Background: Congenital growth hormone deficiency may be isolated (IGHD) or multiple pituitary hormone deficiency (MPHD). The Sonic Hedgehog signalling (SHH) pathway has an important role in the pituitary development and growth, acting early in ventral forebrain. The SHH signalling mediates its effects through three zinc fingers proteins (Gli1, Gli2 and Gli3), which lead to activation or repression of target genes. Several heterozygous GLI2 mutations have been reported in patients with IGHD or MPHD with or without other malformations, most often, ectopic posterior pituitary and postaxial polydactyly.
Aim: To analyse the presence of GLI2 gene alterations in an IGHD 46,XX patient with cleft lip/palate and ectopic posterior pituitary lobe (P1) and in a MPHD 46,XY patient with absent posterior pituitary lobe (P2).
Methods: Automated sequencing of GLI2 gene from gDNA of affected subjects and relatives. In silico tools were applied to identify the functional impact of newly found variants (Polyphen2, SIFT, Mutation Taster).
Results: P1 was found to be heterozygous for the novel p.Arg231Gln variation, while P2 was found to be heterozygous for the novel p.Arg226Leu variation, as well as homozygous for the already described p.Met1444Ile and p.Leu1445Phe variations. Both novel variations affect highly conserved amino acids of the Gli2 protein and were not found in the databases of NCBI and Ensembl Genome Browser. In silico tools suggest that these variations would be disease causing.
Conclusion: We report two novel heterozygous missense mutations in the GLI2 gene that affect the repressor domain of the protein and two homozygous missense mutations in the activator domain of the protein. Our study suggests that GLI2 gene would be one of the candidate genes to analyse when developmental defects in posterior pituitary gland are present. The highly variable phenotype found suggests the presence of additional unknown factors that could contribute to the phenotypic variation observed in these patients.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology