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1. CHARGE syndrome is an autosomal dominant multi-system disease characterized by coloboma, heart defects, choanal atresia, retardation of growth, genital hypoplasia, and ear anomalies/deafness.


2. Mutations in the CHD7 gene are found in approximately 60% of patients with CHARGE syndrome. The exact function of CHD7 has not been elucidated but it is believed to regulate gene transcription.


3. Similar to patients with 22q11.2 deletion syndrome, CHARGE patients can often have features of DiGeorge Syndrome (cardiac defects, hypocalcemia, and T-cell lymphopenia).


4. A spectrum of T-cell immunodeficiency ranging from mild lymphopenia to a severe combined immune deficiency can be seen in patients. Routine immune evaluation following birth is recommended for patients with CHARGE syndrome.


5. The mechanism of immunodeficiency in CHARGE syndrome appears to be similar to 22q11.2 deletion (thymic hypoplasia or aplasia resulting in impaired T-cell development).


6. Patients with mild to moderate decreases in T-cell numbers should be managed similarly to patients with 22q11.2 deletion syndrome. Live viral vaccines are generally safe except for patients with very low CD8 T-cell numbers (<300 cells/mm3).


7. Patients with a complete absence of thymic tissue have a form of severe combined immune deficiency requiring therapy with a thymic transplant (preferred) or a hematopoietic stem cell transplant (non T-cell depleted).






          CHARGE syndrome is a multisystem disease with occurrence between 1 per 10,000 and 1 per 8,500 live births. CHARGE is an acronym which stands for Coloboma, Heart Defect, Atresia choanae, Retarded growth and development, Genital hypoplasia, and Ear anomalies. Additional features of this disease can include cleft lip and palate, tracheoesophageal fistula, hearing loss, and hypocalcemia. There is significant clinical overlap with the 22q11.2 deletion syndrome. CHARGE syndrome patients may also have the classic features of DiGeorge Sydrome (DGS): heart disease, hypocalcemia, immunodeficiency. The presence of shared features can make initial diagnosis challenging.


          Similar to patients with 22q11.2 deletion syndrome, patients with CHARGE syndrome can have a spectrum of T-cell immunodeficiency that may range from mild T-cell lymphopenia to an almost complete absence of T-cells resulting in a severe combined immune deficiency phenotype (this is analogous to complete DGS). This severe phenotype is characterized by very low T-cells, low T-cell function, and hypogammaglobulinemia (B-cells are present but unable to produce antibodies without T-cell help). Despite having absent T-cells, B and NK cell numbers are normal, resulting in a T-B+NK+ phenotype. These patients require a thymic transplant (preferred) or a hemotopoietic stem cell transplant in order to survive.






         Originally CHARGE syndrome was considered to be a non-random association of anomalies rather than a syndrome. In 2004 it was reported that the chromodomain helicase DNA-binding protein-7 (CHD7) was found to be mutated in a majority of CHARGE patients. The exact function of CHD7 has not been elucidated but the chromo domain family of proteins are known to regulate gene transcription.


          The mechanism of T-cell immunodeficiency in CHARGE is not known. However, it is likely similar to 22q11.2 deletion syndrome in which abnormal thymic development leads to defects in T-cell maturation. The fact that CHARGE syndrome patients have been successfully treated with thymic transplants similar to 22q11.2 deletion supports this hypothesis.






We recommend a general evaluation approach that mirrors the current approach for 22q11.2 deletion sydrome patients.



Step 1: Molecular Diagnosis


                      - CHD7 Gene Sequencing


-60% of patients will have a CHD7 mutation


-The absence of the CHD7 mutation does not exclude the diagnosis of CHARGE


-If negative, evaluation for other overlapping syndromes should be pursued with FISH for 22q11.2 deletion or a genome wide array.



Step 2:  Immune Evaluation

An immune evaluation should be considered in newly diagnosed infants with CHARGE syndrome.necessarily required. 


-CBC with Differential

-T-cell subset enumeration by flow cytometry

-IgG, IgA, IgM levels (if older than 6 months)

-Specific Antibody levels (if older than 6 months)

-The absolute lymphocyte count should be calcuated from the CBC with differential.


-T-cell quantification by flow cytometry is especially important if the absolute lymphocyte count from the CBC is low (an ALC < 3000 is very low in an infant).


Step 3: Additional Immune Evaluation


-Naïve (CD45RA) and memory (CD45RO) T-cell numbers by flow cytometry

-T-cell proliferation to Mitogens (PHA)

-TREC Analysis

-Very low naïve (CD45RA) T-cell numbers can be a useful clue for lack of thymic tissue.

-T-cell proliferation to Mitogens wil be decreased in complete thymic aplasia.

-TRECs (T-cell receptor excision circles) are loops of DNA excised during TCR rearrangement in the thymus. Because TRECs are not replicated with cell division, they are gradually diluted as T-cells become activated and expand. Thus, naïve T-cells that are recent thymic emigrants have high TREC numbers. Patients lacking thymic tissue have very low TREC numbers.







1. CHARGE syndrome with Decreased (but not absent) T-cells:

           If T-cell numbers are mildly or moderatey decreased but function is normal, no specific antibiotic prophylaxis is required. The risk of using live viral vaccines (ex. MMR, Varicella, Rotavirus) is quite low except patients have very low T-cells. Patients who fulfill the following criteria can safely receive live viral vaccines:

-CD8+ T-cell count > 300 cells/mm3

-Normal specific antibody responses to non-live viral vaccines

-Normal T-cell proliferation to mitogens and specific antigens


2. CHARGE syndrome with Absent T-cells (T-B+NK+ phenotype):

           Patients with absent thymus and T-cells have a form of severe combined immune deficiency. This is an immunologic emergency and the following management steps should be taken:

          -Avoid all live viral vaccines (rotavirus, MMR, Varicella)

-Start prophylaxis for pneumocystis jiroveci with trimethoprim-sulfamethoxazole

-All blood products should be irradiated and CMV negative

-IVIG therapy should be started

-Duke University thymic transplant team should be contacted

-Alternatively, a HLA identical sibling or unrelated donor should be identified for a non T-cell depleted Hematopoietic stem cell transplantation.







Diagnostic Resources    


1. Gene Dx - CHD7 Gene Sequencing 


2. TREC (T-cell receptor excision circle) AnalysisMayo Clinic TREC assay: Submit with sample and patient information sheet 

10ml lavender (EDTA) tube


3. T-cell Receptor Gene Rearrangement (TCR Spectratyping)Mayo Clinic TCR gene rearrangement


4. Thymic Transplant:

Duke University Medical Center

Durham, NC United States 27710.


Louise Markert, MD, PhD



Elizabeth A. McCarthy, RN, MSN




Literature Resources


1.  Jyonouchi 2008

     Immunologic features of 25 CHARGE patients with CHD7 mutation


2.  Writzl 2007

      Immunologic features of 2 CHARGE patients and literature review


3.  Gennery 2008



4.  Markert 2007

     Thymic transplantation of DGS (11 patients with CHARGE)

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