XLA diagnosis usually begins due to a history of recurrent infections, mostly in the respiratory tract, through childhood. This is due to humoral immunodeficiency. The diagnosis is probable when blood tests show the complete lack of circulating B cells (determined by the B cell marker CD19 and/or CD20), as well as low levels of all antibody classes, including IgG, IgA, IgM, IgE and IgD.

When XLA is suspected, it is possible to do a Western Blot test to determine whether the Btk protein is being expressed. Results of a genetic blood test confirm the diagnosis and will identify the specific Btk mutation, however its cost prohibits its use in routine screening for all pregnancies. Women with an XLA patient in their family should seek genetic counseling before pregnancy.Although the symptoms of a XLA and other primary immune diseases (PID) include repeated and often severe infections, the average time for a diagnosis of a PID can be up to 10 years.

Diagnosis of X-SCID is possible through lymphocyte cell counts, lymphocyte function tests, and genetic testing. A healthy immune system should contain large amounts of lymphocytes, but individuals with X-SCID will contain unusually small amounts of T-cells, non-functional B-cells, and some natural killer cells.

Individuals with X-SCID often have decreased lymphocyte function. This can be tested through the introduction of agents to the immune system; the reaction of the lymphocytes is then observed. In X-SCID, Antibody responses to introduced vaccines and infections are absent, and T-cell responses to mitogens, substances that stimulate lymphocyte transformation, are deficient. IgA and IgM immunoglobulins, substances that aid in fighting off infections, are very low.

The absence of a thymic shadow on chest X-rays is also indicative of X-SCID. In a normal child, a distinctive sailboat shaped shadow near the heart can be seen. The thymus gland in normal patients will gradually decrease in size because the need for the thymus gland diminishes. The decrease in the size of the thymus gland occurs because the body already has a sufficient number of developed T-cells. However, a patient with X-SCID will be born with an abnormally small thymus gland at birth. This indicates that the function of thymus gland, of forming developed T-cells, has been impaired.

Since the mutation in X-SCID is X-linked, there are genetic tests for detecting carriers in X-SCID pedigrees. One method is to look for family-specific IL2RG mutations. Finally, if none of those options are available, there is an unusual pattern of nonrandom X-chromosome inactivation on lymphocytes in carriers, thus looking for such inactivation would prove useful.

If a mother is pregnant and the family has a known history of immunodeficiency, then doctors may perform diagnostic assessment in-utero. Chorionic Villus Sampling, which involves sampling of the placental tissue using a catheter inserted through the cervix, can be performed 8 to 10 weeks into gestation. Alternatively, Amniocentesis, which entails extracting a sample of the fluid which surrounds the fetus, can be performed 15 to 20 weeks into gestation.

Early detection of X-SCID (and other types of SCID) is also made possible through detection of T-cell recombination excision circles, or TRECs. TRECs are composed of excised DNA fragments which are generated during normal splicing of T-cell surface antigen receptors and T-cell maturation. This maturation process is absent across all SCID variants, as evidenced by the low counts of T-lymphocytes. The assay is performed using dried blood from a Guthrie card, from which DNA is extracted. Quantitative PCR is then performed and the number of TRECs determined. Individuals who have the SCID phenotype will have TREC counts as low as <30, compared to approximately 1020 for a healthy infant. A low TREC count indicates that there is insufficient development of T-cells in the thymus gland. This technique can predict SCID even when lymphocyte counts are within the normal range. Newborn screening of X-SCID based on TREC count in dried blood samples has recently been introduced in several states in the United States including California, Colorado, Connecticut, Delaware, Florida, Massachusetts, Michigan, Minnesota, Mississippi, New York, Texas, and Wisconsin. In addition, pilot trials are being performed in several other states beginning in 2013.

The diagnosis of hyper IgM syndrome can be done via the following methods and tests:

- MRI

- Chest radiography

- Pulmonary function test

- Lymph node test

- Laboratory test (to measure CD40)

X-linked SCID is a known pediatric emergency which primarily affects males. If the appropriate treatment such as intravenous immunoglobulin supplements, medications for treating infections or a bone marrow transplant is not administered, then the prognosis is poor. The patients with X-linked SCID usually die two years after they are born. For this reason, the diagnosis of X-linked SCID needs to be done early to prevent any pathogens from infecting the infant.

However, the patients have a higher chance of survival if the diagnosis of X-linked SCID is done as soon as the baby is born. This involves taking preventative measures to avoid any infections that can cause death. For example, David Vetter had a high chance of having X-linked SCID because his elder sibling had died due to SCID. This allowed the doctors to place David in the bubble and prevented infections. In addition, if X-linked SCID is known to affect a child, then live vaccines should not be administered and this can save the infants life. Vaccines, which are pathogens inserted into the body to create an immune response, can lead to death in infants with X-linked SCID. Moreover, with proper treatments, such as a bone marrow transplant, the prognosis is good. The bone marrow transplant has been successful in treating several patients and resulted in a full immune reconstitution and the patient can live a healthy life. The results of bone marrow transplant are most successful when the closest human leukocyte antigen match has been found. If a close match is not found, however, there is a chance of graft-versus-host-disease which means the donor bone marrow attacks the patient's body. Hence, a close match is required to prevent any complications.

Serology (detection on antibodies to a specific pathogen or antigen) is often used to diagnose viral diseases. Because XLA patients lack antibodies, these tests always give a negative result regardless of their real condition. This applies to standard HIV tests. Special blood tests (such as the western blot based test) are required for proper viral diagnosis in XLA patients.

It is not recommended and dangerous for XLA patients to receive live attenuated vaccines such as live polio, or the measles, mumps, rubella (MMR vaccine). Special emphasis is given to avoiding the oral live attenuated SABIN-type polio vaccine that has been reported to cause polio to XLA patients. Furthermore, it is not known if active vaccines in general have any beneficial effect on XLA patients as they lack normal ability to maintain immune memory.

XLA patients are specifically susceptible to viruses of the Enterovirus family, and mostly to: polio virus, coxsackie virus (hand, foot, and mouth disease) and Echoviruses. These may cause severe central nervous system conditions as chronic encephalitis, meningitis and death. An experimental anti-viral agent, pleconaril, is active against picornaviruses. XLA patients, however, are apparently immune to the Epstein-Barr virus (EBV), as they lack mature B cells (and so HLA co-receptors) needed for the viral infection. Patients with XLA are also more likely to have a history of septic arthritis.

It is not known if XLA patients are able to generate an allergic reaction, as they lack functional IgE antibodies.There is no special hazard for XLA patients in dealing with pets or outdoor activities. Unlike in other primary immunodeficiencies XLA patients are at no greater risk for developing autoimmune illnesses.

Agammaglobulinemia (XLA) is similar to the primary immunodeficiency disorder Hypogammaglobulinemia (CVID), and their clinical conditions and treatment are almost identical. However, while XLA is a congenital disorder, with known genetic causes, CVID may occur in adulthood and its causes are not yet understood.

XLA was also historically mistaken as Severe Combined Immunodeficiency (SCID), a much more severe immune deficiency ("Bubble boys").A strain of laboratory mouse, XID, is used to study XLA. These mice have a mutated version of the mouse Btk gene, and exhibit a similar, yet milder, immune deficiency as in XLA.

Five "types" of hyper IgM syndrome have been characterized:

- Hyper-IgM syndrome type 1 (X-linked), characterized by mutations of the "CD40LG" gene. In this type, T cells cannot tell B cells to switch classes.

- Hyper-IgM syndrome type 2 (autosomal recessive), characterized by mutations of the "AICDA" gene. In this type, B cells cannot recombine genetic material to change heavy chain production

- Hyper-IgM syndrome type 3 characterized by mutations of the "CD40" gene. In this type, B cells cannot receive the signal from T cells to switch classes.

- Hyper-IgM syndrome type 4 which is a defect in class switch recombination downstream of the AICDA gene that does not impair Somatic Hypermutation.

- Hyper-IgM syndrome type 5 characterized by mutations of the "UNG" gene.

The basic tests performed when an immunodeficiency is suspected should include a full blood count (including accurate lymphocyte and granulocyte counts) and immunoglobulin levels (the three most important types of antibodies: IgG, IgA and IgM).

Other tests are performed depending on the suspected disorder:

- Quantification of the different types of mononuclear cells in the blood (i.e. lymphocytes and monocytes): different groups of T lymphocytes (dependent on their cell surface markers, e.g. CD4+, CD8+, CD3+, TCRαβ and TCRγδ), groups of B lymphocytes (CD19, CD20, CD21 and Immunoglobulin), natural killer cells and monocytes (CD15+), as well as activation markers (HLA-DR, CD25, CD80 (B cells).

- Tests for T cell function: skin tests for delayed-type hypersensitivity, cell responses to mitogens and allogeneic cells, cytokine production by cells

- Tests for B cell function: antibodies to routine immunisations and commonly acquired infections, quantification of IgG subclasses

- Tests for phagocyte function: reduction of nitro blue tetrazolium chloride, assays of chemotaxis, bactericidal activity.

Due to the rarity of many primary immunodeficiencies, many of the above tests are highly specialised and tend to be performed in research laboratories.

Criteria for diagnosis were agreed in 1999. For instance, an antibody deficiency can be diagnosed in the presence of low immunoglobulins, recurrent infections and failure of the development of antibodies on exposure to antigens. The 1999 criteria also distinguish between "definitive", "probable" and "possible" in the diagnosis of primary immunodeficiency. "Definitive" diagnosis is made when it is likely that in 20 years, the patient has a >98% chance of the same diagnosis being made; this level of diagnosis is achievable with the detection of a genetic mutation or very specific circumstantial abnormalities. "Probable" diagnosis is made when no genetic diagnosis can be made, but the patient has all other characteristics of a particular disease; the chance of the same diagnosis being made 20 years later is estimated to be 85-97%. Finally, a "possible" diagnosis is made when the patient has only some of the characteristics of a disease are present, but not all.

The following types of CVID have been identified, and correspond to mutations in different gene segments.

According to a European registry study, the mean age at onset of symptoms was 26.3 years old. As per the criteria laid out by ESID (European Society for Immunodeficiencies) and PAGID (Pan-American Group for Immunodeficiency), CVID is diagnosed if:

- the person presents with a marked decrease of serum IgG levels (<4.5 g/L) and a marked decrease below the lower limit of normal for age in at least one of the isotypes IgM or IgA;

- the person is four years of age or older;

- the person lacks antibody immune response to protein antigens or immunization.

Diagnosis is chiefly by exclusion, i.e. alternative causes of hypogammaglobulinemia, such as X-linked agammaglobulinemia, must be excluded before a diagnosis of CVID can be made.

Diagnosis is difficult because of the diversity of phenotypes seen in people with CVID. For example, serum immunoglobulin levels in people with CVID vary greatly. Generally, people can be grouped as follows: no immunoglobulin production, immunoglobulin (Ig) M production only, or both normal IgM and IgG production. Additionally, B cell numbers are also highly variable. 12% of people have no detectable B cells, 12% have reduced B cells, and 54% are within the normal range. In general, people with CVID display higher frequencies of naive B cells and lower frequencies of class-switched memory B cells. Frequencies of other B cell populations, such as IgD memory B cells, transitional B cells, and CD21 B cells, are also affected, and are associated with specific disease features. Although CVID is often thought of as a serum immunoglobulin and B cell-mediated disease, T cells can display abnormal behavior. Affected individuals typically present with low frequencies of CD4, a T-cell marker, and decreased circulation of regulatory T cells and iNKT cell. Notably, approximately 10% of people display CD4 T cell counts lower than 200 cells/mm; this particular phenotype of CVID has been named LOCID (Late Onset Combined Immunodeficiency), and has a poorer prognosis than classical CVID.

Bone marrow transplant may be possible for Severe Combined Immune Deficiency and other severe immunodeficiences.

Virus-specific T-Lymphocytes (VST) therapy is used for patients who have received hematopoietic stem cell transplantation that has proven to be unsuccessful. It is a treatment that has been effective in preventing and treating viral infections after HSCT. VST therapy uses active donor T-cells that are isolated from alloreactive T-cells which have proven immunity against one or more viruses. Such donor T-cells often cause acute graft-versus-host disease (GVHD), a subject of ongoing investigation. VSTs have been produced primarily by ex-vivo cultures and by the expansion of T-lymphocytes after stimulation with viral antigens. This is carried out by using donor-derived antigen-presenting cells. These new methods have reduced culture time to 10–12 days by using specific cytokines from adult donors or virus-naive cord blood. This treatment is far quicker and with a substantially higher success rate than the 3–6 months it takes to carry out HSCT on a patient diagnosed with a primary immunodeficiency. T-lymphocyte therapies are still in the experimental stage; few are even in clinical trials, none have been FDA approved, and availability in clinical practice may be years or even a decade or more away.

Patients presenting with this disease undergo antibiotic treatment and gammaglobulin transfusions. Antibiotics are used to fight off the pathogenic organisms and the gammaglobulin helps provide a normal balance of antibodies to fight the infection. Bone marrow transplantation may be an option in some cases.

OMIM: 308230

Most patients with "ETV6-ACSL6"-related disease present with findings similar to eosinophilia, hypereosinophila, or chronic eosinophilic leukemia; at least 4 cases presented with eosinophilia plus findings of the red blood cell neoplasm, polycythemia vera; three cases resembled acute myelogenous leukemia; and one case presented with findings of a combined Myelodysplastic syndrome/myeloproliferative neoplasm. Best treatments for "ETV6-ACSL6"-related disease are unclear. Patients with the polycythemia vera form of the disease have been treated by reducing the circulating red blood cell load by phlebotomy or suppressing red blood cell formation using hydroxyurea. Individual case studies report that "ETV6-ACSL6"-associated disease is insensitive to tyrosine kinase inhibitors. Best treatment currently available, therefore, may involve chemotherapy and bone marrow transplantion.

Immunodeficiency with hyper IgM type 4 is poorly characterized. All that is known is that there is an excess of IgM in the blood, with normal levels of the other immunoglobulins. The exact cause is yet to be determined.

There are 3 possible ways to test the fetal antigen status. Free Cell DNA, Amniocentesis, and Chorionic Villus Sampling. Of the three, CVS is no longer used due to risk of worsening the maternal antibody response. Once antigen status has been determined, assessment may be done with MCA scans.

- Free Cell DNA can be run on certain antigens. Blood is taken from the mother, and using PCR, can detect the K, C, c, D, and E alleles of fetal DNA. This blood test is non-invasive to the fetus and is an easy way of checking antigen status and risk of HDN. Testing has proven very accurate and is routinely done in the UK at the International Blood Group Reference Laboratory in Bristol. Sanequin laboratory in Amsterdam, Netherlands also performs this test. For US patients, blood may be sent to either of the labs. In the US, Sensigene is done by Sequenome to determine fetal D status. Sequenome does not accept insurance in the US, but US and Canadian patients have had insurance cover the testing done overseas.

- Amniocentesis is another recommended method for testing antigen status and risk for HDN. Fetal antigen status can be tested as early as 15 weeks by PCR of fetal cells.

- CVS is possible as well to test fetal antigen status but is not recommended. CVS carries a higher risk of fetal maternal hemorrhage and can raise antibody titers, potentially worsening the antibody effect.

Immunodeficiency with hyper IgM type 5 is caused by a mutation in the Uracil-DNA glycosylase (UNG) gene, which, like AICDA, is located on chromosome 12. This codes for Uracil DNA Glycosylase, which is responsible for excising previous uracil bases that are due to cytosine deamination, or previous uracil misincorporation from double-stranded previous DNA substrates. This enzyme is also responsible for helping with gene conversion during somatic recombination in B cells. The mutation in the gene causes an enzyme that does not function properly, thus gene conversion does not proceed and class switching cannot occur.

Blood is generally drawn from the father to help determine fetal antigen status. If he is homozygous for the antigen, there is a 100% chance of all offspring in the pairing to be positive for the antigen and at risk for HDN. If he is heterozygous, there is a 50% chance of offspring to be positive for the antigen. This test can help with knowledge for the current baby, as well as aid in the decision about future pregnancies. With RhD, the test is called the RhD genotype. With RhCE, and Kell antigen it is called an antigen phenotype.

There are many lymphoproliferative disorders that are associated with organ transplantation and immunosuppressant therapies. In most reported cases, these cause B cell lymphoproliferative disorders; however, some T cell variations have been described. The T cell variations are usually caused by the prolonged use of T cell suppressant drugs, such as sirolimus, tacrolimus, or ciclosporin.

Hyper IgM Syndrome Type 1 (HIGM-1) is the X-linked variant of the Hyper-IgM syndrome. The affected individuals are virtually always male, because males only have one X chromosome, received from their mothers. Their mothers are not symptomatic, even though they are carriers of the allele, because the trait is recessive. Male offspring of these women have a 50% chance of inheriting their mother's mutant allele.

Diagnosis

Originally NEMO deficiency syndrome was thought to be a combination of Ectodermal Dysplasia (ED) and a lack of immune function, but is now understood to be more complex disease. NEMO Deficiency Syndrome may manifest itself in the form of several different diseases dependent upon mutations of the IKBKG gene such as Incontinentia pigmenti or Ectodermal dysplasia.

The clinical presentation of NEMO deficiency is determined by three main symptoms:

1. Susceptibility to pyogenic infections in the form of severe local inflammation

2. Susceptibility to mycobacterial infection

3. Symptoms of Ectodermal Dysplasia

To determine whether or not patient has NEMO deficiency, an immunologic screen to test immune system response to antigen may be used although a genetic test is the only way to be certain as many individuals respond differently to the immunological tests.

Commonly Associated Diseases

NEMO deficiency syndrome may present itself as Incontinentia pigmenti or Ectodermal dysplasia depending on the type of genetic mutation present, such as if the mutation results in the complete loss of gene function or a point mutation.

Amorphic genetic mutations in the IKBKG gene, which result in the loss of gene function, typically present themselves as Incontinetia Pigmenti (IP). Because loss of NEMO function is lethal, only heterozygous females or males with XXY karyotype or mosaicism for this gene survive and exhibit symptoms of Incontinetia Pigmenti, such as skin lesions and abnormalities in hair, teeth, and nails. There are a variety of mutations that may cause the symptoms of IP, however, they all involve the deletion of exons on the IKBKG gene.

Hypomorphic genetic mutations in the IKBKG gene, resulting in a partial loss of gene function, cause the onset of Anhidrotic ectodermal dysplasia with Immunodeficiency (EDA-IP). The lack of NEMO results in a decreased levels of NF-κB transcription factor translocation and gene transcription, which in turn leads to a low level of immunoglobulin production. Because NF-κB translocation is unable to occur without proper NEMO function, the cell signaling response to immune mediators such as IL-1β, IL-18, and LPS are ineffective thus leading to a compromised immune response to various forms of bacterial infections.

Treatment

The aim of treatment is to prevent infections so children will usually be started on immunoglobulin treatment. Immunoglobulin is also known as IgG or antibody. It is a blood product and is given as replacement for people who are unable to make their own antibodies. It is the mainstay of treatment for patients affected by primary antibody deficiency. In addition to immunoglobulin treatment, children may need to take antibiotics or antifungal medicines to prevent infections or treat them promptly when they occur. Regular monitoring and check-ups will help to catch infections early. If an autoimmune response occurs, this can be treated with steroid and/or biologic medicines to damp down the immune system so relieving the symptoms.

In some severely affected patients, NEMO deficiency syndrome is treated using a bone marrow or blood stem cell transplant. The aim is to replace the faulty immune system with an immune system from a healthy donor.

Immunodeficiency is a consistent feature with low serum concentrations of immunoglobulins which may improve with age and a poor immunological response to childhood vaccination. T cell dysfunction and abnormal antibody generation have been reported.

Microscopic analysis of the hair shows twisted hairs of unequal size and different shapes (pili torti, aniso- and poikilotrichosis), longitudinal breaks and breaks located at nodes (trichorrhexis nodosa). Scanning electron microscopy might reveal hair budding (trichorrhexis blastysis). Biochemical analysis may reveal sulfur-deficient brittle hair (trichothiodystrophy; note that disulfide bonds determine hair waviness).

There are 3 possible ways to test the fetal antigen status. Free Cell DNA, Amniocentesis, and Chorionic Villus Sampling. Of the three, CVS is no longer used due to risk of worsening the maternal antibody response. Once antigen status has been determined, assessment may be done with MCA scans.

- Free Cell DNA can be run on certain antigens. Blood is taken from the mother, and using PCR, can detect the K, C, c, D, and E alleles of fetal DNA. This blood test is non-invasive to the fetus and is an easy way of checking antigen status and risk of HDN. Testing has proven very accurate and is routinely done in the UK at the International Blood Group Reference Laboratory in Bristol. Sanequin laboratory in Amsterdam, Netherlands also performs this test. For US patients, blood may be sent to either of the labs. In the US, Sensigene is done by Sequenome to determine fetal D status. Sequenome does not accept insurance in the US, but US and Canadian patients have had insurance cover the testing done overseas.

- Amniocentesis is another recommended method for testing antigen status and risk for HDN. Fetal antigen status can be tested as early as 15 weeks by PCR of fetal cells.

- CVS is possible as well to test fetal antigen status but is not recommended. CVS carries a higher risk of fetal maternal hemorrhage and can raise antibody titers, potentially worsening the antibody effect.

Viral infection is a very common cause of lymphoproliferative disorders. In children, the most common is believed to be congenital HIV infection because it is highly associated with acquired immunodeficiency, which often leads to lymphoproliferative disorders.

Blood is generally drawn from the father to help determine fetal antigen status. If he is homozygous for the antigen, there is a 100% chance of all offspring in the pairing to be positive for the antigen and at risk for HDN. If he is heterozygous, there is a 50% chance of offspring to be positive for the antigen. This test can help with knowledge for the current baby, as well as aid in the decision about future pregnancies. With RhD, the test is called the RhD genotype. With RhCE, and Kell antigen it is called an antigen phenotype.

Patients with hematological disease related to the cited "FLT3" fusion genes present with either a myeloid or lymphoid neoplasm plus eosinophilia. Four of 6 patients with "ETV6-FLT3"-related disease, a patient with "GOLGB1-FLT3"-related disease, and a patient with "TRIP11-FLT3"-related disease presented with findings similar to T-cell lymphoma while a patient with "SPTBN1-FLT3"-related disease had findings of chronic myelogenous leukemia. Two patients with "ETV6-FLT3"-related disease experienced complete hematologic remissions when treated with a multi-kinase inhibitor, sunitinib, that has inhibitory activity against FLT3 protein. However, these remissions were short-lived. A third patient with "ETV6-FLT3"-related disease was treated with a similarly active kinase inhibitor, sorafenib. This patient achieved a complete hematological response and was then given a hematopoietic stem cell transplantation. The latter treatment regimen, FLT3 inhibitor followed by hematopoietic stem cell transplantation, may be the best approach currently available for treating "FLT3"-releated hematological disease.