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Diagnostic criteria for PID

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Published: May 10, 2006

The diagnostic criteria for the most common PID are listed here.

AT diagnostic guidelines
BCG Diagnostic Criteria
Common variable immunodeficiency diagnostic criteria
CGD diagnostic criteria
DiGeorge diagnostic criteria
Differential diagnosis of hypogammaglibulemia
IgA deficiency diagnostic criteria
IgG subclasses diagnostic criteria
Leukocyte adhesion defects diagnostic criteria?
MHC class II deficiency diagnostic criteria
NBS diagnostic criteria
Partial antibody deficiency diagnostic criteria
SCID diagnostic criteria
WHIM diagnostic criteria
WAS diagnostic criteria
X-linked agammaglobulinemia
X-linked hyper IgM
X-linked lymphoproliferative syndrome diagnostic criteria
XSCID diagnostic criteria

Ataxia Telangiectasia

Definitive
Male or female patient with either increased radiation induced chromosomal breakage in cultured cells, or progressive cerebellar ataxia, who has disabling mutations on both alleles of ATM.

Probable
Male or female patient with progressive cerebellar ataxia and three out of the following four findings:
1) Ocular or facial telangiectasia
2) Serum IgA at least 2 SD below normal for age
3) Alpha fetoprotein at least 2 SD above normal for age
4) Increased radiation induced chromosomal breakage in cultured cells

Possible
Male or female patient with progressive cerebellar ataxia and at least one of the following four findings:
1) Ocular or facial telangiectasia
2) Serum IgA at least 2 SD below normal for age
3) Alpha fetoprotein more than 2 SD above normal for age
4) Increased chromosomal breakage after exposure to irradiation

Spectrum of disease
AT is a progressive neurologic disorder. Most patients begin to have difficulty walking at the end of the first year of life and are wheelchair bound by the teenage years. Ocular or facial telangiectasia are usually noted at 4-8 years of life. Many patients have recurrent respiratory infections. Leukemia or lymphomas are seen in 10-15% of patients and may be the presenting finding. Some patients are not recognized to have AT until the second decade of life.

Differential diagnosis
Nijmegen breakage syndrome

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AT Diagnostic guidelines

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Diagnostic criteria for BCG disseminated infections in Primary Immunodeficiencies

Definitive

A male or female patient with systemic symptoms, such as fever or subfebrile states, weight loss, or stunted growth, and at least two areas of involvement beyond the site of a BCG vaccination, such as lymph nodes, skin, soft tissues, lungs, spleen, liver or bones.
Identification by the Mycobacterium bovis BCG substrain from the patient’s organs by culture and/or standard PCR, as well as typical histopathological changes with granulomatous inflammation.

Probable

Systemic symptoms such as fever or subfebrile states, weight loss or stunted growth, and at least two areas of involvement beyond the site of a BCG vaccination, such as lymph nodes, skin, soft tissues, lungs, spleen, liver or bones.
Identification of M. tuberculosis complex from the organs by PCR, without differentiation of M. bovis BCG substrain or other members of the M. tuberculosis complex and with negative mycobacterial cultures, with the presence of typical histopathological changes with granulomatous inflammation.

Possible

Systemic symptoms such as fever or subfebrile condition, weight loss or stunted growth, and at least two areas of involvement beyond the site of a BCG vaccination, such as lymph nodes, skin, soft tissues, lungs, spleen, liver or bones.
No identification of mycobacteria by PCR or culture, with the presence of typical histopathological changes with granulomatous inflammation.

Spectrum of disease

A male or female patient with severe combined immunodeficiencies, deficiency of IFN –g receptor, IL- 12 receptor deficiency, or other genetically - confirmed primary immunodeficiency with disseminated BCG infection.

Exclusion criteria Any inflammation without typical histopathological changes, with no identification of Mycobacterium tuberculosis complex by PCR analysis in male and female with primary immunodeficiency.

Differential diagnosis
Severe, long-term inflammation with granuloma formation in primary immunodeficiency patients.

Prophylaxis and therapeutic guideline of BCG disseminated infection in severe combined immunodeficiency

No signs of local changes at the site of the BCG injection, and no signs of BCGitis

Careful observation

Local changes at the site of the BCG injection

Anti-TB treatment include IHN and RMP should be initiated and continued till complete immunological reconstitution occurs after HSCT.

BCGitis with regional lymph node involvement

Anti-tuberculosis treatment with at least triple anti-TB therapy, followed by long-term prophylactic treatment, as above.

BCGitis

Anti-tuberculosis treatment including four or more anti-TB drugs, until the patient fully recovers. Then, a prophylactic programme with two drugs should be continued, until complete immunological reconstitution after HSCT is achieved.

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BCG diagnostic criteria

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CVID

Probable
Male or female patient who has a marked decrease of IgG (at least 2 SD below the mean for age) and a marked decrease in at least one of the isotypes IgM or IgA, and fulfills all of the following criteria:
1) Onset of immunodeficiency at greater than 2 years of age
2) Absent isohemagglutinins and/or poor response to vaccines
3) Defined causes of hypogammaglobulinemia have been excluded (see ' Differential Diagnosis of Hypogammaglobulinemia')

Possible
Male or female patient who has a marked decrease (at least 2 SD below the mean for age) in one of the major isotypes (IgM, IgG and IgA) and fulfills all of the following criteria:
1) Onset of immunodeficiency at greater than 2 years of age
2) Absent isohemagglutinins and/or poor response to vaccines
3) Defined causes of hypogammaglobulinemia have been excluded (see ' Differential Diagnosis of Hypogammaglobulinemia')

Spectrum of disease
Most patients with CVI are recognized to have immunodeficiency in the second, third or fourth decade of life, after they have had several pneumonias; however children and older adults may be affected. Viral, fungal and parasitic infections as well as bacterial infections may be problematic. The serum concentration of IgM is normal in about half of the patients. Abnormalities in T cell numbers or function are common. The majority of patients have normal numbers of B cells; however, some have low or absent B cells. Approximately 50% of patients have autoimmune manifestations. There is an increased risk of malignancy.

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Chronic Granulomatous Disease

Definitive
Male or female patient with abnormal NBT or respiratory burst in activated neutrophils (less than 5% of control) who has one of the following:
1) Mutation in gp91, p22, p47 or p67 phox
2) Absent mRNA for one of the above genes by northern blot analysis
3) Maternal cousins, uncles or nephews with an abnormal NBT or respiratory burst

Probable
Male or female patient with abnormal NBT or respiratory burst in activated neutrophils (less than 5% of control) who has one of the following:
1) Deep seated infection (liver, perirectal or lung abscess; adenitis; or osteomyelitis) due to staphylococcus, serratia marcescens, candida or aspergillus
2) Diffuse granulomata in respiratory, gastrointestinal or urogenital tracts
3) Failure to thrive and hepatosplenomegaly or lymphadenopathy

Spectrum of disease
Patients with the X-linked form of CGD (60-70% of patients) tend to present earlier and have more severe disease than patients with autosomal recessive forms. Most patients with X-CGD develop failure to thrive, severe bacterial adenitis, abscesses or osteomyelitis within the first year of life. Pneumonia and lymphadenitis due to catalase-positive organisms (particularly Staphylococcus) or fungi are the most common infections. Symptoms of intestinal or urinary tract obstruction can be caused by granuloma formation. Rarely, in both the X-linked and autosomal recessive forms, the first severe symptoms are not recognized until adulthood.

Differential diagnosis
1) LAD
2) Sarcoidosis
3) Hyper IgE syndrome

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CGD diagnostic criteria

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DiGeorge Syndrome diagnostic criteria

Definitive
Male or female patient with reduced numbers of CD3+ T cells (less than 500/mm3) and two of the three following characteristics:
1) Conotruncal cardiac defect (truncus arteriosus, tetrology of Fallot, interrupted aortic arch or aberrant right subclavian)
2) Hypocalcemia of greater than 3 weeks duration that requires therapy
3) Deletion of chromosome 22q11.2

Probable
Male or female patient with reduced numbers of CD3+ T cells (less than 1500/mm3) and a deletion of chromosome 22q11.2.

Possible
Male or female patient with reduced numbers of CD3+ T cells (less than 1500/mm3) and at least one of the following:
1) Cardiac defect
2) Hypocalcemia of greater than 3 weeks duration that requires therapy
3) Dysmorphic facies or palatal abnormalities

Spectrum of disease
The majority of patients with DiGeorge syndrome are recognized to have immunodeficiency in the first few months of life when they are being evaluated for cardiac malformations that are highly associated DiGeorge syndrome and/or deletions of chromosome 22q11.2. A few patients present with persistent viral or fungal infections, or with hypocalcemic tetany. The severity of the T cell defect varies greatly. In many patients the immunodeficiency resolves in the first few years of life. Dysmorphic facial features and mental retardation are common. Autoimmune disorders may be seen in older patients.

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DiGeorge Diagnostic criteria

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Differential diagnosis of hypogammoglobulinemia

Drug Induced
Antimalarial agents
Captopril
Carbamazepine
Glucocorticoids
Fenclofenac
Gold salts
Penicillamine
Phenytoin
Sulfasalazine

Genetic Disorders
Ataxia Telangiectasia
Autosomal forms of SCID
Hyper IgM Immunodeficiency
Transcobalamin II deficiency and hypogammaglobulinemia
X-linked agammaglobulinemia
X-linked lymphoproliferative disorder (EBV associated)
X-linked SCID
Some metabolic disorders
Chromosomal Anomalies
Chromosome 18q- Syndrome
Monosomy 22
Trisomy 8
Trisomy 21

Infectious Diseases
HIV
Congenital Rubella
Congenital infection with CMV
Congenital infection with Toxoplasma gondii
Epstein-Barr Virus

Malignancy
Chronic Lymphocytic Leukemia
Immunodeficiency with Thymoma
Non Hodgkin's lymphoma
B cell malignancy

Systemic Disorders
Immunodeficiency caused by hypercatabolism of immunoglobulin
Immunodeficiency caused by excessive loss of immunoglobulins (nephrosis, severe burns, lymphangiectasia, severe diarrhea)

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IgA deficiency

Definitive
Male or female patient greater than 4 years of age who has a serum IgA of less than 7 mg/dl (0.07 g/L) but normal serum IgG and IgM, in whom other causes of hypogammaglobulinemia have been excluded (see 'Differential Diagnosis of Hypogammaglobulinemia'). These patients have a normal IgG antibody response to vaccination.

Probable
Male or female patient greater than 4 years of age who has a serum IgA at least 2 SD below normal for age but normal serum IgG and IgM, in whom other causes of hypogammaglobulinemia have been excluded (see 'Differential Diagnosis of Hypogammaglobulinemia'). These patients have a normal IgG antibody response to vaccination.

Spectrum of disease
Patients with IgA deficiency have an increased incidence of upper respiratory tract infections, allergies and autoimmune disease. Many individuals with IgA deficiency are asymptomatic. Others have persistent or recurrent infections and some develop CVI over time.

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IgG subclass deficiency

Draft
Male or female patient with recurrent/severe infections and all of the following:

  • aged 7 years
  • normal levels of IgM and IgA and at least two of IgG1-3 sublasses less than the 5th centile for age
  • Poor responsed to some vaccines

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Leukocyte Adhesion Deficiency

Definitive
A male or female patient with decreased intensity of expression of CD18 on neutrophils (less than 5% of normal) and at least one of the following:
1) Mutation in the b2 integrin gene
2) Absence of b2 integrin mRNA in leukocytes

Probable
A male or female patient with defective expression of CD18 on leukocytes (less than 5% of normal) and all of the following:
1) Recurrent or persistent bacterial or fungal infections
2) Leukocytosis (WBC greater than 25,000/mm3)
3) Delayed separation of the umbilical cord and/or defective wound healing

Possible
Infant with marked leukocytosis (WBC greater than 25,000/mm3) and one of the following:
1) Recurrent bacterial infections
2) Severe deep seated infection
3) Absence of pus at sites of infection

Spectrum of disease
Marked leukocytosis and recurrent bacterial infections are the hallmarks of LAD. Staphylococcus, gram negative enteric bacteria and fungal infections are particularly troublesome. Periodontitis is a very common persistent finding. In the severe form, no expression of CD18 is detected on neutrophils and early death occurs without BMT. In the moderate form, a small amount of CD18 is expressed and patients can survive to adulthood. Some patients may have normal CD18 expression with a defective CD18 (b2 integrin) activity.

Exclusion criteria
1) Normal CD18 and CD15a expression on neutrophils
2) Normal neutrophil counts
3) Normal neutrophil adhesion

Differential diagnosis
1) Chronic Granulomatous Disease
2) SLeX deficiency (LAD II)

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MHC class II deficiency diagnostic criteria

Definitive

Male or female patient with decreased intensity of expression (less than 5% of normal) of HLA-DR or DP on B cells or monocytes and a mutation in one of the following genes:

CIITA, RFX-B, RFX-5 or RFX-AP

Probable

Male or female patient with decreased intensity of expression (less then 5% of normal) of HLA-DR or DP on B cells and monocytes and all of the following:
1) Failure to thrive, opportunistic infections or persistent viral infections
2) Normal numbers of T cells and B cells
3) Normal proliferative responses to mitogens

Possible

Male or female patient with decreased intensity of expression (less then 5% of normal) of HLA-DR or DP on B cells or monocytes, and normal numbers of T cells and B cells, who has at least one of the following:
1) Hypogammaglobulinemia
2) Normal mitogen responses but absent T cell proliferation to antigens
3) Reduced numbers of CD4+ cells
4) Failure of mononuclear cells to stimulate a mixed lymphocyte culture

Spectrum of disease

MCH Class II deficiency, which is seen most often in patients from around the Mediterranean sea, results in a clinical phenotype that is very similar to SCID. Patients usually develop severe infections and protracted diarrhea in the first 6 months of life. Pseudomonas, CMV and Cryptosporidium infections are common. The four genetic disorders that result in this syndrome are clinically indistinguishable. In most cases, there is no class II expression; however, in others the intensity of expression may be as high as 5% of normal. Patients with higher expression tend to have a milder course; these patients may survive beyond early childhood. Hepatic abnormalities, particularly sclerosing cholangitis, are frequent.

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Nijmegen breakage syndrome

Definitive
Male or female patient with either increased radiation induced chromosomal breakage in cultured cells or microcephaly, who has NBS-1, the gene defective located on chromosome 8q21 on both alleles.

Probable
Make or female patient with three out of the following five findings:
1. microcephaly
2. typical facial appearance
3. lymphoma, leukemia
4. serum IgG and IgA more than 2 SD below normal for age
5. increased radiation induced chromosomal breakage in cultured cells

Possible
Male or female patient with at least one of the following five findings:
1. microcephaly
2. typical facial appearance
3. lymphoma, leukaemia
4. serum IgG and IgA more than 2 SD below normal for age
5. Increased radiation induced chromosomal breakage in cultured cells

Spectrum of disease
Essential features found in NBS are microcephaly (99.7%), usually without retardation, typical facial appearance with a receding forehead, prominent midface with long nose and long philtrum,, and a receding mandible. Important additional features are café au lait spots, vitiligo and clinodactyly and syndactyly. All NBS patients presented chromosomal instability, X-ray hypersensitivity and increased risk for malignancy. More than 50% developed B or T origin lymphomas before 18 year of age. Many patients have recurrent bacterial and viral respiratory infections (56%) associated with antibody deficiencies.

Differential diagnosis
Ataxia Telangiectasia
Bloom syndrome

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NBS diagnostic criteria

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Partial Antibody Deficiencies

The debate on the differential diagnosis of partial antibody deficiencies is detailed in the power point presentation available for download

Debate re diagnostic criteria. Please send your comments to Dr. Helen Chapel at

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SCID

Definitive
Male or female patient less than 2 years of age with either a) engraftment of transplacentally acquired maternal T cells; or b) less than 20% CD3+ T cells, an absolute lymphocyte count of less than 3000/mm3 and at least one of the following:
1) Mutation in the cytokine common gamma chain (gc)
2) Mutation in JAK3
3) Mutation in RAG1 or RAG2
4) Mutation in IL-7Ra
5) ADA activity of less than 2% of control or mutations in both alleles of ADA

Probable
Male or female patient less than 2 years of age with less than 20% CD3+ T cells, an absolute lymphocyte count of less than 3000/mm3 and proliferative responses to mitogens less than 10% of control; or the presence of maternal lymphocytes in the circulation.

Spectrum of disease
Patients with SCID usually develop failure to thrive and persistent diarrhea, respiratory symptoms and/or thrush in the first 2 to 7 months of life. Pneumocystis pneumonia, significant bacterial infections and disseminated BCG infection are common presenting illnesses. Occasional patients do not have failure to thrive and are not recognized to have immunodeficiency until late in the first year of life. SCID is fatal in the first 2 years of life unless the patient is treated with extremely restrictive isolation, hematopoietic stem cell transplant or therapy that replaces the abnormal gene or gene product.

Differential diagnosis
1) HIV infection
2) Congenital rubella
3) DiGeorge syndrome
4) Zap70 deficiency
5) CD3 deficiency
6) Cartilage hair hypoplasia
7) MHC class II deficiency
8) PNP deficiency

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SCID diagnostic criteria

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ESID-PAGID Diagnostic criteria for WHIM (Warts-Hypogammaglobulinemia-Infections-Myelokathexis) syndrome

Definitive diagnosis
Male or female patient with chronic neutropenia (absolute neutrophil count of less than 500/μL) and myelokathexis (retention of senescent neutrophils in the bone marrow) and one of the following:
1. Mutation in the intracellular C-tail of CXCR4
2. Activating mutation of CXCR4

Probable Diagnosis
Male or female patient with chronic neutropenia (absolute neutrophil count of less than 500/μL) and myelokathexis (retention of senescent neutrophils in the bone marrow) and two of the following:
1. Chronic or recurrent warts
2. Chronic lymphopenia (absolute lymphocyte count of less than 1500/μL)
3. Serum IgG at or below the normal range for age
4. A parent with neutropenia and warts

Possible diagnosis
Male or female patient with chronic neutropenia (absolute neutrophil count of less than 500/μL) and myelokathexis (retention of senescent neutrophils in the bone marrow).

Spectrum of Disease
WHIM syndrome is an autosomal dominant disorder resulting in neutropenia with myelokathexis. Most patients present with recurrent infections at less than 3 years of age. Warts generally begin to appear after five years of age and some patients have hundreds of warts that can include plantar and genital warts. Increased susceptibility to infection from members of the herpes virus family can be seen. Lymphopenia is present in most patients and some patients have very low numbers of B cells. Hypogammaglobulinemia may be present, but the serum immunoglobulin concentrations do not correlate with the number of B cells. Most patients develop a normal neutrophil count during infection.

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WHIM Diagnostic criteria

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Wiskott-Aldrich Syndrome

Definitive
Male patient with congenital thrombocytopenia (less than 70,000 platelets/mm3), small platelets and at least one of the following:
1) Mutation in WASP
2) Absent WASP mRNA on northern blot analysis of lymphocytes
3) Absent WASP protein in lymphocytes
4) Maternal cousins, uncles or nephews with small platelets and thrombocytopenia

Probable
Male patient with congenital thrombocytopenia (less than 70,000 platelets/mm3), small platelets and at least one of the following:
1) Eczema
2) Abnormal antibody response to polysaccharide antigens
3) Recurrent bacterial or viral infections
4) Autoimmune diseases
5) Lymphoma, leukemia or brain tumor

Possible
Male patient with thrombocytopenia (less than 70,000 platelets/mm3) and small platelets; or a male patient splenectomized for thrombocytopenia who has at least one of the following:
1) Eczema
2) Abnormal antibody response to polysaccharide antigens
3) Recurrent bacterial or viral infections
4) Autoimmune diseases
5) Lymphoma, leukemia or brain tumor

Spectrum of disease
Congenital thrombocytopenia with small platelets is the diagnostic hallmark of Wiskott-Aldrich syndrome. Many patients present with bloody diarrhea in the first month of life. Eczema, which occurs in some but not all patients, may be the predominant clinical problem. Otitis and sinusitis, and infections due to herpes simplex and EBV are particularly troublesome. Many patients have increased IgE and IgA, with low IgM. T cell numbers and function decline with age. There is an increased incidence of autoimmune manifestations (vasculitis, hemolytic anemia, glomerulonephritis) and tumors (leukemia, lymphoma, EBV-related brain tumor). Occasional patients have moderate thromboyctopenia (50,000 to 100,000 platelets/mm3) and no other findings.

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WAS diagnostic criteria

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X-Linked Agammaglobulinemia

Definitive
Male patient with less than 2% CD19+ B cells and at least one of the following:
1) Mutation in Btk
2) Absent Btk mRNA on northern blot analysis of neutrophils or monocytes
3) Absent Btk protein in monocytes or platelets
4) Maternal cousins, uncles or nephews with less than 2% CD19+ B cells

Probable
Male patient with less than 2% CD19+ B cells in whom all of the following are positive:
1) Onset of recurrent bacterial infections in the first 5 years of life
2) Serum IgG, IgM and IgA more than 2SD below normal for age
3) Absent isohemagglutinins and /or poor response to vaccines
4) Other causes of hypogammaglobulinemia have been excluded (see Table)

Possible
Male patient with less than 2% CD19+ B cells in whom other causes of hypogammaglobulinemia have been excluded (see Table) and at least one of the following is positive:
1) Onset of recurrent bacterial infections in the first 5 years of life
2) Serum IgG, IgM and IgA more than 2 SD below normal for age
3) Absent isohemagglutinins

Spectrum of disease
Most patients with XLA develop recurrent bacterial infections, particularly otitis, sinusitis and pneumonia, in the first two years of life. The most common organisms are S. pneumonea and H. influenzae. The serum IgG is usually less than 200 mg/dl (2g/L) and the IgG and IgA are generally less than 20 mg/dl (0.2g/L). Approximately 20% of patients present with a dramatic, overwhelming infection, often with neutropenia. Another 10-15% have higher concentrations of serum immunoglobulin than expected or are not recognized to have immunodeficiency until after 5 years of age.

Differential diagnosis
All other causes of hypogammaglobulinemia listed in Table 1:
1) Mu heavy chain deficiency
2) Lambda 5 deficiency
3) IgA deficiency

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X-linked Agammaglobulinemia

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X-linked Hyper IgM

Definitive
Male patient with serum IgG concentration at least 2 SD below normal for age and one of the following:
1) Mutation in the CD40L gene
2) Maternal cousins, uncles, or nephews with confirmed diagnosis of XHIM

Probable
Male patient with serum IgG concentration at least 2 SD below the normal for age and all of the following:
1) Normal number of T cells and normal T cell proliferation to mitogens
2) Normal or elevated numbers of B cells but no antigen specific IgG antibody
3) One or more of the following infections or complications
-Recurrent bacterial infections in the first 5 years of life
-Pneumocystis carinii infection in the first year of life
-Neutropenia
-Cryptosporidium-related diarrhea
-Sclerosing cholangitis
-Parvovirus induced aplastic anemia
4) Absent CD40 ligand cell surface staining on activated CD4+T cells as assessed by binding to soluble CD40 or monoclonal antibody to CD40 ligand

Possible
Male patient with serum IgG concentration at least 2 SD below normal for age, normal numbers of T cells and B cells and one or more of the following:
1) Serum IgM concentration at least 2 SD above normal for age
2) Pneumocystis carinii infection in the first year of life
3) Parvovirus induced aplastic anemia
4) Cryptosporidium-related diarrhea
5) Severe liver disease (sclerosing cholangitis)

Spectrum of disease
Patients with XHIM have recurrent bacterial and opportunistic infections starting in the first year of life. Pneumocystis carinii pneumonia is a common presenting infection. Other patients may have chronic, profuse diarrhea requiring parenteral nutrition. Over 50% of patients have chronic or intermittent neutropenia, often associated with oral ulcers. Cryptosporidium infection may lead to severe bile duct disease and hepatic cancer. Serum concentration of IgG is usually less than 200 mg/dl; IgM may be low, normal or elevated. Atypical cases may present with recurrent infections, anemia or hepatitis in the second or third decade of life.

XHIM exclusion criteria
1) Defects in T cell activation (i.e., defective expression of CD69 or CD25 after in vitro T cell activation)
2) Human immunodeficiency virus infection
3) Congenital rubella infection
4) MHC class II deficiency
5) CD4+T cell deficiency
6) Drug or infection exposure known to influence the immune system

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X-linked hyper IgM

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X-Linked Lymphoproliferative Syndrome

Definitive
Male patient with lymphoma/ Hodgkins disease, fatal EBV infection, immunodeficiency, aplastic anemia or lymphohistiocytic disorder who has a mutation in SH2D1A/SAP/DSHP.

Probable
Male patient experiencing death, lymphoma/Hodgkins disease, immunodeficiency, aplastic anemia or lymphohistiocytic disorder following acute EBV infection and maternal cousins, uncles or nephews with a history of similar diagnoses following acute EBV infection.

Possible
Male patient experiencing death, lymphoma/Hodgkin's disease, immunodeficiency, aplastic anemia or lymphohistiocytic disorder following acute EBV infection.

Spectrum of disease
Males with XLP are usually asymptomatic until they develop EBV infection, which may cause fulminant hepatitis (60% of all patients), particularly in young children.
Hodgkin or non-Hodgkin lymphoma (30%), and/or immune deficiency with low serum IgG and abnormal NK cell function (30%) are more likely to develop in older patients. Less common manifestations include EBV-associated hemophagocytic syndrome and vasculitis. The vast majority of patients die in childhood; survival rate is very poor for males with fulminant hepatitis (<5%), and higher for those with isolated dysgammaglobulinemia (50%).

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X-linked SCID

Definitive
Male patient with either a) engraftment of transplacentally acquired maternal T cells; or b) less than 10% CD3+ T cells, less than 2% CD16/56+ NK cells and more than 75% CD19+ B cells, who has one of the following:
1) Mutation in the cytokine common gamma chain (gc)
2) Absent gc mRNA on northern blot analysis of lymphocytes
3) Absent gc protein on the surface of lymphocytes or lymphocyte cell lines
4) Maternal cousins, uncles or nephews with severe combined immunodeficiency

Probable
Male patient with less than 10% CD3+ T cells, less than 2% CD16/56+ NK cells and more than 75% CD19+ B cells who has all of the following:
1) Onset of failure to thrive before one year of age
2) Serum IgG and IgA more than 2 SD below normal for age
3) Persistent or recurrent diarrhea, URI or thrush

Possible
Male patient with greater than 40% CD19+ B cells in the peripheral circulation and one of the following:
1) Engraftment of transplacetally acquired maternal T cells
2) Maternal cousins, uncles or nephews with a history of severe combined immunodeficiency

Spectrum of disease
Males with XSCID usually develop persistent respiratory infections, diarrhea, and failure to thrive by 4 months of age and are recognized to have immunodeficiency by 6 or 7 months of age. Candidiasis is common. Many patients have normal serum IgM but IgG and IgA are usually very low. Some but not all patients with engraftment of transplacentally acquired maternal T cells show signs of GVH, such as rash and elevated liver function tests. Occasional patients may develop some autologous T and/or NK cells.

Differential diagnosis
1) JAK3 deficiency
2) IL-7Ra deficiency
3) HIV

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XSCID diagnostic criteria

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