Immunodeficiency 16 and TNFRSF4-Deficience D81.4

Immunodeficiency 16 is caused by a homozygous mutation in the TNFRSF4 gene (OX40 gene; 600315) on chromosome 1p36. TNFRSF4-induced immunodeficiency syndrome is an autosomal recessive primary immunodeficiency associated with classic childhood Kaposi's sarcoma and impaired T-cell function due to complete functional deficiency of TNFRSF4 (Byun et al., 2013).

Although human herpesvirus (HHV)-8 infection is asymptomatic in most people, a small proportion develop Kaposi's sarcoma at some point in their lives. The risk of developing Kaposi's sarcoma is increased by HIV-1 infection or immunosuppression due to treatments that allow organ transplantation.

Sahin et al (2010) reported on an HIV-1 seronegative Turkish girl with consanguineous parents and KS. She presented at the age of 9 years with multicentric Kaposi's sarcoma of the left hand, right shoulder, and thigh. There was concomitant massive splenomegaly and pancytopenia. Bone marrow biopsy, culture, and specific IgG diagnosed leishmaniasis due to Leishmania infantum.

The skin lesions, splenomegaly, pancytopenia, and bone marrow abnormality regressed after treatment with liposomal amphotericin. Five years later, KS lesions reappeared on the patient's thighs and feet and were confirmed by biopsy. The biopsy showed evidence of HHV-8, and the lesions regressed with etoposide treatment. The patient's parents and younger sister were healthy, and her younger brother had a history of lower respiratory tract infections.

Byun et al (2013) studied a patient aged 19 years published by Sahin et al (2010). Homozygosity mapping and whole-exome sequencing identified a homozygous arg65-to-cys (R65C; 600315.0001) mutation in the TNFRSF4 gene (OX40 gene). The R65 mutation is not evolutionarily conserved but is adjacent to the highly conserved residue cys64. The patient's parents, a younger sister, and a younger brother were all heterozygous for R65C and HHV-8 seropositive but were KS-free.

The R65C mutation was absent in Turkish and human genome diversity panel controls. Flow cytometric analysis demonstrated that TNFRSF4 protein with the R65C mutation was weakly expressed on T cells. The patient's T cells were unable to bind or respond to TNFRSF4 (603594). This indicates complete functional TNFRSF4 deficiency. Although the patient was seropositive for a number of recall antigens, he showed no T-cell response to these antigens.

Increased TNFRSF4 expression was associated with TP53, FLT3, and NPM1 mutations, as well as poor clinical outcome in "non-M3 AML." TNFRSF4 expression was significantly increased in this form of acute myeloid leukemia (Gu S et al 2020).

Atopic dermatitis: These keratinocytes produce large amounts of thymic stromal lymphopoietin, IL-25, and IL-33, leading to a type 2 immune abnormality via TNFRSF4 signaling (Furue M et al. 2019).

1. Byun M et al (2013) Inherited human OX40 deficiency underlying classic Kaposi sarcoma of childhood. J Exp Med 210: 1743-1759.
2. Furue M et al (2019) Pathogenesis of atopic dermatitis: current paradigm. Iran J Immunol 16: 97-107.
3. Gu S et al (2020) Elevated TNFRSF4 gene expression is a predictor of poor prognosis in non-M3 acute myeloid leukemia. Cancer Cell Int 20:146.
4. Sahin G et al (2012) Classic Kaposi sarcoma in 3 unrelated Turkish children born to consanguineous kindreds. Pediatrics 125: e704-e708.