DiGeorge syndrome: symptoms, diagnosis, treatment

Classic DiGeorge syndrome has been described in patients with a characteristic phenotype including cardiac and facial malformations, endocrinopathy, and thymic hypoplasia. The syndrome may also be associated with other developmental anomalies.

Pathogenesis of DiGeorge syndrome

Most patients with the DiGeorge syndrome phenotype had a characteristic hemizygous chromosomal aberration in the form of a 22qll.2 deletion. This chromosomal abnormality is one of the most common in the population (1:4000). Further studies showed that deletions in the 22qll.2 region lead to various clinical variants of the syndrome. Immunological defects vary from complete thymic aplasia with SCID clinical features (0.1% of all cases of aberration) to virtually normal immune function.

In addition to the most common aberration 22qll.2, the phenotype of DiGeorge syndrome is detected in patients with deletion 10p13-14 (2% of all cases), as well as in newborns with alcoholic fetopathy, maternal diabetes, isotretinoid fetopathy. In this regard, the disease in the main group of patients was decided to be called DiGeorge syndrome with deletion 22qll.2.

In addition, the phenotypic manifestation of the 22qll.2 deletion in many patients is called velocardiofacial syndrome or covotruncal facial anomaly. These syndromes do not include immunological defects.

To date, the gene responsible for the major defects of DiGeorge syndrome has not been identified, but several candidates located on chromosome 22 are being studied. Many of the structures damaged in 22qll deletion syndrome are derivatives of the brachiocephalic apparatus, originating from ganglion cell membranes. It is assumed that the failure of the gene(s) encoding transcription factors expressed on mesoderm and endoderm cells may underlie the development of DiGeorge syndrome. In their absence, the cells of the embryonic leaflets do not migrate correctly during the formation of the neural tube, thymus, heart, and large vessels.

Symptoms of DiGeorge Syndrome

The so-called "complete" DiGeorge syndrome with pronounced immunological abnormalities is extremely rare. In this regard, most patients with the syndrome first come to the attention of specialists in other specialties, primarily cardiologists.

The main clinical manifestations of DiGeorge syndrome are:

• Defects of the heart and large vessels (patent ductus arteriosus, aortic arch anomalies, tetralogy of Fallot and its varieties, transposition of the great arterial vessels, right-sided aortic arch, coarctation of the aorta, aberrant subclavian arteries). Defects of large vessels are often combined with heart defects (aplasia or atresia of the tricuspid valve, defects of the interventricular and interatrial septum).
• Hypocalcemic seizures as a consequence of parathyroid hypoplasia and parathyroid hormone deficiency.
• Growth hormone deficiency.
• Facial skeletal anomalies: Gothic palate, facial clefts, wide nasal bridge, hypertelorism, fish mouth, low-set ears with underdeveloped curl and pointed tip.
• Ophthalmological pathology: retinal vascular pathology, anterior chamber dysgenesis, coloboma.
• Anomalies in the structure of the larynx, pharynx, trachea, inner ear and esophagus (laryngomalacia, tracheomalacia, gastroesophageal reflux, deafness, swallowing disorders).
• Dental anomalies: late eruption, enamel hypoplasia.
• Central nervous system abnormalities: myelomeningocele, cortical atrophy, cerebellar hypoplasia.
• Kidney malformations: hydronephrosis, atrophy, reflux.
• Skeletal anomalies: polydactyly, absence of nails.
• Malformations of the gastrointestinal tract: anal atresia, anal fistulas.
• Delayed speech development.
• Delayed motor development.
• Psychiatric pathology: hyperactivity syndrome, schizophrenia.
• Immunological disorders.

As mentioned above, the degree of immunological disorders varies widely. Some patients are characterized by a clinical picture of combined immunodeficiency, with severe viral infections (disseminated CMV, adenovirus, rotavirus infections), pneumonia. Most patients are not characterized by life-threatening opportunistic infections, but they experience recurrent otitis and sinusitis, partly due to anomalies in the structure of the facial skeleton.

In the presence of severe T-cell deficiency, patients with DiGeorge syndrome often experience autoimmune diseases (cytopenia, autoimmune thyroiditis) and an increased risk of developing cancer.

Characteristic immunological manifestations of the complete form of the syndrome are a significant decrease in the number of circulating CD3+, CD4+, CD8+ cells and a sharp decrease in their proliferative activity induced by mitogens and antigens. The number of B and NK cells is normal. As a rule, the response to polysaccharide antigens is impaired. Serum immunoglobulin concentrations are within normal limits in most cases, however, in some patients various disorders are detected from selective IgA deficiency to agammaglobulinemia.

Treatment of DiGeorge syndrome

In its clinical manifestations and life expectancy of patients, the complete form of DiGeorge syndrome is comparable to SCID. There are isolated descriptions of bone marrow transplants in patients with complete DiGeorge syndrome in the literature, however, given the mechanism of development of the syndrome, in which the maturation of T cells is impaired due to the absence of thymus epithelium, transplantation for such patients is not always effective. Transplantation of thymus epithelial tissue is justified for patients with the complete form of the syndrome. After transplantation of thymus epithelial tissue, restoration of the number and functional activity of T cells was noted.

Patients with partial immune disorders often require prophylactic antimicrobial and antiviral therapy.

In case of decreased serum immunoglobulin concentrations, replacement therapy with intravenous immunoglobulin is performed. Surgical treatment is performed to correct developmental defects.

Forecast

The prognosis and quality of life of patients with DiGeorge syndrome often depend on the severity and degree of correction of cardiological and endocrinological, rather than immunological defects.