Pulmonary Alveolar Proteinosis and Multiple Infectious Diseases in a Child with Autosomal Recessive Complete IRF8 Deficiency

Background Autosomal recessive (AR) complete IRF8 deficiency is a rare severe inborn error of immunity underlying an absence of blood myeloid mononuclear cells, intracerebral calcifications, and multiple infections. Only three unrelated patients have been reported. Materials and Methods We studied a...

Full description

Saved in:
Bibliographic Details
Published in:Journal of clinical immunology 2022-07, Vol.42 (5), p.975-985
Main Authors: Rosain, Jérémie, Bernasconi, Andrea, Prieto, Emma, Caputi, Lucia, Le Voyer, Tom, Buda, Guadalupe, Marti, Marcelo, Bohlen, Jonathan, Neehus, Anna-Lena, Castaños, Claudio, Gallagher, Rosario, Dorgham, Karim, Oleastro, Matias, Perez, Laura, Danielian, Silvia, Dipierri, Jose Edgardo, Casanova, Jean-Laurent, Bustamante, Jacinta, Villa, Mariana
Format: Article
Language:English
Subjects:
Alveoli
Biomedical and Life Sciences
Biomedicine
Child
Communicable Diseases
Dendritic cells
DNA, Complementary
Humans
Immunology
Infant
Infectious Diseases
Interferon Regulatory Factors - genetics
Internal Medicine
Leukocytes (mononuclear)
Life Sciences
Lung diseases
Macrophages
Male
Medical Microbiology
Methionine
Molecular weight
Monocytes
Mutagenesis
Neutrophilia
Original
Original Article
Patients
Pulmonary Alveolar Proteinosis - diagnosis
Pulmonary Alveolar Proteinosis - genetics
Translation initiation
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Background Autosomal recessive (AR) complete IRF8 deficiency is a rare severe inborn error of immunity underlying an absence of blood myeloid mononuclear cells, intracerebral calcifications, and multiple infections. Only three unrelated patients have been reported. Materials and Methods We studied an Argentinian child with multiple infectious diseases and severe pulmonary alveolar proteinosis (PAP). We performed whole-exome sequencing (WES) and characterized his condition by genetic, immunological, and clinical means. Results The patient was born and lived in Argentina. He had a history of viral pulmonary diseases, disseminated disease due to bacillus Calmette-Guérin (BCG), PAP, and cerebral calcifications. He died at the age of 10 months from refractory PAP. WES identified two compound heterozygous variants in IRF8 : c.55del and p.R111*. In an overexpression system, the p.R111* cDNA was loss-of-expression, whereas the c.55del cDNA yielded a protein with a slightly lower molecular weight than the wild-type protein. The mutagenesis of methionine residues downstream from c.55del revealed a re-initiation of translation. However, both variants were loss-of-function in a luciferase assay, suggesting that the patient had AR complete IRF8 deficiency. The patient had no blood monocytes or dendritic cells, associated with neutrophilia, and normal counts of NK and other lymphoid cell subsets. Conclusion We describe the fourth patient with AR complete IRF8 deficiency. This diagnosis should be considered in children with PAP, which is probably due to the defective development or function of alveolar macrophages.
ISSN:0271-9142
1573-2592
DOI:10.1007/s10875-022-01250-4