GLI2 is a downstream transcription factor in Sonic Hedgehog signaling, acting early in ventral forebrain and pituitary development. Heterozygous GLI2 mutations have been reported in patients with isolated or combined pituitary hormone deficiency (CPHD).
Objective: Study of genetic etiology of the hypopituitarism and identification of the genetic alteration in GLI2 gene.
Methodology: Molecular study: Search for variants by NGS sequencing (Ion ProtonSystem, SureSelectXTCustom Agilent) in the coding region and the intronic flanking regions of a panel of genes associated with hypopituitarism and multiple hormonal deficiency. For the interpretation of variants the guidelines of the American College of Medical Genetics and Genomics were followed.
Results: We found three heterozygous GLI2 variants not previously described in 3 patients (see Table 1).
|Patient||Phenotype||GLI2 gene mutation||Variant interpretation|
|1||Male with clinical and biochemical studies concordant with combined pituitary hormone deficiency (CPHD). Microgenisotomy. Postaxial polydactyly. Epilepsy and global developmental delay. Start of hormone replacement therapy in the first year of life. RNM: Absence of pituitary stalk, ectopic neurohypophysis.||NM_005270.4.c.3670C>T (p.Gln1224*) (chr2:121747160).||Pathogenic|
|2||Girl with clinical and biochemical studies concordant with CPHD. Diagnosis and start of treatment was late. RNM: Absence of pituitary stalk, ectopic neurohypophysis.||NM_0052270.4:C.1978G>A (p.Ala660Thr) (chr2:121743875)||Probably pathogenic|
|3||Male with clinical and biochemical studies concordant with GH deficiency. Cryptorchidism and umbilical hernia. Developmental delay. Start of GH therapy in the second year of life. RNM: Small pituitary gland, ectopic neurohypophysis.||NM_005270.4:c.2059G>A (p.Gly687Arg) (chr2:121743956)||Probably pathogenic|
Conclusion: We had find three different variants in GLI2, described for the first time, in three patients with different phenotypes of hypopituitarism.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology