IPEX syndrome

from Wikipedia, the free encyclopedia
Classification according to ICD-10
E31.0 Autoimmune polyglandular insufficiency
ICD-10 online (WHO version 2019)
The healthy mother is the bearer (conductor) of the trait, i. H. the mutation in the FOXP3 gene in one of its two X chromosomes. Statistically, this mutation is passed on to 50% of their children. Daughters with this trait are only carriers and do not have IPEX themselves. Your second, non-mutated FOXP3 gene on the second X chromosome compensates for the loss of function ( loss of function mutation ) of the defective gene. Sons with this trait, on the other hand, develop IPEX because male individuals only have one X chromosome. They do not produce any functional or sufficient quantities of functional scurfin, the gene product of FOXP3 .

The IPEX syndrome is a very rare congenital monogenic polyendocrine autoimmune disease . It is a serious illness that usually begins in the first year of life and is associated with a very high mortality rate . IPEX is an acronym for immune dysregulation-polyendocrinopathy-enteropathy-X-linked . Further terms are, for example, X-linked immune dysregulation , polyendocrinopathy and enteropathy , immune dysregulation-polyendocrinopathy-enteropathy syndrome, X-linked and immune dysregulation, polyendocrinopathy and enteropathy, X-linked .

The cause of the disease is insufficient or complete lack of the body's own production of the protein scurfin, also known as FoxP3 ( forkhead box protein P3 ). Scurfin is a key factor in the formation of regulatory T cells (T Reg ). These cells prevent the development of autoimmune diseases in a healthy organism . In patients with IPEX syndrome, the regulatory T cells are missing, which is why they develop a large number of autoimmune diseases at the same time. IPEX syndrome is therefore a multi-system disease that can affect a large number of organs in the body. Symptoms can vary greatly depending on the organs affected . The individually very different manifestations of the disease and its extreme rarity make diagnosis considerably more difficult .

Cause of the deficit of FoxP3 in most previously known cases, a mutation in the FOXP3 - gene that in humans on the X chromosome is. Due to the X-linked inheritance , only boys develop the IPEX syndrome.

If left untreated, IPEX syndrome is fatal within the first few years of life. A cure is currently only possible through a hematopoietic stem cell transplant .

The IPEX syndrome was first described in 1982. The Scurfy mouse, a special mutant of a color mouse ( Mus musculus domesticus ) bred since 1949 , also has a mutation in the Foxp3 gene. The scurfy mouse has become a valuable animal model for research into IPEX syndrome and other autoimmune diseases.

Epidemiology

The IPEX syndrome is extremely rare. So far, fewer than 150 cases of sick people are known worldwide. Reliable estimates of the prevalence have not yet been published. It is generally assumed that many IPEX cases are not recognized or are attributed to other diseases that have a similar origin (X chromosome) and similar symptoms. This includes, for example, the Wiskott-Aldrich syndrome .

Genetics and molecular biology

The IPEX syndrome is a hereditary disease. It is based on a genetic defect caused by a mutation in the FOXP3 gene, which is located on the female sex chromosome , the X chromosome. Only women pass this genetic defect on to 50% of their offspring. Men do not reach sexual maturity due to the high mortality rate of the IPEX syndrome . Women with a genetic defect in FOXP3 do not develop IPEX syndrome. However, they are carriers ( conductors ) of the mutation. Statistically speaking, they pass this mutation on to 50% of their children - regardless of gender. Daughters with this mutation are again only carriers and do not develop IPEX themselves. Your second, non-mutated FOXP3 gene on the second X chromosome compensates for the loss of function ( loss of function mutation ) of the defective gene. The sons who have inherited this mutation, on the other hand, get IPEX because males have only one X chromosome. They do not produce a functional or sufficiently functional scurfin. This inheritance is known as X-linked recessive .

In humans, the FOXP3 gene affected by the mutation is located on the short arm of the X chromosome (Xp), gene locus Xp11.23. The gene product of FOXP3 ( protein ) is called Scurfin or FoxP3. Four different isoforms of scurfin are currently known in humans. Isoform 1 consists of 431 amino acids and has a molar mass of 47.2  kDa . In isoform 2, the amino acids in positions 72 to 106 are missing. The remaining 396 amino acids give the protein a molar mass of 43.4 kDa. These amino acids are also missing in isoform 3, but there are 60 additional amino acids from position 382 in the protein. The molar mass of this isoform consisting of 456 amino acids is 49.8 kDa. In isoform 4, the amino acids in position 246 to 272 are missing. The molar mass of the remaining 404 amino acids is 44.4 kDa. Scurfin is a transcription factor that, after translation, occurs primarily in the nucleus of mammals. There scurfin binds to the DNA and stimulates the expression of proteins that are needed in the regulatory T cells. FOXP3 is the master gene (selector gene ) for regulatory T cells (T Regs ). If naive T cells, i.e. not activated T cells, come into contact with TGF-β and no interleukin-6 is present at the same time , these cells can differentiate into T Regs . These cells can produce scurfin and, through the release of additional TGF-β and interleukin-10, dampen the immune response. Both are inhibitory cytokines. If functional scurfin is missing, for example due to a mutation in the FOXP3 gene, the immune reaction of the organism is not dampened. The self-tolerance is no longer given and autoimmune diseases develop. T Regs or FOXP3 are essential for the homeostasis of the immune system and are of the utmost importance to avoid autoimmunity and excessive immune reactions.

FOXP3 is an evolutionarily highly conserved gene that consists of 12 exons .

Mutation variants

Overview of the clinically relevant mutations in the FOXP3 gene known up to 2012 .

The defects in the FOXP3 gene caused by mutations are very heterogeneous. By 2012, 63 different FOXP3 mutations had been described in a total of 136. The majority of these mutations (27 out of 63) affect the C-terminal forkhead . This area is the protein domain that binds to DNA . The remaining mutations fall on the proline- rich domain (PRR) at the N-terminus (14/63), the bZIP domain (5/63), the leucine zipper forkhead loop ( LZ-FHK loop , 9/63 ), the region above the initial ATG start codon and the C-terminal region (3/63).

In addition, mutations at the polyadenylation site (5'-AAUAAA-3 ') were described in 2 of 63 cases. These mutations lead to an unstable FOXP3 - mRNA . As with missense , frameshift mutations or splice defects that lead to a premature stop codon , an early and serious onset of the disease ( early-onset ) is very likely in such cases . The severity of the disease does not correlate in all cases with the lack of expression of scurfin. Most IPEX patients have point mutations that lead to reduced or even normal expression of mutated scurfin. However, this scurfin is impaired in its transcription regulatory activity due to changes in the binding sites to DNA, the interaction with other molecules (for example NF-AT , AP-1 or RORα ) or its tendency to dimerize .

In the family in which the IPEX syndrome was first described in 1982, no mutation could later be identified in the coding region of FOXP3 . It is therefore assumed that this is a mutation in the non-coding area that affects transcription regulation or RNA splicing .

Genotype-Phenotype Correlation

Regardless of the type of mutation (the genotype ), the appearance (the phenotype ) of the disease is characterized by gastrointestinal symptoms, especially diarrhea , in over 90% of patients . In general, the genotype-phenotype correlation in the IPEX syndrome is difficult, especially when it comes to the age at the onset of the disease (onset) and the assessment of the course of the disease ( prognosis ). For example, a group of 13 patients has an identical mutation of type p.Ala384Thr. This means that at position 384 the scurfin contains the amino acid threonine instead of the amino acid alanine . In these patients, the onset of the disease varies from immediately after birth (prenatal) to seven months of age. In addition to the low number of cases, therapeutic measures and accompanying infections make the correlation between genotype and phenotype more difficult .

Clinical picture

Most IPEX patients are born to unrelated parents after an uneventful pregnancy . Immediately after birth, they usually have a normal body weight and length. Pathological findings are usually not available. They appear in the first months of life - rarely in the first days or weeks of life. If the disease is not diagnosed and treated appropriately, it can very quickly lead to infant death. The most severe cases are characterized by the early onset of a triad of clinical manifestations : persistent diarrhea , type 1a diabetes mellitus, and eczema .

Autoimmune enteropathy is an essential characteristic of IPEX syndrome: The patients have watery and sometimes mucous (mucoid) or bloody acute diarrhea. This acute severe enteropathy is independent of the infant's diet ( breastfeeding , cow's milk or food containing gluten ). The diarrhea leads to a reduced utilization of nutrients in the digestive tract ( malabsorption ), which seriously affects the health and development of the patient. Therefore parenteral nutrition (artificial nutrition) is often necessary. In addition to diarrhea, the IPEX syndrome can manifest itself through other gastrointestinal disorders. These include: vomiting , gastritis , intestinal obstruction (ileus) and colitis ( chronic inflammatory bowel disease ).

Depending on the patient, type 1a diabetes mellitus can precede or follow enteritis. Diabetes is usually difficult to control. In the majority of cases, autoantibodies can be detected. There are rare cases of diabetes mellitus without autoantibodies in IPEX syndrome. The destruction of the pancreas can usually be easily recognized by histological examinations, imaging procedures or during an autopsy . In the histology, the massive infiltration of lymphocytes into this organ is also clearly visible. This is a clear indication of immune-mediated damage to the pancreas.

diagnosis

The results of the clinical examination, family history and laboratory findings are usually used to make a diagnosis . Molecular genetic tests then serve to finally confirm the diagnosis and are essential for a reliable diagnosis.

The usual laboratory data can be largely normal at the onset of the disease. There are no specific diagnostic findings for IPEX syndrome. Abnormal laboratory values ​​consistent with diabetes and severe entheropathy are the norm. Autoimmune manifestations in other target organs such as hypothyroidism, cytopenia, hepatitis or nephropathy can specifically change certain laboratory values. After the onset of the first symptoms, significantly increased levels of immunoglobulin E and eosinophilic granulocytes ( eosinophilia ) are measured in the majority of patients . The serum levels of immunoglobulin A , immunoglobulin G and immunoglobulin M , on the other hand, are generally normal or - due to protein loss enteropathy - decreased.

The following should be considered in the differential diagnosis : Wiskott-Aldrich and Omenn syndrome , STAT-1 , CD25 , interleukin-10 receptor or STAT5b deficiency , transient neonatal diabetes, Severe Combined Immunodeficiency (SCID, more severe combined immunodeficiency) as well as intermediate forms of SCID, X-linked thrombocytopenia and pancreatic hypoplasia or pancreatic agenesis .

therapy

Controlled clinical studies with statistically relevant patient numbers are not possible due to the very small number of patients with IPEX syndrome. It is therefore extremely difficult to compare different treatment measures with one another. In the specialist literature, only interventions on individual patients are described ( individual case studies ). For these reasons, all therapeutic approaches for the treatment of IPEX syndrome are based on the experience of individual patients. The largely unclear genotype-phenotype correlation, the clinical course of the disease and the response to therapy can be quite variable and not always satisfactory.

General therapy guidelines are currently not possible due to the still largely unclear genotype-phenotype correlation, the variable clinical course and the different response of patients to the therapy. Therapy is therefore tailored to the individual clinical manifestations and their severity. Current treatments for IPEX syndrome are replacement and supportive therapy, immunosuppressive therapy, and hematopoietic stem cell transplant (HSCT). Nutritional support, for example through parenteral nutrition , and immunosuppressive therapy are usually started immediately after the diagnosis is made in order to counteract the acute manifestations. The patients usually receive a combination of different immunosuppressants . Sirolimus has now proven to be advantageous over the calcineurin inhibitors . In the long-term follow-up, a permanent remission was achieved in four patients . The only curative therapy currently available is haematopoietic stem cell transplantation. The problem here, however, is that the search for suitable stem cell donors is in many cases unsuccessful. In addition, the patients are usually already in an extremely bad condition, so that the considerable side effects of conditioning and complications after stem cell transplantation often cannot lead to the desired treatment result. However, it has been shown that in HSCT, partial donor chimerism can be sufficient for a complete remission of the disease if complete engraftment of the T reg compartment is achieved. Obviously, just a few functional regulatory T cells are sufficient to control autoimmunity in IPEX syndrome. Various gene therapy options are being discussed intensively in future treatment options and tested in preclinical studies .

In clinical studies, patients with IPEX syndrome are treated together with patients who have similar immune deficiencies, such as leukocyte adhesion defect syndromes (LAD I, LAD II and LAD III), septic granulomatosis , hyper-IgM syndrome type 1 , agammaglobulinaemia ( e B. Bruton's syndrome ), Wiskott-Aldrich syndrome or Chediak-Higashi syndrome .

forecast

Without a diagnosis and treatment as soon as possible, the IPEX syndrome is usually fatal within the first two years of life. After a successful hematopoietic stem cell transplant, life expectancy is almost normal.

Animal models

The scurfy mouse is a mutant form of the house mouse . The name Scurfy (English for "scabbed") is derived from the flaky skin of the animals. 50% of the male offspring of the Scurfy mice die between three and four weeks of age. These animals show massive changes in the blood count. The number of thrombocytes and erythrocytes is significantly reduced and progressively decreases over the course of the short lifespan. In contrast, the number of leukocytes is increased and increases progressively over time. The animals suffer from gastrointestinal bleeding and diarrhea and usually die of severe anemia . These animals have a genetic defect in the foxp3 gene, which is also located on the X chromosome in mice. In contrast to human scurfin, murine scurfin only exists in one isoform.

The parallels between the cause and course of the disease in Scurfy mice and patients with IPEX syndrome make the Scurfy mouse an extremely valuable model organism, not only for researching the IPEX syndrome and the development of new forms of therapy, but more generally in the complex of autoimmune diseases.

Medical history

Liane Russell 1996 with Fred Thompson at ORNL

In 1947, the Mammalian Genetics Laboratory was founded at Oak Ridge National Laboratory (ORNL) in Tennessee . The task of the laboratory was to investigate the effects of ionizing radiation on mammals in order to be able to draw conclusions about humans. The management of this research facility derived from the Manhattan Project had William "Bill" Russell (1910-2003). For example, these studies included trips to New Mexico to study the effects of radiation from nuclear weapon explosions on mice. The scientifically most interesting change, however, occurred as a spontaneous mutation in a mouse in Oak Ridge in 1949, which was called scurfy . The inherent phenotype in the offspring of this mouse was the first sex-linked disease observed in mice. At that time, sex-linked genes were still unknown in mice. The disease of the affected male animals was caused by a recessive mutation that was ultimately fatal for them. Liane B. Russell (* 1923), the wife of Bill Russell, carried out a number of groundbreaking genetic experiments on scurfy mice. Among other things, she recognized the sex-determining function of the Y chromosome . The scurfy mutation was not published until 1959.

In 1982 Berkley R. Powell, Neil RM Buist and Peter Stenzel published the results of their research on a patient in whose family 17 children died in the first years of life. To do this, they also evaluated the medical records of eight of the deceased. In this first description of the IPEX syndrome, the authors postulate that an unknown genetic mechanism on the X chromosome is responsible for the overactivity of the immune system.

It was established in 1990 that scurfy mice show symptoms similar to those of patients with Wiskott-Aldrich syndrome in humans. However, differences in individual symptoms and a different gene locus showed that the genes must be different. The authors were not aware of any human disease similar to the scurfy mouse. First immunological studies on scurfy mice showed massive infiltration of lymphocytes and myeloid cells in a large number of organs and made the pronounced autoimmune pathology clear.

The gene locus Xp11.2, in the area of ​​which the WAS gene affected by Wiskott-Aldrich syndrome is also located, was identified by a working group headed by Ann O. Shigeoka in 1993 as a location directly related to the IPEX syndrome. In early 2000, a work group at the University of Virginia carried out a linkage analysis on 20 members of a clan affected by IPEX syndrome. As part of this work, the locus was able to be determined on a pericentromere region of the X chromosome in the area Xp11.23-q21.1. The working group also came to the conclusion that IPEX syndrome is a disease that is independent of Wiskott-Aldrich syndrome. In all of the patients examined, the WAS gene was not mutated. In the same year, a working group headed by Talal A. Chatila discovered that the IPEX syndrome is caused by mutations in the FOXP3 gene, which at the time was still called the JM2 gene.

The connection between FoxP3 and the Scurfy mouse, as well as with human neonatal type 1 diabetes, was first established in 2001. In 2003 the key role of FoxP3 in the formation of regulatory T cells was described for the first time.

literature

Footnotes

  1. ↑ The transmission of the genetic defect through a father is impossible due to the early and high mortality of the disease, so that there can be no homozygous carriers of the mutation.
  2. ↑ Exceptions are men with Klinefelter syndrome .

Individual evidence

  1. ↑ a b c d Immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome. In: Orphanet (Rare Disease Database).
  2. ↑ S. Daum, B. Siegmund, M. Zeitz: Immune diseases of the intestinal tract including intestinal lymphomas. In: Helmut Messmann (ed.): Clinical gastroenterology. Georg Thieme Verlag, 2011, ISBN 978-3-131-65991-0 , p. 348 ( limited preview in Google book search).
  3. ^ Mark C. Hannibal, Troy Torgerson: IPEX Syndrome. In: RA Pagon, MP Adam u. a. (Ed.): GeneReviews. University of Washington, Seattle, 2004 (updated 2011), PMID 20301297
  4. ↑ IPEX syndrome.  In: Online Mendelian Inheritance in Man . (English)
  5. ↑ RS Wildin, A. Freitas: IPEX and FOXP3: clinical and research perspectives. In: Journal of autoimmunity. Volume 25 Suppl, 2005, pp. 56-62, doi : 10.1016 / j.jaut.2005.04.008 , PMID 16243487 (review).
  6. ↑ Q9BZS1 (FOXP3_HUMAN) Universal Protein Resource (UniProt), accessed March 15, 2017
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  8. ^ Stefan Rehart: Expertise in orthopedic rheumatology. Georg Thieme Verlag, 2015, ISBN 978-3-131-71421-3 , p. 29 ( limited preview in the Google book search).
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  10. ^ Fritz H. Kayser: Pocket Textbook Medical Microbiology. Georg Thieme Verlag, 2014, ISBN 978-3-131-51443-1 , p. 150 ( limited preview in the Google book search).
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  12. ↑ NM_014009.3 (FOXP3): c.1150G> A (p.Ala384Thr) AND Insulin-dependent diabetes mellitus secretory diarrhea syndrome. National Center for Biotechnology Information, accessed March 16, 2017
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  23. ^ O. Baud, O. Goulet et al. a .: Treatment of the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) by allogeneic bone marrow transplantation. In: The New England Journal of Medicine . Volume 344, Number 23, June 2001, pp. 1758-1762, doi : 10.1056 / NEJM200106073442304 , PMID 11396442 .
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  30. ↑ Clinical study (phase II): Reduced Intensity Conditioning for Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (BMT CTN 1204) (RICHI) at Clinicaltrials.gov of the NIH
  31. ↑ Clinical study (phase II): Immune Disorder HSCT Protocol at Clinicaltrials.gov of the NIH
  32. ↑ RS Wildin, F. Ramsdell et al. a .: X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. In: Nature genetics. Volume 27, Number 1, January 2001, pp. 18-20, doi : 10.1038 / 83707 , PMID 11137992 .
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