DiGeorge syndrome is a genetic disease belonging to the group of primary immunodeficiency and, along with a weakening of immunity, characterized by numerous malformations. Symptoms of this condition are frequent bacterial infections with a tendency to severe course, congenital heart defects, facial malformations and other disorders. Diagnosis is based on the study of the heart, thyroid and parathyroid glands, the study of the immunological status and the data of molecular genetic analyses. Treatment is only symptomatic, includes surgical correction of heart defects and facial abnormalities, replacement immunological therapy, and the fight against bacterial and fungal infections.
General information
DiGeorge syndrome (hypoplasia of the thymus and parathyroid glands, velocardiofacial syndrome) is a genetic disease caused by a violation of the embryonic development of the third and fourth pharyngeal sacs. This condition was first described in 1965 by the American pediatrician Angelo DiGeorge, who classified it as congenital aplasia of the thymus and parathyroid glands. Further research in the field of genetics helped to determine that the disorders in this disease go far beyond the primary immunodeficiency. This gave rise to another name for the Di-Giorgi syndrome. Taking into account the most frequently affected organs (palate, heart, face), some experts call this pathology a bicycle cardiofacial syndrome. A number of modern researchers distinguish between these two conditions and believe that the “true” cyclocardiofacial syndrome is not accompanied by pronounced immunological disorders. The incidence of DiGeorge syndrome is 1:3,000–20,000 – such a significant discrepancy in data is due to the fact that a reliable and clear boundary between this disease and bicycle cardiofacial syndrome has not yet been established. Therefore, the same patient, according to different experts, may have either primary immunodeficiency, accompanied by concomitant disorders, or more numerous malformations against the background of decreased immunity.
Causes
The genetic nature of DiGeorge syndrome consists in damage to the central part of the long arm of the 22nd chromosome, where genes encoding a number of important transcription factors are presumably located. It was possible to identify one of these genes – TBX1, the product of its expression is a protein called T-box. It belongs to the family of proteins that control the processes of embryogenesis. Proof of the relationship between DiGeorge syndrome and TBX1 is the fact that a small percentage of patients have no pronounced damage to the 22nd chromosome, only mutations in this gene are present. There are also suggestions about the role of deletions of other chromosomes in the development of this disease. Thus, manifestations similar to DiGeorge syndrome were detected in the presence of damage to the 10th, 17th and 18th chromosomes.
In most cases of DiGeorge syndrome, the deletion of the 22nd chromosome captures about 2-3 million base pairs. Most often, this genetic defect occurs spontaneously during the formation of male or female germ cells – that is, it is germinative in nature. Only a tenth of all cases of the disease represent a familial form with an autosomal dominant nature of inheritance. The pathogenesis of DiGeorge syndrome is reduced to a violation of the formation of special embryonic formations – pharyngeal sacs (mainly the 3rd and 4th), which are the precursors of a number of tissues and organs. They are mainly responsible for the formation of the palate, parathyroid glands, thymus, mediastinal vessels and heart, therefore, with DiGeorge syndrome, malformations of these organs occur.
Symptoms
Many manifestations of DiGeorge syndrome are detected immediately after the birth of a child, individual malformations (for example, heart) can be detected even earlier – on preventive ultrasound examinations. Most often, the first anomalies of facial development are detected – cleavage of the palate, sometimes in combination with a “harelip”, prognathia of the lower jaw. Often infants with DiGeorge syndrome have a small mouth, a small nose with an enlarged bridge of the nose, deformed or underdeveloped cartilage of the auricles. With a relatively mild course of the disease, all of the above symptoms can be expressed rather weakly, even splitting of the hard palate can occur only in its posterior part and be detected only with a thorough examination by an otolaryngologist.
In the first months of a patient’s life with DiGeorge syndrome, manifestations of congenital heart defects come to the fore – it can be both a tetrad of Fallot and individual disorders: a defect of the interventricular septum, non-infection of the arterial duct and a number of others. They are accompanied by cyanosis, cardiovascular insufficiency and in the absence of qualified medical care (including surgical) can lead to early death of patients. Another common disorder in children with DiGeorge syndrome are seizures and tetany caused by hypoplasia of the parathyroid glands and subsequent hypocalcemia.
The next most important manifestation of DiGeorge syndrome, which distinguishes it from other types of cyclocardiofacial syndrome, is a pronounced primary immunodeficiency. It develops due to aplasia or underdevelopment of the thymus and therefore affects cellular immunity to a greater extent. However, due to the close relationship between the humoral and cellular parts of the immune system, this leads to a general weakening of the body’s defenses. Patients with DiGeorge syndrome are extremely sensitive to viral, fungal and bacterial infections, which often take a prolonged and severe course. Some researchers note the presence of mental retardation of varying degrees, sometimes seizures of neurological origin can be observed.
Diagnosis
To determine the DiGeorge syndrome, the method of physical general examination, cardiological studies (EchoCG, electrocardiogram), ultrasound of the thyroid gland and thymus, immunological tests are used. An auxiliary role is played by conducting general and biochemical blood tests, studying the patient’s anamnesis, genetic studies. When examining patients with DiGeorge syndrome, disorders characteristic of the disease can be determined – cleavage of the hard palate, facial abnormalities, pathology of ENT organs. In the anamnesis, as a rule, frequent episodes of viral and fungal infections are detected, taking a severe course, convulsions caused by hypocalcemia, extensive carious tooth damage is often detected.
Ultrasound examinations of the thymus gland show a significant decrease in mass or even a complete absence of the organ (agenesis). Echocardiography and other cardiological diagnostic methods reveal numerous heart defects (for example, ventricular septal defect) and mediastinal vessels. Immunological studies confirm a significant drop in the level of T-lymphocytes. The same phenomenon is observed in peripheral blood and is often combined with a decrease in the concentration of proteins-immunoglobulins. A biochemical study of the blood indicates a decrease in the level of calcium and parathyroid hormones. A geneticist can search for deletions in the 22nd chromosome by fluorescent DNA hybridization or multiplex polymerase chain reaction.
Treatment
There is no specific treatment for DiGeorge syndrome at the moment, only palliative and symptomatic techniques are used. It is very important to identify congenital heart defects as early as possible and, if necessary, perform their surgical correction, since it is cardiovascular disorders that are the most common cause of neonatal death in this disease. Convulsive seizures caused by hypocalcemia are a significant danger, which requires timely correction of the electrolyte balance of blood plasma. The help of surgeons with DiGeorge syndrome may also be required to eliminate malformations of the face and palate.
Due to severe immunodeficiency, any signs of bacterial, viral or fungal infection are a reason for the urgent use of appropriate drugs (antibiotics, antiviral and fungicidal agents). To improve the immune status of a patient with DiGeorge syndrome, a replacement infusion of immunoglobulins obtained from donor plasma can be performed. In some cases, the thymus gland was transplanted, which stimulated the formation of its own T-lymphocytes – this contributed to improving the quality of life of patients.
Prognosis and prevention
The prognosis of DiGeorge syndrome is assessed by most researchers as uncertain, since this disease is characterized by significant variability of symptoms. In severe cases, there is a high risk of early neonatal death due to a combination of cardiovascular and immunological disorders. More benign forms of DiGeorge syndrome require fairly intensive palliative therapy, it is especially important to pay attention to the treatment and prevention of viral and fungal infections. The intellectual development of patients is somewhat slowed down, however, with proper pedagogical and psychological correction, the manifestations of developmental delay can be leveled. Due to the frequent spontaneous nature of mutations, prevention of DiGeorge syndrome has not been developed.