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

K. Aouchiche; C. Charmensat; P. Morgane; C. Teinturier; P. Bretones; de la Perriere A. Brac; V. Layet; N. Bouhours-Nouet; M.C. Vantyghem; E. Haine; M.L. Nunes-Sanchez; O. Camard; S. Baron; F. Castinetti; A. Barlier; T. Brue; R. Reynaud; A. Saveanu

doi:10.1530/ey.22.1.10

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ESPE Yearbook of Paediatric Endocrinology (2025) 22 1.10 | DOI: 10.1530/ey.22.1.10

ESPEYB25 1. Pituitary and Neuroendocrinology New Treatments and Hopes (5 abstracts)

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

K. Aouchiche , C. Charmensat , P. Morgane , C. Teinturier , P. Bretones , A. Brac de la Perriere , V. Layet , N. Bouhours-Nouet , M.C. Vantyghem , E. Haine , M.L. Nunes-Sanchez , O. Camard , S. Baron , F. Castinetti , A. Barlier , T. Brue , R. Reynaud & A. Saveanu

N. Eur J Endocrinol 192(2) (2025) 110-118.PMID: 39938560

Brief Summary: GLI2 has been identified as the most prevalent genetic cause of syndromic hypopituitarism. This multicenter retrospective study used data from the GENHYPOPIT network on 23 patients with congenital hypopituitarism carrying pathogenic or likely pathogenic GLI2 variants in order to identify genotype–phenotype correlations.

Congenital hypopituitarism (CH) is a heterogeneous and incompletely understood condition, classically divided into two subtypes: non-syndromic CH, characterized by isolated anterior pituitary hormone deficiencies, and syndromic CH, which is characterised by the association of hormonal deficits with structural brain or extracerebral anomalies. GLI2 is a key transcription factor in the Hedgehog pathway, and its role in pituitary development has been recognized with several reports have already associated CH with GLI2 variants [1, 2, 3].

This study identified 17 pathogenic or likely pathogenic GLI2 variants, affecting 23 patients (17 index cases and 6 affected relatives). Of those, 91% had hypopituitarism; 65% with combined pituitary hormone deficiency and 22% with isolated growth hormone deficiency. The authors highlight the incomplete penetrance (67%) and variable expressivity of GLI2 variants. Notably, some patients developed late-onset ACTH deficiency, underscoring the need for lifelong endocrine monitoring. MRI abnormalities, particularly PSIS, were observed in 84% of cases. A range of associated features were identified, including neurocognitive impairment (38%), postaxial polydactyly (27%), Kallmann syndrome, cardiac defects, and renal/urogenital anomalies.

This study supports the need for a systematic malformation workup, including renal and cardiac imaging in affected individuals and also potentially evolving corticotrope deficiency. The study also broadens the phenotypic spectrum of GLI2 to encompass Kallmann syndrome.

References: 1. Arnhold, I.J., et al., Role of GLI2 in hypopituitarism phenotype. Journal of molecular endocrinology, 2015. 54(3): p. R141–R150.2. França, M.M., et al., Novel heterozygous nonsense GLI2 mutations in patients with hypopituitarism and ectopic posterior pituitary lobe without holoprosencephaly. The Journal of Clinical Endocrinology & Metabolism, 2010. 95(11): p. E384–E391.3. Roessler, E., et al., Loss-of-function mutations in the human GLI2 gene are associated with pituitary anomalies and holoprosencephaly-like features. Proceedings of the National Academy of Sciences, 2003. 100(23): p. 13424–13429.