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Diagnostic Pathology

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Open Access 01-12-2018 | Case Report

Novel GLI3 variant causing overlapped Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS) phenotype with agenesis of gallbladder and pancreas

Authors: Saki Ito, Riko Kitazawa, Ryuma Haraguchi, Takeshi Kondo, Ayaka Ouchi, Yasuo Ueda, Sohei Kitazawa

Published in: Diagnostic Pathology | Issue 1/2018

Abstract

Background

A proper balance between the activator and the repressor form of GLI3, a zinc-finger transcription factor downstream of hedgehog signaling, is essential for proper development of various organs during development. Mutations in different domains of the GLI3 gene underlie several congenital diseases including Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS).

Case presentation

Here, we describe the case of an overlapped phenotype of these syndromes with agenesis of the gallbladder and the pancreas, bearing a c.2155 C > T novel likely pathogenic variant of GLI3 gene by missense point mutation causing p.P719S at the proteolytic cleavage site.

Conclusions

Although agenesis of the gallbladder and the pancreas is uncommon in GLI3 morphopathy, a slight difference in the gradient or the balance between activator and repressor in this case may hinder sophisticated spatial and sequential hedgehog signaling that is essential for proper development of gallbladder and pancreas from endodermal buds.

Marigo V, Johnson RL, Vortkamp A, Tabin CJ. Sonic hedgehog differentially regulates expression of GLI and GLI3 during limb development. Dev Biol. 1996;180(1):273–83. doi:https://doi.org/10.1006/dbio.1996.0300. PubMed PMID: 8948590CrossRefPubMed

Vortkamp A, Gessler M, Grzeschik KH. GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families. Nature. 1991;352(6335):539–40. doi:https://doi.org/10.1038/352539a0. PubMed PMID: 1650914CrossRefPubMed

Wang B, Fallon JF, Beachy PA. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell. 2000;100(4):423–34. PubMed PMID: 10693759CrossRefPubMed

Biesecker LG. Pallister-Hall Syndrome. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al., editors. GeneReviews(R). Seattle (WA)1993.

McDonald-McGinn DM, Feret H, Nah HD, Bartlett SP, Whitaker LA, Zackai EH. Metopic craniosynostosis due to mutations in GLI3: a novel association. Am J Med Genet A. 2010;152A(7):1654–60. doi:https://doi.org/10.1002/ajmg.a.33495. PubMed PMID: 20583172CrossRefPubMed

Wild A, Kalff-Suske M, Vortkamp A, Bornholdt D, Konig R, Grzeschik KH. Point mutations in human GLI3 cause Greig syndrome. Hum Mol Genet. 1997;6(11):1979–84. PubMed PMID: 9302279CrossRefPubMed

Walterhouse D, Ahmed M, Slusarski D, Kalamaras J, Boucher D, Holmgren R, et al. Gli, a zinc finger transcription factor and oncogene, is expressed during normal mouse development. Dev Dyn. 1993;196(2):91–102. doi:https://doi.org/10.1002/aja.1001960203. PubMed PMID: 8364225CrossRefPubMed

Krauss S, So J, Hambrock M, Kohler A, Kunath M, Scharff C, et al. Point mutations in GLI3 lead to misregulation of its subcellular localization. PLoS One. 2009;4(10):e7471. doi:https://doi.org/10.1371/journal.pone.0007471. PubMed PMID: 19829694; PubMed Central PMCID: PMCPMC2758996CrossRefPubMedPubMedCentral

Dai P, Akimaru H, Tanaka Y, Maekawa T, Nakafuku M, Ishii S. Sonic hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. J Biol Chem. 1999;274(12):8143–52. PubMed PMID: 10075717CrossRefPubMed

10.

Cao T, Wang C, Yang M, Wu C, Wang B. Mouse limbs expressing only the Gli3 repressor resemble those of sonic hedgehog mutants. Dev Biol. 2013;379(2):221–8. doi:https://doi.org/10.1016/j.ydbio.2013.04.025. PubMed PMID: 23644062; PubMed Central PMCID: PMCPMC3707282.CrossRefPubMedPubMedCentral

11.

Bok J, Dolson DK, Hill P, Ruther U, Epstein DJ, Wu DK. Opposing gradients of Gli repressor and activators mediate Shh signaling along the dorsoventral axis of the inner ear. Development. 2007;134(9):1713–22. doi:https://doi.org/10.1242/dev.000760. PubMed PMID: 17395647CrossRefPubMed

12.

Li J, Wang C, Pan Y, Bai Z, Wang B. Increased proteolytic processing of full-length Gli2 transcription factor reduces the hedgehog pathway activity in vivo. Dev Dyn. 2011;240(4):766–74. doi:https://doi.org/10.1002/dvdy.22578. PubMed PMID: 21337666; PubMed Central PMCID: PMCPMC3071291.CrossRefPubMedPubMedCentral

13.

Qin J, Lin Y, Norman RX, Ko HW, Eggenschwiler JT. Intraflagellar transport protein 122 antagonizes sonic hedgehog signaling and controls ciliary localization of pathway components. Proc Natl Acad Sci U S A. 2011;108(4):1456–61. doi:https://doi.org/10.1073/pnas.1011410108. PubMed PMID: 21209331; PubMed Central PMCID: PMCPMC3029728CrossRefPubMedPubMedCentral

14.

Al-Qattan MM, Shamseldin HE, Salih MA, Alkuraya FS. GLI3-related polydactyly: a review. Clin Genet. 2017; doi:https://doi.org/10.1111/cge.12952. PubMed PMID: 28224613

15.

Biesecker LG. Greig Cephalopolysyndactyly Syndrome. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al., editors. GeneReviews(R). Seattle (WA)1993.

16.

Hall JG. The early history of Pallister-hall syndrome-buried treasure of a sort. Gene. 2016;589(2):100–3. doi:https://doi.org/10.1016/j.gene.2016.01.003. PubMed PMID: 26768579CrossRefPubMed

17.

Motoyama J. Essential roles of Gli3 and sonic hedgehog in pattern formation and developmental anomalies caused by their dysfunction. Congenit Anom (Kyoto). 2006;46(3):123–8. doi:https://doi.org/10.1111/j.1741-4520.2006.00114.x. PubMed PMID: 16922918CrossRef

18.

Lei Q, Zelman AK, Kuang E, Li S, Matise MP. Transduction of graded hedgehog signaling by a combination of Gli2 and Gli3 activator functions in the developing spinal cord. Development. 2004;131(15):3593–604. doi:https://doi.org/10.1242/dev.01230. PubMed PMID: 15215207CrossRefPubMed

19.

Demurger F, Ichkou A, Mougou-Zerelli S, Le Merrer M, Goudefroye G, Delezoide AL, et al. New insights into genotype-phenotype correlation for GLI3 mutations. Eur J Hum Genet. 2015;23(1):92–102. doi:https://doi.org/10.1038/ejhg.2014.62. PubMed PMID: 24736735; PubMed Central PMCID: PMCPMC4266745CrossRefPubMed

20.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24. doi:https://doi.org/10.1038/gim.2015.30. PubMed PMID: 25741868; PubMed Central PMCID: PMCPMC4544753CrossRefPubMedPubMedCentral

21.

Bogue CW, Ganea GR, Sturm E, Ianucci R, Jacobs HC. Hex expression suggests a role in the development and function of organs derived from foregut endoderm. Dev Dyn. 2000;219(1):84–9. doi:https://doi.org/10.1002/1097-0177(2000)9999:9999<::AID-DVDY1028>3.0.CO;2-5. PubMed PMID: 10974674CrossRefPubMed

22.

Slack JM. Developmental biology of the pancreas. Development. 1995;121(6):1569–80. PubMed PMID: 7600975PubMed

23.

Teo AK, Lau HH, Valdez IA, Dirice E, Tjora E, Raeder H, et al. Early developmental perturbations in a human stem cell model of MODY5/HNF1B pancreatic Hypoplasia. Stem Cell Reports. 2016;6(3):357–67. doi:https://doi.org/10.1016/j.stemcr.2016.01.007. PubMed PMID: 26876668; PubMed Central PMCID: PMCPMC4788763CrossRefPubMedPubMedCentral

Title: Novel GLI3 variant causing overlapped Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS) phenotype with agenesis of gallbladder and pancreas
Authors: Saki Ito
Riko Kitazawa
Ryuma Haraguchi
Takeshi Kondo
Ayaka Ouchi
Yasuo Ueda
Sohei Kitazawa
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Diagnostic Pathology / Issue 1/2018
Electronic ISSN: 1746-1596
DOI: https://doi.org/10.1186/s13000-017-0682-8

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Novel GLI3 variant causing overlapped Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS) phenotype with agenesis of gallbladder and pancreas

Abstract

Background

Case presentation

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Case presentation

Conclusions

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