Inherited CARD9 Deficiency in a Child with Invasive Disease Due to Exophiala dermatitidis and Two Older but Asymptomatic Siblings.

PURPOSE: Autosomal recessive CARD9 deficiency predisposes patients to invasive fungal disease. Candida and Trichophyton species are major causes of fungal disease in these patients. Other CARD9-deficient patients display invasive diseases caused by other fungi, such as Exophiala spp. The clinical penetrance of CARD9 deficiency regarding fungal disease is surprisingly not complete until adulthood, though the age remains unclear. Moreover, the immunological features of genetically confirmed yet asymptomatic individuals with CARD9 deficiency have not been reported. METHODS: Identification of CARD9 mutations by gene panel sequencing and characterization of the cellular phenotype by quantitative PCR, immunoblot, luciferase reporter, and cytometric bead array assays were performed. RESULTS: Gene panel sequencing identified compound heterozygous CARD9 variants, c.1118G>C (p.R373P) and c.586A>G (p.K196E), in a 4-year-old patient with multiple cerebral lesions and systemic lymphadenopathy due to Exophiala dermatitidis. The p.R373P is a known disease-causing variant, whereas the p.K196E is a private variant. Although the patient's siblings, a 10-year-old brother and an 8-year-old sister, were also compound heterozygous, they have been asymptomatic to date. Normal CARD9 mRNA and protein expression were found in the patient's CD14+ monocytes. However, these cells exhibited markedly impaired pro-inflammatory cytokine production in response to fungal stimulation. Monocytes from both asymptomatic siblings displayed the same cellular phenotype. CONCLUSIONS: CARD9 deficiency should be considered in previously healthy patients with invasive Exophiala dermatitidis disease. Asymptomatic relatives of all ages should be tested for CARD9 deficiency. Detecting cellular defects in asymptomatic individuals is useful for diagnosing CARD9 deficiency.

Clinical and Immunological Heterogeneity in Japanese Patients with Gain-of-Function Variants in STAT3.

PURPOSE: Germline loss-of-function variants in the signal transducer and activator of transcription 3 (STAT3) gene result in autosomal dominant hyper IgE syndrome, whereas somatic gain-of-function (GOF) variants in STAT3 are associated with some malignancies. In addition, germline GOF variants in STAT3 are linked to disorders involving autoimmunity and lymphoproliferation. In this study, we describe five Japanese families with germline GOF variants in STAT3, including three novel variants. We also present the clinical and immunological characteristics of these patients. METHODS: Eight patients from five families were enrolled in this study. We performed genetic and immunological analyses, and collected the associated clinical information. RESULTS: We identified five heterozygous variants in STAT3 using whole-exome sequencing and target gene sequencing. Two of these (E286G and T716M) were previously reported and three (K348E, E415G, and G618A) were novel. A STAT3 reporter assay revealed that all of the variants were GOF. However, the immunological and clinical characteristics among the patients were highly variable. CONCLUSION: Patients with STAT3 GOF variants exhibited clinical and immunological heterogeneity with incomplete penetrance.

Successful allogeneic bone marrow transplantation using immunosuppressive conditioning regimen for a patient with red blood cell transfusiondependent pyruvate kinase deficiency anemia.

Pyruvate kinase deficiency (PKD) is the rare glycolytic enzyme defect causing hemolytic anemia. Treatments are mainly red cell transfusion and/or splenectomy, leading to iron overload. Allogeneic bone marrow transplantation (BMT) is alternatively curative treatment for severe PKD. The intensity of conditioning is often controversial because of higher risk of graft failure and organ damage. Here, we present a transfusion-dependent PKD patient undergoing BMT from an HLA-identical sibling using intensively immunosuppressive conditioning regimen. This report suggests that BMT using immunosuppressive conditioning regimen may be a feasible and effective treatment for patients with severe PKD with iron overload. We suggest the timing of the transplantation at an earlier age in severe PKD predicted from gene mutation is preferred before cumulative damage of transfusion.

Azacitidine successfully maintained the second remission in an infant with KMT2A-rearranged acute lymphoblastic leukemia who relapsed after unrelated cord blood transplantation.

The outcome for infants with KMT2A (MLL)-rearranged acute lymphoblastic leukemia (MLL-r ALL) is dismal despite intensive therapy, including hematopoietic stem cell transplantation (HSCT). Epigenetic dysregulation is considered a key driver of MLL-r leukemogenesis, which theoretically supports the use of epigenetic modifiers as a treatment option. We report an infant MLL-r ALL case with post-HSCT relapse. After achieving a second remission, which was maintained for 10 months using only the DNA methyltransferase inhibitor, azacitidine, the patient successfully received the second HSCT. This report describes the clinical effectiveness of azacitidine for the treatment of infant MLL-r ALL.