Pallister-Hall syndrome: Unreported skeletal features of a<i>GLI3</i>mutation

Roscioli, Tony; Kennedy, Debra; Cui, Jian; Fonseca, Bob; Gf, Watson; Pereira, John; Yg, Xie; Mowat, David

doi:10.1002/ajmg.a.30818

Cited by 20 publications

(20 citation statements)

References 37 publications

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“…Although associated to a good neurodevelopmental outcome, PHS displays a wide range of severity varying from mild to lethal phenotypes depending on the severity of malformations present in the individuals, in particular bilateral kidney agenesis, craniofacial features (agnathia, absence of oral orifice, cleft palate or premaxillary agenesis in one case), heart defects and/or reductional limb defects. Interestingly, skeletal dysplasia with ulna bowing, tibia and fibula hypoplasia was already reported in other cases described as PHS, 10,29,30 further suggesting that acromesomelic limb shortening with radio-ulnar bowing, tibial and fibular hypolasia/agenesis are part of the phenotypic spectrum of PHS. Interestingly, all mutations found in severe fetal phenotypes of our series were clustered in the middle third of the gene, between c.2941 and c.3324.…”

Section: Discussionmentioning

confidence: 64%

New insights into genotype–phenotype correlation for GLI3 mutations

et al. 2014

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The phenotypic spectrum of GLI3 mutations includes autosomal dominant Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS). PHS was first described as a lethal condition associating hypothalamic hamartoma, postaxial or central polydactyly, anal atresia and bifid epiglottis. Typical GCPS combines polysyndactyly of hands and feet and craniofacial features. Genotype-phenotype correlations have been found both for the location and the nature of GLI3 mutations, highlighting the bifunctional nature of GLI3 during development. Here we report on the molecular and clinical study of 76 cases from 55 families with either a GLI3 mutation (49 GCPS and 21 PHS), or a large deletion encompassing the GLI3 gene (6 GCPS cases). Most of mutations are novel and consistent with the previously reported genotype-phenotype correlation. Our results also show a correlation between the location of the mutation and abnormal corpus callosum observed in some patients with GCPS. Fetal PHS observations emphasize on the possible lethality of GLI3 mutations and extend the phenotypic spectrum of malformations such as agnathia and reductional limbs defects. GLI3 expression studied by in situ hybridization during human development confirms its early expression in target tissues.

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Section: Discussionmentioning

confidence: 64%

New insights into genotype–phenotype correlation for GLI3 mutations

et al. 2014

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“…Reducing the dosage of Gli3 by 50% in a Gli2 -/-background creates a phenotype of EA/TEF, whereas combined knockouts for Gli2 and Gli3 do not form an esophagus, trachea, or lungs at all (Motoyama et al, 1998). As mentioned previously, mutations in GLI3 were found to be the cause of Pallister-Hall syndrome in humans (Verloes et al, 1995;Brunner and Bokhoven, 2005;Johnston et al, 2005;Roscioli et al, 2005).…”

Section: Knockout and Other Mutation Models Of Ea/tefmentioning

confidence: 64%

“…Mutations in the GLI3 gene can cause Pallister-Hall syndrome, in which EA/ TEF is occasionally described (Verloes et al, 1995;Brunner and Bokhoven, 2005;Johnston et al, 2005;Roscioli et al, 2005). Combined Gli2/Gli3 knockout mice display severe foregut anomalies, as described in more detail in (Motoyama et al, 1998).…”

Section: Human Syndromes and Associations Thatmentioning

confidence: 95%

Genetic and environmental factors in the etiology of esophageal atresia and/or tracheoesophageal fistula: An overview of the current concepts

Felix¹,

Jong²,

Torfs³

et al. 2009

Birth Defects Research

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Esophageal atresia and/or tracheoesophageal fistula (EA/TEF) are severe congenital anomalies. Although recent years have brought significant improvement in clinical treatment, our understanding of the etiology of these defects is lagging. Many genes and genetic pathways have been implicated in the development of EA/TEF, but only a few genes have been shown to be involved in humans, in animals, or in both. Extrapolating data from animal models to humans is not always straightforward. Environmental factors may also carry a risk, but the mechanisms are yet to be elucidated. This review gives an overview of the current state of knowledge about both genetic and environmental risk factors in the etiology of EA/TEF.

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“…In fact, HDH should be differentiated from various syndromal forms of HH, in particular Pallister-Hall syndrome (PHS) [Hall et al, 1980;Kuller et al, 1992], caused by mutations in the GLI3 gene. In the molecularly confirmed patients, this condition can be differentiated from HDH by the presence of central polydactyly, which is mandatory in PHS index cases, and the absence of holoprosencephalic features [Biesecker et al, 1996;Johnston et al, 2005;Roscioli et al, 2005]. Moreover, differential diagnosis of HDH includes other conditions usually not associated with HH, such as Meckel-Gruber and hydrolethalus syndromes [Anyane-Yeboa et al, 1987;Encha-Razavi et al, 1992].…”

Section: Introductionmentioning

confidence: 99%

Reassessment of holoprosencephaly–diencephalic hamartoblastoma (HDH) association

Castori

Douzgou

Silvestri

et al. 2007

American J of Med Genetics Pt A

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We report on a 23-week fetus with a hypothalamic hamartoma, lobar holoprosencephaly, right anophthalmia, and facial asymmetry, features which are consistent with the holoprosencephaly-diencephalic hamartoblastoma (HDH) association. In an attempt to better delineate HDH, we reviewed 19 published patients with similar features. The HDH clinical spectrum ranges from classic holoprosencephaly with micro/anophthalmia, multiple additional findings in non-contiguous structures and early lethality, to isolated microforms of holoprosencephaly. Associated cephalic features mainly include cortical/neuronal migration defects (39%), meningeal anomalies (28%), brainstem/posterior fossa malformations (22%), dysmorphic ears (41%), facial asymmetry (35%), and hypoplastic mandible (29%). Fifty-three percent of patients have additional extra-cephalic malformations, for example, vertebral/rib segmentation defects (50%), hypo/aplastic lungs (38%), congenital heart defect (29%), and urinary anomalies (29%). HDH shows etiological heterogeneity, that is, teratogenic exposure, chromosome imbalances, autosomal recessive as well as dominant "de novo" mutations. Several features could directly result from a disruptive sequence caused by an early hamartoma which alters the development of forebrain, hindbrain, meninges, and 1st-2nd branchial arches, although the pleiotropic action of genetic/environmental factors cannot be excluded. HDH does not emerge as a distinct syndrome, but other hypotheses, including separate conditions within a common pathway and the developmental field defect theory, are discussed.

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Pallister-Hall syndrome: Unreported skeletal features of aGLI3mutation

Cited by 20 publications

References 37 publications

New insights into genotype–phenotype correlation for GLI3 mutations

New insights into genotype–phenotype correlation for GLI3 mutations

Genetic and environmental factors in the etiology of esophageal atresia and/or tracheoesophageal fistula: An overview of the current concepts

Reassessment of holoprosencephaly–diencephalic hamartoblastoma (HDH) association

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