Abstract
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.
Highlights
Deficiency of serine/threonine kinase 4 (STK4), referred to as mammalian sterile 20-like protein (MST1), is an autosomal recessive primary immunodeficiency (PID) typically characterized by profound CD4 lymphopenia and recurring infections [1,2,3,4,5,6]
Homozygous STK4 mutations have been described in PID patients presenting with CD4 lymphopenia and recurring infections [1,2,3,4,5,6]
The initial clinical picture of these two cases resembled the phenotype of ALPS like syndromes
Summary
Deficiency of serine/threonine kinase 4 (STK4), referred to as mammalian sterile 20-like protein (MST1), is an autosomal recessive primary immunodeficiency (PID) typically characterized by profound CD4 lymphopenia and recurring infections [1,2,3,4,5,6]. Due to the T cell impairment, many STK4-deficient patients experience fulminant EBV infections leading to lymphoproliferation and lymphoma development [1, 2, 5]. This EBV associated lymphoproliferation can be observed in various PIDs including T cell defects, e.g., in patients with mutations in the Interleukin-2-Inducible T Cell Kinase (ITK) gene or in the Magnesium Transporter 1 (MAGT1) gene [7,8,9]. One of them presented with the first reported case of an EBV negative lymphoma in this patient cohort
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