Inmunodeficiencia combinada grave: Presentación de un caso / Severe Combined Immunodeficiency: Case presentation

Introducción: Las inmunodeficiencias primarias son un grupo heterogéneo de trastornos hereditarios ocasionados por defectos del desarrollo o función del sistema inmunológico. Las inmunodeficiencias combinadas graves constituyen el 15 por ciento de las inmunodeficiencias primarias, son graves y los pacientes rara vez sobreviven sin tratamiento después del primer año de vida, lo que obliga a un diagnóstico y tratamiento oportuno. Objetivo: Presentar un caso con inmunodeficiencia combinada grave, condición reportada con poca frecuencia y evolución desfavorable. Presentación de caso: Lactante masculino de seis meses con antecedentes de cuatro ingresos en Unidad de Terapia Intensiva por infecciones, el último por bronconeumonía bilateral. Fue valorado por Inmunología y se diagnosticó una inmunodeficiencia combinada grave por la clínica (infecciones por gérmenes oportunistas: Candida albicans y Pneumocistys jirovecii) y estudios inmunológicos (con disminución de los anticuerpos IgG: 0,02 g/L, IgM: 0.1 g/L e IgA: 0 g/L), subpoblaciones linfocitarias disminuidas (CD3/CD4: 9,3 por ciento, CD3/CD8: 5,6 por ciento, CD19: 0 por ciento, CD 16: 0,73 por ciento), además hipoplasia tímica severa (120 mm2). Se inició tratamiento con antimicrobianos de amplio espectro e inmunoestimulantes (Hebertrans y Biomodulina T). Evolucionó desfavorablemente y falleció por shock séptico. Conclusiones: La inmunodeficiencia combinada grave es una emergencia pediátrica que debe tenerse en cuenta en pacientes con antecedentes de infecciones recurrentes, es vital conocer las manifestaciones clínicas tempranas que permitan la sospecha diagnóstica, haciendo uso de todas las herramientas disponibles para su confirmación. El diagnóstico precoz es el elemento clave para la reducción de la morbilidad y mortalidad relacionada con estas enfermedades(AU)

Introduction: Primary Immunodeficiencies are a heterogeneous group of inherited disorders caused by defects in development or function of the immune system. Severe Combined Immunodeficiencies constitute 15% of the primary immunodeficiencies, they are acute and patients rarely survive without treatment after the first year of life, requiring a quick diagnosis and treatment. Objective: To present a case on Severe Combined Immunodeficiency, a condition infrequently reported and with unfavorable evolution. Case presentation: Six-month-old male infant with a history of four admissions to the Intensive Care Unit due to infections, in the latter one due to bilateral bronchopneumonia. He was evaluated by Immunology and a Severe Combined Immunodeficiency was diagnosed by the clinic (infections by opportunistic germs: Candida albicans and Pneumocistys jirovecii) and immunological studies (with a decrease in IgG antibodies: 0.02 g/L, IgM: 0.1 g/L and IgA: 0 g/L), decreased lymphocyte subpopulations (CD3/CD4: 9.3 percent, CD3/CD8: 5.6 percent, CD19: 0 percent, CD 16: 0.73 percent), in addition to severe thymic hypoplasia (120 mm2). Treatment with broad spectrum antimicrobials and immunostimulants (Hebertrans and Biomodulin T) was started. He evolved unfavorably and died of septic shock. Conclusions: Severe Combined Immunodeficiency is a pediatric emergency that must be taken into account in patients with a history of recurrent infections, it is vital to know the early clinical manifestations that allow a suspected diagnosis, making use of all the available tools for its confirmation. Early diagnosis is the key element in reducing morbidity and mortality related to these diseases(AU)

Aproximación diagnóstica ultrasonográfica prenatal al síndrome de Omenn: reporte de caso / Prenatal ultrasound diagnostic approach to Omenn syndrome: case report

Objetivo: reportar el caso de una gestante con diagnóstico ultrasonográfico de alteración del sistema tegumentario fetal y diagnóstico posnatal de síndrome de Omenn. Presentación de caso: se presenta el caso de paciente de 27 años con embarazo de 31 semanas, con exploración ultrasonográfica prenatal que evidencia feto con edema significativo del cuero cabelludo, líquido amniótico ecogénico y descamación de la piel abdominal, con aproximación diagnóstica ultrasonográfica de variante de ictiosis. El recién nacido presentó eritrodermia congénita complicada con infección de piel, con posterior choque séptico y muerte. El estudio genético y patológico concluye síndrome de Omenn. Conclusión: el síndrome de Omenn debe ser tomado en cuenta en los diagnósticos diferenciales cuando en la ultrasonografía prenatal existan hallazgos ultrasongráficos de una alteración del sistema tegumentario. Se requieren estudios que evalúen la exactitud del ultrasonido en el diagnóstico antenatal de las eritrodermias.

Objective: To report the case of a pregnant woman with ultrasound diagnosis of altered fetal tegumental system and postnatal diagnosis of Omenn syndrome. Case presentation: A 27-year-old patient who presented at 31 weeks of gestation with prenatal ultrasound evidence of a fetus with significant scalp edema, echogenic amniotic fluid and scaly abdominal skin, with ichtyosis variant impression on diagnostic ultrasound. The baby was born with congenital erythroderma complicated with skin infection, and later developed septic shock and died. The genetic and pathologic workup led to the conclusion of Omenn syndrome. Conclusion: Omenn syndrome must be considered as part of the differential diagnoses when prenatal ultrasound shows findings of altered tegument system. Studies are required to assess the accuracy of ultrasound for prenatal diagnosis of erythroderma.

Supervivenciade pacientes pediátricos con inmunodeficiencias primarias en un hospital público del occidente de México / Survival of pediatric patients with primary immunodeficiencies in a public hospital in western Mexico

Se presenta una serie de casos de inmunodeficiencias primarias y se describen las variables asociadas a supervivencia en pacientes ≤ 16 años. Los diagnósticos fueron acordes a los criterios de la Unión Internacional de las Sociedades de Inmunología. Se realizó un análisis de supervivencia mediante curvas de Kaplan-Meier.Entre los años 2004 y 2019, se diagnosticaron 40 pacientes con inmunodeficiencias primarias. Las más frecuentes fueron inmunodeficiencias que afectaban la inmunidad celular y humoral, el 32,5 %, y deficiencias predominantemente de anticuerpos, el 32,5 %. La mediana de edad al inicio de los síntomas y al momento del diagnóstico fue de 3,01 y 10,4 meses, respectivamente. Fallecieron el 35 % y el riesgo fue mayor en pacientes con inmunodeficiencias que afectaban la inmunidad celular y humoral y en quienes presentaron manifestaciones clínicas y tuvieron el diagnóstico en los primeros seis meses de vida.

A case series of primary immunodeficiencies is presented and outcome measures associated with survival among patients ≤ 16 years old are described. Diagnoses were made based on the criteria by the International Union of Immunological Societies. Survival was analyzed using Kaplan-Meier curves.Between 2004 and 2019, 40 patients were diagnosed with primary immunodeficiencies. The most common were immunodeficiencies affecting humoral and cell-mediated immunity (32.5 %) and predominantly antibody deficiencies (32.5 %). The median age at the onset of symptoms and at the time of diagnosis was 3.01 and 10.4 months, respectively. Thirty-five percent of patients died, and the risk was higher among those with immunodeficiencies affecting humoral and cell-mediated immunity and those who developed clinical manifestations and were diagnosed in the first 6 months of life

Inmunodeficiencia Combinada Severa, reporte de pacientes chilenos diagnosticados durante el período 1999-2020 / Severe combined immunodeficiency, report of Chilean patients diagnosed during the 1999-2020 period

INTRODUCCIÓN: La inmunodeficiencia combinada severa (IDCS) corresponde a una de las formas más graves de inmunodeficiencia primaria, existiendo escasos datos nacionales sobre ésta. OBJETIVO: describir la epidemiología, complicaciones, pronóstico y uso de la vacuna BCG en pacientes chilenos con IDCS. PACIENTES Y MÉTODO: Estudio retrospectivo de pacientes diagnosticados con IDCS entre los años 1999 y 2020 por médicos inmunólogos a lo largo de Chile. El diagnóstico de IDCS se realizó conforme a los criterios propuestos por Shearer: linfocitos T (CD3+) < 300 células/μL y prolife ración 10% del límite de normalidad en respuesta a fitohemaglutinina o presencia de linfocitos T de origen materno. Se obtuvieron de la ficha clínica los datos correspondientes a: sexo, edad al diagnóstico, consanguinidad, región de origen, subpoblaciones linfocitarias, diagnóstico genético, complicaciones infecciosas y no infecciosas, vacunación BCG y sus complicaciones, edad de deriva ción al centro de TPH y causa de mortalidad no relacionada al TPH. RESULTADOS: se diagnosticaron 25 casos de IDCS en 22 familias entre los años 1999-2020. 78% varones, la edad media a la primera manifestación fue 2.3 meses (0-7), mientras que la edad media al diagnóstico fue de 3.4 meses (0 7). Un 16% de los casos tenía un antecedente familiar de IDCS. Un 40% de los casos fueron diag nosticados en la Región Metropolitana. El inmunofenotipo más frecuente fue T-B-NK+ (48%). Se realizaron estudios genéticos en 69,5% de los casos, siendo los defectos genéticos en RAG2 (39%) la causa más frecuente. Un 88% de los casos recibió la vacuna Bacillus Calmette-Guerin (BCG) previo al diagnóstico, incluidos 2 pacientes con historia familiar positiva, 36% de los vacunados experimentó complicaciones de la BCG. La edad media a la derivación a trasplante fue de 7,4 meses (5-16). De los 25 pacientes, 11 fallecieron previo a la derivación a un centro de trasplante. CONCLUSIÓN: En Chile existe un retraso clínicamente significativo entre las primeras manifestaciones y el diagnóstico de IDCS, así como un importante retraso en la derivación a centros de trasplante. La mayoría de los pacientes con IDCS reciben la vacuna BCG, pese a tener antecedentes familiares, y experimentan frecuentemente complicaciones de la vacuna.

INTRODUCTION: Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiency. To date, there is little local information about this disease. OBJECTIVE: To describe the epidemiology, complications, prognosis, and use of the BCG vaccine in Chilean patients with SCID. PATIENTS AND METHOD: Retrospective review of the clinical records of patients diagnosed with SCID by clinical immunologists between 1999 and 2020 throughout Chile. SCID was diagnosed according to the cri teria proposed by Shearer: T lymphocytes (CD3+) < 300 cells/μL and proliferation 10% of the limit of normality in response to phytohemagglutinin or presence of T lymphocytes of maternal origin. Data collected from the clinical records were: sex, age at diagnosis, consanguinity, region of origin, lymphocyte subpopulations, genetic diagnosis, infectious and non-infectious complications, BCG vaccination and its complications, age at referral to the bone marrow transplant (BMT) center, and cause of non-BMT-related mortality. RESULTS: Between 1999 and 2020, 25 patients were diagnosed with SCID. 78% of them were male, mean age at first manifestation of the disease was 2.3 months (0-7), while the mean age at diagnosis was 3.4 months (0-7). 16% of patients had a family history of SCID. 40% of cases were diagnosed within the Metropolitan Region. The most frequent immuno- phenotype was T-B-NK+ SCID (48%). Genetic studies were done in 69.5% of cases, mutations in the RAG2 gene were the most common etiology of SCID (39%). 88% of SCID patients received the Bacillus Calmette-Guerin (BCG) vaccine before diagnosis, including 2 cases with a known family history of SCID. 36% of those who received the vaccine had BCG-related complications. The mean age at referral to a bone marrow transplant center was 7.4 months (5-16). 11/25 patients died before being transferred to a transplant center. DISCUSSION: There is a clinically significant delay between the first manifestations and the diagnosis of SCID in Chilean patients, as well as an important time gap between the diagnosis of SCID and referral to a center for BMT. Most SCID cases in Chile receive the BCG vaccine, despite a known family history of the disease, and frequently develop vaccine-related complications.

Inmunodeficiencia combinada severa: es tiempo de su detección precoz / Severe combined immunodeficiency: the time for newborn screening has come

Las inmunodeficiencias primarias (IDP) son un conjunto de cerca de 350 enfermedades genéticas que afectan el funcionamiento del sistema inmunológico. Los avances en diagnóstico genético han permitido describir nuevos defectos en el sistema inmune, ampliando el espectro de manifestaciones de las IDP más allá de la susceptibilidad a infecciones. Aunque la mayoría de las IDP se presentan con infecciones recurrentes u oportunistas, un subgrupo puede presentarse por el desarrollo precoz de fenómenos autoinflamatorios, tumorales y, paradojalmente, la coexistencia de autoinmunidad e inmunodeficiencia en un mismo paciente. Al igual que sus manifestaciones clínicas, la severidad de las IDP es variable. La inmunodeficiencia combinada severa (IDCS), caracterizada por una falla en la respuesta humoral y celular, es una de las formas más graves de IDP y el único tratamiento curativo disponible en Latino-América es el trasplante de precursores hematopoyéticos. La IDCS es 100% letal durante los dos primeros años de vida si no se diagnostica y trata oportunamente. Por el contrario, si se trasplantan precozmente, estos pacientes pueden alcanzar una sobrevida normal. Pese a los avan ces en el diagnóstico de IDP que se han observado en nuestro país en los últimos años, los recursos diagnósticos no se encuentran disponibles en todas las regiones, lo que dificulta el reconocimiento temprano de la IDCS y otras IDP en grandes áreas del país. El objetivo de esta actualización es revisar conceptos generales sobre la fisiopatología de la IDCS, diagnóstico, manejo inicial y plantear la nece sidad de la implementación del tamizaje neonatal de IDCS en Chile.

Primary immunodeficiencies (PIDs) are a set of about 350 genetic disorders that affect the normal function of the immune system. Advances in genetic diagnosis have allowed the description of new defects in the immune system, broadening the clinical spectrum of PIDs' manifestations beyond susceptibility to infection. Although most PIDs present with recurrent or opportunistic infections, a subgroup of them may be recognized by the early development of auto-inflammatory events, tumors and, paradoxically, the coexistence of autoimmunity and immunodeficiency in the same patient. As their clinical manifestations, the severity of PIDs is highly variable. Severe combined immunodefi ciency (SCID), a PID that affects cellular and humoral immunity, is one of the most severe forms of PIDs and the only available curative treatment in Latin America is hematopoietic stem cells trans plantation. All patients affected by SCID die during the first two years of life if they are not diagnosed and treated opportunely. In contrast, early transplantation of patients with SCID can lead to excellent survival outcomes. Despite recent advances in the diagnosis of PIDs in Chile, diagnostic resources are not available throughout the country, making the early diagnosis of SCID and other forms of PID difficult in big areas of Chile. The objective of this article is to review general concepts on the patho physiology, diagnosis, and initial management of SCID and raise the need for the implementation of neonatal screening for SCID in Chile.

Vacunación BCG e inmunodeficiencias primarias: ¿es momento de un cambio? / BCG vaccine administration schedule and primary immunodeficiencies: Is it time for a change?

Resumen: Los pacientes con Inmunodeficiencias primarias (IDP) tienen un riesgo elevado de complicaciones severas por la vacuna BCG, incluso mortalidad. Es necesario evaluar periódicamente el riesgo versus beneficio de la vacunación universal BCG en el periodo neonatal. Chile es un país con baja incidencia de tuberculosis (TB) pero cuya epidemiología ha cambiado recientemente con un aumento de los casos. Cambios en esquemas de vacunación BCG en países con incidencias mayores o similares de TB y con coberturas de vacunación menores han sido posibles sin aumento de los casos graves de TB que son los que previene la BCG. El cambio ha evitado complicaciones graves en pacientes con IDP. Creemos que un análisis crítico de la fecha de vacunación BCG debe realizarse hoy en Chile. Más aún dada la posibilidad técnica de realizar screening neonatal de IDP.

Abstract: Patients with Primary Immunodeficiencies (PID) are at a higher risk of developing severe morbidities and mortality due to the administration of BCG vaccine. Risk-to-benefit of universal BCG vaccina tion of newborns must be assessed periodically. Chile has a low incidence of tuberculosis (TB) but the local epidemiology has recently changed with an increase of TB cases. Changes in the BCG vaccine schedule have been made in countries with similar or higher TB incidences and lower BCG vaccine coverage, with no increase in the severe TB cases, which are prevented by BCG. These changes have prevented serious complications in PID patients. We propose a critical analysis of the BCG adminis tration date in Chile due to the technical possibility of performing neonatal PID screening.

Inmunodeficiencia combinada severa (SCID) en Neiva, Colombia. Reporte de caso / Severe combined immunodeficiency (SCID) in Neiva, Colombia: Case Report

Resumen Introducción. Las inmunodeficiencias primarias son enfermedades genéticas del sistema inmune que incrementan la susceptibilidad a infecciones. Una de las formas más graves en niños es la inmunodeficiencia combinada severa. Presentación del caso. Se presenta el caso de un niño que fue diagnosticado con inmunodeficiencia combinada severa; este era un paciente masculino de ocho meses que presentó cuadro clínico consistente en múltiples hospitalizaciones debido a infección por citomegalovirus, endocarditis por Candida albicans e infección recurrente de las vías urinarias por Pseudomonas aeruginosa. El perfil inmunológico mostró disminución del número absoluto de células CD3+ y CD19+, lo que permitió realizar el diagnóstico de inmunodeficiencia combinada severa instaurándose manejo; sin embargo, el niño no se recuperó y falleció. Conclusiones. Las inmunodeficiencias primarias son patologías que requieren una intervención oportuna que permita brindar un mejor pronóstico a los pacientes.

Abstract Introduction: Primary immunodeficiencies are genetic disorders of the immune system that increase susceptibility to infections. One of the most serious forms in children is severe combined immunodeficiency. Case presentation: This is the report of the case of an 8-monthold male patient who was diagnosed with severe combined immunodeficiency. The child presented a clinical profile consisting of multiple hospitalizations due to cytomegalovirus infection, endocarditis by Candida albicans and recurrent urinary tract infection by Pseudomonas aeruginosa. The immune profile showed a decrease in the absolute number of CD3+ and CD19+ cells, which led to the diagnosis of severe combined immunodeficiency. Even though management was established, the child did not recover and died. Conclusions: The primary immunodeficiencies are disorders that require timely intervention to provide a better prognosis to patients.

Infección diseminada por Bacilo Calmette-Guérin en un lactante con inmunodeficiencia: reporte de caso / Disseminated infection by Bacillus Calmette-Guérin in an immunodeficient infant: case report

RESUMEN La vacuna Bacillus Calmette-Guerin (BCG) que se administra a los recién nacidos de países con alta incidencia de tuberculosis puede ocasionar reacciones locales hasta infección diseminada en pacientes inmunocomprometidos. Reportamos el caso de un lactante varón de seis meses con antecedente de haber recibido vacuna BCG al nacer, y presentar cuadros infecciosos a repetición, nódulos violáceos blandos en tronco y extremidades con presencia de bacilos ácido alcohol resistentes (BARR) en la histopatología y en cultivo de piel; el estudio molecular reportó la presencia de Micobacterium bovis BCG. En la tomografía se observó opacidades intersticiales en pulmones y en el lavado gástrico se identificó BAAR. El estudio genético del paciente y de la madre reveló la presencia de mutación en el gen IL2RG confirmando el diagnóstico de inmunodeficiencia combinada severa, recibe tratamiento con inmunoglubolina humana y esquema antituberculosis con isoniacida, rifampicina y etambutol. Presentamos el caso por la implicancia en el pronóstico de vida de estos pacientes y por la necesidad de un diagnóstico preciso y oportuno.

ABSTRACT The Bacillus Calmette-Guerin (BCG) vaccine given to newborns in countries with a high incidence of tuberculosis may cause local reactions up to disseminated infection in immunocompromised patients. We report the case of a six-monthold male infant with a history of having received the BCG vaccine at birth, and presenting repeated infectious, soft violet nodules in the trunk and extremities with the presence of acid-alcohol-resistant bacilli (BAAR) in histopathology and skin culture; the molecular study reported the presence of Mycobacterium bovis BCG. In the tomography, interstitial opacities were observed in the lungs and in the gastric lavage BAAR was identified. The genetic study of the patient and the mother revealed the presence of a mutation in the IL2RG gene confirming the diagnosis of severe combined immunodeficiency. Received treatment with human immunoglobulin and anti-tuberculosis scheme with isoniazid, rifampicin, and ethambutol. We present the case because of the implication in the life prognosis of these patients and because of the need for an accurate and timely diagnosis

ORAI1 variation induced combined immunodeficiency: a case report and literature review / 中华儿科杂志

Objective@#To summarize the clinical manifestations and gene variations of combined immunodeficiency caused by ORAI1 variation with a case report and literature review.@*Methods@#The clinical data of the patient who was diagnosed with ORAI1 variation caused combined immunodeficiency in the Department of Pediatrics in Xiangya Hospital of Central South University in February 2018 were extracted and analyzed. The literature till August 2018 was searched with key words of 'ORAI1', and 'immunodeficiency' in both English and Chinese in the database of China national knowledge infrast ructure (CNKI), Wanfang and Pubmed.@*Results@#The patient was a 15 months old girl with acute onset of bilateral ptosis after upper respiratory tract infection, which was rapidly progressed to systemic myasthenia and accompanied with recurrent respiratory tract infection during the treatment. The patient poorly to responded immunomodulatory therapy and anti-infection therapy. Laboratory tests demonstrated decreased complement C3 and NK cell (CD3-CD56+), increased anti-thyroglobulin, thyroid peroxidase antibody and B lymphocyte (CD3-CD19+), and slightly increased anti-acetylcholine receptor antibody. Genetic analysis showed the homozygous variation of ORAI1 gene exon l c.12 G>T (p.E4D), with heterozygostty of both parents. There were only 4 papers reporting this disease in the literature review. A total of 7 patients with ORAI1 gene variation were reported, including 3 homozygous variations, 2 heterozygous variations and 2 complex heterozygous variations. The clinical manifestations included early onset recurrent infection, congenital hypotonia, elevated serum IgA and IgM, decreased NK cells, and family history of hereditary diseases. Four of the 7 reported cases died of pulmonary infection and sepsis, and the other 3 survived with low muscular tone and poor self-care ability.@*Conclusions@#The most common clinical manifestations of ORAI1 variation caused combined immunodeficiency are recurrent infection and congenital hypotonia. Myasthenia induced recurrent respiratory tract infection is an important factor of poor prognosis in severe patients. There is a lack of effective treatment for this disease, and the prognosis is poor.

An Infant with Respiratory Distress and Loose Stools

We present the case of a 3-month-old girl who was admitted with complaints of loose stools and respiratory distress. She also had ahistory of rash and alopecia. Laboratory investigations revealed lymphopenia with reduced immunoglobulin G and immunoglobulin A.Lymphocyte subset analysis by flow cytometry revealed T-B+NK+ severe combined immunodeficiency (SCID). She died due to severepneumonia, shock and pulmonary hemorrhage. Autopsy findings revealed disseminated cytomegalovirus infection in the lung, liver,adrenals and heart. Thymus was found to be dysplastic and showed characteristic histopathologic features of SCID.

Combined immunodeficiency / 中华实用儿科临床杂志

Combined immunodeficiency (CID) is categorized to the first classification from the international union of immunological societies expert committee for primary immunodeficiency.Severe combined immunodeficiency (SCID) is the most fatal disorder for paediatric clinical operation.Without hematopoietic stem cell transplantation,almost all infants would die before 1 year old,few could survive beyond 2 years old.Hypomorphic mutations in SCID genes can lead to atypical phenotypes.The two special SCID should be focused,Omenn syndrome and graft-versus-host disease,which are caused by expension of autologous and maternal activated and memory T lymphocytes,respectively.Patients with radiosensitive-CID usually present later on life,for whom treatment should be monitored carefully.CID caused by T cells with normal development and inborn error was hotspot research field for example zeta chain-associated protein 70 kDa deficiency.More attention should be paid to CID associated with syndromes for example dedicator of cytokinesis 8 deficiency.Now,the pathogenesis,molecular,clinical,laboratory features and treatment and prognosis are described,in order to support clues for paediatrician's clinical practice.

Diagnosis and treatment of atypical severe combined immunodeficiency disease in 7 children / 临床儿科杂志

Objective To explore the diagnosis and treatment of atypical severe combined immunodeficiency disease (SCID). Methods The clinical data of atypical SCID in 7 children with IL2RG,JAK3,and RAG1 mutations were reviewed and analyzed from September 2012 to June 2017. Results In 7 cases (6 males and 1 female), there were 5 infants, 1 toddler and 1 school-age child. Cases 2, 4, and 6 were classic SCID clinical phenotypes. Cases 1, 3, 5, 7 were atypical SCID clinical phenotypes. Case 6 were diagnosed with Omenn syndrome. Cases 2, 5 were classic SCID immune phenotypes, cases 1, 3, 4, 6, 7 were atypical SCID immune phenotypes, and case 1 had maternal chimera. The next generation sequencing indicated that case 1 had a compound heterozygous JAK3 mutation with c.3097-1G>A/c.946-950GCGGA>ACinsGGT.Cases 2,3,and 4 had IL2RG mutations,with c.865C>T/p.R289X,c.664C>T/R222C,52delG,respectively.Case 5 had JAK3 mutations with c.2150A>G/p.E717G and c.1915-2A>G.Sanger sequencing indicated that case 6 had a RAG1 mutation of complex heterozygosity with c.994C>T/p.R332X and c.1439G>A/p.S480N. Case 7 had homozygous RAG1 mutation with c.2095C>T/p.R699W.Conclusion Under certain conditions,gene mutation can lead to atypical clinical and/or immune phenotypic SCID.

Clinical analysis of 10 cases of severe combined immunodeficiency disease / 中国小儿急救医学

Objective To improve the pediatrician's understanding of severe combined immunodefi-ciency disease (SCID),so as to strengthen the early diagnosis and treatment of SCID. Methods The clinical manifestations,related immunological findings,imaging findings and outcomes of 10 SCID children admitted to our hospital from 2007 to 2018 were retrospectively analyzed. Results The clinical manifestations of primary SCID were frequent infections shortly after birth. There were 8 males and 2 females in this study. The average age of onset was 4. 2 months,and the average age of diagnosis was 6 months. Eight cases of thymus shadow were absent,9 cases of pulmonary CT showed severe pneumonia,and 3 cases of pulmonary fungal infection. Six of 7 children died of infection and the age of death was less than 1 year old. Laboratory exami-nation showed that 10 patients had abnormal cell and humoral immune function;10 cases of CD3 +T cells were <20%,3 cases of CD16 +CD56 +( NK%) >85%,7 cases ≤ 2%. There was an increase in B cell reactivity of 7 cases,but the secretion of immunoglobulin in 5 cases was significantly reduced. Seven cases of IgG<2. 0 g/L,3 cases>2. 0 g/L. Eight cases were confirmed of the primary SCID by genetic testing. Con-clusion The clinical manifestations of SCID are frequent bacterial,viral and fungal infections in a short time after birth. In clinical work,when small infants are repeatedly infected after birth,or multiple sites are serious-ly infected and prolonged,we must think of the possibility of SCID and timely related immune function tests, strive to achieve early diagnosis,timely treatment,and early bone marrow stem cell transplantation.

TRIAGEM NEONATAL DE IMUNODEFICIÊNCIAS GRAVES COMBINADAS POR MEIO DE TRECS E KRECS: SEGUNDO ESTUDO PILOTO NO BRASIL / NEWBORN SCREENING FOR SEVERE COMBINED IMMUNODEFICIENCIES USING TRECS AND KRECS: SECOND PILOT STUDY IN BRAZIL

RESUMO Objetivo: Validar a quantificação de T-cell receptor excision circles (TRECs) e kappa-deleting recombination circles (KRECs) por reação em cadeia de polimerase (polymerase chain reaction, PCR) em tempo real (qRT-PCR), para triagem neonatal de imunodeficiências primárias que cursam com defeitos nas células T e/ou B no Brasil. Métodos: Amostras de sangue de recém-nascidos (RN) e controles foram coletadas em papel-filtro. O DNA foi extraído e os TRECs e KRECs foram quantificados por reação duplex de qRT-PCR. O valor de corte foi determinado pela análise de Receiver Operating Characteristics Curve, utilizando-se o programa Statistical Package for the Social Sciences (SSPS) (IBM®, Armonk, NY, EUA). Resultados: 6.881 amostras de RN foram analisadas quanto à concentração de TRECs e KRECs. Os valores de TRECs variaram entre 1 e 1.006 TRECs/µL, com média e mediana de 160 e 139 TRECs/µL, respectivamente. Três amostras de pacientes diagnosticados com imunodeficiência grave combinada (severe combined immunodeficiency, SCID) apresentaram valores de TRECs abaixo de 4/µL e um paciente com Síndrome de DiGeorge apresentou TRECs indetectáveis. Os valores de KRECs encontraram-se entre 10 e 1.097 KRECs/µL, com média e mediana de 130 e 108 KRECs/µL, e quatro pacientes com diagnóstico de agamaglobulinemia tiveram resultados abaixo de 4 KRECs/µL. Os valores de corte encontrados foram 15 TRECs/µL e 14 KRECs/µL, e foram estabelecidos de acordo com a análise da Receiver Operating Characteristics Curve, com sensibilidade de 100% para detecção de SCID e agamaglobulinemia, respectivamente. Conclusões: A quantificação de TRECs e KRECs foi capaz de diagnosticar crianças com linfopenias T e/ou B em nosso estudo, validando a técnica e dando o primeiro passo para a implementação da triagem neonatal em grande escala no Brasil.

ABSTRACT Objective: To validate the quantification of T-cell receptor excision circles (TRECs) and kappa-deleting recombination excision circles (KRECs) by real-time polymerase chain reaction (qRT-PCR) for newborn screening of primary immunodeficiencies with defects in T and/or B cells in Brazil. Methods: Blood samples from newborns and controls were collected on filter paper. DNA was extracted and TRECs, and KRECs were quantified by a duplex real-time PCR. The cutoff values were determined by receiver operating characteristic curve analysis using SPSS software (IBM®, Armonk, NY, USA). Results: Around 6,881 samples from newborns were collected and TRECs and KRECs were quantified. The TRECs values ranged between 1 and 1,006 TRECs/µL, with mean and median of 160 and 139 TRECs/µL, respectively. Three samples from patients with severe combined immunodeficiency (SCID) showed TRECs below 4/µL and a patient with DiGeorge syndrome showed undetectable TRECs. KRECs values ranged from 10 to 1,097 KRECs/µL, with mean and median of 130 and 108 KRECs/µL. Four patients with agammaglobulinemia had results below 4 KRECs/µL. The cutoff values were 15 TRECs/µL and 14 KRECs/µL and were established according to the receiver operating characteristic curve analysis, with 100% sensitivity for SCID and agammaglobulinemia detection, respectively. Conclusions: Quantification of TRECs and KRECs was able to diagnose children with T- and/or B-cell lymphopenia in our study, which validated the technique in Brazil and enabled us to implement the newborn screening program for SCID and agammaglobulinemia.

Preimplantation Genetic Diagnosis of X-linked Severe Combined Immunodeficiency / 中山大学学报(医学科学版)

[Objective]To establish a reliable and accurate preimplantation genetic diagnosis (PGD)method using multiple dis?placement amplification (MDA), which can be applied to the diagnosis of X-linked severe combined immunodeficiency disease (X-SCID).[Methods]Haplotype analysis for the X-SCID family was performedusing five short tandem repeats (STR) markers flanking the both sides of the interleukin-2 (IL-2) receptor gamma chain (IL2RG) gene. MDA technique was used for single-cell whole genomic amplification. The products were used as template in polymerase chain reaction (PCR) of informative STR markers found by linkage analysis for haplotype analysis as well as sequencing of the IL2RG gene exon 5.The amelogenin (AMEL) locus was used to do sex diag?nosis.[Results]Linked analysis revealed 3 STR markers were informative. The method was evaluated with 10 single lymphocytes and 10 single blastomeres. MDA was successful in all single cell. The detection efficiency of gene sequencing of pathogenic IL 2RG exon5 was 100%. The PCR efficiency of 3 STR informative markers and AMEL was 96.3%(77/80)and the average allele drop-out (ADO) rate was 11.5%(7/61). A cycle of PGD was performed on the family, and seven embryos were diagnosed, two of which were normal embry?os. Twin pregnancy occurred after transplantation which were given a healthy baby boy and a healthy baby girl.[Conclusion]In this study, multiple displacement amplification combined with specific amplification/sequencing of pathogenic gene and haplotype analysis in the single cell level of X-linked severe combined immunodeficiency disease were performed. The protocol can avoid misdiagnosis caused by contamination and ADO, and improve the diagnostic efficiency of PGD.

The First Newborn Screening Study of T-Cell Receptor Excision Circle and κ- Deleting Recombination Excision Circle for Severe Combined Immunodeficiency in Korea: A Pilot Study

PURPOSE: Severe combined immunodeficiency (SCID) is the most serious form of primary immunodeficiency. Infants with SCID are susceptible to life-threatening infections. To establish newborn screening for SCID in Korea, we performed a screening test for T-cell receptor excision circle (TREC) and κ-deleting recombination excision circle (KREC) in neonates and investigated the awareness of SCID among their parents. METHODS: Collections of dried blood spots from neonates and parent surveys were performed at the Samsung Medical Center and Cheil General Hospital & Women's Healthcare Center in Korea. The amplification crossing point (Cp) value 39.0 was defined as negative. RESULTS: For TREC/KREC screening, 141 neonates were enrolled; 63 (44.7%) were male. One hundred forty neonates (99.3%) had positive TREC/KREC results at the time of the initial test; 82.3% and 75.9% were positive and 17.0% and 23.4% were weakly positive for TREC and KREC, respectively. In one neonate (0.7%), the initial TREC/KREC test result was negative. However, repeated tests obtained and confirmed a positive result. For an awareness survey, 168 parents were engaged. Only 2% of parents (3/168) knew that the newborn screening test for SCID had been introduced and performed in other countries. Eighty-four percent of parents (141/168) replied that nationwide newborn SCID screening should be performed in Korean newborns. CONCLUSIONS: In this study, newborn SCID screening was performed along with assessment of public awareness of the SCID test in Korea. The study results showed that newborn SCID screening can be readily applied for clinical use at a relatively low cost in Korea.

Eritrodermia en lactante con inmunodeficiencia: A propósito de un caso / Erythroderma in infancy associated with immunodeficiency: A case report

La eritrodermia en niños pequeños es una rara patología. Los médicos debemos estar atentos frente a la sospecha diagnóstica del síndrome de Omenn, un infrecuente trastorno que asocia una inmunodeficiencia combinada severa con: infecciones recurrentes, dermatitis exfoliativa, linfadenopatías, hepatoesplenomegalia, eosinofilia y niveles séricos altos de IgE. El trasplante de células madre hematopoyéticas es fundamental para la sobrevivencia. Presentamos una lactante de siete meses de vida, que cursaba con infección respiratoria y diarrea, asociadas a hepatoesplenomegalia y linfadenopatía diseminada. Se evidenciaron alteraciones complejas de la inmunidad, mediante exámenes de laboratorio.

Exfoliative dermatitis or erythroderma in infancy is rare. Clinicians need to be alert to the possible diagnosis of Omenn syndrome (OS), a rare form of combined immunodeficiency in infants presenting with recurrent infections, erythroderma, lymphadenopathy, hepatosplenomegaly, eosinophilia, and increased serum IgE levels. OS is fatal unless treated by hematopoietic stem cell transplantation. We described a seven months of age female patient with respiratory infection and diarrhea, associated with hepatosplenomegaly and disseminated lymphadenopathy. Were evident laboratory anomalies suspected a complex immunodeficiency problem.

The diverse phenotypes of RAG mutation associated immunodeficiency / 国际儿科学杂志

RAG mutations cause a spectrum of severe immunodeficiencies ranging from classical severe combined immunodeficiency( SCID) and Omenn syndrome to an increasing number of peculiar phenotypes. Based on the distinct levels of RAG expression in various patients, their immunophenotypes, histopathological findings and clinical manifestations are diverse. The subtypes of RAG-defect diseases have been described as classical SCID,SCID with maternal T cells,classical Omenn syndrome,atypical Omenn syndrome,granuloma-tous inflammation,predominance/expansion of γδ-T cells and maternal T-cell engraftment. The complete failure or partial blockage of lymphocyte development and differentiation can cause repeated infections with autoimmune reactions frequently,and may be lethal. Thorough assessment and interpretation of various phenotypes will guide accurate diagnosis,definitive treatment and the mechanism research.

Construction of severe combined immunodeficiency mice based on CRSIPR/Cas9 technology / 中国实验动物学报

Objective To knockout Rag2 and IL2rg genes and construct severe combined immunodeficiency mice based on CRISPR/Cas9 technology. Method Design and synthesis of 25 bp sgRNA were made according to the Rag2 and IL2rg sequences in Genbank. After annealing, sgRNA was cloned into pX330 vector. Recombination plasmid Rag2?sgRNA, IL2rg?sgRN and Cas9 were then transcribed into RNA, these RNA were microinjected into zygotes and the zygotes were transplanted into recipient ICR mice. F0 founders were born and mutated F0 founders mated with wild type mice to obtain F1 generation heterozygous mice. Mutated F1 mice were crossed and got F2 generation homozygous mice. Genotype and phenotype of the knockout mice were identified by sequencing, flow cytometry and xenograft model. Results Rag2?sgRNA and IL2rg?sgRNA recombination plasmids were constructed and transcribed into RNA. After microinjection and mat? ing, F0 founders were born and F2 homozygous mice were obtained. The results of sequencing showed that there were two types of genotype in IL2rg gene, 10 bp or 11 bp deletion;however, there was only one genotype in Rag2 gene, which was 8 bp deletion. Compared with wild?type BALB/c mice, the number of CD3 +, B220 + and NKp46 + cells in peripheral blood of the knockout mice was reduced significantly. After inoculation of human breast cancer cell line SKBR?2HL cells, tumor size in the xenograft mouse model was increased gradually along with time extension. Conclusion CRISPR/Cas9 is an efficient way to mutate Rag2 and IL2rg gene in mice in vivo, leading to aberrant T cells, B cells and NK cells.

Severe combined immunodeficiency mouse-psoriatic human skin xenograft model: A modern tool connecting bench to bedside.

Psoriasis is a multifactorial chronic inflammatory disease. Research into the pathogenesis of this disease is hindered by the lack of a proper animal model. Over the past two decades, many scientists were involved in the development of animal models that nearly mirror the immunopathogenesis of psoriasis. One such model, which has opened doors to the study of molecular complexities of psoriasis as well as its treatment, is the severe combined immunodeficiency (SCID) mouse-human skin chimera model. This model not only mirrors the clinical and histopathological features of psoriasis but also help in the study of cell proliferation, angiogenesis, function of T cells, neurogenic inflammation and cytokines involved in inflammatory reactions. In this article, we have reviewed the prospects and the limitations of the SCID mouse model of psoriasis.