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.
Congenital athymia 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 adults over the age of 60, the thymus is mostly replaced by fat. Children with congenital athymia 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 to three years of age.
The following conditions can result in congenital athymia:
• complete DiGeorge syndrome, also known as complete DiGeorge anomaly
• 22q11.2 deletion syndrome
• CHARGE syndrome
• infant of diabetic mother
• FOXN1 gene deficiency
• TBX1 gene mutation
• TBX2 gene mutation
• PAX1 gene deficiency
• SEMA3E gene mutation
Most infants with congenital athymia have chromosome 22q11.2 deletion syndrome or CHARGE syndrome. Both disorders have symptoms affecting multiple systems of the body. These infants have a set of T cells called “naïve T cells” or “recent thymus emigrants” that are less than the 100/mm3. These T cells are critical for the health of the infant. These infants will die unless placed in permanent complete isolation.
In the past, children with T cells below the 10th percentile for age were said to have DiGeorge syndrome (named after a medical student who first reported the condition). However, most of these patients did well. Only about 1% of children with DiGeorge syndrome have lower than 100 naïve T cells/mm3. This group of patients is the group with congenital athymia. NORD has individual reports on 22q11.2 deletion syndrome and CHARGE syndrome and these reports are accessible on the NORD website in the Rare Disease Database.
By definition, congenital athymia 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. The term “opportunistic infection” refers either to infections caused by microorganisms that usually do not cause disease in individuals with a fully functioning immune system 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 also cannot effectively fight off the infections.
Infants with congenital athymia have additional symptoms including congenital heart defects and/or hypoparathyroidism. These complications can be significant. Congenital heart defects are problems with the structure of the heart. The defects in the heart may include the walls, valves, arteries and veins of the heart. Over 50% of infants with congenital athymia require surgery to fix heart defects.
Hypoparathyroidism is a rare condition in which the parathyroid glands, that are in the neck, fail to produce enough 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 congenital athymia. Approximately 80% of infants with congenital athymia 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 have additional symptoms that are associated with their specific diagnosis. Infants with congenital athymia who are born to diabetic mothers may also have only one kidney (renal agenesis).
Researchers have identified an atypical form of congenital athymia. Affected infants, in addition to immunodeficiency, develop 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; they 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 the atypical form of congenital athymia, there is no thymus (no schoolhouse). However, stem cells in the bone marrow develop into cells that look like T cells but are 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 congenital athymia 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.
Congenital athymia is characterized by the absence of the thymus in an infant. There are several causes of this condition. In some infants, congenital athymia occurs secondarily to 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. This syndrome 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.
There are other causes of congenital athymia. Some infants who do not have a thymus or have an underdeveloped thymus have a mother who is diabetic. The mothers can have type I, type II or gestational diabetes. At this time, it is not known if the diabetes is causing congenital athymia in these patients. However, many patients with congenital athymia have mothers with diabetes.
Congenital athymia can also be found in patients with changes (mutations) in the genes FOXN1, T-box transcription factor 1 (TBX1) and TBX2, paired box 1 (PAX1), and semaphorine 3 (SEMA3E). Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation in a gene occurs, the protein product may be faulty, inefficient, absent or overproduced. Depending upon the functions of the protein, this can affect many organ systems of the body.
Lastly, congenital athymia can be found in a very small number of infants with no identifiable genetic mutations or syndromes.
Congenital athymia affects both males and females. The exact incidence and prevalence of this disorder is unknown.
A diagnosis of congenital athymia 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 (SCID). 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 congenital athymia. In such instances, the infants are put in isolation right away.
Clinical Testing and Workup
Physicians may use a technique called flow cytometry to diagnose congenital athymia. 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. Very low T cell numbers shortly after birth are a sign of congenital athymia.
The diagnosis of congenital athymia cannot be made with a chest x-ray (radiography) or computerized tomography (CT) scan, or by visualization 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 requires 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 plan treatment systematically and comprehensively for a patient with congenital athymia. Specialized healthcare professionals are necessary for infants with chromosome 22q11.2 deletion syndrome and CHARGE syndrome because these children have many other abnormalities and health problems (comorbidities).
Antibiotic and anti-viral medications are used for infections. 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.
On October 8, 2021, the U.S. Food and Drug Administration approved the use of cultured thymus tissue (Rethymic) for treatment of pediatric patients with congenital athymia. Rethymic is composed of thymus tissue from infant donors that has been processed and cultured. Many tissue slices, after culture, are implanted into the thigh muscle of an athymic patient to help improve immune function. (The word “implant” is used in this report because the thymus tissue is processed in a laboratory for at least 12 days prior to use. The word “transplant” refers to an organ taken out of one individual in an operating room which is immediately brought to a neighboring operating room and placed into the recipient.)
The research supporting this approval included 95 patients with congenital athymia previously treated under research studies with investigational cultured thymus tissue implants. The thymus tissue needed for this product is obtained during heart surgery on 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 culture 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 implanted 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 implantation.
Investigational cultured thymus tissue implants for congenital athymia 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 congenital athymia. Stem cells are special cells found in bone marrow that manufacture different types of blood cells such as neutrophils eosinophils, monocytes and lymphocytes. Patients with congenital athymia do not have abnormal stem cells. Hematopoietic stem cell transplantation has not been found to be an effective treatment. Stem cells can’t turn into T cells in a patient lacking a thymus.
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.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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