Background
Immune dysfunction, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a lethal syndrome first described as a unique entity by Powell et al in 1982. [1] It most commonly manifests with early onset, insulin-dependent diabetes mellitus; severe watery diarrhea, often with accompanying failure to thrive; and dermatitis. Other clinical features are more variable in their expression. [1, 2, 3]
Most affected children die within the first 2 years of life. IPEX syndrome is an X-linked recessive disorder with exclusive expression in males. The identification of mutations in the forkhead box protein 3 (FOXP3) gene associated with IPEX syndrome and a murine model has generated a considerable amount of interest and research. [2, 3] This has also extended into the therapeutic spectrum, with new immunosuppressive regimens and use of hematopoietic stem cell transplantation (HSCT).
Pathophysiology
IPEX syndrome is one of the monogenic autoimmune diseases, such as Wiskott-Aldrich syndrome and autoimmune lymphoproliferative syndrome (ALPS). A potential murine model was identified in mice suffering from Scurfy syndrome. Using information gathered from these mice, researchers mapped the forkhead box protein 3 (FOXP3) gene to Xp11.23-Xq13.3. [1, 2, 4] This is a genetic region also closely associated with the WASP gene responsible for Wiskott-Aldrich syndrome. The FOXP3 gene is part of a family of genes that are strongly associated with normal immune responses and thymic development. [5]
FOXP3 has recently been linked with the development of immunosuppressive CD4+ CD25+ regulatory T cells, which form in the thymus and represent a subset (5–10%) of the helper CD4+ T cells. [6] These cells have been noted in previous studies to dampen immune responses, including in the setting of autoimmune diseases. [7] When the FOXP3 gene is absent or dysfunctional, this specific subset of regulatory T-cells (Treg) fails to develop normally, though variable function has been noted in more recent studies. [8, 9] Although the role of Tregs in self-tolerance and immune homeostasis is of critical importance, the mechanism by which they exert these effects has not been fully elucidated. [5, 6]
More recent studies have uncovered links between FOXP3 dysfunction and an inflammatory helper T-cell subtype (Th17), as well as loss of peripheral B-cell tolerance. [10, 11] Ongoing research seeks to better characterize the full extent and implications of these and other manifestations of immune dysregulation.
Although patients with IPEX syndrome share many of the same core clinical and immune manifestations of the disease, the expressed phenotypes vary. Elevated immunoglobulin E (IgE) and immunoglobulin A (IgA) levels and eosinophilia have been noted but are not universally present in affected individuals. Neutrophil activity and complement levels are generally normal, although neutropenia has been reported. [6] Similarly, levels of immunoglobulin G (IgG) and immunoglobulin M (IgM) can be normal but are often slightly depressed in older individuals, likely as a result of protein loss from their enteropathy. [2]
Other clinical effects are also variably present, with some patients demonstrating thrombocytopenia, lymphadenopathy, tubular nephropathy, hypothyroidism, and alopecia in addition to the more common triad of dermatitis, insulin-dependent diabetes, and enteropathy. Although not fully understood, the presence of diabetes appears to be related to inflammatory destruction of the islet cells, supported by the histologic presence of lymphocytic infiltrates of the pancreas. [3, 12] In terms of the enteropathy seen in IPEX syndrome, a celiac-like pattern with villous-blunting is noted along with a similar lymphocytic infiltrate. [13] The cutaneous manifestations are most often eczematous but can also take on a spongiotic psoriasiform appearance histologically. [14]
Epidemiology
Frequency
IPEX syndrome is a rare disorder that affects an estimated 1 in 1.6 million people. [15]
Fewer than 150 individuals have ever been diagnosed with immunodysregulation polyendocrinopathy enterology x-linked (IPEX) syndrome, but there may be many unreported cases. [16]
Mortality/Morbidity
Children who do not receive treatment usually die within the first 2 years of life. Sepsis and complications from failure to thrive are the most common causes of death. [6]
In those patients who developed sepsis, enterococcal, staphylococcal, and candidal species as well as cytomegalovirus were the most commonly identified infectious agents. [5] Enterococcal and staphylococcal species have also been predominant in complications of immunosuppressive treatment, including catheter-associated infections, peritonitis, pneumonitis, and septic arthritis. [3]
Hematopoietic stem cell transplantation (HSCT) is an option, and increased success has been noted with “reduced-intensity” conditioning protocols. However, HSCT in patients with IPEX syndrome has met with significant complications and death rates, which may be increased compared with patients undergoing the procedure for other conditions. [3, 6, 17]
Demographics
The disease manifests shortly after birth and, in most cases, in the first 3–4 months of life. Because the condition is rare, no large scale studies or reports have been completed to aid further delineation of the age-related characteristics of IPEX syndrome. [1, 6]
Only males have been noted to be affected in this X-linked recessive process. Obligate carrier females have all been healthy in cases reviewed in the literature. The female IPEX syndrome carriers do not appear to be subject to disease manifestation related to a skewed pattern of lyonization or inactivation of the unaffected X-chromosome. [3]
No difference in the incidence of IPEX syndrome among individuals of different races is known.
Prognosis
If untreated, death from complications of IPEX syndrome usually occurs within the first 2 years of life. Death is often attributable to metabolic abnormalities, malnutrition secondary to malabsorption, or severe sepsis.
The introduction of immunosuppressive treatments has improved survival in patients with IPEX syndrome. Successful hematopoietic stem cell transplantation (HSCT) with immune reconstitution has been reported and offers hope of a permanent cure. [6]
Patient Education
Educate patients and families about IPEX syndrome and associated infectious and autoimmune complications. Patients should be able to recognize signs of infection, diabetes, thyroid disease, enteropathy, anemia, thrombocytopenia, or neutropenia and seek medical care.
Female carriers should receive appropriate genetic counseling.
Patients with IPEX syndrome should receive nutritional counseling.
Patients with diabetes should receive appropriate diabetic instruction.
