Toward clinical and molecular dissection of frontonasal dysplasia with facial skin polyps: From Pai syndrome to differential diagnosis through a series of 27 patients

Daphné Lehalle^{1

2

3

4}, Ange-Line Bruel^{2

3}, Antonio Vitobello^{2

3}, Anne-Sophie Denommé-Pichon^{2

3}, Yannis Duffourd^{2

3}, Mirna Assoum², Jeanne Amiel⁵, Geneviève Baujat⁵, Bettina Bessieres⁶, Stefania Bigoni⁷, Lydie Burglen⁸, Guillaume Captier⁹, Rodolphe Dard¹⁰, Patrick Edery^{11

12}, Fernanda Fortunato⁷, David Geneviève¹³, Alice Goldenberg¹⁴, Laurent Guibaud¹², Delphine Héron¹⁵, Muriel Holder-Espinasse^{16

17}, Damien Lederer¹⁸, Fermina Lopez Grondona¹⁹, Sarah Grotto¹³, Sandrine Marlin²⁰, Gwenaël Nadeau²¹, Arnaud Picard²², Massimiliano Rossi^{10

11}, Joëlle Roume⁹, Damien Sanlaville^{10

11}, Pascale Saugier-Veber²³, Stéphane Triau²⁴, Maria Irene Valenzuela Palafoll¹⁹, Clémence Vanlerberghe¹⁶, Lionel Van Maldergem²⁵, Myriam Vezain²³, Catherine Vincent-Delorme¹⁶, Einat Zivi²⁶, Julien Thevenon^{1

2}, Pierre Vabres^{2

27}, Christel Thauvin-Robinet^{1

2

3}, Patrick Callier², Laurence Faivre^{1

2

3}

Affiliations

¹ Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est, FHU TRANSLAD, Centre Hospitalier Universitaire Dijon, Dijon, France.
² Equipe GAD, INSERM LNC UMR 1231, FHU TRANSLAD, Faculté de Médecine, Université de Bourgogne Franche-Comté, Dijon, France.
³ Unité Fonctionnelle d'Innovation diagnostique des maladies rares, Pôle de Biologie, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.
⁴ Département de Génétique, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France.
⁵ Service de Génétique, INSERM U781, Hôpital Necker-Enfants Malades, Institut Imagine, University Sorbonne-Paris-Cité, Paris, France.
⁶ Unite d'embryofoetopathologie, Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades APHP, Paris, France.
⁷ UOL of Medical Genetics, Ferrara Hospital University, Ferrara, Italy.
⁸ Département de Génétique et Centre de Référence "malformations et maladies congénitales du cervelet," AP-HP, Hôpital Trousseau, Paris, France.
⁹ Service de chirurgie orthopédique et plastique pédiatrique, Hôpital Lapeyronie, CHU Montpellier, Montpellier, France.
¹⁰ Service de Cytogénétique, Centre Hospitalier Intercommunal de Poissy Saint-Germain-en-Laye, Poissy, France.
¹¹ Service de génétique et Centre de Référence des Anomalies du développement de la région Auvergne-Rhône-Alpes, CHU de Lyon, Lyon, France.
¹² Centre de Recherche en Neurosciences de Lyon, INSERM U1028 CNRS UMR 5292, UCB Lyon 1, Villeurbanne, France.
¹³ Genetic Department for Rare Disease and Personalised Medicine, Clinical Division, Montpellier University, Inserm U1183, Montpellier, France.
¹⁴ Department of Genetics, Rouen University Hospital, Normandy Centre for Genomic and Personalized Medicine, Rouen, France.
¹⁵ Department of Genetics, Intellectual Disability and Autism Clinical Research Group, Pierre and Marie Curie University, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France.
¹⁶ Department of Clinical Genetics, CHU Lille, Lille, France.
¹⁷ Clinical Genetics Department, Guy's Hospital, London, UK.
¹⁸ Center for Human Genetics, Institut de Pathologie et Génétique (I.p.G.), Gosselies, Belgium.
¹⁹ Àrea de Genètica Clínica i Malalties Minoritàries, Hospital Vall d'Hebron, Barcelona, Spain.
²⁰ Laboratory of Embryology and Genetics of Malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Université de Paris, Paris, Spain.
²¹ Unité fonctionnelle de cytogénétique, CH de Valence, Valence, France.
²² Service de Chirurgie Maxillofaciale, Hôpital Necker, Paris, France.
²³ Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France.
²⁴ Service de Foetopathologie, CHU Angers, Angers, France.
²⁵ Service de Génétique, CHU Besançon, Besançon, France.
²⁶ Medical Genetics Institute, Shaare Zedek Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.
²⁷ Service de Dermatologie, CHU Dijon, Dijon, France.

PMID: 35445792
DOI: 10.1002/ajmg.a.62739

Review

Toward clinical and molecular dissection of frontonasal dysplasia with facial skin polyps: From Pai syndrome to differential diagnosis through a series of 27 patients

Daphné Lehalle et al. Am J Med Genet A. 2022 Jul.

. 2022 Jul;188(7):2036-2047.

doi: 10.1002/ajmg.a.62739. Epub 2022 Apr 21.

Authors

Affiliations

¹ Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est, FHU TRANSLAD, Centre Hospitalier Universitaire Dijon, Dijon, France.
² Equipe GAD, INSERM LNC UMR 1231, FHU TRANSLAD, Faculté de Médecine, Université de Bourgogne Franche-Comté, Dijon, France.
³ Unité Fonctionnelle d'Innovation diagnostique des maladies rares, Pôle de Biologie, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.
⁴ Département de Génétique, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France.
⁵ Service de Génétique, INSERM U781, Hôpital Necker-Enfants Malades, Institut Imagine, University Sorbonne-Paris-Cité, Paris, France.
⁶ Unite d'embryofoetopathologie, Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades APHP, Paris, France.
⁷ UOL of Medical Genetics, Ferrara Hospital University, Ferrara, Italy.
⁸ Département de Génétique et Centre de Référence "malformations et maladies congénitales du cervelet," AP-HP, Hôpital Trousseau, Paris, France.
⁹ Service de chirurgie orthopédique et plastique pédiatrique, Hôpital Lapeyronie, CHU Montpellier, Montpellier, France.
¹⁰ Service de Cytogénétique, Centre Hospitalier Intercommunal de Poissy Saint-Germain-en-Laye, Poissy, France.
¹¹ Service de génétique et Centre de Référence des Anomalies du développement de la région Auvergne-Rhône-Alpes, CHU de Lyon, Lyon, France.
¹² Centre de Recherche en Neurosciences de Lyon, INSERM U1028 CNRS UMR 5292, UCB Lyon 1, Villeurbanne, France.
¹³ Genetic Department for Rare Disease and Personalised Medicine, Clinical Division, Montpellier University, Inserm U1183, Montpellier, France.
¹⁴ Department of Genetics, Rouen University Hospital, Normandy Centre for Genomic and Personalized Medicine, Rouen, France.
¹⁵ Department of Genetics, Intellectual Disability and Autism Clinical Research Group, Pierre and Marie Curie University, Pitié-Salpêtrière Hospital, Public Hospital Network of Paris, Paris, France.
¹⁶ Department of Clinical Genetics, CHU Lille, Lille, France.
¹⁷ Clinical Genetics Department, Guy's Hospital, London, UK.
¹⁸ Center for Human Genetics, Institut de Pathologie et Génétique (I.p.G.), Gosselies, Belgium.
¹⁹ Àrea de Genètica Clínica i Malalties Minoritàries, Hospital Vall d'Hebron, Barcelona, Spain.
²⁰ Laboratory of Embryology and Genetics of Malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Université de Paris, Paris, Spain.
²¹ Unité fonctionnelle de cytogénétique, CH de Valence, Valence, France.
²² Service de Chirurgie Maxillofaciale, Hôpital Necker, Paris, France.
²³ Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France.
²⁴ Service de Foetopathologie, CHU Angers, Angers, France.
²⁵ Service de Génétique, CHU Besançon, Besançon, France.
²⁶ Medical Genetics Institute, Shaare Zedek Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel.
²⁷ Service de Dermatologie, CHU Dijon, Dijon, France.

PMID: 35445792
DOI: 10.1002/ajmg.a.62739

Abstract

Unique or multiple congenital facial skin polyps are features of several rare syndromes, from the most well-known Pai syndrome (PS), to the less recognized oculoauriculofrontonasal syndrome (OAFNS), encephalocraniocutaneous lipomatosis (ECCL), or Sakoda complex (SC). We set up a research project aiming to identify the molecular bases of PS. We reviewed 27 individuals presenting with a syndromic frontonasal polyp and initially referred for PS. Based on strict clinical classification criteria, we could confirm only nine (33%) typical and two (7%) atypical PS individuals. The remaining ones were either OAFNS (11/27-41%) or presenting with an overlapping syndrome (5/27-19%). Because of the phenotypic overlap between these entities, OAFNS, ECCL, and SC can be either considered as differential diagnosis of PS or part of the same spectrum. Exome and/or genome sequencing from blood DNA in 12 patients and from affected tissue in one patient failed to identify any replication in candidate genes. Taken together, our data suggest that conventional approaches routinely utilized for the identification of molecular etiologies responsible for Mendelian disorders are inconclusive. Future studies on affected tissues and multiomics studies will thus be required in order to address either the contribution of mosaic or noncoding variation in these diseases.

Keywords: Pai syndrome; exome/genome sequencing; frontonasal dysplasia; oculoauriculofrontonasal syndrome.

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References

REFERENCES

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Toward clinical and molecular dissection of frontonasal dysplasia with facial skin polyps: From Pai syndrome to differential diagnosis through a series of 27 patients

Affiliations

Toward clinical and molecular dissection of frontonasal dysplasia with facial skin polyps: From Pai syndrome to differential diagnosis through a series of 27 patients

Authors

Affiliations

Abstract

References

REFERENCES

Publication types

MeSH terms

Supplementary concepts

LinkOut - more resources

Full Text Sources