Abstract
Most autosomal genetic causes of childhood-onset hypogammaglobulinemia are currently not well understood. Most affected individuals are simplex cases, but both autosomal-dominant and autosomal-recessive inheritance have been described. We performed genetic linkage analysis in consanguineous families affected by hypogammaglobulinemia. Four consanguineous families with childhood-onset humoral immune deficiency and features of autoimmunity shared genotype evidence for a linkage interval on chromosome 4q. Sequencing of positional candidate genes revealed that in each family, affected individuals had a distinct homozygous mutation in LRBA (lipopolysaccharide responsive beige-like anchor protein). All LRBA mutations segregated with the disease because homozygous individuals showed hypogammaglobulinemia and autoimmunity, whereas heterozygous individuals were healthy. These mutations were absent in healthy controls. Individuals with homozygous LRBA mutations had no LRBA, had disturbed B cell development, defective in vitro B cell activation, plasmablast formation, and immunoglobulin secretion, and had low proliferative responses. We conclude that mutations in LRBA cause an immune deficiency characterized by defects in B cell activation and autophagy and by susceptibility to apoptosis, all of which are associated with a clinical phenotype of hypogammaglobulinemia and autoimmunity.
Highlights
In 86% of cases, childhood-onset agammaglobulinemia is an X-linked condition (XLA, [MIM 300755]) affecting male offspring.[1]
Since the age of 2 years, his growth has been severely retarded, and he has presented with significant clubbing
A magnetic resonance image (MRI) of his head showed a cerebral mass, which is currently being evaluated for granuloma formation
Summary
In 86% of cases, childhood-onset agammaglobulinemia is an X-linked condition (XLA, [MIM 300755]) affecting male offspring.[1]. Childhood-onset hypogammaglobulinemias are characterized by the presence of B cells in the periphery and by some residual immunoglobulin production. They might be transient or persistent and primary (inborn) or secondary as a result of, e.g., nephrosis, enteric protein loss, medication (immunosuppressive or antiepileptic drugs), or connatal infection, such as HIV or measles. Primary T cell deficiencies combined with either the lack of peripheral B cells or a functional defect of persisting B cells (such as T-Bþ severe combined immune deficiency or immunodeficiency, centromeric instability, and facial anomalies [ICF] syndrome [MIM 601457 and 242860, respectively]) might include childhood-onset hypogammaglobulinemia as part of the phenotype.[5,6]
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