TY - JOUR
T1 - Case Report
T2 - Hypomorphic Ligase 4 deficiency – a paradigm of immunodysregulation
AU - Andrade, Catarina
AU - Cordeiro, Ana Isabel
AU - Pinto, Marta Valente
AU - Neves, Conceição
AU - Martins, Catarina
AU - Villartay, Jean Pierre
AU - Neves, João Farela
N1 - Funding Information:
The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. The present publication was funded by Funda\u00E7\u00E3o Ci\u00EAncia e Tecnologia, IP national support through UID/04923 - Comprehensive Health Research Centre. Acknowledgments
Publisher Copyright:
Copyright © 2025 Andrade, Cordeiro, Pinto, Neves, Martins, Villartay and Neves.
PY - 2025/2
Y1 - 2025/2
N2 - DNA Ligase 4 is critical to nonhomologous end joining, necessary for V(D)J recombination in T and B cell development. Ligase 4 deficiency is a rare autosomal recessive disorder caused by hypomorphic mutations in the DNA Ligase 4 gene, that can lead to a wide range of phenotypes. We describe a case of Ligase 4 deficiency causing a type of T-B-NK+ atypical SCID, highlighting the clinical and immunologic manifestations. An eight-year-old female, from São Nicolau Island (Cape Verde), presented at our hospital with a history of recurrent pneumonia and suppurative otitis, multiple skin lesions attributed to fungal and bacterial infections since the age of two, and recurrent diarrhea and growth impairment, beginning at the age of four. The laboratory workup showed almost absent B cells, marked hypogammaglobulinemia, and an impaired response to protein antigens. Flow cytometry revealed normal NK and T cell counts, but with nearly absent naïve T cells and TCR-Va7 expressing T lymphocytes, and reduced proliferative responses to mitogens and antigens. An oligoclonal Vβ repertoire was identified by FACS, and PROMIDISa analysis revealed a skewed TCRa repertoire signature. A 477 PID-related genes NGS panel identified a homozygous R278H mutation in the DNA Ligase 4 gene, previously reported to cause Ligase 4 deficiency. Immunoglobulin replacement and prophylactic therapies were started while waiting for hematopoietic stem cell transplantation. She has experienced fluctuating transaminase levels. The cutaneous biopsy was suggestive of lupus pernio. She has shown recurrent inflammatory signs in her limbs, with documented tenosynovitis on ultrasound. Homozygous R278H in Ligase 4 has been linked to various ranges of manifestations in Ligase 4 deficient patients. In our report, this genotype resulted in T-B-NK+ atypical SCID, that after proper prophylaxis has a predominant autoimmune phenotype.
AB - DNA Ligase 4 is critical to nonhomologous end joining, necessary for V(D)J recombination in T and B cell development. Ligase 4 deficiency is a rare autosomal recessive disorder caused by hypomorphic mutations in the DNA Ligase 4 gene, that can lead to a wide range of phenotypes. We describe a case of Ligase 4 deficiency causing a type of T-B-NK+ atypical SCID, highlighting the clinical and immunologic manifestations. An eight-year-old female, from São Nicolau Island (Cape Verde), presented at our hospital with a history of recurrent pneumonia and suppurative otitis, multiple skin lesions attributed to fungal and bacterial infections since the age of two, and recurrent diarrhea and growth impairment, beginning at the age of four. The laboratory workup showed almost absent B cells, marked hypogammaglobulinemia, and an impaired response to protein antigens. Flow cytometry revealed normal NK and T cell counts, but with nearly absent naïve T cells and TCR-Va7 expressing T lymphocytes, and reduced proliferative responses to mitogens and antigens. An oligoclonal Vβ repertoire was identified by FACS, and PROMIDISa analysis revealed a skewed TCRa repertoire signature. A 477 PID-related genes NGS panel identified a homozygous R278H mutation in the DNA Ligase 4 gene, previously reported to cause Ligase 4 deficiency. Immunoglobulin replacement and prophylactic therapies were started while waiting for hematopoietic stem cell transplantation. She has experienced fluctuating transaminase levels. The cutaneous biopsy was suggestive of lupus pernio. She has shown recurrent inflammatory signs in her limbs, with documented tenosynovitis on ultrasound. Homozygous R278H in Ligase 4 has been linked to various ranges of manifestations in Ligase 4 deficient patients. In our report, this genotype resulted in T-B-NK+ atypical SCID, that after proper prophylaxis has a predominant autoimmune phenotype.
KW - autoimmunity
KW - case reports
KW - DNA damage repair
KW - hypogammaglobulinemia
KW - inborn errors immunity
KW - V(D)J recombination
UR - http://www.scopus.com/inward/record.url?scp=86000548959&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2025.1545630
DO - 10.3389/fimmu.2025.1545630
M3 - Article
C2 - 40093007
AN - SCOPUS:86000548959
SN - 1664-3224
VL - 16
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 1545630
ER -