Novel Heterozygous Nonsense GLI2 Mutations in Patients with Hypopituitarism and Ectopic Posterior Pituitary Lobe without Holoprosencephaly

França, Marcela M.; Jorge, Alexander A L; Carvalho, Luciani R.; Costalonga, Everlayny Fiorot; Vasques, Gabriela A; Leite, Cláudia C.; Mendonca, Berenice B.; Arnhold, Ivo J.P.

doi:10.1210/jc.2010-1050

Cited by 99 publications

(124 citation statements)

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“…The two patients reported by Paulo et al (2015). had a median solitary maxillary incisor, one with cleft palate, but this was not observed in the patients studied by França et al (2010). Therefore, the phenotypic variability in this family with the same mutation ranged from polydactyly only to IGHD or CPHD, with the presence or absence of cleft palate and of a median solitary maxillary incisor.…”

Section: Human Mutationsmentioning

confidence: 75%

“…The largest family with GLI2 mutations reported to date had the p.Leu788fsX794 mutation (França et al 2010, Paulo et al 2015. In the family reported by França et al (2010), the ten subjects who tested positive for the mutation also had polydactyly, whereas in the two distant relatives with the same mutation studied by Paulo et al (2015) in a different city, polydactyly was not observed. Among the six patients with hypopituitarism, four had IGHD and two had CPHD, independent of age.…”

Section: Human Mutationsmentioning

confidence: 97%

“…The authors observed an autosomal dominant inheritance with incomplete penetrance and inferred that pituitary and facial structures were more sensitive to a reduction in GLI2 activity than the ventral forebrain was. Subsequently, Rahimov et al (2006) screened GLI2 in patients with isolated midfacial defects, and França et al (2010) screened patients with isolated pituitary hormone deficiency without HPE. In this review, we concentrate on the GLI2 mutations in patients that have a pituitary phenotype with or without additional abnormalities.…”

Section: Human Mutationsmentioning

confidence: 99%

“…Similar findings have been observed by Bear et al (2014): 16/26 (62%) of severe mutations had polydactyly in addition to pituitary abnormalities, whereas only 1/58 (2%) with milder variants had both hand and pituitary defects. The presence of polydactyly in a patient with hypopituitarism or in one of his relatives may be an additional indication that the GLI2 gene should be studied (França et al 2010). Interestingly, mice with targeted disruption of Gli2 have not been shown to have digit abnormalities unless Gli1 is also deleted, which emphasizes the difference between Gli protein functions in vertebral species (Roessler et al 2005).…”

Section: Human Mutationsmentioning

confidence: 99%

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Role of GLI2 in hypopituitarism phenotype

Arnhold¹,

França²,

Carvalho³

et al. 2015

Journal of Molecular Endocrinology

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GLI2 is a zinc-finger transcription factor involved in the Sonic Hedgehog pathway. Gli2 mutant mice have hypoplastic anterior and absent posterior pituitary glands. We reviewed the literature for patients with hypopituitarism and alterations in GLI2. Twenty-five patients (16 families) had heterozygous truncating mutations, and the phenotype frequently included GH deficiency, a small anterior pituitary lobe and an ectopic/undescended posterior pituitary lobe on magnetic resonance imaging and postaxial polydactyly. The inheritance pattern was autosomal dominant with incomplete penetrance and variable expressivity. The mutation was frequently inherited from an asymptomatic parent. Eleven patients had heterozygous non-synonymous GLI2 variants that were classified as variants of unknown significance, because they were either absent from or had a frequency lower than 0.001 in the databases. In these patients, the posterior pituitary was also ectopic, but none had polydactyly. A third group of variants found in patients with hypopituitarism were considered benign because their frequency was R0.001 in the databases. GLI2 is a large and polymorphic gene, and sequencing may identify variants whose interpretation may be difficult. Incomplete penetrance implies in the participation of other genetic and/or environmental factors. An interaction between Gli2 mutations and prenatal ethanol exposure has been demonstrated in mice dysmorphology. In conclusion, a relatively high frequency of GLI2 mutations and variants were identified in patients with congenital GH deficiency without other brain defects, and most of these patients presented with combined pituitary hormone deficiency and an ectopic posterior pituitary lobe. Future studies may clarify the relative role and frequency of GLI2 alterations in the aetiology of hypopituitarism.

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Section: Human Mutationsmentioning

confidence: 75%