The role of the sonic hedgehog signalling pathway in patients with midline defects and congenital hypopituitarism

Summary Introduction The Gli family of zinc finger (GLI) transcription factors mediates the sonic hedgehog signalling pathway (HH) essential for CNS, early pituitary and ventral forebrain develop- ment in mice. Human mutations in this pathway have been described in patients with holoprosencephaly (HPE), isolated congenital hypopituitarism (CH) and cranial/midline facial abnormalities. Mutations in Sonic hedgehog (SHH) have been associated with HPE but not CH, despite murine studies indicat- ing involvement in pituitary development. Objectives/Methods We aimed to establish the role of the HH pathway in the aetiology of hypothalamo-pituitary disorders by screening our cohort of patients with midline defects and/or CH for mutations in SHH, GLI2, Shh brain enhancer 2 (SBE2) and growth-arrest specific 1 (GAS1). Results Two variants and a deletion of GLI2 were identified in three patients. A novel variant at a highly conserved residue in the zinc finger DNA-binding domain, c.1552G > A (pE518K), was identified in a patient with growth hormone deficiency and low normal free T4. A nonsynonymous variant, c.2159G > A (p.R720H), was identified in a patient with a short neck, cleft palate and hypogonadotrophic hypogonadism. A 26� 6 Mb dele- tion, 2q12� 3-q21� 3, encompassing GLI2 and 77 other genes, was identified in a patient with short stature and impaired growth. Human embryonic expression studies and molecular characteri- sation of the GLI2 mutant p.E518K support the potential pathogenicity of GLI2 mutations. No mutations were identified in GAS1 or SBE2. A novel SHH variant, c.1295T>A (p.I432N), was identified in two siblings with variable midline defects but normal pituitary function. Conclusions Our data suggest that mutations in SHH, GAS1 and SBE2 are not associated with hypopituitarism, although GLI2 is an important candidate for CH.