Variant in the PLCG2 Gene May Cause a Phenotypic Overlap of APLAID/PLAID: Case Series and Literature Review

Abstract

Background: Variants in the phospholipase C gamma 2 (PLCG2) gene can cause PLCG2-associated antibody deficiency and immune dysregulation (PLAID)/autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID) syndrome. Linking the clinical phenotype with the genotype is relevant in making the final diagnosis. Methods: This is a single center case series of five related patients (4–44 years), with a history of autoinflammation and immune dysregulation. Clinical and laboratory characteristics were recorded and a literature review of APLAID/PLAID was performed. Results: All patients had recurrent fevers, conjunctivitis, lymphadenopathy, headaches, myalgia, abdominal pain, cold-induced urticaria and recurrent airway infections. Hearing loss was detected in two patients. Inflammatory parameters were slightly elevated during flares. Unswitched B-cells were decreased. Naïve IgD+CD27− B-cells and unswitched IgD+CD27+ B-cells were decreased; switched IgD-CD27+ B-cells were slightly increased. T-cell function was normal. Genetic testing revealed a heterozygous missense variant (c.77C>T, p.Thr26Met) in the PLCG2 gene in all patients. Genotype and phenotype characteristics were similar to previously published PLAID (cold-induced urticaria) and APLAID (eye inflammation, musculoskeletal complaints, no circulating antibodies) patients. Furthermore, they displayed characteristics for both PLAID and APLAID (recurrent infections, abdominal pain/diarrhea) with normal T-cell function. Conclusion: The heterozygous missense PLCG2 gene variant (c.77C>T, p.Thr26Met) might cause phenotypical overlap of PLAID and APLAID patterns.

Interstitial lung diseases in inborn errors of immunity

“…There have been documented cases of ILD manifesting as interstitial pneumonitis in APLAID syndrome [51,52]. A 2022 case series and literature review shows ILD is less frequently seen in APLAID syndrome compared to other more common manifestations previously described [53].…”

Tailored treatments in inborn errors of immunity associated with atopy (IEIs-A) with skin involvement

“…Systemic corticosteroids seem to improve symptoms and partially control the disease. In addition, the use of other drugs such as antihistamines, omalizumab, dapsone, and hydroxychloroquine shows improvement in skin symptoms ( 94 ). As a future option, the use of specific inhibitors to normalize PLCG2 function at body temperature and to avoid uncontrolled activation at cold exposure has been proposed, but no data are available ( 92 ).…”

Enfermedad inflamatoria intestinal de inicio muy temprano con mutación en el gen fosfolipasa gama 2 (PLCG2) y defectos de la inmunidad

“…Considerando la asociación de la activación de proteína-cinasa con la alteración de las proteínas desmosómicas y la pérdida de adhesión celular, es plausible que la activación de PKC inducida por las variantes patogénicas del gen PLCG2 provoca la pérdida de adhesión celular, lo que resulta en acantólisis. 11 Las mutaciones monoalélicas en PLCG2 se asocian con inmunodeficiencia humoral variable y desregulación inmunitaria en los síndromes de deficiencia de anticuerpos y desregulación inmunitaria asociada con PLCG2, y autoinflamación, deficiencia de anticuerpos y desregulación inmunitaria asociada con PLCG2. Las alteraciones de las células B observadas en los pacientes con autoinflamación, deficiencia de anticuerpos y desregulación inmunitaria asociada con PLCG2 son variables, desde pacientes con bajas concentraciones de células B hasta ausencia de células B.…”