Pneumocystis jirovecii pneumonia as an initial manifestation of hyper-IgM syndrome in an infant: A case report

Kim, Danbi; Shin, Ju Ae; Han, Seung Beom; Chung, Nack-Gyun; Jeong, Dae Chul

Most cases of PCP in infancy were reported as epidemics in premature and malnourished infants around the time of World War II. [1, 2] After then, in developed countries, PCP has occurred sporadically in immunocompromised children rather than epidemically in infants. [1, 2] HIV infection has been regarded as an important risk factor for PCP; however, immunocompromised patients who are HIV-negative have recently occupied a greater proportion of patients with PCP than patients with HIV infection. [3] Although most immunocompromised children who are HIV-negative are those with hematologic malignancies or solid tumors and hematopoietic cell or solid-organ transplant recipients, children with PID are also at risk for PCP. [3] CD4+ T cells play an essential role in the host immune defense to P. jirovecii infection, [7] and therefore, T cell impairment rather than B cell or phagocytic impairment, is thought to be a risk factor for PCP among children with PID. [2] Severe combined immune deficiency, Wiskott-Aldrich syndrome, and HIGM syndrome are the most common PIDs among children with PCP. [3] HIGM syndrome is caused by a defect in the CD40-CD40L signaling pathway. [8, 9] It causes a limitation in immunoglobulin isotype switching in B cells, and therefore, normal or elevated IgM levels with low IgG, IgA, and IgE levels are observed. [8, 9] Our patient showed normal IgG levels, which were thought to be due to maternal antibodies transferred across the placenta. The normal IgM levels and undetected IgA and IgE levels with an increased proportion of CD19+ cells raised the suspicion of HIGM syndrome. HIGM syndrome manifests as a T cell dysfunction rather than a B cell dysfunction, despite hypogammaglobulinemia, because most cases are caused by a mutation of www.md-journal.com the CD40L gene located at the X chromosome which encodes CD40L on the T cell surface. [8] [9] [10] [11] Therefore, X-linked HIGM syndrome is the most frequent form of HIGM syndrome. [8, 9] However, several other genes mutated and involved in CD40-CD40L signaling pathway or DNA repairing system in immunoglobulin isotype switching can cause HIGM syndrome, namely: CD40, activation-induced cytidine deaminase (AICDA), uracil-DNA glycosylase (UNG), phosphatidylinositol 3-kinase catalytic delta (PIK3CD), phosphatidylinositol 3-kinase regulatory subunit 1 alpha (PIK3R1), nuclear factor-kappa-B essential modulator (NEMO/IKKg), inhibitor of kappa light chain gene enhancer in B cells, alpha (IkBa), nuclear factor kappa-B subunit 1 (NFKB1) genes participating in CD40-CD40L signaling pathway and post meiotic segregation increased 2 (PMS2), MutS Homolog 6 (MSH6), MutS Homolog 2 (MSH2), ataxia telangiectasia mutated (ATM), Nibrin/Nijmegen breakage syndrome 1 (NBS1/NBN) genes involved in DNA repairing system. [8, 9] Most forms of these mutations are expressed through autosomal recessive inheritance, although autosomal dominant inheritance has also been reported. [8, 9] Therefore, genetic evaluation should be performed in patients with HIGM syndrome phenotype to verify the exact disease mechanism and perform accurate genetic counseling. Traditional therapies for HIGM syndrome include immunoglobulin replacement therapy, antibiotic prophylaxis for P. jirovecii infection, hygienic measures to prevent infection, and careful monitoring for other complications. [8, 9] With these therapies, the median survival rate after diagnosis of HIGM syndrome was reported as 25 years. [12] However, hematopoietic