eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

X-linked Immunodeficiency With Hyper IgM

Author: C Lucy Park, MD, Head, Division of Allergy, Immunology, and Pulmonology, Associate Professor, Department of Pediatrics, University of Illinois at Chicago
Contributor Information and Disclosures

Updated: Feb 20, 2009

Introduction

Background

X-linked immunodeficiency with hyper–immunoglobulin M (XHIGM or HIGM1) is a rare form of primary immunodeficiency disease caused by mutations in the gene that codes for CD40 ligand (CD40L, also known as CD154 and gp39). CD40 ligand is expressed on activated T lymphocytes and is necessary for T cells to induce B cells to undergo immunoglobulin (Ig) class-switching from immunoglobulin M (IgM) to immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin E (IgE).

Thus, patients with XHIGM have markedly reduced levels of IgG, IgA, and IgE but have normal or elevated levels of IgM. Because CD40 ligand is required in the functional maturation of T lymphocytes and macrophages, patients with XHIGM also have a variable defect in T-lymphocyte and macrophage effector function. Clinically, patients with XHIGM have increased susceptibility to infection with a wide variety of bacteria, viruses, fungi, and parasites. In addition, they are at increased risk for developing autoimmune disorders and malignancies.

Since the first description of patients with XHIGM by Rosen et al in 1961, numerous genetic defects have been found to be responsible for defective Ig class-switch recombination (CSR). In 1974, a World Health Organization (WHO) working party named the syndrome immunoglobulin deficiency with increased IgM (hyper-IgM syndrome [HIGM]).¹ The most common form of HIGM is XHIGM (or HIGM1) and is inherited as an X-linked recessive (XR) trait. Another XR form of the syndrome is associated with hypohidrotic ectodermal dysplasia. In addition, several autosomal recessive forms (AR) and an autosomal dominant form of HIGM have been reported (see Differentials).

Pathophysiology

Humoral immunity, or antibody-mediated immune responses, plays a central role in defense against extracellular pathogens and some viruses. Humoral immunity depends on the generation of exquisite specificity and diversity of Igs. During the primary antibody response, B cells in the bone marrow produce IgM and immunoglobulin D (IgD) antibodies of low avidity. This process is largely antigen-independent.
Once IgM B cells are engaged with antigens, B cells start the secondary antibody repertoire generation by undergoing 2 genetic alterations to improve specificity and avidity of the antibody to specific microorganisms.

The first step is generation of Ig diversity by recombination of Ig heavy chain, known as CSR, switching from IgM to IgG, IgA, or IgE.

The second step is somatic hypermutation (SHM) and involves the introduction of point mutations in the V regions (antigen-binding sites) of the Ig genes, 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 CD40 ligand (CD154), expressed on activated CD4⁺ T cells, and CD40, expressed on B cells.

B cells of patients with XHIGM are intrinsically normal, in that they can be induced to proliferate and undergo CSR upon in vitro activation by CD40 agonists and appropriate cytokines. CD40 activation is also necessary for B cells to act as antigen-presenting cells, further enhancing the adaptive (acquired) immune response of T cells and other cells. Although B cells mature to express CD19 and surface immunoglobulins in the absence of CD40 ligand on T cells, differentiation to plasma cells does not occur.

Because CD40 is also expressed on monocytes and dendritic cells, impaired CD40 ligand expression leads to defective T-cell interactions with monocytes and dendritic cells, resulting in abnormal cell-mediated immune function and increased susceptibility to opportunistic infections, malignancy, and autoimmune diseases.

Neutropenia is also a common feature of XHIGM and may result from a defective, stress-induced, CD40-dependent granulopoiesis as myeloid progenitors express CD40 molecules.

Increased incidence of autoimmune disorders have been reported among patients with HIGM syndrome. Furthermore CD40L-CD40 interactions may play an important role in T-regulatory (T-reg) cells that are required for the establishment and maintenance of immune tolerance. Patients with CD40L deficiency displayed low numbers of T-reg cells and defects in B-cell tolerance.  

Frequency

United States

In 2003, the US XHIGM registry reported that the minimal incidence rate of XHIGM was approximately 1 in 1,000,000 live births from 1984-1993.² This may be an underestimation because not all physicians in the United States participated in the registry.

International

Establishing reasonable estimates of XHIGM incidence has been difficult because most primary immunodeficiency disease registries combine data regarding XHIGM with data regarding genetic defects with resultant hyper-IgM. All forms of HIGM constitute 0.3-2.9% of all patients with primary immunodeficiencies in Europe, Asia, and South America. One registry in Spain reported that the incidence rate of all forms of HIGM is 1 per 20 million live births. XHIGM represents about 65-70% of all HIGMs.³

Mortality/Morbidity

A retrospective study of the Registry of the European Society for Immune Deficiency of 56 affected males showed a 20% survival rate in individuals aged 25 years.⁴ The US XHIGM Registry reported that 11 of 61 surviving patients were aged 20 years or older.²

The leading cause of death was pneumonia, encephalitis, or malignancy. Other patients died of liver failure secondary to sclerosing cholangitis and cirrhosis.

Major causes of morbidity include infection with bacteria, fungi, or viruses and opportunistic infections such as those involving Pneumocystis carinii. The respiratory (sinopulmonary) system, CNS, hepatobiliary system, and skin are commonly affected. Chronic diarrhea with or without infection has been frequently reported. Neutropenia, anemia, and thrombocytopenia are common. An increased risk of GI tract malignancies has been reported. Morbidity due to infection has markedly improved with the advent of intravenous immunoglobulin (IVIG) replacement therapy and better recognition of Pneumocystis jiroveci pneumonia and early initiation of Pneumocystis prophylaxis.

Race

Studies are inadequate to provide ethnic data regarding XHIGM incidence. The US XHIGM Registry reported the racial background of 75 patients.² Fifty two of the patients were white, 12 were black, 9 were Asian, 1 was both black and Asian, and 1 was white and Asian.

Sex

CD40 ligand deficiency affects males because it is an inherited in XR trait. Female carriers, even with extreme lyonization, have been immunocompetent and without clinical illness. Females with hypogammaglobulinemia and high IgM levels should be tested for gene mutations that affect other forms of HIGM.

Age

Most patients are diagnosed before age 4 years. Over one half of patients develop symptoms of immunodeficiency by age 1 year, and nearly all develop symptoms by age 4 years.

Clinical

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.

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.

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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