GLI3 is rarely implicated in OFD syndromes with midline abnormalities

Avila, Magali; Gigot, Nadège; Aral, Bernard; Callier, Patrick; Gautier, Élodie; Thévenon, Julien; Pasquier, Laurent; Lopez, Estelle; Gueneau, Lucie; Duplomb, Laurence; Goldenberg, Alice; Baumann, Clarisse; Cormier, V.; Marlin, Sandrine; Masurel‐Paulet, Alice; Huet, Frédéric; Attié‐Bitach, Tania; Faivre, Laurence; Thauvin‐Robinet, Christel

doi:10.1002/humu.21570

Cited by 6 publications

(8 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The majority of hypothalamic hamartomas are sporadic and approximately 5% are associated with the diagnosis of Pallister-Hall syndrome (PHS, OMIM 146510) [56-59]. Patients with PHS and mutations in the GLI3 gene may have also clinical manifestations that overlap the OFD VI-phenotype, namely mesoaxial or postaxial polydactyly and oral findings including additional frenula, tongue hamartomas, and cleft palate [60,61]. In PHS patients with a GLI3 mutation however, the MTS has never been reported, and its presence allows the differentiation of OFD VI from PHS.…”

Section: Discussionmentioning

confidence: 99%

“…In PHS patients with a GLI3 mutation however, the MTS has never been reported, and its presence allows the differentiation of OFD VI from PHS. Johnston et al reported two patients with presumed PHS, a phenotype overlapping OFD, and a MTS [60], and Avila et al reported also a similar patient [61]; however, none of these patients carried mutations in the GLI3 gene. Therefore it remains uncertain whether these patients have PHS or in fact may be examples of OFD VI.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Delineation and Diagnostic Criteria of Oral-Facial-Digital Syndrome Type VI

Poretti

Vitiello

Hennekam

et al. 2012

Orphanet J Rare Dis

View full text Add to dashboard Cite

Oral-Facial-Digital Syndrome type VI (OFD VI) represents a rare phenotypic subtype of Joubert syndrome and related disorders (JSRD). In the original report polydactyly, oral findings, intellectual disability, and absence of the cerebellar vermis at post-mortem characterized the syndrome. Subsequently, the molar tooth sign (MTS) has been found in patients with OFD VI, prompting the inclusion of OFD VI in JSRD. We studied the clinical, neurodevelopmental, neuroimaging, and genetic findings in a cohort of 16 patients with OFD VI. We derived the following inclusion criteria from the literature: 1) MTS and one oral finding and polydactyly, or 2) MTS and more than one typical oral finding. The OFD VI neuroimaging pattern was found to be more severe than in other JSRD subgroups and includes severe hypoplasia of the cerebellar vermis, hypoplastic and dysplastic cerebellar hemispheres, marked enlargement of the posterior fossa, increased retrocerebellar collection of cerebrospinal fluid, abnormal brainstem, and frequently supratentorial abnormalities that occasionally include characteristic hypothalamic hamartomas. Additionally, two new JSRD neuroimaging findings (ascending superior cerebellar peduncles and fused thalami) have been identified. Tongue hamartomas, additional frenula, upper lip notch, and mesoaxial polydactyly are specific findings in OFD VI, while cleft lip/palate and other types of polydactyly of hands and feet are not specific. Involvement of other organs may include ocular findings, particularly colobomas. The majority of the patients have absent motor development and profound cognitive impairment. In OFD VI, normal cognitive functions are possible, but exceptional. Sequencing of known JSRD genes in most patients failed to detect pathogenetic mutations, therefore the genetic basis of OFD VI remains unknown. Compared with other JSRD subgroups, the neurological findings and impairment of motor development and cognitive functions in OFD VI are significantly worse, suggesting a correlation with the more severe neuroimaging findings. Based on the literature and this study we suggest as diagnostic criteria for OFD VI: MTS and one or more of the following: 1) tongue hamartoma(s) and/or additional frenula and/or upper lip notch; 2) mesoaxial polydactyly of one or more hands or feet; 3) hypothalamic hamartoma.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Delineation and Diagnostic Criteria of Oral-Facial-Digital Syndrome Type VI

Poretti

Vitiello

Hennekam

et al. 2012

Orphanet J Rare Dis

View full text Add to dashboard Cite

show abstract

“…The existence of OFD‐Pallister–Hall overlap syndrome as a true entity was questioned by Avila et al because the main oral abnormality in the cases reported by Johnston et al was the oral frenulae. Oral frenulae are known to be unspecific to OFD and have previously been described in PHS with GLI3 mutations.…”

Section: Gli3‐related Syndromes/conditionsmentioning

confidence: 99%

“…Oral frenulae are known to be unspecific to OFD and have previously been described in PHS with GLI3 mutations. Hence, Avila et al questioned the diagnosis of OFD‐Pallister–Hall overlap syndrome in the series of Johnston et al . On the other hand, OFD syndromes are ciliopathies and the GLI3 protein interacts with several proteins in the primary cilium, which explains why hypothalamic hamartomas are seen in both PHS and OFD1 .…”

Section: Gli3‐related Syndromes/conditionsmentioning

confidence: 99%

GLI3‐related polydactyly: a review

et al. 2017

View full text Add to dashboard Cite

GLI3 mutations are known to be associated with nine syndromes/conditions in which polydactyly is a feature. In this review, the embryology, pathogenesis, and animal models of GLI3-related polydactyly are discussed first. This is followed by a detailed review of the genotype-phenotype correlations. Based on our review of the literature and our clinical experiences, we recommend viewing GLI3-related syndromes/conditions as four separate entities; each characterized by a specific pattern of polydactyly. These four entities are: the preaxial polydactyly type IV-Greig-acrocallosal spectrum, postaxial polydactyly types A/B, Pallister-Hall syndrome (PHS), and oral-facial-digital overlap syndrome. We also provide illustrative clinical examples from our practice including a family with a novel GLI3 mutation causing PHS. The review also introduces the term 'Forme Fruste' preaxial polydactyly and gives several conclusions/recommendations including the recommendation to revise the current criteria for the clinical diagnosis of PHS.

show abstract

“…Interestingly, variants in GLI3 have also been recently correlated to features of orofaciodigital syndromes, in particular OFD VI (MIM#277170) (Avila et al, 2011; Johnston et al, 2010). Other GLI3 ‐related phenotypes include isolated polydactyly, namely postaxial polydactyly, types A1 and B (MIM#174200), as well as preaxial polydactyly type IV (MIM#174700).…”

Section: Introductionmentioning

confidence: 99%

Homozygous GLI3 variants observed in three unrelated patients presenting with syndromic polydactyly

Mouatani

Winckel

Zaafrane-Khachnaoui

et al. 2021

American J of Med Genetics Pt A

View full text Add to dashboard Cite

Polydactyly is a hallmark of GLI3 pathogenic variants, with Greig cephalopolysyndactyly syndrome and Pallister-Hall syndrome being the two main associated clinical presentations. Homozygous GLI3 variants are rare instances in the literature, and mendelian dominance is the accepted framework for GLI3-related diseases. Herein, we report three unrelated probands, presenting with polydactyly, and homozygous variants in the GLI3 gene. First, a 10-year-old girl, whose parents were first-degree cousins, presented with bilateral postaxial polydactyly of the hands, developmental delay and multiple malformations. Second, a male newborn, whose parents were first-degree cousins, presented with isolated bilateral postaxial polysyndactyly of the hands and the feet. Third, an adult male, whose parents were first-degree cousins, had bilateral mesoaxial polydactyly of the hands, with severe intellectual disability and multiple malformations. All three probands carried homozygous GLI3 variants. Strikingly, the parents also carried the child's variant, in the heterozygous state, without any clinical sign of GLI3 disease. Given the clinical presentation of our patients, the rarity and predicted high pathogenicity of the variants observed, and the absence of other pathogenic variants, we suggest that these GLI3 homozygous variants are causal. Moreover, the parents were heterozygous for the observed variants, but were clinically unremarkable, suggesting that these variants are hypomorphic alleles.

show abstract

GLI3 is rarely implicated in OFD syndromes with midline abnormalities

Cited by 6 publications

References 12 publications

Delineation and Diagnostic Criteria of Oral-Facial-Digital Syndrome Type VI

Delineation and Diagnostic Criteria of Oral-Facial-Digital Syndrome Type VI

GLI3‐related polydactyly: a review

Homozygous GLI3 variants observed in three unrelated patients presenting with syndromic polydactyly

Contact Info

Product

Resources

About