Serine/threonine kinase 4 (STK4) deficiency is an autosomal recessive genetic condition that leads to primary immunodeficiency (PID) typically characterized by
lymphopenia,
recurrent infections and Epstein Barr Virus (EBV) induced lymphoproliferation and -
lymphoma. State-of-the-art treatment regimens consist of prevention or treatment of
infections,
immunoglobulin substitution (
IVIG) and restoration of the immune system by
hematopoietic stem cell transplantation. Here, we report on two patients from two consanguineous families of Turkish (patient P1) and Moroccan (patient P2) decent, with PID due to homozygous STK4 mutations. P1 harbored a previously reported frameshift (c.1103 delT, p.M368RfsX2) and P2 a novel
splice donor site mutation (P2; c.525+2 T>G). Both patients presented in childhood with
recurrent infections, CD4
lymphopenia and dysregulated
immunoglobulin levels. Patient P1 developed a highly malignant
B cell lymphoma at the age of 10 years and a second, independent
Hodgkin lymphoma 5 years later. To our knowledge she is the first STK4 deficient case reported who developed
lymphoma in the absence of detectable EBV or other common viruses.
Lymphoma development may be due to the lacking
tumor suppressive function of STK4 or the perturbed immune surveillance due to the lack of CD4+ T cells. Our data should raise physicians' awareness of [1]
lymphoma proneness of STK4 deficient patients even in the absence of
EBV infection and [2] possibly underlying STK4 deficiency in pediatric patients with a history of
recurrent infections, CD4
lymphopenia and
lymphoma and unknown genetic make-up. Patient P2 experienced recurrent
otitis in childhood, but when she presented at the age of 14, she showed clinical and immunological characteristics similar to patients suffering from
Autoimmune Lymphoproliferative Syndrome (ALPS): elevated
DNT cell number, non-malignant
lymphadenopathy and hepatosplenomegaly, hematolytic
anemia,
hypergammaglobulinemia. Also patient P1 presented with ALPS-like features (
lymphadenopathy, elevated
DNT cell number and increased
Vitamin B12 levels) and both were initially clinically diagnosed as ALPS-like. Closer examination of P2, however, revealed active
EBV infection and genetic testing identified a novel STK4 mutation. None of the patients harbored typically ALPS-associated mutations of the
Fas receptor mediated apoptotic pathway and Fas-mediated apoptosis was not affected. The presented case reports extend the clinical spectrum of STK4 deficiency.