D2.316 - Novel Homozygous Mutation in CARD11 gene Predisposing To Recurrent Infections and Atopies, and Response to Immunoglobulin therapy

CARD11 gene encodes Caspase Recruitment Domain Family Member 11 (CARD11), which is mainly expressed in lymphocytes. The protein is critical for development, maturation, activation, and proliferation of both B and T cells.  Mutations affect development and function of immune cells causing clinical overlaps between atopic and immunological disorders.

9-year-old child, was referred because of severe dermatitis (on extensive moisturizing, steroid and tacrolimus 0.03% ointment), asthma, allergic rhinitis, food allergies (urticarial rash triggered by eggs, fish, banana, cacao) and recurrent infections. She was hospitalized 10-times for recurrent infections (severe tonsillitis and gastroenteritis), and treated 3-times for H. pylori. She developed itchy vesicular rash over 3 trunk’s dermatomes, then received varicella-zoster-Ig and intra-venous acyclovir for 3-weeks for herpes-zoster infection. Parents are first-degree consanguineous, mother has ulcerative colitis and the father has dermatitis and rhinitis on biologic treatments.

investigations showed white cell counts of 6.8×10⁹/L, neutrophils count= 2.91×10⁹/L, lymphocyte count= 3.27×10⁹/L, eosinophil count=0.0×10⁹/L, Hb level= 12.6 g/dL (normal: 10.6-14.5), platelet count= 414×10⁹/L (normal; 150-450). ESR; 29mm/hr and CRP; 13.3mg/L. Immunoglobins; normal IgG=11.5 (g/L), but low IgM=0.30 (0.5-1.9) and elevated IgA=4.43 (0.5-2.2) and IgE=437 KU/L. Normal antibody titers; diphtheria-IgG> 1.00 (immune >0.10), tetanus-IgG= 0.64 IU/ml (protective > 0.51), and measles-IgG=94.5 U/ml (positive >16), but low varicella-IgG=91.8mIU/Ml (positive >165), negative varicella-IgM and rubella-IgG; 0.22 unit (positive > 11). Lymphocyte markers (cells/µL); CD3+/CD4+/CD8+=3350, CD3+/CD4+/CD8-=1895, CD3+/CD4-/CD8+=1385, CD19+=342, CD3-/CD16+/CD56+=199. CD3⁺TCR alpha/beta=96%, CD3⁺TCR gamma/delta= 4%, CD4^-/CD8^-double negative T-cells=4%. The genetic testing showed homozygous mutation in CARD11 gene; c.926G>A p.(Arg309His) and both parents are heterozygous for the same mutation. CARD11 related diagnoses were established with T- and B-cell dysfunction. Over 2 years on monthly intra-venous immunoglobulin (0.5 grams/kg) infusion therapy, there was significant reduction in infection rate, only 3 reported infections (RSV, parainfluenza virus 1, and E.coli gastroenteritis), dermatitis, asthma and rhinitis improved. Anaphylaxis action plan for food allergies was undertaken, including Epi-pen autoinjector for accidental exposure.

we described novel mutation with CARD11-related disease with T- and B-cell dysfunction that showed great response to immunoglobulin infusion therapy. High index of suspicion facilitates early diagnosis and treatments.