EBV lymphoproliferative-associated disease and primary cardiac T-cell lymphoma in a STK4 deficient patient

Sherkat, Roya; Sabri, Mohammad Reza; Dehghan, Bahar; Bigdelian, Hamid; Reisi, Nahid; Afsharmoghadam, Nooshin; Rahimi, Hojjatolah; Rahmanian, Narges; Klein, Cristoph

doi:10.1097/md.0000000000008852

Cited by 23 publications

(24 citation statements)

References 21 publications

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“…Two caspase cleavage sites are described that lead to truncation of the protein before the SARAH domain similar to the M368RfsX2 mutation of P1. Mutations identified in our patients are presented in green, other previously reported mutations in black [M368RfsX2, previously also described by ( 2 )] ( 2 , 3 , 4 , 5 , 6 ). (C) Left : STK4 transcript expression is reduced in both patients compared to healthy controls.…”

Section: Introductionsupporting

confidence: 55%

“…Homozygous STK4 mutations have been described in PID patients presenting with CD4 lymphopenia and recurring infections ( 1 – 6 ). Here, we report on two additional patients with STK4 deficiency, one of them (P2) harboring the first homozygous splice site mutation (c.525+2 T>G) described in this patient entity and the other carrying a previously reported homozygous frameshift mutation (P1; c.1103 delT, p.M368RfsX2) (Table 1 ) ( 2 ).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, similar to other related disorders associated with EBV infections (such as MAGT1 or ITK deficiency), the lymphoma incidence in STK4 deficient patients is assumed to be increased although the absolute number of reported cases, including the case presented here is still low ( n = 3). Sherkat et al reported on a patient who presented first with a B cell lymphoproliferative syndrome and developed later an EBV+ primary cardiac T cell lymphoma, a very rare pediatric malignancy ( 1 , 6 ). Nehme et al reported on a case who suffered from an EBV+ Hodgkin B cell lymphoma ( 2 ).…”

Section: Discussionmentioning

confidence: 99%

“…Deficiency of serine/threonine kinase 4 (STK4), also 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 – 6 ). STK4 deficiency in humans leads to decreased proliferation, increased susceptibility to apoptosis and dysregulation of the transcription factor Forkhead box protein O1 (FOXO1) and its downstream targets in T cells ( 1 – 3 ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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Section: Introductionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Halaçlı¹,

Çağdaş²,

Tezcan³

2020

Asthma Allergy Immunol

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Objective: STK4 (serine-threonine protein kinase 4) deficiency is categorized under combined immunodeficiencies, which are a subgroup of primary immunodeficiencies that profoundly affect T cells. Autosomal recessive STK4 deficiency is characterized by recurrent bacterial and viral infections, mucocutaneous candidiasis, and CD4 + T cell lymphopenia. Autoimmune comorbidities including hemolytic anemia and idiopathic thrombocytopenic purpura, and cardiac problems have been reported in STK4-deficient individuals. Current diagnostic tools for STK4 deficiency include next-generation sequencing (NGS) and Sanger sequencing that detect DNA sequence variations, and western blotting, which evaluates altered protein expression. However, all of these assays are timeconsuming; and in particular, NGS is a costly clinical use tool for a diagnostic laboratory. In comparison, flow cytometry is a rapid and reliable system commonly employed in the diagnosis of a wide range of primary immunodeficiency disorders. Materials and Methods: This study aimed to evaluate STK4 protein expression by flow cytometry among four patients with genetically confirmed STK4 gene mutations and seven healthy individuals. We calculated ΔMFI/cell values to investigate differences in protein expression among the subjects. Results: STK4 protein expression was reduced in the peripheral blood mononuclear cells obtained from all STK4-deficient patients compared to those from the healthy controls. Flow cytometry data was validated by western blotting. Conclusion: Flow cytometry is a rapid and reliable method to detect STK4 protein expression, qualified as a diagnostic tool to study STK4 deficiency.

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