Duncan’s disease is an X—linked lymphoproliferative syndrome, a rare primary immunodeficiency that manifests after infection with Epstein-Barr herpesvirus. It is manifested by a fulminant form of infectious mononucleosis, lymphoproliferative processes (leukemia, lymphoma), severe disorders of hematopoiesis. To detect pathology, genetic, histological, serological and immunological diagnostic methods are necessary. The most effective method of treatment is bone marrow transplantation, immunoglobulins, cytostatics, and antibiotics are also prescribed.
D82.3 Immunodeficiency due to a hereditary defect caused by the Epstein-Barr virus
The syndrome was first described by Dr. Purtilo, who during 1969-1975 observed identical symptoms in boys belonging to three unrelated families. The generally accepted name “Duncan’s disease” was formed from the surname of the first proband. Pathology occurs with a frequency of 1-3 cases per 1 million male newborns, clinical manifestations do not develop in girls, but they may be carriers of a mutant gene. The peak of the manifestation of the disease occurs at the age of up to 5 years.
Duncan’s disease is caused by a genetic mutation. There are 3 variants of defects, according to which three subtypes of the disease are distinguished: SH2D1A — type 1, XIAP – type 2, MAGT1 — type 3. They are united in one group because they have a similar clinical picture, the same type of inheritance — X-linked. Pathology manifests itself when Epstein-Barr herpesvirus enters the body of a predisposed person, although some geneticists do not consider this a prerequisite.
The disease is based on a violation of the transmission of stimulating signals from herpesvirus-affected subtype 4 B-lymphocytes to natural killer cells (NK cells) and T-lymphocytes. As a result, the immune system cannot cope with the removal of infected cells, the body does not produce antiviral gamma interferon. This condition is accompanied by uncontrolled polyclonal activation of B-lymphocytes.
The molecular prerequisite for Duncan’s type 1 disease is a deficiency of SAP protein encoded by the SH2D1A gene. In healthy people, it interacts with immune cell receptors, triggering the processes of T- and NK-cell cytotoxicity. In type 2 syndrome, the pathogenesis is different, since the formation of the cytoplasmic protein XIAP, a regulator of apoptosis and a participant in several signaling pathways necessary for the functioning of immunity, is disrupted.
The clinical picture is represented by four typical symptom complexes that appear in isolation or in various combinations. The most common is fatal infectious mononucleosis, detected in 58-60% of patients. It is characterized by an increase in several groups of lymph nodes, an increase in temperature to 39-40 ° C, severe sore throat. Hepatosplenomegaly and intoxication syndrome are also detected.
Up to 33% of patients face lymphoproliferative processes — leukemias, lymphomas. The most common are B-cell lymphomas formed as a result of uncontrolled polyclonal reproduction of lymphocytes infected with viral particles. About 31% of patients have severe anemia or pancytopenia, which is a natural consequence of lymphoproliferation in the bone marrow. Systemic necrotizing lymphoid vasculitis with retinitis is most rarely diagnosed.
A significant difference in the clinical picture of Duncan’s disease II subtype is the development of hemorrhagic colitis, observed in at least 19% of patients. Patients are much more likely to experience splenomegaly (88%), which is fraught with rupture of the spleen, and also have transient dysgammaglobulinemia in 28% of cases, whereas those suffering from subtype I syndrome have permanent immunological disorders.
In lymphoproliferative conditions, normal hematopoiesis leaves are displaced from the bone marrow. The condition is manifested by progressive immunological disorders due to the absence of leukocytes, spontaneous massive bleeding on the background of platelet deficiency, severe forms of anemia resulting in heart failure, hypoxic coma.
With fulminant infectious mononucleosis, extensive liver necrosis often occurs, which is accompanied by acute liver failure, which accounts for 50% of all causes of death of sufferers of Duncan’s disease. A fatal outcome is also possible with the progression of malignant blood diseases, with generalized infections associated with total dysfunction of the immune system.
Diagnosis is often difficult because Duncan’s disease is characterized by polymorphism, the absence of pathognomonic symptoms. In 10% of cases, doctors assess the condition as a general variable immune deficiency, and the correct diagnosis is determined only by the results of a consultation with a geneticist. For the examination of patients with a clinic similar to X-linked lymphoproliferative syndrome, the following methods are prescribed:
- Instrumental visualization. In all suspicious cases, ultrasound of the lymph nodes, mediastinum is performed, with hepatosplenomegaly — ultrasound of the abdominal cavity. Skull radiography, chest CT, bone scintigraphy are also performed.
- Blood test. It is possible to suspect a fatal infection caused by the Epstein-Barr virus by increasing the percentage of atypical mononuclears in the blood test. To confirm viral infection, tests are performed for antibodies to capsid and nuclear antigens, and a PCR test is performed.
- Histological examination. In the lymphoproliferative process, various variants of diagnostic operations are shown: lymph node biopsy, bone marrow puncture, laparoscopic material sampling. Then the cellular substrate is examined by immunohistochemical, cytological methods.
- Molecular genetic testing. To verify the diagnosis, sequencing is recommended to detect mutations of SH2D1A, XIAP or MAGT1. Since they are found only in 60-70% of patients, it is advisable to supplement the diagnosis by studying the expression of the SAP protein.
Although gene therapy is currently being actively researched for patients with X-linked lymphoproliferative syndrome, generally accepted etiotropic treatment regimens have not yet been developed. The selection of therapy is carried out with the participation of a multidisciplinary team (immunologist, hematologist, geneticist), taking into account the leading manifestations. The following groups of medications are used:
- Intravenous immunoglobulins. The drugs are recommended as a replacement treatment to prevent or alleviate the clinical symptoms of EBV infection. With bacterial complications, the treatment regimen is enhanced with antibiotics.
- Monoclonal antibodies. The use of anti-CD20 antibodies (ritusuximab) is justified in the severe course of infectious mononucleosis. The drug reduces the number of affected B-lymphocytes, reduces the level of viral load.
- Immunosuppressors. In Duncan’s disease of the 2nd subtype, glucocorticosteroids, tumor necrosis factor inhibitors, cytostatics are indicated for the correction of inflammatory bowel lesions.
- Chemotherapy drugs. Personalized protocols for taking antitumor medications are prescribed for lymphomas and leukemias. The intrathecal administration of drugs to increase their effectiveness is being considered.
Hematopoietic stem cell transplantation from HLA-compatible donors has been recognized as a radical method of treating Duncan’s disease. This method allows you to restore the immune system through the introduction of properly functioning donor cells. Before the procedure, an individually selected conditioning mode is performed. After transplantation, about 50% of patients recover without long-term negative consequences.
Prognosis and prevention
If transplantation is not performed, the disease is characterized by an unfavorable, steadily progressive course, therefore 70% of patients die before the age of 10 years. In case of successful bone marrow transplant treatment, the prognosis is favorable. Specific prevention of Duncan’s disease has not been developed, since the Epstein-Barr virus is widespread everywhere, more than 90% of people are infected with it, and in 70% of cases infection occurs in children under 3 years old.