Heterozygous GLI2 loss of function mutations in humans have been reported in holoprosencephaly (HPE), HPE-like phenotypes associated with pituitary anomalies and combined pituitary hormone deficiency with or without other extra-pituitary findings.
Although normally indistinguishable from wild-type littermates, we demonstrate that mice with single-allele Gli2 mutations exhibit increased penetrance and severity of HPE in response to low-dose teratogen exposure.
Sonic Hedgehog (SHH) and GLI2, an obligatory mediator of SHH signal transduction, are holoprosencephaly (HPE)-associated genes essential in pituitary formation.
However, the family presented here is unique as none of the three identified individuals with a GLI2 deletion showed any typical signs of holoprosencephaly, whereas all patients reported so far were referred for genetic testing because at least one member exhibited holoprosencephaly and related features.
Pituitary insufficiency other than isolated diabetes insipidus is a rare finding of HPE, and occurs most frequently in patients with GLI2 mutations (the phenotype of which typically does not include frank neuroanatomic anomalies such as HPE); ours is the only described patient with a ZIC2 mutation and both anterior and posterior pituitary dysfunction.
Genomic GLI2 aberrations that mainly result in truncated proteins have been reported to cause holoprosencephaly or holoprosencephaly-like features, sometimes associated with hypopituitarism.
Heterozygous nonsense GLI2 mutations have been reported in patients with isolated or combined pituitary hormone deficiency (CPHD), with or without holoprosencephaly.
Mutations in GLI2 have been found in association with holoprosencephaly (HPE) and HPE-like phenotype, with and without pituitary hormone deficiencies; as well as in patients with pituitary dysfunction with and without HPE craniofacial features.
Mutations in the human GLI2 gene were first reported in association with defective anterior pituitary formation, panhypopituitarism, and forebrain anomalies represented by typical holoprosencephaly (HPE) and holoprosencephaly-like (HPE-L) phenotypes and postaxial polydactyly.
We report here on a patient with a mild holoprosencephaly spectrum phenotype (bilateral cleft lip and palate and abnormal pituitary gland formation with panhypopituitarism) and normal psychomotor development, who was found to carry a 1.3 Mb submicroscopic heterozygous deletion in 2q14.2, encompassing the GLI2 gene.
We present the description of a family simultaneously segregating two novel variants in the HPE-associated genes, ZIC2 and GLI2, as well as the results of extensive population-based studies of the variant region in GLI2.
Genetic causes are responsible for about 20% of cases: they are chromosomal abnormalities and gene mutations: up to date, nine genes (SHH, ZIC2, SIX3, TGIF, PATCHED1, TDGF1/CRIPTO, FAST1, GLI2 and DHCR) are definitely associated with HPE, but many others candidate gene are under investigation.
We report 22 patients with normal neuropsychological development and a holoprosencephaly-like (HPE-like) phenotype screened for SHH, SIX3, TGIF, and GLI2.
Here, we show that loss-of-function mutations in the human GLI2 gene are associated with a distinctive phenotype (within the HPE spectrum) whose primary features include defective anterior pituitary formation and pan-hypopituitarism, with or without overt forebrain cleavage abnormalities, and HPE-like midfacial hypoplasia.