CHARGE syndrome (OMIM#214800) is a rare hereditary monogenic disease with an autosomal-dominant pattern of inheritance. It is characterized by multiple congenital malformations and is caused by pathogenic variants in the CHD7 gene. Immunological disorders are typically associated with thymic hypoplasia or aplasia and vary in their clinical manifestations. The diagnosis of immunological disorders in patients with CHARGE syndrome requires a comprehensive assessment that includes the analysis of immunoglobulin levels, the evaluation of T and B lymphocyte function, and the assessment of the response to vaccination. Early detection and appropriate treatment of immunodeficiencies in children with CHARGE syndrome are crucial for preventing severe infections and improving the prognosis.
The patients’ phenotype was assessed based on the results of a clinical examination and instrumental and laboratory tests. The children’s physical development was evaluated using the World Health Organization program Anthro. A cytogenetic study was conducted on lymphocytes using standard protocols (G-banding). A molecular genetic study was performed on the probands using full exome sequencing, and the segregation of the identified variants in the families was determined using Sanger sequencing. The functioning of the T and B cell immune system was assessed by determining the quantitative analysis of T cell receptor excision circles (TREC)/kappa-deleting recombination excision circles (KREC) using real-time quantitative (RQ) PCR.
4 patients from 4 families were diagnosed with CHARGE syndrome based on clinical data and genetically verified variants in the CHD7 gene. The family histories of these families were not affected. All patients had a normal karyotype. An immunological study showed that the absolute number of lymphocytes was low (1,050[1,010;1,400] cells/ml). Examination of blood samples from neonatal screening forms revealed a decrease in the TREC (0.0[0; 300] copies x10 6 leukocytes) at normal KREC 3,420[3,050–4,980] copies x10 6 leukocytes).
The results we obtained demonstrate the clinical significance of the TREC/KREC study within the framework of neonatal screening, not only in relation to the diagnosis of primary immunodeficiencies but also for syndromic diseases accompanied by immune system insufficiency. These data can serve as a basis for in-depth immunological examination of patients, timely initiation of preventive measures to prevent infectious diseases, and timely prescription of replacement therapy.
