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X-Linked Immunodeficiency With Hyper IgM - Causes and Treatment

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X-linked immunodeficiency with hyper immunoglobulin M is a rare disease caused by mutations in the CD40 ligand.

Written by

Dr. Kavya

Medically reviewed by

Dr. Vedprakash Verma

Published At February 9, 2023
Reviewed AtDecember 1, 2023

Introduction

Individuals with X-linked immunodeficiency have reduced, or low IgG, IgA, and IgE levels but have normal or elevated levels of IgM. The CD40 ligand is essential for the functional maturation of T lymphocytes, macrophage effector function, and dendritic cells. Individuals with X-linked immunodeficiency have increased susceptibility to infection with viruses, bacteria, fungi, and parasites.

What Is the Pathophysiology for X-Linked Immunodeficiency With Hyper IgM?

Antibody-mediated immune response or humoral immunity helps defend against extracellular pathogens and viruses. B cells produce IgM and IgD of low avidity. Once IgM cells start associating with antigens, B cells start the secondary antibody production by undergoing alterations to improve the specificity and avidity of the antibody to specific microorganisms.

B cells of individuals with X-linked immunodeficiency with hyper IgM are normal and can be induced to proliferate and undergo in vitro activation by CD40. Neutropenia is also a common sign which results from a defective CD40-dependent granulopoiesis. In addition, increased incidences of autoimmune disorders have been reported among individuals with X-linked immunodeficiency with hyper IgM.

What Is the Epidemiology of X-Linked Immunodeficiency With Hyper IgM?

Frequency:

In 2003, the US X-linked immunodeficiency with hyper IgM registry reported a minimal incidence rate of approximately 1 in 1000000 live births from 1984 to 1993. The primary immunodeficiencies in Asia, Europe, and South America.

Morbidity and Mortality:

X-linked immunodeficiency with hyper IgM shows a 20 % survival rate in individuals aged 25. The common cause of death in X-linked immunodeficiency with hyper IgM is pneumonia, encephalitis, or malignancy. Other causes of death include liver failure secondary to cirrhosis and sclerosing cholangitis. Morbidity may also be caused by infection with bacteria, fungi, viruses, and opportunistic infections such as pneumocystis carinii.

The hepatobiliary system, respiratory sinopulmonary system, CNS (central nervous system), and skin are commonly affected. Chronic diarrhea with or without infection has been reported. Anemia, thrombocytopenia, and neutropenia are common. Morbidity rates may be managed with intravenous immunoglobulin replacement therapy and for a better treatment approach in the case of Pneumocystis jiroveci pneumonia.

Sex:

X-linked immunodeficiency with hyper IgM affects males because it is an inherited trait. Females are usually carriers, and even with extreme lyonization, the cases have been immunocompetent and without clinical illness. Females with hypogammaglobulinemia and high IgM levels should be checked for gene mutations.

Age:

Most cases are diagnosed before the age of four. However, over one-half of individuals develop immunodeficiency symptoms in one year and four years.

What Are the Signs and Symptoms of X-Linked Immunodeficiency With Hyper IgM?

The signs and symptoms include the following:

  • Pneumonia is common among all infections occurring in almost 80 % of individuals. Other commonly observed clinical signs include otitis, sinusitis, recurrent or protracted diarrhea, CNS infections, sepsis, sclerosing cholangitis, and sepsis.

  • Other less common infections include subcutaneous abscesses, herpes stomatitis, oral candidiasis, parvovirus B19 infection, warts, Molluscum contagiosum, and candida esophagitis.

  • Microbial pathogens that cause pneumonia are cytomegalovirus, P jiroveci, adenovirus, Pseudomonas species, herpes virus type 1, histoplasmosis, respiratory syncytial virus, pneumococcus species, Haemophilus influenzae type b, staphylococcus species, and other unidentified pathogens, infections with atypical mycobacterium species or mycobacterium bovis have been observed.

  • Pathogens that cause diarrhea include Giardia lamblia, Cryptosporidium species, Rotavirus, Yersinia enterocolitica, Clostridium difficile, and other unknown species.

  • Causes of CNS infection include Cryptococcus species and Pneumococcus species. In addition, neurological deterioration in the following cognitive functions, such as ataxia and hemiplegia seen in association with meningoencephalitis, has been reported.

  • Hepatitis was seen in a significant number of cases.

Physical Examination Findings:

  • Individuals may complain of chronic diarrhea and failure to thrive.

  • Pulmonary infections such as cough. Tachypnea, dyspnea, accessory muscle use, retraction, hypoxia, or abnormal breath sound on auscultation.

  • Lymphadenopathy.

  • Pruritus, jaundice and hepatomegaly.

  • Perirectal and oral mucosal ulcerations may be seen in individuals with neutropenia.

What Are the Causes of X-Linked Immunodeficiency With Hyper IgM?

X-linked immunodeficiency with hyper IgM is caused due to mutation in the gene that helps in coding the CD40 ligand, a T-cell molecule required for T-cell-driven immunoglobulin.

  • In most individuals, activated T lymphocytes fail to express CD40 ligand.

  • In about 20 % of the cases, the individuals may require testing of the capability of T cells to bind to CD40 using CD40-Ig protein.

What Is the Differential Diagnosis of X-Linked Immunodeficiency With Hyper IgM?

The differential diagnosis includes the following:

  • Agammaglobulinemia.

  • Pediatric Bruton agammaglobulinemia.

  • Pediatric common variable immunodeficiency.

  • Severe combined immunodeficiency.

  • Transient hypogammaglobulinemia of infancy.

Investigations:

  • Laboratory tests.

  • Imaging Studies: Sinus radiographs and chest radiographs or CT (computed tomography) scans are initially needed. Individuals with chronic sinopulmonary disease are evaluated with CT imaging. Abdominal CT or magnetic resonance imaging (MRI) is done in individuals with hepatomegaly, cholangitis, or abnormal liver function test findings.

  • Other Tests: Pulmonary function tests are important for diagnosis and monitoring chronic lung disease.

  • Investigative Procedures: Bronchoscopy and bronchoalveolar lavage for individuals who do not respond to antibiotic therapy. Endoscopy in inflammatory bowel disease. Liver biopsy in individuals with abnormal liver function.

What Is the Treatment for X-Linked Immunodeficiency With Hyper IgM?

The treatment involves the following:

Medical Care:

Medical care mainly focuses on treating and preventing infection. Infections can be prevented with a regular infusion of human immunoglobulin early prophylaxis. Antimicrobial therapy is done based on culture and sensitivity.

Bone Marrow Transplantation:

It is considered an option in young individuals without bronchiectasis or severe infections. Cord blood stem cells partially or fully matched or bone marrow from a matched donor.

Surgical Care:

Individuals may need to undergo endoscopic sinus surgery to manage chronic sinusitis.

Diet:

Individuals with chronic lung disease may require high-calorie diet supplementation due to high energy expenditure. In addition, individuals with chronic enteropathy require an elemental diet and occasionally supplemental parenteral nutrition.

Conclusion

X-linked immunodeficiency with hyper immunoglobulin M is a rare disease caused by mutations in the CD40 ligand. Individuals with X-linked immunodeficiency with hyper immunoglobulin M have reduced or low levels of IgG, IgA, and IgE but have normal or elevated levels of IgM. Treatment involves medical care, surgical care, and managing diet.

Frequently Asked Questions

1.

Is Hyper-IgM Syndrome an X-Linked Condition?

An X-linked recessive pattern of inheritance characterizes Hyper-IgM syndrome. One of the two sex chromosomes, the X chromosome, has the gene linked to this disease. One mutated copy of the gene in each cell is sufficient to induce the disease in males (who have only one X chromosome).

2.

What Is Hyper-IgM Syndrome Deficiency?

The immunoglobulin (Ig) deficit known as hyper-IgM syndrome makes a person more susceptible to bacterial infections since it is characterized by normal or high blood IgM levels and low or absent levels of other serum immunoglobulins. Antibodies are another name for immunoglobulins. The immune system produces antibodies, which are proteins, to combat pathogens like viruses and bacteria. The body creates distinct antibodies that are intended only to kill those particular germs when one is exposed to them.

3.

What Is Hyper IgM Type 2 Immunodeficiency?

The unusual immunodeficiency known as hyper-IgM syndrome type 2 (HIGM2) causes an extreme susceptibility to bacterial infections due to normal or high serum IgM levels and the absence of IgG, IgA, and IgE. Allogeneic hematopoietic cell transplantation is one kind of treatment for high IgM syndrome. In addition, immunosuppressants, granulocyte colony-stimulating factor usage, anti-microbial therapy, and other treatments can be required.

4.

What Is Immunodeficiency With Hyper IgM Type 3?

A subtype of hyper-IgM syndrome known as type 3 is characterized by CD40 gene alterations. This type prevents helper T cells from delivering signal 2, which is required for immature B cells to develop into mature ones. A homozygous mutation in the CD40 gene on chromosome 20q12–q13.2 causes autosomal recessive hyper-IgM immunodeficiency type 3 (HIGM3).

5.

What Is Immunodeficiency With Hyper IgM Type 1?

The most frequent deficiency in immunoglobulin isotype class switching is the X-linked hyper-IgM syndrome type. The mutations in CD40LG, the gene that encodes the transmembrane CD40L glycoprotein (CD154), expressed on the surface of activated CD4+ T cells, are the cause of this uncommon primary immunodeficiency that is X-linked. Increased vulnerability to bacterial and intracellular infections results from disruption of B-lymphocyte isotype switching and T-lymphocyte/dendritic cell communication caused by decreased costimulatory T-lymphocyte activity.

6.

What Types of High IgM Syndrome Are There?

X-linked hyper IgM syndrome is brought on by a CD40LG gene variant. AICDA (also known as AID) gene variant leads to type 2 Hyper IgM syndrome. A CD40 gene variant results in hyper IgM syndrome type 3. Type 4 hyper IgM syndrome does not have a known hereditary etiology.

7.

Is Hyper IgM Serious?

Patients with Hyper-IgM (HIGM) syndrome are more prone to recurring, serious infections, as well as opportunistic infections and an elevated risk of malignancy in specific kinds of HIGM syndrome. Immunoglobulin G (IgG) levels in the blood are low, whereas IgM levels are normal or increased, which defines the condition. The only curative treatment for hyper IgM syndromes is a bone marrow transplant, however, this procedure carries a high risk of long-term side effects, such as graft-versus-host disease. 

8.

What Age Is Hyper IgM Common?

Clinical signs in children with hyper IgM syndrome typically appear in the first or second year of life. Increased susceptibility to bacterial and viral infections, particularly recurrent GI infections and upper and lower respiratory tract infections, are among the most typical symptoms of hyper IgM syndrome.

9.

What Is the Cause of High Levels of IgM?

Rare immunological conditions including hyper IgM (HIGM) syndromes and autoimmune or acquired infectious diseases are both characterized by high IgM levels. B-cell lymphoproliferative diseases (LPD) are also characterized by elevated monoclonal IgM levels. Nijmegen syndrome, ataxia telangiectasia, and common variable immunodeficiency (CVID) are further conditions that can cause increased IgM levels. Some of these ailments have been covered by the National Organization for Rare Disorders.

10.

How Is Hyper IgM Syndrome Different in Adults?

Patients with Hyper-IgM (HIGM) syndrome are more prone to recurring, serious infections, as well as opportunistic infections and an elevated risk of malignancy in specific kinds of HIGM syndrome. Immunoglobulin G (IgG) levels in the blood are low, whereas IgM levels are normal or increased, which defines the condition. Types 2, 4, and 5 of hyper IgM syndrome are frequently responsive to immunoglobulin replacement therapy alone. However, preventive antibiotic medication may occasionally be advised for people who experience long-term side effects including bronchiectasis or recurring sinus infections.

11.

What Happens if an Individual Is IgM Positive?

When a virus assaults, IgM is typically the first antibody made by the immune system. An IgM test that is positive suggests that one may have recently been exposed to a virus or received a vaccination and that their immune system has begun to fight the infection or the immunization. The presence of IgM is typically a sign of an acute infection.

12.

How Typical Is Hyper-IgM Syndrome?

Hyper IgM syndrome autosomal recessive types are relatively uncommon. In the general community, less than 1 in 1,000,000 people are thought to have type 2 Hyper IgM syndrome. Only a relatively small number of patients have been described with the various types of excessive IgM syndrome in the medical literature. Less than 1 in 1 million members of the general population are affected by the autosomal recessive variants of HIgM.

13.

Is IgM a Marker for Acute or Chronic Infection?

The first antibody the adaptive immune system produces in response to a foreign antigen is IgM. IgM is regarded as a marker of acute infection, and for the majority of viral infections, a drop to undetectable levels is anticipated 2-3 months after infection. IgM is the initial line of immune protection and can be detected as early as 3 days after infection.
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Dr. Kavya

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