[Culler-Jones syndrome polymorphism]

Culler-Jones syndrome is a rare autosomal dominant disease caused by nucleotide sequence changes in the GLI2 gene. The prevalence of this pathology is unknown, as the number of observations is small, some carriers of variants in the GLI2 gene have no manifestations of the disease. The clinical phenotype of the disease is heterogeneous and includes hypopituitarism, malformations of internal organs, facial dysmorphisms, and polydactyly. Since the discovery of the GLI2 gene by Roessler E. et al. in 2003, the spectrum of clinical manifestations, as well as the understanding of the pathogenesis of the disease components, has expanded considerably. Incomplete penetrance has been described for the GLI2 gene, and the clinical phenotype of the disease differs even among members of the same family with the same nucleotide variant.

Study clinical and molecular genetic polymorphism in patients with Culler-Jones syndrome.

A single-center, non-interventional, single-stage, non-comparative study was conducted. Children with Culler-Jones syndrome with a confirmed genetic cause of the disease were examined. All patients underwent a comprehensive examination, including laboratory and instrumental diagnostic methods and sequencing (by NGS (next-generation sequencing).

18 children (7 girls; 11 boys) with variants in the GLI2 gene were included in the study. The age at the time of examination was 8.95 years [4,6; 12.4]. Growth hormone deficiency was noted in all children at age of 2 years [1; 6,5]. Central hypothyroidism was diagnosed in 13 children at the age of 1.5 years [1; 3.5]. Free thyroxine level at the time of diagnosis was 8.9 pmol/L [7.5; 11.3]. Secondary hypoadrenocorticism was diagnosed in 10 children at the age of 2 years [1.5; 2.8], with a cortisol level of 84 nmol/L at the time of diagnosis [47; 152]. Extrahypophyseal manifestations characteristic of the syndrome were detected in half of the patients and included maxillofacial anomalies, malformations of the cardiovascular and urinary systems and eye malformations. Polydactyly was detected in two children.

The present study demonstrates the clinical polymorphism of Culler-Jones syndrome and the lack of genotype-phenotype correlation for this disease.