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Interferón-alfa , Humanos , Interferón-alfa/uso terapéutico , Masculino , Antivirales/uso terapéutico , FemeninoAsunto(s)
Pancitopenia , Humanos , Niño , Pancitopenia/etiología , Pancitopenia/genética , Deleción Cromosómica , Cromosomas Humanos Par 7RESUMEN
The clinical syndrome caused by cleavage-resistant RIPK1 is known as CRIA (Cleavage-resistant RIPK1-induced autoinflammatory) syndrome. We present a family with three generations affected by CRIA syndrome. Our index patient (P1), a boy born of a non-consanguineous marriage, developed recurrent episodes of fever after 5 months of age, with variable periodicity. His father (P2) and paternal grandmother also had periodic fever. At 23 months of age, P1 was diagnosed with renal biopsy-proven steroid-responsive nephrotic syndrome. His first visit to our center was at 2 years of age. At presentation, he had failure to thrive, microcytic hypochromic anemia, and elevated inflammatory markers and interleukin-6 levels. Amyloid A protein was elevated, serum creatinine was normal, and proteinuria resolved after addition of steroids. Next-generation sequencing showed heterozygous mutation (c.970G>A, p.Asp324His) in RIPK1. This mutation has been reported to cause CRIA syndrome. P2 and P1's asymptomatic younger brother had the same mutation. All the affected members showed variability with respect to frequency and duration of periodic fever as well as the age of onset. Both P1 and P2 had elevated amyloid A, with no evidence of renal dysfunction. P1 and P2 showed improvement in the intensity of fever spikes with colchicine treatment; however, both continue to have periodic fever.
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Amiloidosis , Fiebre Mediterránea Familiar , Masculino , Humanos , Colchicina/uso terapéutico , Fiebre Mediterránea Familiar/diagnóstico , Amiloidosis/diagnóstico , Fiebre/diagnóstico , Fiebre/tratamiento farmacológico , Fiebre/genética , Mutación , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/uso terapéuticoRESUMEN
DOCK8 deficiency affects various cell subsets belonging to both the innate and adaptive immune systems. Clinical diagnosis is challenging, as many cases present with severe atopic dermatitis as the only initial manifestation. Though flow cytometry helps in the presumptive diagnosis of DOCK8-deficient patients by evaluating their DOCK8 protein expression, it requires subsequent confirmation by molecular genetic analysis. Currently, haematopoietic stem cell transplantation (HSCT) is the only curative treatment option available for these patients. There is a paucity of data from India on the clinical diversity and molecular spectrum of DOCK8 deficiency. In the present study, we report the clinical, immunological and molecular findings of 17 DOCK8-deficient patients from India diagnosed over the last 5 years.
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Síndrome de Job , Humanos , India , Factores de Intercambio de Guanina Nucleótido/genéticaAsunto(s)
Anemia Hemolítica , Síndrome de Activación Macrofágica , Adenosina Desaminasa , Agammaglobulinemia , Humanos , Péptidos y Proteínas de Señalización Intercelular , Síndrome de Activación Macrofágica/diagnóstico , Síndrome de Activación Macrofágica/etiología , Inmunodeficiencia Combinada GraveRESUMEN
Mendelian Susceptibility to Mycobacterial diseases (MSMD) are a group of innate immune defects with more than 17 genes and 32 clinical phenotypes identified. Defects in the IFN-γ mediated immunity lead to an increased susceptibility to intracellular pathogens like mycobacteria including attenuated Mycobacterium bovis-Bacillus Calmette-Guérin (BCG) vaccine strains and non-tuberculous environmental mycobacteria (NTM), Salmonella, fungi, parasites like Leishmania and some viruses, in otherwise healthy individuals. Mutations in the IL12RB1 gene are the commonest genetic defects identified. This retrospective study reports the clinical, immunological, and molecular characteristics of a cohort of 55 MSMD patients from 10 centers across India. Mycobacterial infection was confirmed by GeneXpert, Histopathology, and acid fast bacilli staining. Immunological workup included lymphocyte subset analysis, Nitro blue tetrazolium (NBT) test, immunoglobulin levels, and flow-cytometric evaluation of the IFN-γ mediated immunity. Genetic analysis was done by next generation sequencing (NGS). Disseminated BCG-osis was the commonest presenting manifestation (82%) with a median age of presentation of 6 months due to the practice of BCG vaccination at birth. This was followed by infection with Salmonella and non-typhi Salmonella (13%), Cytomegalovirus (CMV) (11%), Candida (7%), NTM (4%), and Histoplasma (2%). Thirty-six percent of patients in cohort were infected by more than one organism. This study is the largest cohort of MSMD patients reported from India to the best of our knowledge and we highlight the importance of work up for IL-12/IL-23/ISG15/IFN-γ circuit in all patients with BCG-osis and suspected MSMD irrespective of age.
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Predisposición Genética a la Enfermedad/genética , Inmunidad Innata/genética , Mutación , Infecciones por Mycobacterium/genética , Infecciones por Mycobacterium/inmunología , Adolescente , Adulto , Vacuna BCG/inmunología , Niño , Preescolar , Coinfección/epidemiología , Coinfección/microbiología , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Humanos , India/epidemiología , Lactante , Recién Nacido , Masculino , Infecciones por Mycobacterium/epidemiología , Infecciones por Mycobacterium/microbiología , Fenotipo , Receptores de Interleucina-12/genética , Receptores de Interleucina-12/inmunología , Estudios Retrospectivos , Adulto JovenRESUMEN
In 2014, a child with broad combined immunodeficiency (CID) who was homozygous for a private BCL10 allele was reported to have complete inherited human BCL10 deficiency. In the present study, we report a new BCL10 mutation in another child with CID who was homozygous for a BCL10 variant (R88X), previously reported as a rare allele in heterozygosis (minor allele frequency, 0.000003986). The mutant allele was a loss-of-expression and loss-of-function allele. As with the previously reported patient, this patient had complete BCL10 deficiency. The clinical phenotype shared features, such as respiratory infections, but differed from that of the previous patient that he did not develop significant gastroenteritis episodes or chronic colitis. Cellular and immunological phenotypes were similar to those of the previous patient. TLR4, TLR2/6, and Dectin-1 responses were found to depend on BCL10 in fibroblasts, and final maturation of T cell and B cell maturation into memory cells was affected. Autosomal-recessive BCL10 deficiency should therefore be considered in children with CID.
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Proteína 10 de la LLC-Linfoma de Células B/genética , Linfocitos B/inmunología , Síndromes de Inmunodeficiencia/genética , Mutación/genética , Linfocitos T/inmunología , Células Cultivadas , Trastornos de los Cromosomas , Homocigoto , Humanos , Memoria Inmunológica , Lactante , Lectinas Tipo C/metabolismo , Masculino , Infecciones del Sistema Respiratorio , Receptores Toll-Like/metabolismoRESUMEN
BACKGROUND: Children with very early onset inflammatory bowel diseases (VEO-IBD) often have a refractory and severe disease course. A significant number of described VEO-IBD-causing monogenic disorders can be attributed to defects in immune-related genes. The diagnosis of the underlying primary immunodeficiency (PID) often has critical implications for the treatment of patients with IBD-like phenotypes. METHODS: To identify the molecular etiology in 5 patients from 3 unrelated kindred with IBD-like symptoms, we conducted whole exome sequencing. Immune workup confirmed an underlying PID. RESULTS: Whole exome sequencing revealed 3 novel CARMIL2 loss-of-function mutations in our patients. Immunophenotyping of peripheral blood mononuclear cells showed reduction of regulatory and effector memory T cells and impaired B cell class switching. The T cell proliferation and activation assays confirmed defective responses to CD28 costimulation, consistent with CARMIL2 deficiency. CONCLUSION: Our study highlights that human CARMIL2 deficiency can manifest with IBD-like symptoms. This example illustrates that early diagnosis of underlying PID is crucial for the treatment and prognosis of children with VEO-IBD.
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Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/inmunología , Proteínas de Microfilamentos/deficiencia , Edad de Inicio , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Humanos , Linfocitos/inmunología , Masculino , Mutación , Fenotipo , Secuenciación del ExomaAsunto(s)
Enfermedad Granulomatosa Crónica/complicaciones , Enfermedad Granulomatosa Crónica/genética , Síndrome Mucocutáneo Linfonodular/complicaciones , Mutación , NADPH Oxidasas/genética , Alelos , Biomarcadores , Niño , Análisis Mutacional de ADN , Femenino , Genotipo , Enfermedad Granulomatosa Crónica/diagnóstico , Humanos , Inmunofenotipificación , Síndrome Mucocutáneo Linfonodular/diagnóstico , LinajeRESUMEN
AIM: To assess the safety and feasibility of transfusing autologous bone marrow stem cells (ABMSC) into the culprit coronary artery after an acute anterior wall myocardial infarction (MI) and further to see the ability of ABMSC to promote improvement in Left Ventricular lsqb;LV] function at follow-up. METHODS: In an ongoing phase I clinical trial, twenty-seven patients of uncomplicated acute anterior wall MI treated as per the current practicing guidelines have been included. Among these, seventeen patients received intra-coronary unfractionated ABMSCs from 77ndash;15 days after acute MI (ABMSC group) and ten patients acted as controls. RESULTS: All the procedures carried out were without any complications. After 6 months, cardiac function analysis of ten patients from the ABMSC group by LV angiography and Cardiac Magnetic Resonance Imaging (MRI) demonstrated a significant rise of 12.74% (p = 0.001) and 7.1% (p = 0.001), respectively in the LV ejection fraction [LVEF]. There was an improvement in the LV systolic function wherein LV end systolic volume (LVESV) decreased significanty to 28.75% (p = 0.010) and 16.49% (p = 0.022) by LV angiography and cardiac MRI, respectively. LV end diastolic volume (LVEDV) decreased marginally by LV angiography (p = 0.548) and by cardiac MRI (p = 0.514). Five patients of the control group by LV angiography demonstrated non-significant rise of 1.0% (p = 0.706) in LVEF, 12.79% (p = 0.332) in LVEDV and 22.56% (p = 0.308) in LVESV. By cardiac MRI controls demonstrated significant rise in EF of 3.2% (p = 0.0367rpar; but non-significant fall of only 2.32% (p = 0.812) in LVEDV and 6.47% (p 7equals; 0.508) in LVESV. CONCLUSION: This study shows that intracoronary infusion of ABMSC is safe and feasible after acute MI and shows a favourable trend towards the improvement of LV function and prevention of ventricular remodeling which determines long-term survival.