Immunodeficiency 78 With Autoimmunity And Developmental Delay D81.4

Immunodeficiency-78 with autoimmunity and developmental delay (IMD78) is a very rare (described in a few families), autosomal recessive, systemic immunodeficiency syndrome caused by a homozygous or compound heterozygous mutation in the TPP2 gene (190470) on chromosome 13q33.

Initial manifestation in early childhood.

Affected individuals exhibit characteristics of immunodeficiency. There is an increased susceptibility to bacterial, viral and fungal infections of the nasopharynx and skin. Furthermore, autoimmunological phenomena such as autoimmune cytopenias, hemolytic anemia, and thrombocytopenia occur. Less common are autoimmune hepatitis or thyroid disorders and vasculitides of the central nervous system with a tendency to apoplexy.

In parallel with the symptoms of immunodeficiency and autoimmunity, global developmental delays with speech delay and varying degrees of mental retardation are also demonstrated.

Laboratory studies show lymphopenia with advanced differentiation and premature senescence of CD8+ T cells and B cells. Some patients may have hypergammaglobulinemia. The findings suggest dysregulation of the immune system.

Hematopoietic bone marrow transplantation can be curative. (Lu et al. 2014; Atallah et al. 2021).

Many patients die prematurely.

Lu et al (2014) reported four children from two unrelated families with a complex syndromic immune disorder. The patients presented in early infancy with recurrent infections such as otitis media, lower respiratory tract infections, hepatitis, and eczematous dermatitis caused by bacterial, viral, and mycotic pathogens, including H. influenza, hepatitis A, varicella, herpes simplex virus (HSV)-1, cytomegalovirus (CMV), and Aspergillus species. These chronic infections resulted in bronchiectasis and conductive hearing loss. All patients also had various severe autoimmune abnormalities, including hemolytic anemia, immune thrombocytopenic purpura, and autoimmune neutropenia associated with autoantibodies.

One patient developed systemic central nervous system lupus erythematosus with stroke, and another developed severe autoimmune hepatitis. Patients also had mild to moderate global developmental delay with delayed walking and poor language development. Laboratory tests revealed decreased circulating T, B, and NK cell counts and hypergammaglobulinemia. Levels of naïve CD8 and CD4 T cells were decreased.

Stepensky et al (2015) reported on a 12-year-old boy born to consanguineous Palestinian parents who had autoimmune hemolytic anemia, thrombocytopenia, lymphadenopathy, and intermittent splenomegaly during the first years of life. Furthermore, multiple viral infections with varicella, CMV, and human papillomavirus (HPV). Laboratory tests revealed elevated IgG and IgM levels, mild leukopenia with lymphopenia, and decreased naive CD4+ T-cell and B-cell counts. He also had mild developmental delay and required special education. Clinically, the boy was diagnosed with Evans syndrome. Therapeutic curative hematopoietic stem cell transplantation was performed.

Atallah et al (2021) reported 4 patients from 2 unrelated Swiss families with IMD78. The patients, who ranged in age from 5 to 27 years, presented in infancy or early childhood with recurrent upper and lower respiratory tract infections, acute otitis media (in one case with conductive hearing loss), and bronchiectasis. They also had episodic or chronic thrombocytopenia or pancytopenia and global developmental delay with language delay and behavioral problems requiring special schooling. Other common features included diffuse livedo racemosa, brittle nails, paronychia, dermohypodermitis, alopecia, and cutaneous papillomavirus infections.

1. Atallah I et al. (2021) Immune deficiency, autoimmune disease and intellectual disability: a pleiotropic disorder caused by biallelic variants in the TPP2 gene. Clin. Genet. 99: 780-788.
2. Huai J et al (2008) Activation of cellular death programs associated with immunosenescence-like phenotype in TPPII knockout mice. Proc Nat Acad Sci 105: 5177-5182.
3. Lu W et al (2014) Dual proteolytic pathways govern glycolysis and immune competence. Cell 159: 1578-1590.
4. Stepensky P et al (2015) Early-onset Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency. Blood 125: 753-761.