T-Cell Immunodeficiency, Recurrent Infections, And Autoimmunity With Or Without Cardiac Malformations

A number sign (#) is used with this entry because this primary T-cell immunodeficiency syndrome can be caused by homozygous mutation in the STK4 gene (604965) on chromosome 20q13.

Description

STK4 deficiency results in a primary T-cell immunodeficiency syndrome characterized by progressive loss of naive T cells, recurrent bacterial, viral, and fungal infections, warts, and abscesses, autoimmune manifestations, and cardiac malformations, including atrial septal defect (Abdollahpour et al., 2012; Nehme et al., 2012).

Clinical Features

Abdollahpour et al. (2012) reported 3 patients, a brother and sister and their niece, from a consanguineous Iranian family who presented with a primary immunodeficiency resulting in bacterial and viral infections, mucocutaneous candidiasis, cutaneous warts, and recurrent skin abscesses. Two sibs of the brother and sister died in their first year of life due to septicemia. All patients showed continuous or intermittent neutropenia, with normal maturation of neutrophils in bone marrow. Immunologic investigation revealed lymphopenia with a paucity of T and B cells in the brother and sister. Their niece, who had episodes of lymphopenia in her records, had low CD4 (186940)-positive T cells and B cells but elevated CD8 (see 186910)-positive T cells, possibly due to generalized Epstein-Barr virus (EBV)-associated lymphadenopathy. Lymph node biopsy in this patient showed an EBV-associated B-lymphoproliferative disorder that phenotypically resembled lymphoplasmacytic lymphoma. Systematic echocardiography identified structural cardiac abnormalities, including atrial septal defect type II and patent foramen ovale in the sister and brother, respectively, and patent foramen ovale associated with mitral, tricuspid, and pulmonary insufficiency in their niece. These cardiac aberrations had not caused clinical symptoms.

Nehme et al. (2012) investigated 4 patients with combined immunodeficiency from 2 unrelated consanguineous Turkish families who presented with recurrent bacterial and viral infections, autoimmune manifestations, dermatitis, hypergammaglobulinemia G and A, and contrasting defective antibody responses. The affected child from 1 family was successfully treated for EBV-positive Hodgkin B-cell lymphoma at age 5 years. Two of the 3 affected children from the second family, who had developed EBV-associated B-cell lymphoproliferative syndrome and autoimmune hemolytic anemia with persistent EBV viremia, respectively, died following hematopoietic stem cell transplantation (HSCT) due to graft-versus-host disease and persistent infections. HSCT at the age of 4 years apparently cured the immunodeficiency in the third affected child from this family. This patient was found to have tricuspid valve insufficiency and moderate right ventricular hypertrophy at the age of 5 years.

Inheritance

The primary T-cell immunodeficiency syndrome resulting from STK4 deficiency reported by Abdollahpour et al. (2012) and Nehme et al. (2012) is inherited in an autosomal recessive fashion.

Molecular Genetics

In the 3 members of the consanguineous Iranian kindred with a primary T-cell immunodeficiency syndrome that they reported, Abdollahpour et al. (2012) identified a homozygous premature termination mutation in the STK4 gene (W250X; 604965.0003). Parents and healthy sibs were heterozygous. Western blot analysis showed that patients with homozygous mutations expressed no STK4, while heterozygous carriers expressed intermediate levels compared to wildtype homozygous subjects. STK4-deficient lymphocytes and neutrophils exhibited enhanced loss of mitochondrial membrane potential and increased susceptibility to apoptosis.

In the 2 consanguineous unrelated Turkish families with 4 patients affected by a T-cell immunodeficiency syndrome that they reported, Nehme et al. (2012) identified putative truncation mutations in the STK4 gene. The patient in the first family was homozygous for an arg117-to-ter substitution (604965.0001). The 3 affected sibs in the second family were homozygous for a 1-bp deletion that resulted in a frameshift at residue 368 and a contiguous nonsense codon at residue 369 (604965.0002). Parents and healthy sibs in both families were heterozygous for the mutations. RT-PCR analysis showed loss of function and expression of STK4 in patients. Lymphoproliferative responses and lymphocyte survival were also impaired.