O slideshow foi denunciado.
Utilizamos seu perfil e dados de atividades no LinkedIn para personalizar e exibir anúncios mais relevantes. Altere suas preferências de anúncios quando desejar.

Hyper IgM syndrome

Hyper IgM syndrome

Presented by Nattasasi Suchamalawong, MD.

September18, 2020

  • Seja o primeiro a comentar

  • Seja a primeira pessoa a gostar disto

Hyper IgM syndrome

  1. 1. Hyper IgM Syndrome Nattasasi Suchamalawong, MD. 18 September 2020 Pediatric Allergy and Immunology Department King Chulalongkorn Memorial Hospital
  2. 2. Outline Definition SurvillancePathogenesis Epidemiology Clinical manifestation Prognosis Treatment
  3. 3. Definition
  4. 4. Hyper-IgM syndromes de la Morena et al. J Allergy Clin Immunol Practice 2016;4:1023-36 Immunodeficiency (recurrent infection) with Marked elevation of serum IgM with low or absent IgG, IgA, and IgE or normal/moderately elevated IgM with low but not absent other immunoglobulins Mechanism : defect in Ig class switching recombination (CSR)
  5. 5. Class swicthing recombinant defects and HIGM syndromes ESID Registry - Working definitions for clinical diagnosis of PID November, 27, 2018 At least one of the following: - increased susceptibility to infections(recurrentand/or opportunistic,including cryptosporidium) - immune dysregulation(autoimmunity,lymphoproliferation,sclerosing cholangitis) - cytopenia (neutropenia or autoimmune) - malignancy(lymphoma) - affectedfamily member AND marked decrease of IgG (measured at least twice) AND normal or elevated IgM (measured at least twice) AND defined causes of hypogammaglobulinemia have been excluded AND no evidence of profound T-cell deficiency AND no evidence of Ataxia telangiectasia (cafe-au lait spots, ataxia, telangiectasia, raised AFP)
  6. 6. Epidemiology
  7. 7. Epidemiology R.Yazdani et al. Clinical Immunology 198 (2019) 19–30 - US X-HIGM registry, the prevalence of X-HIGM was approximately 1 in 1,000,000 live births - X-linked Hyper-IgM syndrome (X-HIGM), which is caused by CD40L mutations, is the most common form of HIGM and accounts for about 65–70% of all case (2:1,000,000 in males ) - Globally, all forms of HIGM constitute 0.3–2.9% of all patients with PIDs. - European Society for Immune Deficiency (ESID) demonstrated that 3.08% of PID patients enrolled had CSR defects, the most prevalent being CD40L deficiency with a frequency of 1.16%
  8. 8. Epidemiology Durandy and Kracker. Class-switch recombination defect. Stiehm’s immune deficiencies, 2014 CD40-ligand deficiency is the most common CSR-D
  9. 9. Incidence in Thailand P. Benjasupattanan et al. J Clin Immunol. 2009; 29:357-364. O. Luecha et al. J Allergy Clin Immunol. 2012. Primary Immunodeficiency Diseases; A 20 Years Experience in a Tertiary University Hospital at Ramathibodi
  10. 10. Pathogenesis
  11. 11. B cell responses to antigen Abbas,Abul K. Cellular and molecular immunology, 9th ed, 2018 T- independent response T- dependent response
  12. 12. Class Switching Recombination (CSR) 3 Important steps 1.) Induction of CSR : primary & secondary stimuli 2.) Double-strand breaking (DSB) : Cleavage of S region 3.) Resolution of DSB (S-S synapsis) : recombination M.Teresa de la, Morena et al.J allergy Clin Immunol Pract 2016;4:1-23-36
  13. 13. Abbas,Abul K. Cellular and molecular immunology, 9th ed, 2018 2.Double-Strand Breaking (DSB): molecular AID - Activation-induced cytidine deaminase UNG - Uracil N glycosylase APE - Apurinic/Apyrimidinic endonuclease
  14. 14. Mechanism of heavy chain isotype switching Abbas,Abul K. Cellular and molecular immunology, 9th ed, 2018 I = initiator of transcription S = switch region
  15. 15. Isotype class switching Abbas,Abul K. Cellular and molecular immunology, 9th ed, 2018 Regulated by cytokine from helper T cells
  16. 16. Affinity maturation Abbas,Abul K. Cellular and molecular immunology, 9th ed, 2018
  17. 17. Pathogenesis
  18. 18. Pathogenesis Dunn CP, de la Morena MT. X-Linked Hyper IgM Syndrome , GeneReviews .2020 february
  19. 19. Pathogenesis R. Yazdani et al. The hyper IgM syndromes, Clinical Immunology 198 (2019) 19–30
  20. 20. Clinical pheotype & Treatment
  21. 21. PID with elevated IgM M.Teresa de la, Morena et al.J allergy Clin Immunol Pract 2016;4:1-23-36 Congenital Acquired - Multiple myeloma, CLL, lymphoma -Nephrotic syndrome -Congenital rubella syndrome -Medications: calcineurin inhibitors and phenytoin -Autoimmune diseases: AIHA, Primary biliary cirrhosis, Multiple sclerosis, cryoglobulinemia - Classic : HIGM types 1 to 5 (CD40L,AID,CD40,UNG) - Other defect in CSR : MSH6 deficiency , PMS2 deficiency , APDS , INO 80 defect - NEMO (defects in nuclear factor kappa B essential modulator) - Syndromes associated with HIGM & Low IgG Ataxia telangiectasia (AT) Nijmegen breakage syndrome (NBS) Cernunnos/XRCC4-like factor
  22. 22. CLASSIC HIGM SYNDROMES: X-Linked HIGM (HIGM type 1; CD40Ligand gene) ● Mutations in CD40 Ligand gene (CD40LG) on Xq26.3 ● The most common and well-recognized form of HIGM syndrome M.Teresa de la, Morena et al.J allergy Clin Immunol Pract 2016;4:1-23-36
  23. 23. X-Linked HIGM: Clinical manifestations ● Onset: childhood, up to 40s ● Prevalence 1: 1,000,000 ● > 80% recurrent upper and lower respiratory tract infections ● 40% gastrointestinal manifestations : chronic diarhea ● Others: Neutropenia, common and may be intermittent Parvovirus aplastic anemia Liver disease and sclerosing cholangitis are “red flags” for HIGM and important predictor of mortality ● Opportunistic infections : in young infants : Pneumocystis jirovecii infection. Cryptosporidium infection >> associated sclerosing cholangitis. ● Malignancy: frequently classified as neuroendocrine tumor Pathology : biopsy LN not seen germinal center. Common M.Teresa de la, Morena et al.J allergy Clin Immunol Pract 2016;4:1-23-36 H.Buckley ,S.orange et al.Primary immune deficiency .middleton’s Allergy (9th edition) 2019
  24. 24. Predictor of Mortality Vian Azzu & Lucinda Kennard et al. J ALLERGY CLIN IMMUNOL JANUARY 2018
  25. 25. GI manifestations in X-Linked HIGM M.Teresa de la, Morena et al.J allergy Clin Immunol Pract 2016;4:1-23-36
  26. 26. Neutropenia in XHIGM Rawat et al.Clin Immunol .2018 October ;195:59-66. ▪ Etiology of neutropenia is not known in XHIGM ▪ CD40-40L interaction play a role in myelopoiesis >> neutropenia ▪ An arrest of myelopoiesis at promyelocyte or myelocyte ▪ Treatment : recombinant G-CSF : increase neutrophil counts and significantly reduction in infection ▪ Presence of neutropenia probably did not influence mortality outcome ▪ Survival rates in XHIGM following HSCT : have proven to be superior compared to patient who are not transplanted
  27. 27. Cabral-Marques et al.J Allergy Clin Immunol 2018;142:1571-88. Patients with XHIGM caused by CD40L deficiency often present with episodic, cyclic, or chronic neutropenia, suggesting abnormal neutrophil development. CD40L-deficient patients are susceptible to life-threatening infections caused by opportunistic pathogens, suggesting impaired phagocyte function Similar to CD40L-deficient patients, CD40L knockout mice were found to have impaired neutrophil responses. In parallel, we demonstrated that soluble CD40L induces the promyelocytic cell line to proliferate and mature
  28. 28. X-Linked HIGM: Treatment ● Curative treatment: hematopoietic stem cell transplantation (HSCT) ● IVIG replacement ● Prevention of opportunistic infections: ○ Pneumocystis jirovecii: Trimethroprim- sulfamethoxazole ○ Cryptosporidium: chlorine-tolerant - Drinking only boiled ± filtered water - Avoidance of public swimming pools, lakes, and ponds - Limiting contact with livestock - Practicing extra caution when traveling - Prophylactic use of azithromycin: not recommended ● Prognosis : 20% survival by age 25 year M.Teresa de la, Morena et al.J allergy Clin Immunol Pract 2016;4:1-23-36
  29. 29. Causes of death in patients undergoing HSCT Infection 2 Acute GVHD 1 Liver failure 1 Mitsui-Sekinaka, et al. J Allergy Clin Immunol. 2015 Oct;136(4):1018-24.
  30. 30. Mitsui-Sekinaka, et al. J Allergy Clin Immunol. 2015 Oct;136(4):1018-24. Conclusion: - Prognosis of XHIGM was poor - HSCT showed significant benefit - Younger patients received HSCT had significantly higher survival, event-free survival, and disease-free survival rate. Overall survival Event-free survival Disease-free survival
  31. 31. J Allergy Clin Immunol. 2017 Apr;139(4):1282-1292. Conclusion - General prognosis of XHIGM is poor - Liver disease is a significantpredictor of poor prognosis - HSCT showed no significant survival benefit, but did improve performance status - Younger age and absence of liver disease are predictor of good HSCT outcome Non- HSCT HSCT Overall study (176) 109 (62%) 67 (38%) North American 52 36 South American 20 5 Europe 25 26 Other 12 0 Large sample of patient with XHIGM to 1.Compare long term overall survival of Pt treated with/ w/o HSCT 2.Clinical factor associatedmortality risk
  32. 32. E Table 1. Affected Organ/System involvement at diagnosis for patients with XHIGM (N=176). Patients may have been described as having more than one organ/system involved. J Allergy Clin Immunol. 2017 Apr;139(4):1282-1292.
  33. 33. HSCT Non HSCT W/O liver disease liver disease
  34. 34. J Allergy Clin Immunol. 2017 Apr;139(4):1282-1292. No HSCT HSCT
  35. 35. FIG 4. Karnofsky/Lansky scores (as percentages) of surviving patients with XHIGM. J Allergy Clin Immunol. 2017 Apr;139(4):1282-1292. P < .001 Non HSCT HSCT
  36. 36. Kaplan-Meier estimates of post transplantation survival by year of diagnosis: before 1993 (1964-1992) and after 1993 (1993-2013). HSCT outcome by year of diagnosis
  37. 37. Management Ferrua and Galimberi et al. J Allergy Clin Immunol 2019;143:2238-53. -HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. -Myeloablative conditioning is associated with better overall survival CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, only curative treatment is “ Hematopoietic stem cell transplantation (HSCT) ”
  38. 38. Ferrua and Galimberi et al. J Allergy Clin Immunol 2019;143:2238-53. Management
  39. 39. Management Ferrua and Galimberi et al. J Allergy Clin Immunol 2019;143:2238-53. Result & Conclusion - HSCT can be curative in patients with CD40L deficiency, with the best outcome if performed before 10 years of age and without organ damage, especially sclerosing cholangitis. - Superior OS was achieved with matched donors. HSCT early after diagnosis and use of myeloablative regimens resulted in greater OS and DFS. EFS resulted improved with MSDs, MAC, and BM as stem cell source. - Reduced intensity and nonmyeloablative conditioning were associated with poor donor cell engraftment.
  40. 40. Clinical trial therapy based on correcting CD40/CD40L pathway • In a mouse model of HIGM1, treatment with human recombinant CD40L protein protected the mice from opportunistic infections, restored the mice’s ability to make gamma globulin and improved survival. • Three children with HIGM were administered recombinant CD40L. The specific Ab responses to T cell-dependent Ag was still absent. • Ab synthesis recovered partially in a mouse model , this may not predict the outcome in humans. • Gene therapy was supposed to be the fundamental therapeutic solution for HIGM; however, gene therapy for HIGM still remains at the animal testing stage Meng et al. Innate Immunity.2018 Vol.24 : 4-10.
  41. 41. Management Hubbard et al.Blood. MAY 2016;volume127(number 21):2513-2522. Gene therapy • The CD40LG locus can be specifically targeted and repaired in primary human T cells by insertion of a spliced CD40LG complementary DNA. • Gene editing restores regulated CD40L expression in X-HIGM T cells, reconstituting B-cell immunoglobulin class switching
  42. 42. Autosomal-recessive HIGM type 2 (activation-induced cytidine deaminase [AID]) ● Biallelic mutation in AID (or AICDA) on chromosome 12p13, rare : 20% of CSR-D ● Defect intrinsic to B cell CSR ● AID also important in controlling of autoreactive B cell ● Early onset recurrent sinopulmonary infections (similar to XHIGM) ● Hallmark : Lymphadenopathy ,diffuse lymphoid hyperplasia ● No opportunistic infections (≠ XHIGM) ● Histology : Giant germinal centers ● Autoimmune cytopenia : Hemolytic anemia , thrombocytopenia M.Teresa de la, Morena et al.J allergy Clin Immunol Pract 2016;4:1-23-36
  43. 43. Autosomal-recessive HIGM type 2 (activation-induced cytidine deaminase [AID]) Treatment ● Regular IVIG replacement : reduce frequency of infection ● IVIg replacement : not prevent lymphadenopathy , autoimmune ● N0 PCP prophylaxis : AID deficiency (pure B cell defect) ● If Life-threatening autoimmunity : Corticosteroid , anti CD20 monoclonal antibodies M.Teresa de la, Morena et al.J allergy Clin Immunol Pract 2016;4:1-23-36
  44. 44. Autosomal-recessive HIGM type 3 (CD40 deficiency; TNFSFR5) ● Mutations in CD40, TNF Receptor Superfamily Receptor 5 (TNFRSF5), on 20q12-q13.12. ● Very rare <1% , affects both male ,female ; consanguineous families ● CD40 expressed in B cells, dendritic cells, monocytes, macrophages and other tissues such as endothelial cells, neuronal cells, bronchial epithelial cells, and bile duct epithelial cells. ● It is crucial for cognate T-B-cell interactions ● Clinical phenotype is a combined immunodeficiency (similar to XHIGM) ● Treatment: IVIG replacement Antibiotic prophylaxis : PCP prophylaxis HSCT(HLA identical donor) : may be less efficacious than CD40L deficiency M.Teresa de la, Morena et al.J allergy Clin Immunol Pract 2016;4:1-23-36 H.Buckley ,S.orange et al.Primary immune deficiency .middleton’s Allergy (9th edition) 2019
  45. 45. Autosomal-recessive HIGM type 4 ● Associated with normal class switch recombination (CSR) but abnormal somatic hypermutation (SHM) ● Unknown molecular mechanism, proposed to lie downstream of AID ● milder clinical phenotype than HIGM type 2 ○ Sinopulmonary infections, sepsis, lymphadenitis, and osteomyelitis ○ Lymphadenopathy and autoimmunity along with myelodysplasia ● Management: Regular IVIG replacement : reduce frequency of infection M.Teresa de la, Morena et al.J allergy Clin Immunol Pract 2016;4:1-23-36
  46. 46. Autosomal-recessive HIGM type 5 (Uracil-DNA-glycosylase [UNG]) ● Very rare , UNG gene is located on chromosome 12q24.11 ● Absence of UNG prevent DNA double-stranded breaks (DSBs) to form within the switch region (S) and variable region (V) ● Clinical characteristics: similar to AID defects: - Susceptibility to bacterial infections in early childhood - Lymphoid hyperplasia - Elevated levels of IgM with variable levels of IgG ● Treatment: Regular IVIG replacement : reduce frequency of infection If Life-threatening autoimmunity : Corticosteroid , anti CD20 monoclonal antibodies M.Teresa de la, Morena et al.J allergy Clin Immunol Pract 2016;4:1-23-36
  47. 47. Classic : HIGM M.Teresa de la Morena et al.J allergy Clin Immunol Pract 2016;4:1-23-36
  48. 48. DNA repair genes mutation ● Mutator S homolog 6 (MSH6) deficiency ● PMS2 deficiency (mismatch repair gene; PMS2) ● Phosphoinositide 3-kinase δ syndrome (activated PI3K-δ, activated PI3 Kinase-δ syndrome [APDS]; PIK3CD) ● Deficiency in the INO80 chromatin remodeling complex R. Yazdani et al. The hyper IgM syndromes, Clinical Immunology 198 (2019) 19–30 M.Teresa de la Morena et al.J allergy Clin Immunol Pract 2016;4:1-23-36
  49. 49. Other defects in class switch recombination M.Teresa de la Morena et al.J allergy Clin Immunol Pract 2016;4:1-23-36
  50. 50. Phosphoinositide 3-kinase δ syndrome (activated PI3K-δ, activated PI3 Kinase-δ syndrome [APDS]; PIK3CD) Jhamnani et al. CSR/HIGM Syndromes and PIK3 Defects. Frontiers in Immunology. Sep 2018 R. Yazdani et al. The hyper IgM syndromes, Clinical Immunology 198 (2019) 19–30 - PI3K pathway represent a distinctive subset of CSR/HIGM syndromes - autosomal dominant gain-of-function (GOF) mutations in PIK3CD and PIK3R1 >> hyperactivation of the enzyme PI3Kδ-Akt pathway >> reduce antibody production & T cell lymphopenia - Clinical : combined immunodeficiency , recurrent sinopulmonary tract infection , recurrent and severe herpes infection (Hallmark) Treatment - prophylactic measures, such as antibiotics, antivirals - Immunoglobulin replacement. - Immunosuppressive therapy (control lymphoproliferation and/or autoimmunity) : Rapamycin , Rituximab
  51. 51. Phosphoinositide 3-kinase δ syndrome (activated PI3K-δ, activated PI3 Kinase-δ syndrome [APDS]; PIK3CD) Coulter and Cant. The Treatment of Activated PI3Kδ Syndrome. Frontiers in Immunology. Sep 2018 R. Yazdani et al. The hyper IgM syndromes, Clinical Immunology 198 (2019) 19–30 Treatment - prophylactic measures, such as antibiotics, antivirals - Immunoglobulin replacement. - Immunosuppressive therapy (control lymphoproliferation and/or autoimmunity) : Rapamycin , Rituximab
  52. 52. Phosphoinositide 3-kinase δ syndrome (activated PI3K-δ, activated PI3 Kinase-δ syndrome [APDS]; PIK3CD) Jhamnani et al. CSR/HIGM Syndromes and PIK3 Defects. Frontiers in Immunology. Sep 2018 R. Yazdani et al. The hyper IgM syndromes, Clinical Immunology 198 (2019) 19–30 Treatment : - PI3Kδ blockage : Idelalisib , Leniolosib Study : In 2017 : Leniolisib, PI3K δ inhibitor >> therapeutic option in patients with PIK3CD GOF mutations. 6 patients were treated 12-weeks period >> decreased lymphadenopathy and splenomegaly. - Curative treatment : HSCT in 2017 : 81% survival 9/11 APDS patients who underwent HSCT in seven pediatric centers. Acute GvHD was a common complication (81%), 2/3 (6/11) of APDS : surviving patients are off immunosuppressive therapy and immunoglobulin replacement.
  53. 53. Okano et al.J Allergy Clin Immunol 2019;143:266-75. Conclusion 30 yrs overall survival was 86.1%, but event-free survival was 39.6%. Indication HSCT : progressive combined immunodeficiency or massive lymphoproliferation, Complication : graft rejection
  54. 54. D. Notarangelo et al .J Allergy Clin Immunol 2019;143:91-3. - survival rate in the 2 series was comparable (9/11 and 7/9, respectively), - complication severe graft-versus-host disease, - Outcome significant improvement of humoral immunity. - Transplantation from matched donors, use of more intense conditioning, and inclusion of alemtuzumab might have improved engraftment. Administration of mTOR and PI3Kd inhibitors might represent a useful bridge therapy to control immune dysregulation and bring patients to transplantation in better clinical status.
  55. 55. PID Syndrome associated with HIGM and low IgG ● Ataxia Telangiectasia (ataxia telangiectasia mutated [ATM]) ● Nijmegen breakage syndrome (NBS1) ● Cernunnos/XRCC4-like factor deficiency (SCID T-B-SCID; nonhomologous end-joining 1) M.Teresa de la Morena et al.J allergy Clin Immunol Pract 2016;4:1-23-36
  56. 56. Syndromic HIGM M.Teresa de la Morena et al.J allergy Clin Immunol Pract 2016;4:1-23-36 Treatment : no cure ,avoidance of ionizing radiation Symptomatic & supportive physical & speech therapy IVIG infusion (evidence immunodeficiency) Treatment : IVIG infusion (immunodeficiency) avoidance of ionizing radiation Increase mortality : lymphoreticular Treatment : IVIG infusion , antibiotic therapy , HSCT
  57. 57. Mutations in NEMO and IKBA can lead to NF-κB signaling defects . - X-linked Anhidrotic (hypohydrotic) Ectodermal Dysplasia with Immunodeficiency (EDA-ID) : mutations in NEMO/IKKγ gene. leading to an abnormal expression of multiple enzymes required for antibody switching such as AID and UNG. -Autosomal dominant mutations of IKBA/IκBα, result in blockage of NF-κB release into the nucleus interfering with NF-κB and downstream CD40 signaling. X-linked Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) R.Yazdani et al. Clinical Immunology 198 (2019) 19–30
  58. 58. ● NEMO mutation : Hypohidrotic ectodermal dysplasia with immune deficiency; anhidrotic ectodermal dysplasia with immunodeficiency, osteopetrosis, and lymphedema; inhibitor of kappa B kinase gamma) M.Teresa de la Morena et al.J allergy Clin Immunol Pract 2016;4:1-23-36 Treatment : HSCT , IVIG replacement , antibiotic prophylaxis
  59. 59. •Study in 29 patient : 23 different hypomorphic IKBKG mutations. •Engraftment was documented in 24 patients (83%), and GVHD in 13 patients (45%) •Global survival rate was 74% (22/29 Pts )at a median follow-up after HSCT of 57 months. •Preexisting mycobacterial infection and colitis were associated with poor HSCT outcome. Miot ,Imai et al. HSCT in 29 NEMO deficiency , Blood. 2017;130(12):1456-1467. Overall, HSCT can cure most clinical features of patients with a variety of IKBKG mutations. Transplantation did not appear to cure colitis, possibly as result of cell-intrinsic disorders of the epithelial barrier.
  60. 60. Treatment in HIGM
  61. 61. Summary of management of HIGM syndrome - Multiple therapeutic approaches to control the complications of HIGM syndromes, including - Immunoglobulin replacement therapy : decrease severity/frequency of infection - Antimicrobial therapy - PCP prophylaxis : Bactrim , IV/inhaled pentamidine - Cryptosporidium infection : nitazoxanide and azithromycin , adequate hygiene - Monitoring liver and biliary tract function : LFT , CBC , ultrasound , biopsy - G-CSF (Granulocyte-colony stimulating factor) : if neutropenia - CD40-agonist therapy - Immune-suppressive therapy : AID , APDS - HSCT : CD40 ligand deficiency , AR-CD40 deficiency , NEMO mutation , APDS - Gene therapy : more complicated R. Yazdani et al. The hyper IgM syndromes, Clinical Immunology 198 (2019) 19–30 M.Teresa de la Morena et al.J allergy Clin Immunol Pract 2016;4:1-23-36
  62. 62. Treatment of Manifestations in Individuals with X-Linked Hyper IgM Syndrome Manifestation/ Concern Treatment Considerations/Other Recurrent infections •Immunoglobulin replacement IV or SC • Initial dosing for IgG replacement: 0.4-0.6 g/kg every 3-4 wks for IV, or ≥100 mg/kg dose weekly for SCIg. •Titrate IgG levels as for primary antibody deficiency syndromes. •Prophylactic antibiotics against opportunistic infections include : P jirovecii •Aggressively evaluate pulmonary infections (include use of diagnostic bronchoalveolar lavage) to define specific etiology. Discussion re prophylactic use of azithromycin or nitazoxanide for all affected individuals for prevention of Crypstosporidium is ongoing. While not standard of care, it should be considered for those living in / traveling to an area↑ Cryptosporidium rates. Immunodeficiency Only current curative treatment is HSCT, preferably at age <10 yrs. Modified conditioning regimens may be needed in those w/preexisting liver disease, & hepatic transplant along w/HSCT may be required. Dunn CP, de la Morena MT. X-Linked Hyper IgM Syndrome , GeneReviews .2020 February
  63. 63. Treatment of Manifestations in Individuals with X-Linked Hyper IgM Syndrome Manifestation/ Concern Treatment Chronic neutropenia Recombinant GCSF Malnutrition & poor growth Total parenteral nutrition & consultation w/clinical dietary nutritionist may be required to optimize caloric intake. Sclerosing cholangitis end-stage sclerosing cholangitis have been treated successfully with orthotopic liver transplantation closely associated allogeneic bone marrow transplantation. - Infectious etiologies need to be pursued & treated prior to transplantation. Autoimmune disorders Treatment of autoimmune disorders usually involves judicious use of immunosuppressants tailored to individual's diagnosis. Cancer Treatment should follow standard protocols/therapies for individual cancers in conjunction w/immunologist. Dunn CP, de la Morena MT. X-Linked Hyper IgM Syndrome , GeneReviews .2020 February
  64. 64. Disease Gene Ig G replace ment HSCT Gene therapy PCP prophylaxis Note Classic HIGM HIGM1 CD40LG ✓ ✓ - ✓ - Avoid live vaccine, - Blood product irradiation ,CMV neg If neutropenia >> G-CSF - Adequate hygiene ,drink boiled/filter waterHIGM3 CD40 ✓ ✓ - ✓ HIGM2 AID ✓ - - - HIGM5 UNG ✓ - - - DNA repair gene mutation MSH6 def MSH6 ✓ - - - PSM2 def PSM2 ✓ - - - INO80 INO80 ✓ - - - APDS PIK3CD ✓ ✓ - ✓ Reduction in lymphoproliferative - mTOR inhibitor (Sirolimus) - Selective PI3Kδ inhibitors (Leniolisib) NEMO IKBKG ✓ ✓ - ✓ -Avoid live vaccine -Fluconazole prophylaxis Management in HIGM syndrome
  65. 65. Prognosis
  66. 66. Prognosis R.Yazdani et al. Clinical Immunology 198 (2019) 19–30 -The Registry of the ESID on 56 affected males showed a 20% survival rate in individuals aged ~25 years . -US X-HIGM Registry reported that 11 out of 61 surviving patients were aged >20 years. -Cause of death was pneumonia, encephalitis or malignancy and liver failure secondary to sclerosing cholangitis , cirrhosis. -In a national study of morbidity and mortality of 38 Iranian HIgM patients, 10-years survival rate was 67.8% and the most common cause of death is respiratory failure.
  67. 67. Survillance in HIGM
  68. 68. Recommended Evaluations Following Initial Diagnosis in X-Linked Hyper IgM Syndrome System/Concern Evaluation Comment Hematology/ Immunology •CBC w/differential •IgG levels •T, B, & NK cell numbers For evidence of cytopenia Pulmonary Baseline chest radiograph & pulmonary function testing For chronic lung changes due to infection; if present, consider pulmonology evaluation. Gastrointestinal PCR-based testing of stools Nutritional assessment For presence of Cryptosporodium or other enteric pathogens; if present, consult gastroenterologist. Hepatobiliary Baseline liver function testing & liver / biliary tree ultrasound For evidence of hepatocyte dysfunction & developing biliary dilation Transplantation All individuals should be offered HLA typing at diagnosis. For consideration of HSCT Other Consultation clinical geneticist Dunn CP, de la Morena MT. X-Linked Hyper IgM Syndrome , GeneReviews .2020 February.
  69. 69. Recommended Surveillance for X-Linked Hyper IgM Syndrome System/Concern Evaluation Frequency Hematology CBC w/differential to monitor for Cytopenia At least every 6 months to yearly if stable or any change in clinical status Immunology IgG levels •IgG frequency depends on time needed to achieve adequate IgG levels; similar to those with primary antibody deficiency syndromes. •Adults: at least yearly Lymphocyte subpopulations: T, B, & NK cell numbers Given progressive T, B, & NK loss over time, consider obtaining yearly in non-transplanted adolescents & adults. CD40L expression in transplanted individuals Monitor CD40L expression in activated T-cells at least yearly in those who have had HSCT, or if any change in clinical status. Dunn CP, de la Morena MT. X-Linked Hyper IgM Syndrome , GeneReviews .2020 February
  70. 70. Recommended Surveillance for X-Linked Hyper IgM Syndrome System/Concern Evaluation Frequency Pulmonary Pulmonary function tests Yearly for those age >7 yrs or if change in clinical status Chest radiograph w/follow up of pulmonary infiltrates w/high-resolution CT scan As clinically indicated Gastrointestinal PCR-based testing of stools for infectious etiologies At least every 6 months or if diarrhea present or exposure occurs Liver function tests •Children: at least every 4-6 months or if change in clinical status •Adults: at least 1-2 time/year or if change in clinical status Liver ultrasound ≥1x/yr or if change in clinical status •Monitor growth in children. •Measure weight in adolescents & adults at least 2 time/yr •Children: at every visit; at least every 4-6 months •Adolescents/adults: at least 2 times/year •If any change in clinical status Oncology Physical exam •Children: at least every 4-6 months •Adolescents/adults: at least 1-2 time/year •Low threshold for lymph node biopsy Dunn CP, de la Morena MT. X-Linked Hyper IgM Syndrome , GeneReviews .2020 February
  71. 71. Summary of HIGM
  72. 72. Disease Gene Inherit IgM Ig G/A/E Features HIGM1 CD40LG XR N/↑ N/↓ Neutropenia 30%, Opportunistic infection Sclerosing cholangitis Neuroendocrine tumorHIGM3 CD40 AR N/↑ N/↓ HIGM2 AID AR ↑↑ ↓ Lymphoid hyperplasia, giant germinal center, splenomegaly Autoimmune cytopeniaHIGM5 UNG AR ↑↑ ↓ MSH6 def MSH6 AR N/↑ N/↓ Solid cancer (esp. colon) PSM2 def PSM2 AR N/↑ N/↓ APDS PIK3CD AD ↑ N/↓ Lymphopenia, lymphoma, HSV infection, bronchiectasis INO80 INO80 AR N ↓ COPD Ataxia telangiectasia ATM AR N/↑ N/↓ Lymphopenia, cancer Ataxia, telangiectasia, oculomotor apraxia, dysarthria Nijmegen breakage NBS1 AR N/↑ ↓ Lymphopenia, cancer Microcephaly, autoimmune cytopenia, café-au-lait, vitiligo Cernunnos/XLF SCID NHEJ1 AR N/↑ ↓ T- B- SCID Microcephaly, autoimmune cytopenia NEMO IKBKG XR Ig M: ↑ in 20%, may N/↓ Ig G: ↓ Ig A: may ↑ Non-tuberculous mycobacterial infection Ectodermal dysplasia, osteoporosis, lymphedema Summary of clinical and laboratory features
  73. 73. Durandy and Kracker. Class-switch recombination defect. Stiehm’s immune deficiencies, 2014
  74. 74. Treatment of HIGM Meng et al. Innate Immunity.2018 Vol.24 : 4-10. CD 154 NEMO
  75. 75. Thank you for you attention

×