Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX syndrome) is a rare
autoimmune disease
An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...
. It is one of the
autoimmune polyendocrine syndromes. Most often, IPEX presents with
autoimmune enteropathy,
dermatitis
Dermatitis is a term used for different types of skin inflammation, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened ...
(eczema), and autoimmune
endocrinopathy (most often
Type 1 diabetes
Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that occurs when the body's immune system destroys pancreatic cells (beta cells). In healthy persons, beta cells produce insulin. Insulin is a hormone require ...
), but other presentations exist.
IPEX is caused by mutations in the gene ''FOXP3'', which encodes transcription factor forkhead box P3 (
FOXP3
FOXP3 (forkhead box P3), also known as scurfin, is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator of the regulatory pathway in the development and function of r ...
). FOXP3 is widely considered to be the
master regulator of the
regulatory T cell
The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain immune tolerance, tolerance to self-antigens, and prevent autoimmune disease. Treg  ...
(T
reg) lineage.
''FOXP3'' mutation can lead to the dysfunction of CD4
+ T
regs. In healthy people, T
regs maintain immune
homeostasis
In biology, homeostasis (British English, British also homoeostasis; ) is the state of steady internal physics, physical and chemistry, chemical conditions maintained by organism, living systems. This is the condition of optimal functioning fo ...
.
When there is a deleterious ''FOXP3'' mutation, T
regs do not function properly and cause
autoimmunity
In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease ...
.
IPEX onset usually happens in
infancy
In common terminology, a baby is the very young offspring of adult human beings, while infant (from the Latin word ''infans'', meaning 'baby' or 'child') is a formal or specialised synonym. The terms may also be used to refer to juveniles of ...
. If left untreated, it is often fatal by the age of 2 or 3.
A
bone marrow transplant
Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood, in order to replicate inside a patient and produce a ...
is generally considered the best treatment option.
IPEX exclusively affects males and is inherited in an
X-linked recessive ''Main Article'': Sex linkage
X-linked recessive inheritance is a mode of Mendelian inheritance, inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males (who are necessarily hemizygous for ...
manner;
female carriers of pathogenic ''FOXP3'' mutations do not have symptoms and no female cases are known.
[update 2011]
Presentation
Classical triad
The classical triad describes the most common symptoms of IPEX: intractable
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 ...
,
type 1 diabetes
Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that occurs when the body's immune system destroys pancreatic cells (beta cells). In healthy persons, beta cells produce insulin. Insulin is a hormone require ...
, and
eczema
Dermatitis is a term used for different types of skin inflammation, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened ...
. Symptoms usually begin shortly after birth.
Other symptoms include:
thyroid disease
Thyroid disease is a medical condition that affects the structure and/or function of the thyroid gland. The thyroid gland is located at the front of the neck and produces thyroid hormones that travel through the blood to help regulate many other ...
,
kidney
In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...
dysfunction,
blood
Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells.
Blood is com ...
disorders, frequent infections,
autoimmune hemolytic anemia
Autoimmune hemolytic anemia (AIHA) occurs when a person's immune system produces antibodies directed against their own red blood cells (RBCs). These antibodies attach to red cells, causing them to break down ( lyse), and reducing the number of ox ...
, and food allergies, among others.
Endocrinopathy
The most common
endocrinopathy associated with IPEX is
type 1 diabetes
Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that occurs when the body's immune system destroys pancreatic cells (beta cells). In healthy persons, beta cells produce insulin. Insulin is a hormone require ...
, especially
neonatal diabetes. In this type of diabetes, the immune system attacks
insulin-producing cells. This makes the pancreas unable to produce
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
. Diabetes can permanently damage the
pancreas
The pancreas (plural pancreases, or pancreata) is an Organ (anatomy), organ of the Digestion, digestive system and endocrine system of vertebrates. In humans, it is located in the abdominal cavity, abdomen behind the stomach and functions as a ...
.
Thyroid disorders are also common.
Enteropathy
The most common
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 ...
associated with IPEX is intractable
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 ...
. Vomiting and
gastritis
Gastritis is the inflammation of the lining of the stomach. It may occur as a short episode or may be of a long duration. There may be no symptoms but, when symptoms are present, the most common is upper abdominal pain (see dyspepsia). Othe ...
are also common. Other manifestations include
Celiac disease
Coeliac disease (British English) or celiac disease (American English) is a long-term autoimmune disorder, primarily affecting the small intestine. Patients develop intolerance to gluten, which is present in foods such as wheat, rye, spel ...
,
ulcerative colitis
Ulcerative colitis (UC) is one of the two types of inflammatory bowel disease (IBD), with the other type being Crohn's disease. It is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary sympto ...
, and
ileus
Ileus is a disruption of the normal propulsive ability of the intestine. It can be caused by lack of peristalsis or by mechanical obstruction.
The word 'ileus' derives . The term 'subileus' refers to a partial obstruction.
Signs and symptoms
S ...
.

= Skin manifestations
=
The most common form of skin involvement is
dermatitis
Dermatitis is a term used for different types of skin inflammation, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened ...
. It can occur in three forms: eczematiform (mainly
atopic dermatitis
Atopic dermatitis (AD), also known as atopic eczema, is a long-term type of inflammation of the skin. Atopic dermatitis is also often called simply eczema but the same term is also used to refer to dermatitis, the larger group of skin conditi ...
), ichthyosiform, psoriasiform, or a combination. Other skin manifestations can include
cheilitis
Cheilitis also called and known as chapped lips, is a medical condition characterized by inflammation of the lips. The inflammation may include the perioral skin (the skin around the mouth), the vermilion border, or the Oral mucosa#Types, labial ...
,
onychodystrophy, and
alopecia
Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scarring ...
.
Early life
IPEX patients are usually born with normal weight and length at term. Nevertheless, the first symptoms may present in the first days of life, and some reported cases labeled newborns with
intrauterine growth restriction
Intrauterine growth restriction (IUGR), or fetal growth restriction, is the poor growth of a fetus while in the womb during pregnancy. IUGR is defined by clinical features of malnutrition and evidence of reduced growth regardless of an infant's ...
and evidence of
meconium
Meconium is the earliest stool of a mammalian infant resulting from defecation. Unlike later feces, meconium is composed of materials ingested during the time the infant spends in the uterus: intestinal epithelial cells, lanugo, mucus, am ...
in the
amniotic fluid
The amniotic fluid is the protective liquid contained by the amniotic sac of a gravid amniote. This fluid serves as a cushion for the growing fetus, but also serves to facilitate the exchange of nutrients, water, and biochemical products betwee ...
.
Genetics
''FOXP3'' gene
IPEX syndrome is inherited in males in an
X-linked recessive ''Main Article'': Sex linkage
X-linked recessive inheritance is a mode of Mendelian inheritance, inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males (who are necessarily hemizygous for ...
pattern through the ''FOXP3'' gene. ''FOXP3s
cytogenetic
Cytogenetics is essentially a branch of genetics, but is also a part of cell biology/cytology (a subdivision of human anatomy), that is concerned with how the chromosomes relate to cell behaviour, particularly to their behaviour during mitosis an ...
location is Xp11.23.
The ''FOXP3'' gene has 12
exon
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...
s and its full reading open frame encodes 431
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s. FOXP3 is a member of the FKH family of
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 and contains a proline‐rich (PRR)
amino‐terminal domain, central
zinc finger
A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) which stabilizes the fold. The term ''zinc finger'' was originally coined to describe the finger-like appearance of a ...
(ZF) and
leucine zipper
A leucine zipper (or leucine scissors) is a common three-dimensional structural motif in proteins. They were first described by Landschulz and collaborators in 1988 when they found that an enhancer binding protein had a very characteristic 30-amin ...
(LZ) domains important for protein–protein interactions. It also has a
carboxyl‐terminal FKH domain required for nuclear localization and DNA‐binding activity. In humans, exons 2 and 7 may be spliced and excluded from the
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
.
''FOXP3'' mutations
A large variety of
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
s have been found, including single base substitutions, deletions, and splicing mutations. Data from 2018 describes over 70 mutations in the ''FOXP3'' gene leading to IPEX syndrome. This number has grown dramatically in the past decade.
In 2010 there were only 20 mutations of ''FOXP3'' known in the literature.
Some mutations cause ''FOXP3'' expression to malfunction, which leads to a defect in T
reg production. Those individuals do not have circulating CD4+/CD25+/FOXP3+ T
reg cells. Reduced expression of FOXP3 has been described, and these individuals may express normal levels of dysfunctional protein, which leads to mild symptoms during the
neonatal
In common terminology, a baby is the very young offspring of adult human beings, while infant (from the Latin word ''infans'', meaning 'baby' or 'child') is a formal or specialised synonym. The terms may also be used to refer to Juvenile (orga ...
period or later in life. Other individuals express no FOXP3 protein.
A common location for mutation of ''FOXP3'' leading to expression of malfunctioning protein is the
DNA-binding domain
A DNA-binding domain (DBD) is an independently folded protein domain that contains at least one structural motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence (a recognition sequence) or have a gener ...
called the
forkhead
FOX (forkhead box) proteins are a family of transcription factors that play important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation, and longevity. Many FOX proteins are important to embryonic ...
domain. The mutation makes the truncated protein unable to bind to its
DNA
Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
binding site. This impairs its function concerning T
reg development and functioning. The absence or dysfunction of T
regs causes
autoimmune
In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease" ...
symptoms.
FOXP3 pathways
FOXP3 can function as both a
repressor
In molecular genetics, a repressor is a DNA- or RNA-binding protein that inhibits the expression of one or more genes by binding to the operator or associated silencers. A DNA-binding repressor blocks the attachment of RNA polymerase to the ...
and a
''trans''‐activator of T
reg cells depending on its interactions with other proteins. FOXP3 expression is characterised by controlling
transcription, influencing
epigenetic
In biology, epigenetics is the study of changes in gene expression that happen without changes to the DNA sequence. The Greek prefix ''epi-'' (ἐπι- "over, outside of, around") in ''epigenetics'' implies features that are "on top of" or "in ...
changes and
post-transcriptional modification
Transcriptional modification or co-transcriptional modification is a set of biological processes common to most eukaryotic cells by which an RNA primary transcript is chemically altered following transcription from a gene to produce a mature, f ...
s. The N‐terminal repressor domain of FOXP3 can change transcription or epigenetic regulation of T
reg cells. Transcriptional activity is altered through interactions between the N-terminal domain and
Eos
In ancient Greek mythology and Ancient Greek religion, religion, Eos (; Ionic Greek, Ionic and Homeric Greek ''Ēṓs'', Attic Greek, Attic ''Héōs'', "dawn", or ; Aeolic Greek, Aeolic ''Aúōs'', Doric Greek, Doric ''Āṓs'') is the go ...
- which associates with
CtBP1 and forms a
corepressor
In genetics and molecular biology, a corepressor is a molecule that represses the expression of genes. In prokaryotes
A prokaryote (; less commonly spelled procaryote) is a single-celled organism whose cell lacks a nucleus and other membra ...
complex. This complex binds the ''
IL2''
promoter and enables FOXP3 to repress ''IL2'' transcription in T
reg cells. FOXP3 forms complexes with histone deacetylase
(HDAC)7,
HDAC9
Histone deacetylase 9 is an enzyme that in humans is encoded by the ''HDAC9'' gene.
Function
Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alter ...
, and the
histone acetyl transferase TIP60, which alters epigenetic activity of T
reg cells. The N‐terminal domain of FOXP3 can also antagonize the transcription factors
RORγ and RORα, thereby inhibiting
TH17 cell differentiation
Cellular differentiation is the process in which a stem cell changes from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellular ...
. FOXP3 is linked to TCR signaling by downstream transcription factors. All of these findings verify the importance of FOXP3 in the regulation of transcriptional activity and repression in T
reg cells.
[
]
Diagnosis
Early detection of the disease is crucial because IPEX has a high mortality level if left untreated. IPEX is usually diagnosed based on the following criteria:
* Clinical triad
* Family history
Genealogy () is the study of families, family history, and the tracing of their lineages. Genealogists use oral interviews, historical records, genetic analysis, and other records to obtain information about a family and to demonstrate kins ...
* Laboratory
A laboratory (; ; colloquially lab) is a facility that provides controlled conditions in which scientific or technological research, experiments, and measurement may be performed. Laboratories are found in a variety of settings such as schools ...
findings: elevated serum concentration of IgE
Immunoglobulin E (IgE) is a type of antibody (or immunoglobulin (Ig) " isoform") that has been found only in mammals. IgE is synthesised by plasma cells. Monomers of IgE consist of two heavy chains (ε chain) and two light chains, with the ε ...
, eosinophilia
Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds . Hypereosinophilia is an elevation in an individual's circulating blood eosinophil count above 1.5 billion/ L (1,500/ μL). The hypereosinophilic syndrome ...
, autoimmune anemia and decreased number of FOXP3 Treg cells.
* Genetic testing
Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...
: single-gene testing and multigene panel.
Treatment
Individuals with IPEX will usually need supportive care in a hospital. Most common is nutritional treatment for enteropathy and insulin therapy for T1D. IPEX treatment tends to focus on managing symptoms, reducing autoimmunity, and/or treating secondary conditions. Usually, treatment will involve immunosuppression.
Drugs used include:
* Cyclosporin A
Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, nephrotic syndrome, eczem ...
* Tacrolimus
Tacrolimus, sold under the brand name Prograf among others, is an immunosuppressive drug. After Allotransplantation, allogenic organ transplant, the risk of organ Transplant rejection, rejection is moderate. To lower the risk of organ rejectio ...
* Sirolimus
Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease called lymphangioleiomyomatosis ...
* Rituximab
Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia (in children and ad ...
Currently, the standard treatment for IPEX is a bone marrow transplant. If donor-recipient chimerism is achieved, individuals with IPEX can achieve complete remission.
Research
In 1982, Powel et al. published a case report of a family with 19 males who were affected by an X-linked syndrome with symptoms including polyendocrinopathy and diarrhea. The most common symptoms in this family were severe enteropathy, T1D, and dermatitis. Only 2 of the 19 affected males in the family survived past 3 years old. These individuals lived to 10 and 30 years old. Powel's study is now widely considered the first documentation of IPEX.
''Scurfy'' mouse
''Scurfy'' is a type of model mouse used for immunology
Immunology is a branch of biology and medicine that covers the study of Immune system, immune systems in all Organism, organisms.
Immunology charts, measures, and contextualizes the Physiology, physiological functioning of the immune system in ...
research. ''Scurfy'' mice have had 2 base pair
A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...
s inserted within the FOXP3 gene. This leads to a frameshift mutation
A frameshift mutation (also called a framing error or a reading frame shift) is a genetic mutation caused by indels ( insertions or deletions) of a number of nucleotides in a DNA sequence that is not divisible by three. Due to the triplet natur ...
in FOXP3 gene and the expressed protein is truncated, causing functional deficiency of Treg cells. Then, autoreactive CD4+T cells and inflammatory cells cause tissue damage. ''Scurfy'' mice have an enlarged spleen
The spleen (, from Ancient Greek '' σπλήν'', splḗn) is an organ (biology), organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter.
The spleen plays important roles in reg ...
and lymph node
A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that includ ...
s, squinted red eyes, and scaly or "ruffled" skin. The mice also have immunity problems and tend to die approximately 3 weeks after birth. From 2000 - 2001, multiple studies confirmed that IPEX is the human equivalent of ''scurfy'' mice and that the FOXP3 gene is responsible.
See also
* Autoimmune polyendocrine syndrome
* FOXP3
FOXP3 (forkhead box P3), also known as scurfin, is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator of the regulatory pathway in the development and function of r ...
* Autoimmune polyendocrine syndrome type 2
References
Further reading
*
*
*
External links
{{Transcription factor deficiencies
Autoimmune diseases
Transcription factor deficiencies
Diseases of immune dysregulation
Syndromes affecting immunity
Rare genetic syndromes