Congenital athymia is an extremely rare disorder marked by the absence of the

thymus The thymus (: thymuses or thymi) is a specialized primary lymphoid organ of the immune system. Within the thymus, T cells mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. The thymus ...

at birth.

T cell T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...

maturation and selection depend on the

, and newborns born without a

experience severe

immunodeficiency Immunodeficiency, also known as immunocompromise, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that aff ...

. A significant

T cell deficiency T, or t, is the twentieth letter of the Latin alphabet, used in the modern English alphabet, the alphabets of other western European languages and others worldwide. Its name in English is ''tee'' (pronounced ), plural ''tees''. It is d ...

, recurrent infections, susceptibility to

opportunistic infection An opportunistic infection is an infection that occurs most commonly in individuals with an immunodeficiency disorder and acts more severe on those with a weakened immune system. These types of infections are considered serious and can be caused b ...

s, and a tendency to develop autologous

graft-versus-host disease Graft-versus-host disease (GvHD) is a syndrome, characterized by inflammation in different organs. GvHD is commonly associated with bone marrow transplants and stem cell transplants. White blood cells of the donor's immune system which rema ...

(GVHD) or, in the case of complete

DiGeorge syndrome DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a syndrome caused by a microdeletion on the long arm of chromosome 22. While the symptoms can vary, they often include congenital heart problems, specific facial features, frequent ...

, a "atypical" phenotype are characteristics of congenital athymia.

Signs and symptoms

Congenital athymia's clinical symptoms are directly related to the thymus's absence and its incapacity to generate

s with the necessary immune capabilities. An increased vulnerability to bacterial, viral, and fungal infections results from

T-cell T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their ce ...

. These patients have an especially high incidence of

pneumonia Pneumonia is an Inflammation, inflammatory condition of the lung primarily affecting the small air sacs known as Pulmonary alveolus, alveoli. Symptoms typically include some combination of Cough#Classification, productive or dry cough, ches ...

s. M. bovis and the

respiratory syncytial virus Respiratory syncytial virus (RSV), also called human respiratory syncytial virus (hRSV) and human orthopneumovirus, is a virus that causes infections of the respiratory tract. It is a negative-sense, single-stranded RNA virus. Its name is derive ...

have been linked to additional cases of severe pulmonary infections. This group is also prone to

gastrointestinal infection Gastrointestinal diseases (abbrev. GI diseases or GI illnesses) refer to diseases involving the Human gastrointestinal tract, gastrointestinal tract, namely the esophagus, stomach, small intestine, large intestine and rectum; and the accessory or ...

s, such as those caused by the

rotavirus Rotaviruses are the most common cause of diarrhea, diarrhoeal disease among infants and young children. Nearly every child in the world is infected with a rotavirus at least once by the age of five. Immunity (medical), Immunity develops with ...

norovirus Norovirus, also known as Norwalk virus and sometimes referred to as the winter vomiting disease, is the most common cause of gastroenteritis. Infection is characterized by non-bloody diarrhea, vomiting, and stomach pain. Fever or headaches may ...

enterovirus ''Enterovirus'' is a genus of positive-sense single-stranded RNA viruses associated with several human and mammalian diseases. Enteroviruses are named by their transmission-route through the intestine ('enteric' meaning intestinal). Serologic ...

, M. bovis, and

C. difficile ''Clostridioides difficile'' ( syn. ''Clostridium difficile'') is a bacterium known for causing serious diarrheal infections, and may also cause colon cancer. It is known also as ''C. difficile'', or ''C. diff'' (), and is a Gram-positive spec ...

viruses.

Diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...

malabsorption Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal (GI) tract. Impairment can be of single or multiple nutrients depending on the abnormality. This may lead to malnutrition and a varie ...

, and

failure to thrive Failure to thrive (FTT), also known as weight faltering or faltering growth, indicates insufficient weight gain or absence of appropriate physical growth in children. FTT is usually defined in terms of weight, and can be evaluated either by a low ...

can result from these infections. Although gastrointestinal and lung infections are the most frequently reported infection types, congenital athymia patients can present with a wide range of other infection types. There have been reports of infections of the head, ears, nose, and throat, including

meningitis Meningitis is acute or chronic inflammation of the protective membranes covering the brain and spinal cord, collectively called the meninges. The most common symptoms are fever, intense headache, vomiting and neck stiffness and occasion ...

sinusitis Sinusitis, also known as rhinosinusitis, is an inflammation of the mucous membranes that line the sinuses resulting in symptoms that may include production of thick nasal mucus, nasal congestion, facial congestion, facial pain, facial pressure ...

, mastoiditis, and thrush, as well as infections of the

urinary tract The human urinary system, also known as the urinary tract or renal system, consists of the kidneys, ureters, bladder, and the urethra. The purpose of the urinary system is to eliminate waste from the body, regulate blood volume and blood pressu ...

caused by K. pnuemoniae, E. faecium, and echovirus.

s may expand extrathymic oligoclonally in congenital athymia. These cells can infiltrate organs and result in autologous

, but they confer little to no protective

immunity Immunity may refer to: Medicine * Immunity (medical), resistance of an organism to infection or disease * ''Immunity'' (journal), a scientific journal published by Cell Press Biology * Immune system Engineering * Radiofrequence immunity ...

. Individuals who have an expansion of oligoclonal

s usually have an eczematous rash and accompanying

lymphadenopathy Lymphadenopathy or adenopathy is a disease of the lymph nodes, in which they are abnormal in size or consistency. Lymphadenopathy of an inflammatory type (the most common type) is lymphadenitis, producing swollen or enlarged lymph nodes. In c ...

infiltration can result in

enteropathy Enteropathy refers to any pathology of the intestine. Although enteritis specifically refers to an inflammation of the intestine, and is thus a more specific term than "enteropathy", the two terms are sometimes used interchangeably. __TOC__ Types ...

and transaminitis in the

gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the Digestion, digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascula ...

. Congenital athymia patients also have other autoimmune-mediated manifestations, such as autoimmune thyroiditis,

hypothyroidism Hypothyroidism is an endocrine disease in which the thyroid gland does not produce enough thyroid hormones. It can cause a number of symptoms, such as cold intolerance, poor ability to tolerate cold, fatigue, extreme fatigue, muscle aches, co ...

, and Coombs-positive

hemolytic anemia Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular). This most commonl ...

Causes

Congenital athymia is linked to a number of

genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders ...

s, congenital syndromes, and environmental variables. Genetic abnormalities that are either (1) specific to thymic development or (2) related to the development of the midline region as a whole can cause congenital athymia.

Risk factors

Congenital athymia is linked to multiple environmental etiologies. Affected fetal thymus size and other congenital anomalies like

renal agenesis Renal agenesis is a medical condition in which one (unilateral) or both (bilateral) fetal kidneys fail to develop. Unilateral and bilateral renal agenesis in humans, mice and zebra fish has been linked to mutations in the gene GREB1L. It has also ...

and butterfly vertebrae are linked to diabetic embryopathy. It has been shown that babies of diabetic mothers have thymic aplasia.

Retinoic acid Retinoic acid (simplified nomenclature for all-''trans''-retinoic acid) is a metabolite of vitamin A1 (all-''trans''-retinol) that is required for embryonic development, male fertility, regulation of bone growth and immune function. All-''trans ...

exposure during fetal development is also linked to phenotypes associated with

, such as hypoplasia and thymic developmental abnormalities such as aplasia and ectopia.

Genetics

The most well-known gene associated with thymic development is Forkhead Box N1 ( FOXN1). As a member of the transcription factor family known as the forkhead box gene family, FOXN1 plays a role in the growth and differentiation of skin

epithelial cells Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...

as well as the development, differentiation, and maintenance of thymic epithelial cells during embryonic and postnatal life. The

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...

s known as the paired box family, which control tissue differentiation, includes Paired Box 1 ( PAX1). Numerous studies have reported on patients with autosomal recessive otofaciocervical syndrome type 2 (OTFCS2) and mutations in PAX1. Because of altered thymus development, OTFCS2 is associated with a syndromic form of SCID. The two most common genetic syndromes linked to thymus development defects are

22q11.2 deletion syndrome DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a syndrome caused by a microdeletion on the long arm of chromosome 22. While the symptoms can vary, they often include congenital heart problems, specific facial features, frequent i ...

and

CHARGE syndrome CHARGE syndrome (formerly known as CHARGE association) is a rare syndrome caused by a genetic disorder. First described in 1979, the acronym "CHARGE" came into use for newborn children with the congenital features of coloboma of the eye, heart ...

. Patients with these syndromes exhibit a variety of symptoms because the genes TBX1 and CHD7, associated with these disorders, play a role in the development of the entire midline region. Additional genes that may be involved in healthy thymus development are FOXI3 and TBX2.

Treatment

In October 2021, the thymus tissue product

Rethymic Allogeneic processed thymus tissue, sold under the brand name Rethymic, is a thymus tissue medical therapy used for the treatment of children with congenital athymia. It takes six months or longer to reconstitute the immune function in treate ...

was approved by U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) as a

medical therapy A therapy or medical treatment is the attempted remediation of a health problem, usually following a medical diagnosis. Both words, ''treatment'' and ''therapy'', are often abbreviated tx, Tx, or Tx. As a rule, each therapy has indications an ...

for the treatment of children with congenital athymia. It takes six months or longer to reconstitute the immune function in treated children.

References

External links

Immune Deficiency Foundation
{{DEFAULTSORT:Congenital Athymia Congenital disorders Thymus Immunodeficiency