NORD gratefully acknowledges M. Louise Markert, MD, PhD, Professor of Pediatrics and Immunology, Duke University Medical Center, for assistance in the preparation of this report.
Complete DiGeorge syndrome is a rare disorder in which children have no detectable thymus (athymia). The thymus is a gland located on top of the heart. The thymus produces specialized white blood cells called T cells that fight infections, especially viral infections. The T cell count is the highest in infants in the first 2 years of life and then slowly decreases with time. In older adults over the age of 60, the thymus is mostly replaced by fat. Children with complete DiGeorge syndrome are born without a thymus and are therefore profoundly deficient in T cells and extremely susceptible to infections. Without treatment, the disorder is usually fatal by two or three years of age.
Some individuals have DiGeorge syndrome as part of a larger disorder, specifically chromosome 22q11.2 deletion syndrome or CHARGE syndrome. Both of these disorders have symptoms affecting multiple systems of the body. DiGeorge syndrome typically refers to individuals who have T cell counts less than the 10th percentile for age, plus they have heart defects and/or low calcium levels. Many but not all of infants with 22q11.2 deletion syndrome and CHARGE syndrome have T cell counts less than the 10th percentile for age and are often referred to as having DiGeorge syndrome. (Children with 22q11.2 deletion syndrome or CHARGE syndrome who have normal T cell counts are not considered as having DiGeorge syndrome.)
Only about 1% of children with DiGeorge syndrome have absence of the thymus. To determine that a child had no thymus, blood testing must not detect T cells emerging from the thymus. Newly developed T cells emerging from the thymus have special proteins on the cell surface. Those T cells are called “naïve” T cells. Children with 22q11.2 deletion syndrome or CHARGE syndrome who have very low naïve T cells counts (less than 50 per mm3 in the blood) are said to have complete DiGeorge syndrome. Children with complete DiGeorge syndrome are all athymic by definition. NORD has individual reports on both 22q11.2 deletion syndrome and CHARGE syndrome patients with athymia. These reports are accessible through the NORD Rare Disease Database. Lastly, for affected infants who are infants of diabetic mothers and other infants with no identifiable genetic defects or syndromes, the cause of athymia remains unknown.
By definition, complete DiGeorge syndrome is characterized by absence or underdevelopment (hypoplasia) of the thymus resulting in very low T cell counts. Absence or underdevelopment of the thymus results in an increased susceptibility to viral, fungal and bacterial infections (immunodeficiency). The degree of susceptibility can vary. Specific symptoms will vary depending upon the type of infection, overall health of the infant, and other factors. Respiratory infections are common often leading to respiratory distress. Opportunistic infections are also common. Opportunistic infection refers either to infections caused by microorganisms that usually do not cause disease in individuals with fully functioning immune systems or to widespread (systemic) overwhelming disease by microorganisms that typically cause only localized, mild infections. Not only are affected infants more susceptible to infections, but their bodies cannot effectively fight off the infections either.
Infants with complete DiGeorge syndrome have additional symptoms including congenital heart defects and/or hypoparathyroidism. These complications can be significant. Congenital health defects are problems with the structure of the heart. This include the walls, valves, and arteries and veins of the heart. Over 50 percent of infants with complete DiGeorge syndrome require surgery to fix the heart defects.
Hypoparathyroidism is a rare condition in which the parathyroid glands, that are located in the neck, fail to produce sufficient amounts of parathyroid hormone. Parathyroid hormone plays a role in regulating the levels of calcium and phosphorus in the blood. Due to a deficiency of parathyroid hormone, individuals with hypoparathyroidism may exhibit abnormally low levels of calcium in the blood (hypocalcemia) and high levels of phosphorus. Low levels of calcium in the blood can result in seizures. Management of calcium levels can be difficult in infants with complete DiGeorge syndrome. Although infants with partial DiGeorge syndrome usually outgrow the hypoparathyroidism in approximately 12 months, approximately 80% of infants with complete DiGeorge syndrome have long term problems maintaining safe calcium levels.
Some infants have softening of the tissues of the voice box (larynx), a condition called laryngomalacia. This can cause noisy breathing. Sometimes, it can cause difficulties eating.
Infants with chromosome 22q11.2 deletion syndrome and CHARGE syndrome will have additional symptoms that are associated with their specific diagnosis. Infants with complete DiGeorge syndrome who are born to diabetic mothers may also have only one kidney (renal agenesis).
Researchers have identified an atypical form of complete DiGeorge syndrome. Affected infants, in addition to immunodeficiency, have a red, often itchy, rash and enlargement of the lymph nodes (lymphadenopathy). They develop oligoclonal T cells. To understand this process, it can be helpful to think of the thymus as a schoolhouse. In normal children, stem cells from the bone marrow go to the thymus (the “schoolhouse”) to develop into T cells. The developing T cells learn to not attack the infant’s body (self) and to fight infections. If the developing T cells are successful learning these two lessons, they “graduate,” and leave the schoolhouse. The graduates have special proteins on the surface of the cell and are called “naïve” T cells. After the naïve T cells fight an infection, they lose the special markers and are called memory T cells. Memory T cells can quickly fight an infection if it recurs. In atypical complete DiGeorge syndrome, there is no thymus (no schoolhouse). However, stem cells in the bone marrow develop into a cell that looks like a T cell, but is missing the “naïve” T cell markers. These “atypical” T cells have not gone to “school” and have not learned what is “self.” The atypical T cells then attack the body causing rash, and often also diarrhea or liver damage. The diagnosis of atypical DiGeorge syndrome is made when a patient has the rash and high numbers of T cells but no, or very few, naïve T cells in the blood.
Complete DiGeorge syndrome is characterized by the absence of the thymus in an infant. There are several causes of this condition. In some infants, complete DiGeorge syndrome occurs as part of a larger syndrome such as chromosome 22q11.2 deletion syndrome or CHARGE syndrome. Chromosome 22q11.2 deletion syndrome is characterized by the absence of a small piece of chromosome 22. Chromosome 22q11.2DS is associated with a range of problems including: congenital heart disease, palate abnormalities, immune system dysfunction including autoimmune disease, low calcium (hypocalcemia) and other endocrine abnormalities such as thyroid problems and growth hormone deficiency, gastrointestinal problems, feeding difficulties, kidney abnormalities, hearing loss, seizures, skeletal abnormalities, minor facial differences, and learning and behavioral differences. CHARGE is an acronym that stands for [C]oloboma, congenital [H]eart defects, choanal [A]tresia, growth [R]etardation, [G]enital hypoplasia and [E]ar anomalies or deafness.
Some infants who do not have a thymus or have an underdeveloped thymus have mothers who are diabetic. The mothers can have type I or type II or gestational diabetes. At this time, it is not known that the diabetes is causing DiGeorge syndrome in these patients. However, many patients with DiGeorge syndrome have mothers with diabetes.
In a small percentage of children with complete DiGeorge syndrome, there is no identifiable genetic cause for the disorder, and no symptoms indicative of a larger syndrome. In these children, the underlying cause of complete DiGeorge syndrome is unknown.
Complete DiGeorge syndrome affects both boys and girls. The exact incidence or prevalence of this disorder is unknown.
A diagnosis of complete DiGeorge syndrome is based upon identification of characteristic symptoms, a detailed patient and family history, and a thorough clinical evaluation.
Some infants are diagnosed via newborn screening. All 50 states have added newborn screening for severe combined immunodeficiency. Some states, however, do not require that every hospital include the newborn screening for SCID. Newborn screening identifies infants with low levels of T cells, which can lead to identification of newborns with complete DiGeorge syndrome. In such instances, the infants are kept in isolation right away.
Clinical Testing and Workup
Physicians may use a technique called flow cytometry to diagnose complete DiGeorge syndrome. Flow cytometry of the peripheral blood means that the peripheral blood (the blood that is circulating through the body) is studied using a machine called a flow cytometer. The flow cytometer can determine the number and percentage of various cell types in the blood sample.
A diagnosis cannot be made with a chest x-ray (radiography) or computerized tomography (CAT) scan, or during heart surgery because the thymus can be small or may be found in a different part of the body such as in the neck (ectopic thymus).
Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in diagnosing and treating immune system disorders (immunologists), physicians who specialize in diagnosing and treating blood disorders (hematologists), physicians who specialize in diagnosing and treating endocrine disorders (endocrinologists), and other healthcare professionals may need to systematically and comprehensively plan treatment. Additional healthcare professionals are necessary for affected infants with chromosome 22q11.2 deletion syndrome or CHARGE syndrome.
Antibiotic and anti-viral medications are used for infections until an investigational cultured thymus tissue transplant can be undergone. Congenital heart defects may require surgery. Some infants require supplementation with calcium or a synthetic version of vitamin D3 called calcitriol for hypoparathyroidism.
Affected infants with laryngomalacia or aspiration may require a tracheostomy. This is the creation of a surgical opening in the neck to gain access to the windpipe (trachea). A tube is placed into this opening to allow for breathing. Other children may require a gastrostomy tube (a tube going into the stomach) for feeding the child.
As of August 2019, one hundred severely immunocompromised infants have undergone investigational cultured thymus tissue transplants. To make this product, thymus tissue is obtained during heart surgery for an infant. Thymus tissue may need to be removed during infant heart surgery to allow for the surgeon to access the heart. Instead of being discarded, it is put in a sterile container and sent to a laboratory. The tissue is processed into slices and maintained in cultured for 12 to 21 days. The cultured tissue is then brought to the operating room and implanted into the child’s quadriceps muscle. That location was chosen because it has a good blood supply to get oxygen and nutrients to the thymus tissue slices. The transplanted cultured thymus tissue slices will produce the T cells missing from the affected infant’s immune system. It takes approximately six months for the immune system to begin functioning. Over 6-9 months, infants will develop T cells that are able to fight infections. The most common adverse effect of this therapy is autoimmunity in the first year prior to development of diverse T cells. Autoimmunity is when the body’s immune system accidentally harms healthy tissue. Autoimmunity is treatable and is less frequent after the first year after transplantation. Investigational cultured thymus tissue transplants for complete DiGeorge syndrome have resulted in survival of approximately 72% of patients. More research and follow up is necessary to determine the long-term safety and effectiveness of this procedure. In the United States, Duke Children’s Hospital is the only medical center that performs this procedure.
Researchers have studied hematopoietic stem cell transplantation (HSCT) for the treatment of infants with complete DiGeorge syndrome. Stem cells are special cells found in bone marrow that manufacture different types of blood cells including T cells. However, patients with DiGeorge syndrome do not have abnormal stem cells and HSCT has not been found to be an effective treatment. Stem cells can’t turn into T cells in a patient with DiGeorge syndrome. Whole blood with T cells from a matched sibling can function for a decade or two.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
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Duke Health. Thymus Transplant. Updated May 21, 2018. Available at: https://www.dukehealth.org/treatments/pediatric-allergy-and-immunology/thymus-transplantation Accessed August 19, 2019.
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