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:
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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.
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Other less common infections include subcutaneous abscesses, herpes stomatitis, oral candidiasis, parvovirus B19 infection, warts, Molluscum contagiosum, and candida esophagitis.
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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.
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Pathogens that cause diarrhea include Giardia lamblia, Cryptosporidium species, Rotavirus, Yersinia enterocolitica, Clostridium difficile, and other unknown species.
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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.
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Hepatitis was seen in a significant number of cases.
Physical Examination Findings:
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Individuals may complain of chronic diarrhea and failure to thrive.
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Pulmonary infections such as cough. Tachypnea, dyspnea, accessory muscle use, retraction, hypoxia, or abnormal breath sound on auscultation.
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Lymphadenopathy.
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Pruritus, jaundice and hepatomegaly.
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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.
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In most individuals, activated T lymphocytes fail to express CD40 ligand.
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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:
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Agammaglobulinemia.
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Pediatric Bruton agammaglobulinemia.
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Pediatric common variable immunodeficiency.
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Severe combined immunodeficiency.
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Transient hypogammaglobulinemia of infancy.
Investigations:
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Laboratory tests.
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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.
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Other Tests: Pulmonary function tests are important for diagnosis and monitoring chronic lung disease.
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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.
