Phenotype and genotype of 23 patients with hypopituitarism and pathogenic GLI2 variants

To analyze the phenotype and genotype of patients with congenital hypopituitarism and pathogenic GLI2 variants. A large cohort of patients with hypopituitarism was screened for GLI2 variants using a next-generation sequencing panel. Genotype-phenotype correlations were then assessed using GENHYPOPIT phenotypic data. Of the 39 GLI2 variants identified in 717 index cases, 17 were classified as pathogenic or likely pathogenic. All these GLI2 variants were identified in 23 patients (17 index cases and 6 relatives) with associated pituitary stalk interruption syndrome or extrapituitary manifestations. GLI2 variants were the most frequent identified genetic cause in patients with syndromic hypopituitarism (68%): 88% (15/17) of mutations were truncating variants, and 45% were de novo. Most patients with a GLI2 variant (21/23, 91%) had hypopituitarism, including 21.7% (5/23) presenting isolated growth hormone deficiency. Two patients had Kallman syndrome. Pituitary morphological abnormalities were present in 84% of the patients with pathogenic GLI2 variants (index cases and affected relatives). The remaining signs included neurocognitive disorders (38%), hexadactyly (27%), cardiac septal defects and renal/vesical abnormalities. A possible digenic origin (GLI2/HESX1) is proposed in one family. In this large multicentric international cohort, GLI2 was the most frequently identified genetic cause of syndromic congenital hypopituitarism with constant association pituitary stalk interruption syndrome or extrapituitary clinical features. In addition to polydactyly and neurocognitive disorders, cardiac and renal abnormalities were also frequently observed and should be investigated further. The variable expression of GLI2-associated phenotypes justifies further research in this area.