Booth, C

Gilmour, K

Nademi, Z

Radwan, N

Rao, K

Worth, A

English

UCL Discovery

X-Linked Lymphoproliferative Disease: A disease with many presentations Zohreh Nademi, PhD 1; Nesrine Radwan MD 2; Kanchan Rao, MD 3; Kimberly Gilmour, PhD 1; Austen Worth, PhD 1; Claire Booth, PhD 1  1Department of Pediatric Immunology, Great Ormond Street Hospital, London, UK 2Pediatric Allergy and Immunology Unit, Children’s Hospital, Ain Shams University, Cairo, Egypt 3Bone Marrow Transplant Unit, Great Ormond Street Hospital, London, UK  Corresponding author: Zohreh Nademi, Department of Pediatric Immunology, Great Ormond Street Hospital, London,  WC1N 3JH, UK, Email: zohreh.nademi@gosh.nhs.uk, Tel: +44 (0) 207 405 9200, Fax: +44 (0) 207 813 8552  Keywords: X-linked lymphoproliferative, Hemophagocytic lymphohistiocytosis, Lymphoma, EBV infection, Hematopoietic stem cell transplant  Capsule Summary: XLP1 can present in many different ways with no genotype phenotype correlation making close monitoring extremely important, especially in those with a family history  Word Count: 1014 Abstract Background: X-linked lymphoproliferative disease (XLP1) is caused by mutations in the SH2D1A gene, which affect SLAM-associated protein (SAP). Children with this condition may present with hemophagocytic lymphohistiocytosis (HLH), lymphoma, severe immune dysregulation and dysgammaglobulinemia. It is associated with increased susceptibility to EBV, however, a third of patients have no evidence of previous EBV infection and many patients are diagnosed based on family history alone. Objective and Method: Here we report 3 siblings from a family with hemizygous deletions of exon 2 of the SH2D1A gene manifesting with different phenotypes at different ages.  Results: Patient 1 presented with chest infection and hypogammaglobulinaemia at 21 months of age. He commenced immunoglobulin replacement and later developed persistent EBV viremia and cytopenias . Patient 2 developed EBV-negative non-Hodgkin lymphoma at 3 years old and underwent hematopoietic stem cell transplant (HSCT). Patient 3 developed EBV-negative CNS-HLH at 11 months of age and also underwent HSCT but died of multi-organ failure.  Conclusion: It is strongly recommended that genetic screening be carried out in families with a history of XLP1. However, patients diagnosed at birth still carry a significant risk of mortality despite close monitoring as demonstrated here. Early curative treatment with HSCT may improve outcome especially if undertaken before developing significant morbidities as we know that active disease at the time of transplant and a mismatched donor reduce survival to almost 50%. To the Editor, X-linked lymphoproliferative disease (XLP1) was first described in the 1970s1 and is a rare primary immunodeficiency (PID) caused by mutations in the SH2D1A gene. This gene encodes the SLAM-associated protein (SAP) which is a key regulator of immune function in T, NK, and NKT cells and defects in this protein may lead to the cellular and humoral immune defects characterized in patients2. Clinical manifestations vary and include hemophagocytic lymphohistiocytosis (HLH), lymphoma and dysgammaglobulinemia2-4 but patients can experience a wide range of phenotypes associated with immune dysregulation, even independent of Epstein-Barr virus (EBV) infection4-5. Although historically associated with EBV infection, a recent study showed 35% of patients with XLP1 had no evidence of previous EBV infection and many patients are diagnosed based on positive family history alone5-7. No clear genotype phenotype correlation has been identified 5, 8. Here we report 3 siblings from a nonconsanguineous Yemeni family with hemizygous deletions of exon 2 of the SH2D1A gene who manifested different phenotypes at different ages (Table 1).  Patient 1 was well until 21 months of age when he developed bilateral bronchopneumonia and pleural effusion requiring hospital admission. Further investigation confirmed severe hypogammaglubulinemia, marked lymphocytosis and subsequently a hemizygous deletion of exon 2 of the SH2D1A gene. He commenced immunoglobulin replacement therapy and was monitored regularly. A donor search for hematopoietic stem cell transplant (HSCT) identified no suitable donor therefore HSCT was not undertaken at an early age. He developed EBV viremia first at 6 years old and received several courses of rituximab over the next few years.  Upon depletion of B cells, EBV viremia persisted and further analysis confirmed the presence of EBV in T and NK cells. Recently he developed autoimmune hemolytic anemia (AIHA) requiring Rituximab and intravenous immunoglobulin (IVIG). He developed lower lobe lung collapse associated with Hemaphilus influenza and chest CT confirmed bronchiectasis. He remains on immunoglobulin therapy and prophylactic antibiotics awaiting HSCT. Patient 2 was diagnosed at birth based on the positive family history. He remained well until 3 years of age when he developed intermittent abdominal pain. This was not associated with fever, night sweats or diarrhea/constipation. Further investigation confirmed raised LDH, anemia and negative EBV PCR. Abdominal CT scan demonstrated marked thickening of the distal ileum with pathological mesenteric and  right iliac fossa enlarged lymph nodes. A biopsy was consistent with non-Hodgkin lymphoma and he received 2 cycles of R-GRAB (Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone, Methotrexate, Folinic acid, Etoposide, Tioguanine, Cytarabine, Intrathecal Methotrexate and Rituximab) chemotherapy before proceeding to a mismatched (8/10) unrelated cord blood transplant (Table 2) and successfully engrafted with 100% donor engraftment at last follow up 2 years post-HSCT. He developed gut and skin graft versus host disease (GvHD) with complete resolution. He also developed AIHA post-HSCT requiring steroid, rituximab, high dose IVIG and cyclosporine (which was stopped following the development of posterior reversible encephalopathy syndrome (PRES)). Currently he is fit and well.  Patient 3 was again diagnosed in infancy based on family history. He thrived and developed normally until 11 months of age when he developed generalised seizures. Brain CT and MRI scans showed multiple areas of signal abnormality in the cerebral hemispheres, internal capsules and cerebellum but no hydrocephalus or hemorrhage (Figure 1). He required PICU admission and ventilation to control his seizures. A lumbar puncture showed a raised protein in CSF with no cells present. There was no evidence of hemophagocytosis on bone marrow aspirate and trephine. He never developed any systemic features of HLH; ferritin was modestly raised to a peak of around 2,000 µg/L, triglycerides of 3 mmol/L and soluble CD25 of 10,000 pg/ml. He was commenced on the HLH 94 protocol9; however, he received only 2 doses of etoposide due to developing mucositis.  A repeat brain MRI showed more significant abnormalities and progressive lesions with herniation. An external ventricular device was inserted to relieve oedema and brain biopsy confirmed a lymphocytic infiltrate and features of immune dysregulation but no specific hemophagocytosis. He then was treated with Campath 1-H 0.3 mg/kg in total which led to modest improvement. He developed a right lower zone consolidation which impaired his ventilation. His nasopharyngeal secretion was positive for Respiratory syncytial virus and treatment with zanamivir and ribavirin was initiated. A lung biopsy performed pre-transplant showed scarring with significant fibrosis and macrophage infiltrates with negative cultures and PCRs. He underwent a TCR alpha/beta CD19 depleted HSCT from a MMUD (8/10) (details in Table 2) with100% donor engraftment on whole blood. However, he developed numerous complications post-transplant including thrombotic microangiopathy (TMA), Grade III skin GvHD, Mycobacterium abscessus and Stenotrophomonas lung infection and widespread skin breakdown.  After several months abdominal distention and discomfort was noted with raised lactate and an abdominal CT scan demonstrated fatty infiltration of a grossly distended liver. He rapidly developed liver failure progressing to multi-organ failure and sadly died.   XLP1 is a disorder of severe immune dysregulation, with HLH, lymphoma and humoral abnormalities amongst its spectrum of manifestations5-6. It is associated with an increased susceptibility to severe EBV infection, however, 35% of patients are EBV negative at diagnosis and may already display a clinical phenotype.  There appears to be no significant difference in mortality seen between EBV positive and EBV negative patients5. Considering the high morbidity and mortality rate, it is strongly recommended that genetic screening and counselling be carried out in families with a history of XLP1. However, patients diagnosed at birth due to positive family history still carry a significant risk of mortality despite monitoring as demonstrated here; highlighting the severity of this disorder. Considering the lack of genotype-phenotype correlation and unpredictable course of XLP-1 5,8,10, close monitoring remains critical to allow the prevention of infections, organ damage such as bronchiectasis, and to permit early treatment of EBV infection and other serious complications. Early curative treatment with HSCT may improve outcome especially if it is carried out before developing significant morbidities as we know that active disease at the time of transplant and use of a mismatched donor reduce survival to almost 50%5.    Author Contribution: ZN and NR equally contributed in writing the manuscript . Zohreh Nademi, PhD 1  Nesrine Radwan MD 2  Kanchan Rao, MD 3  Kimberly Gilmour, PhD 1  Austen Worth, PhD 1  Claire Booth, PhD 1  1Department of Pediatric Immunology, Great Ormond Street Hospital, London, UK 2Pediatric Allergy and Immunology Unit, Children’s Hospital, Ain Shams University, Cairo, Egypt 3Bone Marrow Transplant Unit, Great Ormond Street Hospital, London, UK     References: 1. Purtilo DT, Cassel CK, Yang JP, Harper R. X-linked recessive progressive combined variable immunodeficiency (Duncan’s disease). Lancet (1975) 1(7913):935–40.  2. Worth AJ, Houldcroft CJ, Booth C. Severe Epstein–Barr virus infection in primary immunodeficiency and the normal host. Br J Haematol (2016) 175(4):559–76.  3. Harrington DS, Weisenburger DD, Purtilo DT. Malignant lymphoma in the X-linked lymphoproliferative syndrome. Cancer (1987) 59(8):1419–29.  4. Panchal N, Booth C, Cannons JL, Schwartzberg PL. X-Linked Lymphoproliferative Disease Type 1: A Clinical and Molecular Perspective. Front. Immunol. (2018) 9:666. 5. Booth C, Gilmour KC, Veys P, Gennery AR, Slatter MA, Chapel H, et al. X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease. Blood (2011) 117(1):53–62.  6. Sumegi J, Huang D, Lanyi A, Davis JD, Seemayer TA, Maeda A, et al. Correlation of mutations of the SH2D1A gene and Epstein–Barr virus infec-tion with clinical phenotype and outcome in X-linked lymphoproliferative disease. Blood (2000) 96(9):3118–25. 7. Gilmour KC, Cranston T, Jones A, Davies EG, Goldblatt D, Thrasher A, et al. Diagnosis of X-linked lymphoproliferative disease by analysis of SLAM-associated protein expression. Eur J Immunol (2000) 30(6):1691–7. 8. Sumegi J, Seemayer TA, Huang D, Davis JR, Morra M, Gross TG, et al. A spectrum of mutations in SH2D1A that causes X-linked lymphoproliferative disease and other Epstein–Barr virus-associated illnesses. Leuk Lymphoma (2002) 43(6):1189–201.  9.  Henter J, Samuelson-Home AC, Arico M, Egeler M, Elinder G, Filipovich A et al. Treatment of Hemophagocytic   lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood (2002) 100 (7): 2367- 2373. 10.  Houlston RS, Tomlison IP. Modifier genes in humans: strategies for identification. Eur J Hum Genet (1998): 7:1537-45.                 Table 1: Patients Characteristic  Age @ DX Age @ presentation SAP expression Presentation Ig (g/L) Vaccine responses Lymphocyte subset  (Cells x 10^9/L) Pre-transplant prophylactic Infections Pre-transplant P1 2 years 21 months Absent Chest infection  bronchiectasis panhypogamma-globulinemia IgG 4.3 IgA <0.06 IgM 0.05 NA CD3 6.13 CD19 2 CD56 0.35 CD4 3.4 CD8 2.6 Naïve T cells  normal  IVIG EBV P2 birth 3 years Absent Non-Hodgkin lymphoma in ileum IgG 4.5 IgA 0.52 IgM 0.66 Low then normal after booster vaccine CD3 5.4 CD19 0.36 CD56 0.64 CD4 4.5 CD8 0.86 Naïve T cells  normal Nil before presentation Then IVIG Nil P3 8 months 11 months Absent Uncontrollable seizures  CNS HLH  Chest infection IgG 2.76 IgA 0.36 IgM 0.58 Normal CD3 6.7 CD19 1.25 CD56 1.54 CD4 5.66 CD8 0.96 Naïve T cells  normal  Nil before presentation then IVIG/ABx RSV Adenovirus HHV6  Dx: Diagnosis; P: Patient; CNS: Central nerve system; HLH: Hemophagocytic lymphohistiocytosis; EBV: Epstein Barr Virus; RSV: Respiratory Syncytial virus; HHV6: Human herpes virus type 6; Ig: Immunoglobulin; IVIG: Intravenous immunoglobulin; ABx: Antibiotic, NA: Not available.    Table 2: Hematopoietic stem cell transplant characteristic  Donor Conditioning GVHD Prophylaxis CD34 dose  Donor Engraftment Infection  post-HSCT Complication  post-HSCT outcome P2 MMUD Cord   1 A mm  1 DQ mm Treosulfan 14 g/m2 Fludarabin 150 mg/m2 Thiotipa 10 mg/kg  CSA MMF 4.6 x 10^5/kg 100% CMV Adenovirus EBV Engraftment syndrome Alive & well  P3  MMUD PBSC  1 A mm 1 DQ mm  TCR ab depleted  Treosulfan 14 g/m2 Fludarabin 160 mg/m2 Thiotipa 10 mg/kg ATG 15 mg/kg Rituximab 200 mg/m2  CSA  10 x 10^6/kg  100%  Coronavirus Mycobacteria Stenotrophomonas  TMA Skin GVHD ATM lung infection MOF  Died  P: Patient; MMURD: Mismatched unrelated donor; mm: mismatched; TCR ab: T cell receptor alpha/beta; CSA: Cyclosporin A; MMF: Mycophenolate mofetil; CMV: Cytomegalovirus; EBV: Epstein Barr Virus; TMA: Thrombotic microangiopathy; GvHD: Graft versus host disease; ATM: Atypical mycobacteria; MOF: Multi organ failure; GVHD: Graft versus host diseases.                                A          B Figure 1: Brain Imagings A: Brain MRI at the time of diagnosis of CNS HLH: There are multifocal enhancing lesions involving white matter, area of cortical and deep grey matter. Leptomeningeal enhancement is also noted. B: Brain MRI post-HLH 94 protocol therapy: The  multiple  brain  lesions  appear  more extensive in keeping with disease progression. 

Different Phenotypic Presentations of X-Linked Lymphoproliferative Disease in Siblings with Identical Mutations

https://discovery.ucl.ac.uk/id/eprint/10118406/1/Gilmour_XLP-ZN%208.1.19.docx_%20ZN%2015.11.18%20JACI%20with%20abstract_CB%20kg.pdf

Different Phenotypic Presentations of X-Linked Lymphoproliferative Disease in Siblings with Identical Mutations

Abstract

Similar works

Full text

Available Versions

UCL Discovery