X-linked Immunodeficiency With Hyper IgM Clinical Presentation

  • Author: C Lucy Park; Chief Editor: Harumi Jyonouchi, MD   more...
 
Updated: Sep 28, 2010
 

History

According to the US X-linked immunodeficiency with hyper–immunoglobulin M [XHIGM] Registry (2003), the initial presentation of patients with XHIGM usually involves increased susceptibility to infection.[2] Two prominent clinical problems are Pneumocystis carinii pneumonia (PCP) and neutropenia. Nearly one half of patients with XHIGM presented with PCP prior to, or at the time of, diagnosis.

  • Among all infections, pneumonia is the most common, occurring in more than 80% of patients. Other infections frequently observed in patients with XHIGM include sinusitis (43%), otitis (43%), recurrent and/or protracted diarrhea (34%), CNS infections (14%), sepsis (13%), hepatitis (9%), and sclerosing cholangitis (6%). Other, less common, infections include cellulites, subcutaneous abscesses, herpes stomatitis, oral candidiasis, parvovirus B19 infection, molluscum contagiosum, warts, and Candida esophagitis.
  • Microbial pathogens that cause pneumonia include P jiroveci (59%), cytomegalovirus (CMV) (3%), adenovirus (2%), Pseudomonas species (3%), herpesvirus type 1 (2%), respiratory syncytial virus (2%), histoplasmosis (2%), Pneumococcus species (2%), Staphylococcus species (2%), Haemophilus influenzae type b (2%), and other unknown pathogens (27%). Infections with Mycobacterium bovis or atypical Mycobacterium species have been reported.
  • Pathogens that cause diarrhea include Cryptosporidium species (21%), Giardia lamblia (8%), rotavirus (8%), Clostridium difficile (4%), Yersinia enterocolitica (4%), and other unknown pathogens (63%).
  • Causes of CNS infection include echovirus (27%), Cryptococcus species (9%), Pneumococcus species (9%), and other unknown causes (55%). Neurological deterioration in cognitive functions, ataxia, and hemiplegia associated with progressive meningoencephalitis has been described in patients with CNS infection due to enteroviruses or CMV. One case with rapidly progressing multifocal leukoencephalopathy due to JC virus infection has been reported.[5] Cerebral toxoplasmosis was the very first presenting event in a middle aged man that lead to the diagnosis of XHIGM.
  • Hepatitis occurred in a significant number of patients (7 of 79 patients) in the US XHIGM Registry; causative agents included hepatitis C virus, echovirus, histoplasmosis, and Bartonella species.
  • Cryptosporidium infection was the etiology of sclerosing cholangitis in 80% of patients.
  • Chronic diarrhea without identifiable infectious agents that leads to failure to thrive is common. Some patients may need parenteral nutrition. Intestinal nodular lymphoid hyperplasia and inflammatory bowel disease have been reported. Chronic hepatitis frequently progresses to cirrhosis and liver failure. Oral ulcers, gingivitis, proctitis, and perianal ulcers have also been described.
  • Neutropenia was the most common hematologic finding (63-68%). Nearly one half of patients had chronic neutropenia, whereas others had cyclic or episodic neutropenia. In 38% of patients with neutropenia, it was present at the time of diagnosis. Antineutrophil antibodies were negative. Bone marrow examination revealed maturation arrest of the myeloid lineage at the promyelocyte-myelocyte stage. In 48% of patients with neutropenia, oral ulcers were occasionally present. Anemia and/or thrombocytopenia also occurred but with much less frequency than neutropenia.
  • Hepatocellular carcinoma and carcinoid tumor of the pancreas were reported. Lymphoma, neuroectodermal tumor of the colon, and gastroenteropancreatic neuroendocrine tumors have also been reported.
  • Seronegative arthritis, degenerative encephalopathy, hypothyroidism, and autoimmune nephropathy have been reported in patients with XHIGM. In the European XHIGM Registry, generalized lymphadenopathy was reported in 7 of 56 patients. Osteopenia is a prominent and previously underappreciated feature of XHIGM.[6] CD40L mediated T-cell priming is required in induction of osteoclast differentiation, and CD40L deficiency may contribute to an imbalance in bone mineral homeostasis. Patients may present with spontaneous rib fractures without obvious antecedent trauma history.
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Physical

Physical examination findings are related to the manifestation of infection and/or associated conditions.

  • Patients with chronic diarrhea may present with failure to thrive.
  • Patients with pulmonary infections may have cough, tachypnea, dyspnea, retraction, accessory muscle use, hypoxia, or abnormal breath sound on auscultation.
  • Lymphadenopathy may be present.
  • Jaundice, pruritus, and hepatomegaly may be present.
  • Oral mucosal and perirectal ulcerations may be present, especially in patients with concomitant neutropenia.
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Causes

XHIGM is caused by mutation in the gene that codes for CD40 ligand, a T-cell surface molecule required for T-cell–driven immunoglobulin class-switching by B cells. CD40L is located on the long arm of the X chromosome (Xq26-27.2). CD40L belongs to the tumor necrosis factor superfamily. More than 100 unique mutations of CD40L have been reported.

  • In most patients, activated T lymphocytes fail to express CD40 ligand.
  • About 20% of patients with XHIGM express nonfunctional CD40 ligand on T cells, which can bind anti–CD40 ligand monoclonal antibodies. Therefore, these patients may require testing of the capability of T cells to bind to CD40, using CD40-Ig fusion protein. The final molecular diagnosis may depend on sequence analysis of CD40L using complementary DNA (cDNA) or genomic DNA.
  • In a minority of patients, milder mutations that allow binding of CD40 at reduced intensity are associated with less severe clinical course. Among these, a few cases presented with parvovirus B19–related anemia.
  • A case report described a patient with XHIGM due to mutation in the promotor region resulting in decreased transcription of CD40L. Sequence analysis of CD40L genomic DNA showed no mutations.[7]
  • CD40-CD40L interactions may be involved in the selection of T-cell repertoire and priming of T cells, and absence of CD40-CD40L interaction may result in defective development of regulatory T cells (T-reg). This may cause development of autoimmune manifestations in patients with XHIGM.
  • Neutropenia is a common feature of XHIGM and may result from a defective, stress-induced, CD40-dependent granulopoiesis as myeloid progenitors express CD40 molecules. Autoantibodies to neutrophils are generally absent.
  • CD40-CD40L interactions are important in hematopoiesis and innate/adaptive immunity. CD40-CD40L interactions may have a critical role in the development of effector cell functions on monocytes, CD34+ multilineage progenitor cells, and endothelial cells. The generation of dendritic cells that prime immune reactions during antigen-driven responses to pathogenic invasion also depends on functional CD40 molecules.
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Contributor Information and Disclosures
Author

C Lucy Park  MD, Head, Division of Allergy, Immunology, and Pulmonology, Associate Professor, Department of Pediatrics, University of Illinois at Chicago College of Medicine

C Lucy Park is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Medical Association, Chicago Medical Society, Clinical Immunology Society, and Illinois State Medical Society

Disclosure: Nothing to disclose.

Specialty Editor Board

James M Oleske  MD, MPH, François-Xavier Bagnoud Professor of Pediatrics, Director, Division of Pulmonary Allergy Immunology and Infectious Diseases, Department of Pediatrics, New Jersey Medical School; Professor, Department of Quantitative Methods, University of Medicine and Dentistry of New Jersey

James M Oleske is a member of the following medical societies: Academy of Medicine of New Jersey, American Academy of Allergy Asthma and Immunology, American Academy of HIV Medicine, American Academy of Hospice and Palliative Medicine, American Academy of Pain Management, American Academy of Pediatrics, American Association of Pediatrics, American Association of Public Health Physicians, American College of Preventive Medicine, American Pain Society, American Public Health Association, American Society for Microbiology, American Thoracic Society, Arab Board of Family Medicine, Association of Clinical Researchers and Educators (ACRE), Infectious Diseases Society of America, Infectious Diseases Society of America, Infectious Diseases Society of New Jersey, Medical Society of New Jersey, National Association of Pediatric Nurse Practitioners, Pediatric Infectious Diseases Society, and Pediatric Infectious Diseases Society

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

David J Valacer, MD  Consulting Staff, Hoffman La Roche Pharmaceuticals

David J Valacer, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American Thoracic Society, and New York Academy of Sciences

Disclosure: Nothing to disclose.

David Pallares, MD  Clinical Assistant Professor, Department of Pediatrics, Division of Allergy and Immunology, University of Louisville School of Medicine

David Pallares, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology

Disclosure: Nothing to disclose.

Chief Editor

Harumi Jyonouchi, MD  Associate Professor, Division of Pulmonary, Allergy/Immunology, and Infectious Diseases, Department of Pediatrics, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Mucosal Immunology, and Society for Pediatric Research

Disclosure: Nothing to disclose.

References

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  3. Matamoros Flori N, Mila Llambi J, Espanol Boren T, et al. Primary immunodeficiency syndrome in Spain: first report of the National Registry in Children and Adults. J Clin Immunol. Jul 1997;17(4):333-9. [Medline].

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  5. Aschermann Z, Gomori E, Kovacs GG, et al. X-linked hyper-IgM syndrome associated with a rapid course of multifocal leukoencephalopathy. Arch Neurol. Feb 2007;64(2):273-6. [Medline].

  6. Lopez-Granados E, Temmerman ST, Wu L, et al. Osteopenia in X-linked hyper-IgM syndrome reveals a regulatory role for CD40 ligand in osteoclastogenesis. Proc Natl Acad Sci U S A. Mar 20 2007;104(12):5056-61. [Medline].

  7. Van Hoeyveld E, Zhang PX, De Boeck K, Fuleihan R, Bossuyt X. Hyper-immunoglobulin M syndrome caused by a mutation in the promotor for CD40L. Immunology. Apr 2007;120(4):497-501. [Medline].

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  16. Durandy A, Schiff C, Bonnefoy JY, et al. Induction by anti-CD40 antibody or soluble CD40 ligand and cytokines of IgG, IgA and IgE production by B cells from patients with X-linked hyper IgM syndrome. Eur J Immunol. Sep 1993;23(9):2294-9. [Medline].

  17. Durandy A, Taubenheim N, Peron S, Fischer A. Pathophysiology of B-cell intrinsic immunoglobulin class switch recombination deficiencies. Adv Immunol. 2007;94:275-306. [Medline].

  18. Eijkhout HW, van Der Meer JW, Kallenberg CG, et al. The effect of two different dosages of intravenous immunoglobulin on the incidence of recurrent infections in patients with primary hypogammaglobulinemia. A randomized, double-blind, multicenter crossover trial. Ann Intern Med. Aug 7 2001;135(3):165-74. [Medline]. [Full Text].

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  21. Hollenbaugh D, Wu LH, Ochs HD, et al. The random inactivation of the X chromosome carrying the defective gene responsible for X-linked hyper IgM syndrome (X-HIM) in female carriers of HIGM1. J Clin Invest. Aug 1994;94(2):616-22. [Medline]. [Full Text].

  22. Lin Q, Rohrer J, Allen RC, Larché M, Greene JM, Shigeoka AO, et al. A single strand conformation polymorphism study of CD40 ligand. Efficient mutation analysis and carrier detection for X-linked hyper IgM syndrome. J Clin Invest. Jan 1 1996;97(1):196-201. [Medline]. [Full Text].

  23. Ochs HD. Patients with abnormal IgM levels: assessment, clinical interpretation, and treatment. Ann Allergy Asthma Immunol. May 2008;100(5):509-11. [Medline].

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  25. Ramesh N, Geha RS, Notarangelo LD. CD40 ligand and the hyper-IgM syndrome. In: Primary Immunodeficiency Diseases: A Molecular and Genetic Approach. Oxford University Press; 1999:233-49.

  26. Razanajaona D, van Kooten C, Lebecque S, et al. Somatic mutations in human Ig variable genes correlate with a partially functional CD40-ligand in the X-linked hyper-IgM syndrome. J Immunol. Aug 15 1996;157(4):1492-8. [Medline].

  27. Revy P, Muto T, Levy Y, et al. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell. Sep 1 2000;102(5):565-75. [Medline].

 
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This infant with X-linked immunodeficiency with hyper-immunoglobulin M (XHIGM) developed severe diarrhea and hypoproteinemia and presented to a clinic with high fever. Blood culture grew Pseudomonas aeruginosa. Marked leukocytosis was present. The WBC count was 26,000/mL, with 67% neutrophils. Stool culture and examination findings were negative for cryptosporidia, Giardia species, bacteria, or viruses.
During the primary antibody response, B cells in the bone marrow produce immunoglobulin M (IgM) and immunoglobulin D (IgD) antibodies of low avidity. This process occurs largely in an antigen-independent way (pro-B cells, pre-B cells). Once IgM B cells are engaged with antigens, B cells start the secondary antibody repertoire generation by undergoing 2 genetic alterations; class-switch recombination (switching from IgM to IgG, IgA, or IgE) and somatic hypermutation (introduction of point mutations in the V regions of the Ig genes, the antigen-biding sites, resulting in an expansion of the antibody repertoire to generate high-affinity antigen-specific antibodies). The secondary antibody repertoire generation is antigen and T-cell dependent and occurs in peripheral lymphoid organs, mainly through the interaction between CD40L (CD154) expressed on activated CD4+ T cells and CD40 expressed on B cells.
Table 1. Clinical and Immunologic Features of Hyper-IgM Syndromes[8]
XHIGMCD40 defectEDA-IDAR-AIDAID- CterAID-Δ CUNG defectCSR defect- upstream from DNA cleavageCSR defect-downstream from DNA cleavage
DefectCD40LCD40NEMOAIDAIDAIDUNGUnknownUnknown
InheritanceXLARXLARARADARARAR
Lymphadenopathy---+++++++++
Opportunistic Infection++-------
Autoimmunity±±++++--+
Serum IgMN or ↑ N or ↑ N or ↑ ↑ ↑ ↑ ↑ ↑↑ ↑ N or ↑ N or ↑
CD40-induced CSRNUDVariableUDUDUDUDUDUD
SHM↓↓Variable↓ ↓ NNN but biasedNN
Table 2. Immune Globulin, Intravenous[9, 10, 11, 12]
Brand(Manufacturer)Manufacturing ProcesspHAdditives (IVIG products containing sucrose are more often associated with renal dysfunction, acute renal failure, and osmotic nephrosis, particularly with preexisting risk factors [eg, history of renal insufficiency, diabetes mellitus, age >65 y, dehydration, sepsis, paraproteinemia, nephrotoxic drugs].) Parenteral Form and Final ConcentrationsIgA Content (mcg/mL)
Carimune NF



(CSL Behring)



Kistler-Nitschmann fractionation; pH 4 nanofiltration6.4-6.86% solution: 10% sucrose, < 20 mg NaCl/g proteinLyophilized powder 3%, 6%, 9%, 12%Trace
Flebogamma



(Grifols USA)



Cohn-Oncley fractionation, PEG precipitation, ion-exchange chromatography, pasteurization5.1-6Sucrose free, contains 5% D-sorbitolLiquid 5%< 50
Gammagard Liquid 10%



(Baxter Bioscience)



Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation 4.6-5.10.25 M glycineReady-for-use liquid 10%37
Gamunex



(Talecris Biotherapeutics)



Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation4-4.5Contains no sugar, contains glycineLiquid 10%46
Gammaplex



(Bio Products)



Solvent/detergent treatment targeted to enveloped viruses; virus filtration using Pall Ultipor to remove small viruses including nonenveloped viruses; low pH incubation4.8-5.1Contains sorbitol (40 mg/mL); do not administer if fructose intolerantReady-for-use liquid 5%< 10
Iveegam EN



(Baxter Bioscience)



Cohn-Oncley fraction II/III; ultrafiltration; pasteurization6.4-7.25% solution: 5% glucose, 0.3% NaClLyophilized powder 5%< 10
Polygam S/D



Gammagard S/D



(Baxter Bioscience for the American Red Cross)



Cohn-Oncley cold ethanol fractionation, followed by ultracentrafiltration and ion exchange chromatography; solvent detergent treated 6.4-7.25% solution: 0.3% albumin, 2.25% glycine, 2% glucoseLyophilized powder 5%, 10%< 1.6 (5% solution)
Octagam



(Octapharma USA)



9/24/10: Withdrawn from market because of unexplained reports of thromboembolic events



Cohn-Oncley fraction II/III; ultrafiltration; low pH incubation; S/D treatment pasteurization5.1-610% maltoseLiquid 5%200
Panglobulin



(Swiss Red Cross for the American Red Cross)



Kistler-Nitschmann fractionation; pH 4.0 incubation, trace pepsin, nanofiltration6.6Per gram of IgG: 1.67 g sucrose, < 20 mg NaClLyophilized powder 3%, 6%, 9%, 12%720
Privigen Liquid 10%



(CSL Behring)



Cold ethanol fractionation, octanoic acid fractionation, and anion exchange chromatography; pH 4 incubation and depth filtration4.6-5L-proline (approximately 250 mmol/L) as stabilizer; trace sodium; does not contain carbohydrate stabilizers (eg, sucrose, maltose) Ready-for use liquid 10%< 25
Table 3. Subcutaneous Immune Globulin
Brand(Manufacturer)Manufacturing ProcesspHAdditivesParenteral Form and Final ConcentrationsIgA Content mcg/mL
Vivaglobin



(ZLB Behring)



Cold ethanol fractionation; pasteurization6.4-7.22.25% glycine, 0.3% NaClLiquid 16% (160 mg/mL)< 50 mcg/mL
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