autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation

Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation is a multisystem condition characterized by both autoinflammatory episodes and features of immune deficiency. It is caused by pathogenic variants in the PLCG2 gene, which plays a key role in immune cell signaling and regulation of inflammation. Affected individuals typically experience recurrent inflammatory and infectious symptoms involving the lungs, gastrointestinal tract, and skin, often presenting in childhood. The condition is inherited in an autosomal dominant manner and is extremely rare, affecting fewer than one in a million people.

Individuals with this condition display a complex clinical picture marked by recurrent inflammatory and infectious symptoms. Nearly all affected individuals experience bronchiolitis, interstitial pneumonitis, and recurrent sinopulmonary infections, which frequently prompt early medical evaluations. Enterocolitis is also a characteristic manifestation, and skin involvement is evident through persistent erythema and episodes of cellulitis. Musculoskeletal complaints, particularly arthralgia, are common. Laboratory evaluations typically reveal decreased circulating concentrations of IgA and IgM, as well as a reduction in class-switched memory B cells, reflecting an underlying antibody deficiency. Additionally, a subset of patients may develop features such as ulcerative colitis, corneal erosions, and cataracts. Not all individuals experience all of these features, and the severity and specific symptoms can vary considerably.

The underlying cause of the condition is linked to pathogenic variants in the PLCG2 gene. The PLCG2 gene encodes an enzyme that is crucial for transducing signals in immune cells; disruptions in its function lead to abnormalities in inflammatory responses as well as antibody production. The disorder follows an autosomal dominant inheritance pattern, meaning that inheriting a single altered copy of the gene is sufficient to lead to the condition. However, even within families, there can be noticeable differences in the severity and combination of symptoms. Genetic counseling is recommended for families to discuss recurrence risks and understand the implications for family planning.

Currently, management focuses on supportive care and symptom management since there are no FDA-approved treatments specifically for this condition. A multidisciplinary approach is essential, with care coordinated by specialists such as immunologists, rheumatologists, pulmonologists, and gastroenterologists to address the varied manifestations. Treatment strategies are tailored to the individual and may include interventions to control inflammation, prompt management of infections, and supportive therapies for gastrointestinal and skin symptoms. Genetic counseling is also advised to help families understand the inheritance pattern and explore family planning options. Regular surveillance and coordination among care providers are key to managing this complex condition.

The long-term outlook for individuals affected by this condition is highly variable, with outcomes differing based on the severity of symptoms, the age of diagnosis, and access to coordinated, multidisciplinary care. Many patients benefit from early intervention and regular monitoring, which can lead to improved quality of life and better management of inflammatory episodes. While some individuals continue to experience recurrent inflammatory flares and complications, others may achieve stability with supportive treatment. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with genetic counselors and specialist support groups to navigate the uncertainties and plan for future care needs.