RESUMO
PURPOSE: Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by an inability of phagocytes to produce reactive oxygen species, impairing their killing of various bacteria and fungi. We summarize here the 93 cases of CGD diagnosed in Mexico from 2011 to 2019. METHODS: Thirteen Mexican hospitals participated in this study. We describe the genetic, immunological, and clinical features of the 93 CGD patients from 78 unrelated kindreds. RESULTS: Eighty-two of the patients (88%) were male. All patients developed bacterial infections and 30% suffered from some kind of fungal infection. Fifty-four BCG-vaccinated patients (58%) presented infectious complications of BCG vaccine. Tuberculosis occurred in 29%. Granulomas were found in 56% of the patients. Autoimmune and inflammatory diseases were present in 15% of patients. A biological diagnosis of CGD was made in 89/93 patients, on the basis of NBT assay (n = 6), DHR (n = 27), and NBT plus DHR (n = 56). The deficiency was complete in all patients. The median age of biological diagnosis was 17 months (range, 0-186 months). A genetic diagnosis was made in 83/93 patients (when material was available), corresponding to CYBB (n = 64), NCF1 (n = 7), NCF2 (n = 7), and CYBA (n = 5) mutations. CONCLUSIONS: The clinical manifestations in these Mexican CGD patients were similar to those in patients elsewhere. This cohort is the largest in Latin America. Mycobacterial infections are an important cause of morbidity in Mexico, as in other countries in which tuberculosis is endemic and infants are vaccinated with BCG. X-linked CGD accounted for most of the cases in Mexico, as in other Latin American countries. However, a significant number of CYBA and NCF2 mutations were identified, expanding the spectrum of known causal mutations.
Assuntos
Doença Granulomatosa Crônica/imunologia , Mutação/genética , Infecções por Mycobacterium/epidemiologia , Mycobacterium/fisiologia , NADPH Oxidase 2/genética , NADPH Oxidases/genética , Adolescente , Autoimunidade , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Genes Ligados ao Cromossomo X , Doença Granulomatosa Crônica/epidemiologia , Doença Granulomatosa Crônica/genética , Humanos , Lactente , Recém-Nascido , Inflamação , Masculino , México/epidemiologiaRESUMO
Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defective phagocytic NADPH oxidase, causing a complete lack or significant decrease in the production of microbicidal reactive oxygen metabolites. It mainly affects male children; however, there are scarce reports of adult females diagnosed with X-linked-CGD attributed to an extremely skewed X-chromosome inactivation. This condition is characterized by severe and recurrent infections that usually develop after childhood. In clinical practice, physicians who usually confront these patients should suspect this entity and differentiate it from a secondary immunodeficiency. Here, we report a 38-year-old Mexican female with juvenile-onset X linked-CGD, caused by a de novo mutation and extremely skewed X-inactivation, whose clinical features were similar to those in patients with classic X-linked-CDG.
Assuntos
Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/genética , Heterozigoto , Fenótipo , Inativação do Cromossomo X , Adolescente , Biomarcadores , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Avaliação de SintomasRESUMO
Mutations in the genes coding for cytokines, receptors, second messengers, and transcription factors of interferon gamma (IFN-γ) immunity cause Mendelian susceptibility to mycobacterial disease (MSMD). We report the case of a 7-year-old male patient with partial dominant (PD) IFN-γ receptor 1 deficiency who had suffered from multifocal osteomyelitis attributable to bacille Calmette-Guérin vaccination since the age of 18 months. He developed hemophagocytic lymphohistiocytosis (HLH), a hyper-inflammatory complication, and died with multiorgan dysfunction, despite having been diagnosed and treated relatively early. Patients with PD IFN-γR1 deficiency usually have good prognosis and might respond to human recombinant subcutaneous IFN-γ. Several monogenic congenital defects have been linked to HLH, a catastrophic "cytokine storm" that is usually ascribed to lymphocyte dysfunction and thought to be triggered by interferon gamma. This is the sixth patient with both MSMD and HLH of whom we are aware. The fact that patients with macrophages that cannot respond to IFN-γ still develop HLH, bring these assumptions into question.
RESUMO
Patients with Mendelian Susceptibility to Mycobacterial Diseases (MSMD) exhibit variable vulnerability to infections by mycobacteria and other intramacrophagic bacteria (e.g., Salmonella and Klebsiella) and fungi (e.g., Histoplasma, Candida, Paracoccidioides, Coccidioides, and Cryptococcus). The hallmark of MSMD is the inherited impaired production of interferon gamma (IFN-γ) or the lack of response to it. Mutations in the interleukin (IL)-12 receptor subunit beta 1 (IL12RB1) gene accounts for 38% of cases of MSMD. Most IL12RB1 pathogenic allele mutations, including ten known stop-gain variants, cause IL-12Rß1 complete deficiency (immunodeficiency-30, IMD30) by knocking out receptor cell-surface expression. IL12RB1 loss-of-function genotypes impair both IL-12 and IL-23 responses. Here, we assess the health effects of a rare, novel IL12RB1 stop-gain homozygous genotype with paradoxical IL-12Rß1 cell-surface expression. We appraise four MSMD children from three unrelated Brazilian kindreds by clinical consultation, medical records, and genetic and immunologic studies. The clinical spectrum narrowed down to Bacillus Calmette-Guerin (BCG) vaccine-related suppurative adenitis in all patients with one death, and recrudescence in two, histoplasmosis, and recurrence in one patient, extraintestinal salmonellosis in one child, and cutaneous vasculitis in another. In three patients, we established the homozygous Trp7Ter predicted loss-of-function inherited genotype and inferred it from the heterozygote parents of the fourth case. The Trp7Ter mutation maps to the predicted IL-12Rß1 N-terminal signal peptide sequence. BCG- or phytohemagglutinin-blasts from the three patients have reduced cell-surface expression of IL-12Rß1 with impaired production of IFN-γ and IL-17A. Screening of 227 unrelated healthy subjects from the same geographic region revealed one heterozygous genotype (allele frequency 0.0022) vs. one in over 841,883 public genome/exomes. We also show that the carriers bear European ancestry-informative alleles and share the extended CACCAGTCCGG IL12RB1 haplotype that occurs worldwide with a frequency of 8.4%. We conclude that the novel IL12RB1 N-terminal signal peptide stop-gain loss-of-function homozygous genotype confers IL-12Rß1 deficiency with varying severity and early-onset age through diminished cell-surface expression of an impaired IL-12Rß1 polypeptide. We firmly recommend attending to warning signs of IMD30 in children who are HIV-1 negative with a history of adverse effects to the BCG vaccine and presenting with recurrent Histoplasma spp. and extraintestinal Salmonella spp. infections.