Cockayne syndrome: peculiarities of clinical manifestations and algorithm of observation in childhood

BACKGROUND: Cockayne syndrome is an ultra-rare (1:2.5 million) hereditary disease from the group of progeroid syndromes caused by pathogenic and probable-pathogenic variants in DNA repair genes (ERCC8, ERCC6, XPB (ERCC3), XPD (ERCC2) and XPG (ERCC5)) and characterized by abnormal photosensitivity, congenital cataract, microcephaly, sensorineural hearing loss, nervous system pathology and other multisystem changes. In this manuscript, for the first time in the Russian Federation, we present the results of a clinical and genetic study and follow-up of a Russian cohort of patients.

MATERIALS AND METHODS: During 2 years, from 2023 to 2025, 7 patients with Cockayne syndrome (4 girls and 3 boys) aged from 3 years 11 months to 16 years 3 months were under clinical observation, of whom 3 patients were diagnosed with Cockayne syndrome type A (causative variants in ERCC8 gene) and 4 patients with type B (causative variants in ERCC6 gene). All patients underwent a comprehensive multidisciplinary examination with evaluation of the results of laboratory and instrumental methods of investigation.

RESULTS: Based on observational data, we confirmed the incomplete correlation between genotype and phenotype previously described in the literature. With the genotype of Cockayne syndrome type B, previously correlated with severe course of the disease, only one patient had a severe course of the syndrome, two patients had a moderate course, and one patient had a mild course, indicating the variability of the clinical picture within a single gene lesion, and the severity of the course correlated rather with the age of the disease debut: early onset (before 1 year of age) was associated with faster disease progression. Also, regardless of the genotype and severity of the disease course, major diagnostic criteria were identified in all patients: congenital cataract was diagnosed in 5 of 7 observed patients, sensorineural hearing loss in two patients of moderate and mild course of the disease, progressive pathology of the nervous system in 6 of 7 patients, and microcephaly was diagnosed in all patients.

CONCLUSION: This study expands our understanding of the natural course of Cockayne syndrome and our knowledge of the variability of clinical manifestations and severity of the disease course within a single gene lesion. Timely diagnosis and personalized approach of a multidisciplinary team of specialists can slow the progression of complications and improve the quality of life of patients. The work is of value for physicians of various specialties involved in the diagnosis and treatment of orphan genetic diseases, as well as researchers studying the mechanisms of DNA repair and premature aging.

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