autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity

Autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity is a condition affecting the immune system, particularly the function of natural killer cells. It is associated with pathogenic variants in the FCGR3A gene, which plays a key role in natural killer cell activity. This condition typically presents in early childhood with recurrent infections and other immune challenges, and it is very rare, affecting fewer than 1 in 1 million people. Inheritance is autosomal recessive, meaning that an affected individual has inherited two copies of the altered gene, one from each parent.

Characteristic clinical features include severe varicella zoster infection, persistent wheezing, and recurrent sinusitis. Individuals often experience repeated episodes of viral upper respiratory tract infections, otitis media, and episodes of oral herpes, as well as BCGitis. Abnormal natural killer cell physiology is a consistent finding, and while reduced total natural killer cell count is seen in a subset of patients, not every individual exhibits every feature. Not all individuals experience all features, and severity varies considerably.

This condition is caused by pathogenic variants in the FCGR3A gene, which is essential for the spontaneous cytotoxic activity of natural killer cells. Disruption in the function of the FCGR3A protein can impair the immune system's ability to combat viral and bacterial infections. The condition is inherited in an autosomal recessive pattern, meaning that affected individuals inherit two copies of the pathogenic variant. It is more common when parents share a common ancestor, as both are more likely to carry the same rare genetic variant. Families are encouraged to seek genetic counseling to understand the recurrence risk of 25% for each pregnancy in autosomal recessive conditions. Associated genes include FCGR3A.