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

Abstract

Rationale:Primary cardiac lymphoma (PLC) is an extremely uncommon malignancy. PCL is more common in secondary immunodeficient patients. In this report, we describe a unique case of PLC who had been diagnosed as a STK4 deficient patient. This case is the first Primary immunodeficiency (PID) patient developing PCL in the world.Patient concerns:An eleven-year-old girl, a known case of PID, was referred to the pediatric cardiology department because of chest pain and dyspnea. Her CXR revealed cardiomegaly without mediastinal involvement and the echocardiography showed a mild pericardial effusion and cystic-shape echogenic masses.Diagnoses:After a period of missed follow up, she presented with respiratory distress following with syncope at the clinic because of a pressure effect of a large mass on the right ventricular outflow tract (RVOT) .An emergency operation was done for debulking of the tumors and resolving of RVOT obstruction. Biopsy and immunohistochemical staining was revealing “T-cell lymphoma”, non-Hodgkin's type.Interventions:Chemotherapy was done with cyclophosphamide, methotrexate, adriamycine, vincristine, hydrocortisone and allopurinol.Outcomes:The tumors shrank after chemotherapy initiation and she stayed stable for almost one month. Finally, she developed sever thrombocytopenia during her chemotherapy and died because of lung hemorrhage two months after her operation.Lessons:Although PCL is very rare, it must be considered in the differential diagnosis of intracardiac mass or refractory pericardial effusions, especially in PIDs which are widely known for developing EBV-associated diseases such as lymphoma.

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

“…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.…”

“…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 ).…”

“…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 ).…”

“…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 ).…”

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

“…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.…”