to screening and follow up in first-degree relatives, twin brothers and a sister and parents to provide them with appropriate genetic counseling. Nowadays, new horizons could open a new therapeutic management until definitive cure of these diseases through gene therapy or mutation-specific genome editing. CONCLUSIONS: Genetic testing can provide an early diagnosis and facilitates the search for a suitable donor for transplantation.