Endocrine Abstracts

Introduction: The Gli-family of zinc-finger transcription factors regulates the Sonic Hedgehog (Shh) signalling pathway, critical for normal CNS development. Gli2 is essential for early pituitary and ventral forebrain development in mice, with mutations described in humans with holoprosencephaly (HPE), isolated hypopituitarism (HP) and cranial/midline facial defects. SHH mutations have been associated with phenotypes including HPE but not HP, despite murine studies implicating SHH in early hypothalamo-pituitary development.

Objective: We aimed to establish whether disorders of hypothalamo-pituitary development were associated with mutations in SHH, GLI2, the highly conserved Shh Brain Enhancer 2 (SBE2) and growth-arrest specific 1 (GAS1), a membrane bound glycoprotein antagonistic of Shh signalling.

Methods: Using direct sequencing analysis we screened 96 HP patients for GLI2 mutations, 158 HP and HPE-related patients for SHH and GAS1 and 346 septo-optic dysplasia (SOD) patients for SBE2.

Results: A novel heterozygous mutation was identified at a highly conserved zinc finger DNA-binding domain residue (c.1552G>A,pE518K) in GLI2 in a female patient with evolving CPHD (GH and TSH), a small anterior pituitary and absent posterior pituitary. A paternally inherited sequence variant (c.2159G>A, p.R720H) was identified in a conserved region of the GLI2 activation domain in a patient with a short neck, cleft palate, partial deafness and hypogonadotrophic hypogonadism. A novel mutation (c.1295T>A, p.I431T) was discovered in the C-terminus autocatalytic cleavage domain of SHH in two siblings with variable HPE phenotypes, such as a single central incisor. These variants were not identified in 100 controls. No mutations were identified in SBE2 or GAS1.

Conclusion: Our data suggest that mutations in SHH, GAS1 and SBE2 are not associated with hypopituitarism, although GLI2 is an important candidate for complex hypopituitarism disorders.