Clinical Diagnosis

ZAP70-related severe combined immunodeficiency (ZAP70-related SCID) is a cell-mediated immunodeficiency caused by abnormal T-cell receptor (TCR) signaling leading to a selective absence of CD8⁺ T cells and normal or elevated numbers of non-functional CD4⁺ T cells [Arpaia et al 1994, Chan et al 1994, Elder et al 1994].

Children usually present in the first year of life with failure to thrive and recurrent viral, bacterial, and opportunistic infections.

Testing

The diagnosis of ZAP70-related SCID relies on lymphocyte subset analysis of CD3, CD4, and CD8 T cells, lymphocyte function testing, ZAP-70 protein expression, and ZAP70 molecular genetic testing.

Lymphocyte counts and lymphocyte cell surface expression. In ZAP70-related SCID, total lymphocyte counts can range from normal to high.

• T cell counts

  • CD8⁺ cells are absent or cell counts are very low. Note: T cells expressing CD8⁺ make up 0%-2% of the child’s total T-cell count [Monafo et al 1992, Arpaia et al 1994, Elder et al 1995, Gelfand et al 1995, Matsuda et al 1999, Noraz et al 2000].

  • CD4⁺ cell counts are normal or elevated. Note: CD4⁺ cells account for 60%-80% of mononuclear cells in the lymphocyte count of individuals with ZAP70-related SCID.

  • CD3⁺ cell counts are normal. Note: Most CD3⁺ cells are composed of CD4⁺ cells in ZAP70-related SCID.

• B cell counts and NK cell counts. Normal

Lymphocyte function. T-cell responses to stimuli that act through the T-cell receptor (TCR) are absent or severely diminished:

• Absence of proliferation of CD4⁺ cells in response to mitogens (e.g., PHA)

• Absence of proliferation of CD4⁺ cells in response to antigens (e.g., ConA)

• Defective CD4⁺ cell-cell activation manifest as impaired Ca²⁺ flux in response to CD3 (OKT3) stimulation [Arpaia et al 1994, Chan et al 1994, Gelfand et al 1995, Elder et al 2001, Turul et al 2009]

Note: T-cell responses to phorbol myristic acetate and ionomycin stimulation (which bypasses the TCR) are normal [Elder et al 1994, Elder 1997].

ZAP-70 protein expression. Immunocytochemistry testing of CD4⁺ T cells reveals absence of ZAP-70 protein in most cases. Note: (1) Two reports have described defects leading to protein expression with either rapid protein degradation [Matsuda et al 1999] or no catalytic function [Elder et al 2001]. (2) One report describes a hypomorphic ZAP70 mutation leading to decreased protein expression and function with late-onset combined immunodeficiency [Picard et al 2009].

Immunoglobulin concentrations and function

• Immunoglobulin levels vary by individual. A majority of affected individuals have severe hypogammaglobulinemia, but hypergammaglobulinemia and normal immunoglobulin levels have been seen [Turul et al 2009].

• Although functional antibody responses to immunization are present in a few persons [Turul et al 2009], this finding does not indicate that all specific antigenic responses are intact.

Molecular Genetic Testing

Gene. ZAP70 is the only gene in which mutations cause ZAP70-related severe combined immunodeficiency.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in ZAP70-Related Severe Combined Immunodeficiency

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
ZAP70	Sequence analysis	Sequence variants 2	15/15 3	Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

3. At least 15 individuals meeting diagnostic criteria have had identifiable ZAP70 mutations [Arpaia et al 1994, Chan et al 1994, Elder et al 1994, Matsuda et al 1999, Noraz et al 2000, Elder et al 2001, Meinl et al 2001, Toyabe et al 2001, Picard et al 2009, Turul et al 2009].

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

Testing Strategy

To confirm/establish the diagnosis in a proband, the following evaluations should be considered:

• Lymphocyte cell surface expression of CD3, CD4, and CD8

• Lymphocyte functional response to mitogens, antigens, and biochemical agents like phorbol myrsitate acetate and ionomycine

• Immunohistochemistry for presence of ZAP-70 protein

• Immunoglobulin level and specific antibody responses

• Molecular genetic testing for mutations in ZAP70 may be helpful to confirm a diagnosis due to the clinical heterogeneity of ZAP70-related SCID [Turul et al 2009] (see Testing).

Newborn screening. The use of routine newborn screening for T^– SCID by measuring T-cell receptor excision circle (TREC) levels continues to increase. Despite normal quantitative levels of CD4 cells in individuals with ZAP70-related SCID, TREC levels in already known cases of ZAP70-related SCID were found to be very low compared to age-matched controls [Roifman et al 2010], suggesting that detection of ZAP70-related SCID may be possible through newborn screening methods utilizing TREC quantitation.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in ZAP70.

Natural History

Individuals with ZAP70-related SCID usually present in the first year of life with recurrent bacterial, viral, and opportunistic infections, diarrhea, and failure to thrive. Severe lower respiratory infections are typically seen, most notably Pneumocystis jiroveci infections and viral infections. Oral moniliasis is common.

Whereas the above presentation is characteristic of ZAP70-related SCID, there are exceptions:

• Reports of milder phenotypes in sibs of children who had died from ZAP70-related SCID include a five-month-old with recurrent lower respiratory disease but no severe infections [Turul et al 2009] and a child with persistent dermatitis resistant to therapy [Katamura et al 1999].

• Picard et al [2009] described a nine-year-old with a ZAP70 hypomorphic intronic mutation and an attenuated clinical and immunologic phenotype (see Genotype-Phenotype Correlations).

• Newell et al [2011] reported an 11-month old with ZAP70-related SCID who presented with lymphoma.

• Santos et al [2010] reported ZAP70 defects in cousins (ages 5 and 6 months) presenting as axillary lymphadenitis following BCG vaccine.

Other presenting findings [Elder et al 1995, Parry et al 1996, Turul et al 2009]:

• Subcutaneous nodules

• Lymphadenopathy

• Exfoliative dermatitis

• Thrombocytopenia

• Chronic gastroenteritis

• Ulcerative colitis

The long-term prognosis of untreated ZAP70-related SCID is death from infection. Affected children have a declining quality of life and usually do not survive past their second year without HSCT. A long-term study found that following HSCT, three-year survival rates were 77% and 54% for HLA-identical and HLA-mismatched transplants respectively [Antoine et al 2003, Müller & Friedrich 2005]. Note: Survival rates given are for cohorts that comprise various forms of SCID, including ZAP70-related SCID; statistical outcomes specifically for ZAP70-related SCID are unknown.

Children with preexisting viral infections are at increased risk of developing graft-versus-host disease (GVHD) following HSCT, leading to a poor prognosis [Dvorak & Cowan 2008].

Genotype-Phenotype Correlations

A possible genotype-phenotype correlation is illustrated in a child with a hypomorphic intronic mutation (837+121G>A in intron 7) who had had chronic eczema from age two months and recurrent infections from age two years. Other findings in this child:

• Low levels of alternative splicing resulting in 20% expression of ZAP-70 protein in T cells and partial T-cell activation

• Low overall T-lymphocyte count

• Low CD8⁺ cell count typical of ZAP70-related SCID

• Low CD4⁺ cell counts (atypical for ZAP70-related SCID)

Each infection was treated individually until age six years, when the frequency of infection declined following introduction of cotrimoxazole and IVIG prophylaxis. Of note, an older sib with a history of multiple infections had died at age one year [Picard et al 2009].

Prevalence

The prevalence of ZAP70-related SCID is unknown but much lower than that of all forms of SCID, which is estimated at 1:50,000.

ZAP70-related SCID was first described in 1994. About 20 cases have been described in the literature [Fischer et al 2010].

Most cases of ZAP70-related SCID have occurred in genetically isolated Mennonite communities and/or in offspring of consanguineous relationships.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with ZAP70-related severe combined immunodeficiency (SCID), the following evaluations are recommended:

• Evaluation for common and opportunistic viral, bacterial, and fungal disease-causing agents

• Assessment of growth

• Complete metabolic panel (liver and renal function) and CBC with differential and platelet count

• Medical genetics consultation

• Immunology consultation, if not performed already

Treatment of Manifestations

Treatment relies on prompt reconstitution of the individual’s immune system (see Prevention of Primary Manifestations).

Short-term treatment includes immediate intravenous immunoglobulin (IVIG) and antibacterial, antifungal, and anti-protozoal prophylaxis to control and reduce the occurrence of infections.

Prevention of Primary Manifestations

The standard of therapy to cure SCID is allogeneic hematopoietic stem cell transplantation (HSCT). The outcome of HSCT in children with SCID is significantly improved by performing HSCT in the first three months of life [Buckley 2004]. Several children with ZAP70-related SCID have been transplanted [Arpaia et al 1994, Elder et al 1994, Elder et al 2001, Noraz et al 2000].

• Outcomes are the best with HLA-matched, related donors.

• If a related, HLA-matched donor is not available, alternatives include:

  • Matched unrelated donor

  • Umbilical cord blood donor

  • Haploidentical parental bone marrow or mobilized peripheral blood stem cells that have been T cell depleted

• In contrast to individuals with other forms of SCID, individuals with ZAP70-related SCID are typically treated with a chemotherapeutic conditioning regimen prior to HSCT.

  • Hönig et al [2012] described the successful use of lymphocyte transfusion from a previously transplanted HLA identical sib without the use of conditioning for reconstituting the immune system in an individual with ZAP70-SCID.

• Cellular reconstitution following HSCT takes three to four months and restoration of humoral immunity can take one to two years or more.

• Complications from HSCT include graft-versus-host disease, failure to reconstitute the humoral immune compartment, graft failure over time, and post-transplant lymphoproliferative disease [Skoda-Smith et al 2001].

• Affected individuals with poor humoral reconstitution are maintained on long-term immunoglobulin replacement.

Individuals with mild initial findings are maintained on immunoglobulin replacement and prophylactic antimicrobial therapy. They need to be monitored for worsening of immune function manifest by increased susceptibility to severe or opportunistic infections (see also Surveillance). If clinical status worsens, curative HSCT should be considered.

Prevention of Secondary Complications

The following are appropriate:

• Use of irradiated, CMV-negative blood products
  
  Note: While not routinely screened for, the use of blood products from a known Epstein-Barr virus (EBV)-negative source should be considered as EBV-related lymphoma has been described in ZAP70-SCID [Newell et al 2011].

• Delay of immunizations until immune reconstitution

Surveillance

Following a successful HSCT, the following should be monitored every six to 12 months:

• Immune status

• Liver and renal function

• Complete blood count

• Growth

• Psychomotor development

Individuals with milder findings need to be monitored for worsening of immune function with at least semiannual assessment of clinical status and functional lymphocyte responsiveness.

Agents/Circumstances to Avoid

Individuals with ZAP70-related SCID should never receive the following:

• Non-irradiated blood products

• Live virus vaccinations

• Mycobacterium bovis (BCG) vaccine against tuberculosis, Salmonella typhi (Ty21a) vaccine against typhoid fever, and Vibrio cholerae (CVD 103-HgR) vaccine against cholera, which may be part of the routine vaccination schedule in countries where these diseases are endemic

Evaluation of Relatives at Risk

Because the outcome of HSCT in children with SCID is significantly improved by performing HSCT in the first three months of life, early testing of at-risk sibs should be considered.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

An affected pregnant mother should receive prenatal counseling. Appropriately screened blood products should be available, if needed, during the course of the pregnancy or delivery.

Therapies Under Investigation

Gene therapy. While gene therapy has been used for other forms of SCID (notably ADA deficiency and X-linked SCID), it has not been performed in ZAP70-related SCID. Experimental studies utilizing gene therapy for this disease have been conducted on murine models [Adjali et al 2005, Irla et al 2008] as well as human cells in vitro [Steinberg et al 2000, Kofler et al 2004].

Adverse oncogenic reactions have been documented in some individuals with X-linked SCID transduced with retroviral vector [Buckley 2003, Fischer et al 2005]. The role of nonviral transfer methods (e.g., electro-gene transfer) have been used to correct ZAP-70 deficiency in a murine model [Irla et al 2008].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Registries

Contact information for voluntary patient registries is provided by GeneReviews staff.

European Society for Immunodeficiencies (ESID) Registry
Phone: 49-761-270-34450
Email: registry@esid.org
Web: www.esid.org

Primary Immunodeficiency Diseases Registry at USIDNET
Phone: 800-296-4433
Email: info@usidnet.org
Web: www.usidnet.org

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

ZAP70-related severe combined immunodeficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• Each parent is a carrier for a mutation in ZAP70.

• While parents do not usually have SCID-like symptoms, Turul et al [2009] analyzed the ZAP70 expression in the parents of probands and demonstrated that parents have intermediate expression levels compared to healthy controls. The implications of this finding have not been determined [Turul et al 2009].

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier.

• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

• Even if the sibs of a proband are asymptomatic, molecular genetic testing to determine their gene status should be considered for the purpose of early diagnosis and treatment of those who have inherited both disease-causing mutations.

Offspring of a proband

• The offspring of an individual with ZAP70-related severe combined immunodeficiency will inherit one disease-causing mutation from the proband.

• The genetic status of the offspring will depend on the genetic status of the reproductive partner of the proband.

  • If the reproductive partner is not affected and not a carrier, all offspring will be carriers.

  • If the reproductive partner is a carrier of a disease-causing mutation in ZAP70, each child will have a 50% chance of being affected and a 50% chance of being a carrier.

  • If the reproductive partner is also affected, all offspring will be affected.

• Most individuals with ZAP70-related SCID are from genetically isolated Mennonite communities and/or have consanguineous parents.

Other family members. A detailed family history that includes the ancestry and culture of the proband’s family may reveal consanguinity, geographic isolation, and genetic isolation, which are risk factors that increase the likelihood of autosomal recessive diseases in a family. Some of the grandparents of the proband are carriers for ZAP70 mutations; therefore, sibs of the proband’s parents and their offspring are at risk of being carriers.

Carrier Detection

Carrier testing for at-risk family members is possible once the mutations have been identified in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

No laboratories offering molecular genetic testing for prenatal diagnosis of ZAP70-related severe combined immunodeficiency are listed in the GeneTests™ Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutations have been identified. For laboratories offering custom prenatal testing, see .

An affected fetus does not require any specific management prior to delivery. Following delivery, early evaluation for potential HSCT should be performed because of the known benefit of early HSCT.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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Suggested Reading

1. Pessach IM, Notarangelo LD. Gene therapy for primary immunodeficiencies: looking ahead, toward gene correction. J Allergy Clin Immunol. 2011;127:1344–50. [PMC free article: PMC3105180] [PubMed: 21440291]

Author History

Tara Capece, MPH; University of Pittsburgh (2009-2012)
Marc Ikeda, MD (2012-present)
Allyson Larkin, MD (2012-present)
David Nash, MD; Children’s Hospital of Pittsburgh (2009-2012)

Revision History

• 1 March 2012 (me) Comprehensive update posted live

• 20 October 2009 (me) Review posted live

• 1 June 2009 (tc) Original submission