ESPE Abstracts

Background: The transcription factor (TF) SOX2 is expressed early in the embryological development and is essential for the development of many structures like neural system, pituitary gland, eyes, ears, esophagus, and gonads. The most common clinical manifestations of mutations in the SOX2 gene are eye abnormalities (anophthalmia/microphthalmia, coloboma, nystagm, and refractive errors) and hypopituitarism (deficiency of gonadotropic, GH, TSH, and ACTH). Molecular genetic studies in children with combined pituitary hormone deficiency (CPHD) started in Bulgaria in 2001 by screening of PROP1 using the candidate gene approach. An allele frequency of PROP1 mutations was found for 12.2% of the preselected patients, mostly 150delA, followed by 301–302delAG. The mutational screening panel was extended by POU1F1, HESX1, SOX3 between 2011 and 2013.

Objective and hypotheses: To extend further the TF mutational screen by implementation of screening for SOX2 as a diagnostic tool in congenital CPHD.

Method: Study population: 22 patients, aged (x±S.D.) 8.5±4.0, median 8.3 years, 13 females (8.1±4.2, median 7.6 years), nine males (8.5±4.0, median 8.3 years). Inclusion criteria: obligate congenital GH deficiency; additional criteria: CPHD, ophthalmologic abnormalities; pathologic findings on hypothalamo-pitutary region MRI; phenotype characterization based on: auxology, bone age, hormonal tests (GH, TSH, fT₄, Prl, LH, FSH, T, E₂ by Delfia, IGF1 and BP3, cortisol by ELISA); molecular genetic analysis by direct sequencing of the single exon of the SOX2 gene.

Results: No mutations of SOX2 in the selected patients could be verified.

Conclusion: Mutations in SOX2 are a rare cause of hypopituitarism in Bulgarian patients. Therefore, PROP1 mutational screening should be the first to be performed in children with congenital CPHD. Changes in the mutational screening strategy (next generation sequencing instead of single gene candidate approach) could help in revealing the complex etiology of congenital hypopituitarism.