ACUTE JUVENILE PARACOCCIDIOIDOMYCOSIS REVEALING A POSSIBLE

@article{santosbueno2026acute,
  title = {{ACUTE JUVENILE PARACOCCIDIOIDOMYCOSIS REVEALING A POSSIBLE}},
  author = {Filipe Vicente dos SANTOS-BUENO and Priscila Marques de MACEDO and Bárbara Carvalho Santos dos REIS and Flavia Amendola Anisio de CARVALHO and Cristiane C. LAMAS and Dayvison Francis Saraiva FREITAS and Bruna Nunes da Silva AGONIGI and Daiane Oliveira MATIAS and Geraldo Moura Batista PEREIRA and Adriano GOMES-SILVA and Roberta Soares FACCION and Tamiris Azamor da Costa BARROS and Maria S. POMBO-DE-OLIVEIRA and Daniela P. MENDES-DE-ALMEIDA and Zilton Farias Meira de VASCONCELOS},
  journal = {Hematology, Transfusion and Cell Therapy},
  year = {2026},
  month = oct,
  doi = {10.1016/j.htct.2026.106767},
  url = {https://doi.org/10.1016/j.htct.2026.106767},
  note = {CC BY},
}

TY  - JOUR
TI  - ACUTE JUVENILE PARACOCCIDIOIDOMYCOSIS REVEALING A POSSIBLE
AU  - Filipe Vicente dos SANTOS-BUENO
AU  - Priscila Marques de MACEDO
AU  - Bárbara Carvalho Santos dos REIS
AU  - Flavia Amendola Anisio de CARVALHO
AU  - Cristiane C. LAMAS
AU  - Dayvison Francis Saraiva FREITAS
AU  - Bruna Nunes da Silva AGONIGI
AU  - Daiane Oliveira MATIAS
AU  - Geraldo Moura Batista PEREIRA
AU  - Adriano GOMES-SILVA
AU  - Roberta Soares FACCION
AU  - Tamiris Azamor da Costa BARROS
AU  - Maria S. POMBO-DE-OLIVEIRA
AU  - Daniela P. MENDES-DE-ALMEIDA
AU  - Zilton Farias Meira de VASCONCELOS
PY  - 2026
DA  - 2026/10/23
JO  - Hematology, Transfusion and Cell Therapy
DO  - 10.1016/j.htct.2026.106767
UR  - https://doi.org/10.1016/j.htct.2026.106767
AB  - Background: Paracoccidioides spp. are endemic fungal pathogens in Latin America that cause severe acute juvenile paracoccidioidomycosis (PCM), characterized by extensive lymphatic involvement. Although most cases occur in apparently immunocompetent hosts, genetic factors are increasingly recognized as determinants of disease severity. Variants in NFKB2, a key regulator of the non-canonical NF-κB signaling pathway, are associated with CVID-like phenotypes, hypogammaglobulinemia, impaired vaccine responses, immune dysregulation, and increased susceptibility to infections and lymphomas. Case Presentation: A 26-year-old man from Rio de Janeiro presented fever, weight loss, generalized lymphadenopathy, and jaundice. Histopathological examination of a cervical lymph node, fungal culture, and serology confirmed PCM, while HIV serology was negative. The disease followed a severe course with hepatosplenic involvement, severe malnutrition, profound hypoalbuminemia, cholestatic liver dysfunction, refractory ascites, and transfusion-dependent anemia. During a 106-day hospitalization, he developed spontaneous bacterial peritonitis caused by Escherichia coli and Klebsiella pneumoniae, as well as herpesvirus esophagitis. Antifungal treatment resulted in complete clinical and serological remission after two years. Four months after treatment completion, he developed chronic diarrhea, lower-limb edema, severe hypoalbuminemia, suspected protein-losing enteropathy, and trace result in XPERT MTB/RIF ULTRA on colonic biopsy, prompting anti-tuberculosis therapy. Given infection severity, an immunological investigation was undertaken. Exams demonstrated low IgG (300 mg/dL), low IgM (36 mg/dL), low-normal IgA, non-protective rubella/mumps IgG despite prior vaccination. CD4+ T-cell counts were reduced, with an inverted CD4/CD8 ratio. Flow cytometry (%CD45+ live cells) revealed granulocyte expansion, severe B-cell lymphopenia, dendritic cell depletion, reduced CD14+ monocytes, CD4+ and naïve T-cell lymphopenia, and TEMRA expansion. Whole-genome sequencing identified a heterozygous missense variant in NFKB2 exon 19 (NM_001322934.2.2156G>A;p.Gly719Glu), absent from worldwide or Brazilian genomic databases. Sanger sequencing confirmed the variant in the proband, but not his mother or son. In silico 3D modeling predicted the substitution, 55 amino acids upstream of the C-terminal death domain, alters protein conformation, impairs p100-to-p52 processing, causing p52 haploinsufficiency. Discussion: Disseminated fungal disease, opportunistic bacterial and viral infections, hypogammaglobulinemia, impaired vaccine responses, and T-cell abnormalities raised suspicion for an underlying CVID-like disorder. Although secondary protein loss may have contributed, primary immunodeficiency remains a plausible explanation. The extreme rarity of the NFKB2 p.Gly719Glu variant (ACMG VUS), together with Sanger confirmation (father to be evaluated for inheritance), structural modeling predicting impaired p100-to-p52 processing, and the biologically plausible clinical phenotype, support further functional studies. Conclusion: This case highlights the importance of investigating inborn errors of immunity in adult patients with unusually severe PCM. Molecular diagnosis can directly influence patient management by supporting immunoglobulin replacement therapy, immune monitoring, and long-term surveillance for recurrent infections, lymphomas, autoimmune diseases, and endocrinopathies.
SN  - 2531-1379
SN  - 2531-1387
ER  -