Double Trouble: A DOCK8- and CFI-Deficient Infant Presenting With Acute Necrotizing Meningoencephalitis

İngilizce (OpenAlex)

To the Editors: Primary immunodeficiencies (PIDs) are rare monogenic disorders. It is also uncommon for 2 PIDs to coexist. Here, we present the first case with dedicator of cytokinesis 8 (DOCK8) and complement factor I (CFI) deficiency diagnosed after necrotizing meningoencephalitis. A 45-day-old baby boy with Streptococcus agalactiae meningitis and status epilepticus was admitted to our pediatric intensive care unit. On admission, cranial magnetic resonance imaging was performed and revealed necrotizing meningoencephalitis and brain edema. On follow-up, his clinical status deteriorated due to increased intracranial pressure. An external ventricular drain was placed, and new cerebrospinal fluid sampling revealed both S. agalactiae and cytomegalovirus positivity. He also had cytomegalovirus viremia and urinary tract infection with Candida albicans. Because of his complicated clinical course, a pediatric immunology consultation was planned. Background history revealed that he was born to consanguineous parents at term, and his neonatal period was uncomplicated. An elder brother (patient 2) was newly under intravenous immunoglobulin treatment with suspicion of chronic mucocutaneous candidiasis. An immunologic workup was performed for either. While patient 1 had low IgG, IgM and C3 levels and a reversed CD4/CD8 ratio, patient 2 had low IgM and elevated IgE levels with normal serum complement levels. Patient 2 also had low CD3+ T cell, CD3+CD4+ T cell levels, lymphocyte proliferation responses and a reversed CD4/CD8 ratio compatible with combined immunodeficiency (Table 1). Exome sequencing was performed and identified a homozygous likely pathogenic variant [c.4507C>T (p. Gln1503*)] in the DOCK8 gene and a homozygous likely pathogenic variant [c.262C>T (p. Gln88*)] in the CFI gene in the patient 1. Patient 2 had the same variant of the DOCK8 gene but was a carrier for the CFI variant. Sanger sequencing confirmed the variants in both siblings. Unfortunately, we could not assess CFI levels. Antibacterial-antifungal prophylaxis and intravenous immunoglobulin treatments were started along with donor screening for hematopoietic stem cell transplantation. TABLE 1. - Immunologic Evaluation of Patients Patient 1 Age References Patient 2 Age References IgG, mg/dL 222 294–1165 1180 640–2010 IgA, mg/dL 36 13–72 225 44–244 IgM, mg/dL <16 33–154 <18 52–297 T.IgE, IU/L <17.5 5420 16.86 C3, g/L 0.54 0.9–1.8 1.23 0.9–1.8 C4, g/L 0.28 0.1–0.4 0.26 0.1–0.4 Absolute lymphocyte count, /mm3 3400 2450–8890 2900 1130–5520 Absolute eosinophil count, /mm3 390 0–400 510 0–400 CD3+T cells, % (/mm3) 762584 51–792400–8100 35 1015 55–791900–3600 CD3+CD4+ T cells, % (/mm3) 32 1088 31–541400–5200 13 377 26–49600–2000 CD3+CD8+ T cells, % (/mm3) 461564 10–31600–3000 24696 9–35300–1300 CD4+CD45RA+ T cells, % (/mm3) 26 884 25–451200–5600 10 290 20–41500–6600 CD19+ B cells, % (/mm3) 13 442 14–44500–3600 351015 11–31300–1200 CD3-CD16+CD56+ NK cells, % (/mm3) 5 170 5–23200–1800 16464 5–28200–1200 γδ cells, % 22 5 CD45RA+CD31+, % 60 >50 42 >50 CD4/CD8 ratio 0.69 0.54 Lymphocyte activation response to PHA, % CD3+CD25+ 84 52–94 33 43–97 CD3+CD69+ 84 45–85 32 45–100 Lymphocyte activation response to anti-CD3, % CD4+CD25+ 76 15 CD4+CD69+ 74 17 CD4+ 77 15 Bold values indicate abnormal laboratory levels.NK indicates natural killer cells; PHA, phytohemagglutinin. Infections, autoimmunity, allergies, malignancies and autoinflammatory diseases are clinical signs of PIDs. Despite diverse clinical spectrum, most patients present with infections, and the infection is the most common reason for referral to a clinical immunologist1 Biallelic loss of function variants in DOCK8 results in a combined immunodeficiency. DOCK8-deficient patients present with not only severe, recurrent and life-threatening sinopulmonary and mucocutaneous viral (molluscum contagiosum virus, herpes simplex virus and human papillomavirus), bacterial (Staphylococcus aureus) and fungal (C. albicans) infections but also severe eczemas/dermatitis, allergies and malignancies.2 To date, over 200 patients have been reported globally. The only curative treatment modality is hematopoietic stem cell transplantation. CFI negatively regulates alternative and classical complement pathways. CFI deficiency is a rare autosomal recessive disease leading to secondary reduction of C3 through consumption. To date, only 60 patients are reported to have complete factor I deficiency.3,4 Complete absence of factor I results in severe and recurrent infections (encephalitis, meningitis or bacteremia with Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis), glomerulonephritis, autoimmune disease and central nervous system inflammation.5 Specific vaccination or prophylactic antibiotics should be offered. Consanguinity may result in a high likelihood of concomitant immunodeficiencies, and clinicians should consider this situation. ACKNOWLEDGMENTS The authors thank the patient and his family for their support for this publication.