IPEX syndrome is a rare severe hereditary disease characterized by impaired immune system functions, autoimmune damage to the endocrine organs and skin. Clinically, it is most often manifested by skin rashes resembling eczema or psoriasis, diabetes mellitus, profuse diarrhea. Almost any infection immediately becomes generalized until the development of a septic condition. The final diagnosis is made after a genetic study. The main method of treatment is stem cell transplantation. Immunosuppressive, hormone replacement and symptomatic therapy is carried out.
E31.0 Autoimmune polyglandular insufficiency
IPEX syndrome (I – immune dysregulation, P – polyendocrinopathy, E – enteropathy, X- linked to the X chromosome) belongs to the group of primary immunodeficiency with an autoimmune component. The disease manifests itself from birth and, without specific treatment, almost always ends fatally quickly. The condition was first described in 1982. In total, about 150 clinical cases have been registered in the world. There is no information about the true prevalence. Only boys get sick.
Reasons of IPEX syndrome
The disease occurs due to a mutation in the FOXP3 gene, localized at the Xp11 locus.23. This gene encodes the formation of the scarfin protein. Scarfin is responsible for the maturation and functioning of a special group of T-lymphocytes – T-suppressors (CD4+, CD25), suppressing the excessive activity of immune cells. They are regulators of the immune response.
As a result of the FOXP3 mutation, the regulation of the immune response is disrupted, auto-tolerance is lost, and immune autoaggression reactions occur. Lymphocytes begin to attack their own cells, mistaking them for foreign ones. Any organs can be involved in the pathological process, the skin, endocrine glands and intestines are most often affected. The defeat of the pancreas and thyroid gland leads to type 1 diabetes mellitus and hypothyroidism.
Pathomorphological examination of the intestine reveals atrophy of villi with mononuclear infiltration of the mucous membrane, necrosis of epithelial cells, the formation of crypt abscesses. Pancytopenia often occurs, i.e. a decrease in the blood level of all shaped elements – erythrocytes, leukocytes, platelets. In addition to autoimmune changes, resistance to bacterial and viral infections worsens.
Clinically, the disease does not always proceed in the same way, which is probably due to various mutations of FOXP3. There are 2 types of IPEX syndrome:
- The classic form. It is characterized by a complete loss of the function of the scarfin protein, developed severe symptoms and high mortality in the first year of life.
- Incomplete form. Due to the residual functioning of scarfin, a milder monosymptomatic course with a life expectancy of 20 to 30 years is observed.
Symptoms of IPEX syndrome
Clinical manifestation occurs almost immediately after birth. Manifestations can be extremely diverse, but there is a classical triad of signs that is present in the overwhelming number of patients – autoimmune enteropathy (100% of cases), polyendocrinopathy (70-80% of cases), skin lesions (65-70% of cases).
The most constant symptom is considered to be profuse secretory diarrhea, due to which protein-energy deficiency is rapidly increasing. The child does not gain weight well, lags behind in growth. During the first 6 months, diabetes mellitus debuts – constant thirst, increased urination, muscle weakness begin to bother.
Diabetes with IPEX syndrome is often accompanied by hypothyroidism, due to which the patient becomes sluggish, drowsy and edematous, significantly lags behind in neuropsychiatric development. Rashes are similar in nature to eczema or psoriatic. Red spots, flaky plaques, bubbles appear on the skin, which leave ulcers after the rupture.
A distinctive feature of the skin elements is resistance to therapy with local antihistamines and corticosteroids. Due to autoimmune pancytopenia, patients often experience pallor of the skin and mucous membranes with a jaundice tinge, nasal and gingival bleeding, spontaneous bruising. Autoimmune hepatitis, nephropathy, reactive enlargement of the spleen and peripheral lymph nodes are possible.
IPEX syndrome is characterized by a large number of complications. The most common are secondary bacterial or fungal infections that attach to skin rashes. Due to severe immunodeficiency, the child is also susceptible to other infectious diseases (pneumonia, meningitis, tuberculosis), which are prone to generalization, sometimes to a septic state.
Other adverse effects are less frequent. Neonatal diabetes mellitus can debut with such an acute and urgent condition as ketoacidosis or ketoacidotic coma. Massive bleeding and intestinal obstruction are possible. Autoimmune nephropathy in adults can lead to chronic renal failure.
Diagnostics of IPEX syndrome
Pediatricians and geneticists are involved in the curation of patients with IPEX syndrome. The male sex of the child, a combination of enteropathy, endocrinopathy and skin rashes helps to suspect the disease. To confirm the diagnosis, an examination is prescribed, including:
- General laboratory tests. In the general blood test, many patients have a decrease in the level of hemoglobin, leukocytes, platelets, erythrocytes. Eosinophilia is often detected. The biochemical analysis of blood reveals a low content of albumin, electrolytes, an increase in the concentration of hepatic transaminases, glucose, glycated hemoglobin. Proteinuria is possible in the urine analysis.
- Immunological studies. Elevated IgE, antibodies to intestinal cell antigens (AIE-75, villin), thyroperoxidase, thyroglobulin, pancreatic beta cells, glutamate dehydrogenase, tyrosine phosphatase are detected in the blood. The immunogram is characterized by a decrease in the immunoregulatory index (CD4+ /CD8+).
- Genetic research. The main analysis that allows to reliably establish the diagnosis of IPEX syndrome. A mutation of the FOXP3 gene is detected by polymerase chain reaction.
Differential diagnosis is carried out with hereditary primary immunodeficiency (Wiskott-Aldrich syndrome, Di Giorgi syndrome), genetic metabolic disorders, autoimmune polyglandular syndrome. Isolated autoimmune enteropathy with monosymptomatic course requires differential diagnosis with food intolerance (celiac disease), infectious diarrhea, hormone-producing tumors (gastrinomas, VIPomas).
Treatment of IPEX syndrome
- Patients are subject to mandatory hospitalization. At the time of diagnosis, due to severe malabsorption, there is a need for parenteral nutrition and albumin infusions. Bone marrow stem cell transplantation is recognized as the only effective method of treatment. Early HSCT helps prevent the development of complications. Drug therapy is supportive and symptomatic:
- Immunosuppressors. To suppress autoimmune damage to internal organs, glucocorticosteroids (prednisone), cytostatics (cyclophosphamide, tamoxifen), anti-cytokine drugs (infliximab) are used. The effectiveness of these drugs is often insufficient.
Hormonal agents. For the treatment of diabetes mellitus, insulin injections are prescribed for life. The selection of short- and long-acting drugs is carried out strictly individually. Glycated hemoglobin is regularly monitored to monitor the effectiveness of treatment. With the development of hypothyroidism, L-thyroxine is used under the control of TSH levels.
Prognosis and prevention
IPEX syndrome is a serious disease. In the classical form, without timely diagnosis and bone marrow transplantation, death occurs by the end of the first year of life in almost 100% of cases. The main causes of death are generalized viral and bacterial infections. Fatal outcomes associated with vaccination are described.
The life expectancy of people with an incomplete defect of immune regulation is 20-30 years. The only method of prevention is considered to be prenatal diagnostics – molecular genetic examination of a sample of chorionic villi. The analysis is prescribed in cases where a FOXP3 mutation has been detected in close relatives.