IPEX syndrome

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IPEX (syndrome)
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IPEX syndrome
Other namesAutoimmune enteropathy type 1[1]
IPEX syndrome is inherited via X-linked recessive
SpecialtyImmunology Edit this on Wikidata
SymptomsLymphadenopathy[2]
CausesFOXP3 gene mutation[1]
Diagnostic methodFamily history, Genetic test[1]
TreatmentTPN(nutritional purpose), Cyclosporin A and FK506, Bone marrow transplant[3][4]

Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX syndrome) is a rare

endocrinopathy (most often Type 1 diabetes), but other presentations exist.[5]

IPEX is caused by mutations in the gene FOXP3, which encodes transcription factor forkhead box P3 (

master regulator of the regulatory T cell (Treg) lineage.[6][7] FOXP3 mutation can lead to the dysfunction of CD4+ Tregs. In healthy people, Tregs maintain immune homeostasis.[8] When there is a deleterious FOXP3 mutation, Tregs do not function properly and cause autoimmunity.[8][9]

IPEX onset usually happens in

X-linked recessive manner;[1][2] female carriers of pathogenic FOXP3 mutations do not have symptoms and no female cases are known.[4]

Presentation

Classical triad

The classical triad describes the most common symptoms of IPEX: intractable

eczema. Symptoms usually begin shortly after birth.[12]

Other symptoms include: thyroid disease, kidney dysfunction, blood disorders, frequent infections, autoimmune hemolytic anemia, and food allergies, among others.[10]

Endocrinopathy

The most common

endocrinopathy associated with IPEX is type 1 diabetes, especially neonatal diabetes. In this type of diabetes, the immune system attacks insulin-producing cells. This makes the pancreas unable to produce insulin. Diabetes can permanently damage the pancreas.[13]

Thyroid disorders are also common.[14]

Enteropathy

The most common enteropathy associated with IPEX is intractable diarrhea. Vomiting and gastritis are also common. Other manifestations include Celiac disease, ulcerative colitis, and ileus.[14]

Eczema
Skin manifestations

The most common form of skin involvement is

alopecia.[14]

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,[15] and some reported cases labeled newborns with intrauterine growth restriction and evidence of meconium in the amniotic fluid.[16]

Genetics

Mutations in FOXP3 gene causing IPEX syndrome - known in the year 2012.

FOXP3 gene

IPEX syndrome is inherited in males in an

X-linked recessive pattern through the FOXP3 gene. FOXP3's cytogenetic location is Xp11.23.[6][7] The FOXP3 gene has 12 exons and its full reading open frame encodes 431 amino acids. FOXP3 is a member of the FKH family of transcription factors and contains a proline‐rich (PRR) amino‐terminal domain, central zinc finger (ZF) and leucine zipper (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.[17]

FOXP3 mutations

A large variety of

autoimmune symptoms.[19]

FOXP3 pathways

FOXP3 can function as both a

TH17 cell differentiation. 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 Treg cells.[17]

Diagnosis

Early detection of the disease is crucial because IPEX has a high mortality level if left untreated.[20] IPEX is usually diagnosed based on the following criteria:[1][4]

Treatment

Tacrolimus

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.[11]

Drugs used include:

Currently, the standard treatment for IPEX is a bone marrow transplant. If donor-recipient chimerism is achieved, individuals with IPEX can achieve complete remission.[11]

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.[21] Powel's study is now widely considered the first documentation of IPEX.[citation needed]

Scurfy mouse

Scurfy is a type of model mouse used for immunology research. Scurfy mice have had 2 base pairs inserted within the FOXP3 gene. This leads to a frameshift mutation 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.[22] Scurfy mice have an enlarged spleen and lymph nodes, squinted red eyes, and scaly or "ruffled" skin. The mice also have immunity problems and tend to die approximately 3 weeks after birth.[18] From 2000 - 2001, multiple studies confirmed that IPEX is the human equivalent of scurfy mice and that the FOXP3 gene is responsible.[10]

See also

References

  1. ^ a b c d e "Orphanet: Immune dysregulation polyendocrinopathy enteropathy X linked syndrome". www.orpha.net. Retrieved 2017-04-18.
  2. ^ a b "Immunodysregulation, polyendocrinopathy and enteropathy X-linked | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Archived from the original on 2019-01-09. Retrieved 2017-04-16.
  3. ISBN 9781603274784
    .
  4. ^
    PMID 20301297
    .update 2011
  5. ^ "Embase". www.embase.com. Retrieved 2023-04-04.
  6. ^ a b "IPEX syndrome". Genetics Home Reference. Retrieved 2017-04-16.
  7. ^ a b "FOXP3 gene". Genetics Home Reference. Retrieved 2017-04-16.
  8. ^
    S2CID 211231953
    .
  9. S2CID 11149833
    .
  10. ^
    S2CID 11149833
    .
  11. ^
    PMID 33668198
    .
  12. S2CID 214768010
    .
  13. ^ CDC (2022-03-11). "What Is Type 1 Diabetes?". Centers for Disease Control and Prevention. Retrieved 2023-04-16.
  14. ^
    S2CID 214768010
    .
  15. PMID 23060872
    .
  16. PMID 25546394
    .
  17. ^
    PMID 26918796
    .
  18. ^
    PMID 26918796
    .
  19. ^
    S2CID 20395564
    .
  20. ^
    S2CID 208377306
    , retrieved 2021-01-29
  21. PMID 7040622
    .
  22. PMID 31068947
    .

Further reading

External links

Scholia has a topic profile for IPEX syndrome.
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