EBV Negative Lymphoma and Autoimmune Lymphoproliferative Syndrome Like Phenotype Extend the Clinical Spectrum of Primary Immunodeficiency Caused by STK4 Deficiency

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.

Flow Cytometry is a Reliable Tool in the Diagnosis of STK4 Deficiency

“…A wide range of the clinical spectrum is observed in STK4 deficient patients ranging from recurrent infections and autoimmune manifestations to a very rare form of malignancies such as primary cardiac lymphoma as well as EBV-associated lymphoma. Until now, 18 patients were diagnosed with STK4 deficiency with nine different novel mutations, and they were diagnosed at least after 6 years old even with early onset of their diseases and clinical severity (8)(9)(10)(11)(12)(13)(14)(15). Methods performed in the diagnosis of STK4 deficiency such as NGS (panels, WES, WGS) need confirmation by Sanger sequencing, western blotting, and some functional assays that require extra time for the final decision (8)(9)(10)(11)(12)(13)(14)(15).…”

“…Diagnosis of STK4 deficiency currently depends on gene sequencing via NGS (Next-generation sequencing) panel, Whole-exome sequencing (WES) or Sanger sequencing, and rarely western blotting (8)(9)(10)(11)(12)(13)(14)(15). Early diagnosis of the diseases allows for better prognosis and improved quality of life due to exact treatment options.…”

The Hippo Pathway and Viral Infections

“…Defects in human STK4 cause primary immunodeficiency syndrome reducing T cell and B cell (Zhou et al, 2008;Abdollahpour et al, 2012). Case reports indicate that many patients with STK4 deficiency are highly susceptible to EBV infection, leading to lymphoid hyperplasia and lymphoma development (Schipp et al, 2018). Therefore, STK4 is critical for the control of unrestricted EBV-induced lymphoproliferation.…”

Síndrome linfoproliferativo autoinmune. Actualización y revisión

“…Se han descrito varias inmunodeficiencias ALPS-like incluyendo deficiencia de ADA2, deficiencia de LRBA, deficiencia de MST1 por variantes patogénicas en STK4 y haploinsuficiencia de TN-FAIP3. 35,36,37,38,39,40 Tratamiento La determinación de la etiología genética es de particular importancia para el tratamiento de los pacien- tes con ALPS. Los fármacos citotóxicos o citostáticos, incluidos el metotrexato, la mercaptopurina y sus derivaciones o el micofenolato de mofetilo, han demostrado gran eficacia en pacientes con ALPS-FAS, sin embargo, pueden tener una toxicidad importante a largo plazo.…”