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

D. Lehalle (1) , A. L. Bruel (2) , A. Vitobello (3) , A. S. Denommé-Pichon (4) , Y. Duffourd (2) , M. Assoum (5) , J. Amiel (6) , G. Baujat (7) , B. Bessieres (6) , S. Bigoni (8) , L. Burglen (9) , G. Captier (10, 11) , R. Dard (12) , P. Edery (13) , F. Fortunato (8) , D. Geneviève (14, 15) , A. Goldenberg (16) , L. Guibaud (13) , D. Héron (17) , M. Holder-Espinasse (18, 19) , D. Lederer (20) , F. Lopez Grondona (21) , S. Grotto (22) , S. Marlin (23) , G. Nadeau (24) , A. Picard (6) , M. Rossi (25) , J. Roume (26) , D. Sanlaville (27) , P. Saugier-Veber (28) , S. Triau (29) , M. I. Valenzuela Palafoll (21) , Clemence Vanlerberghe (30) , L. van Maldergem (31) , M. Vezain (28) , C. Vincent-Delorme (32) , E. Zivi (33) , J. Thevenon (1) , P. Vabres (1) , C. Thauvin-Robinet (1) , P. Callier (34) , L. Faivre (2)

1 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
2 FHU TRANSLAD (CHU de Dijon)
3 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
4 CHU Dijon
5 LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
6 Hôpital Necker - Enfants Malades [AP-HP]
7 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
8 UniFE - Università degli Studi di Ferrara = University of Ferrara
9 CHU Trousseau [APHP]
10 UM - Université de Montpellier
11 LIRMM - Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier
12 CHI Poissy-Saint-Germain
13 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
14 Inserm U781 - Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement
15 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
16 CHU Rouen
17 CHU Pitié-Salpêtrière [AP-HP]
18 Institut de Pathologie [CHU Lille]
19 Guy's Hospital [London]
20 I.P.G. - Institut de Pathologie et Génétique [Gosselies]
21 Vall d'Hebron University Hospital [Barcelona]
22 UM - Université de Montpellier
23 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
24 Centre hospitalier de Valence
25 Université de Lyon
26 CHU - Hôpital Lapeyronie [Montpellier]
27 Centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy]
28 UNIROUEN - Université de Rouen Normandie
29 CHU Angers - Centre Hospitalier Universitaire d'Angers
30 RADEME - Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364
31 CHRU Besançon - Centre Hospitalier Régional Universitaire de Besançon
32 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
33 HUJ - The Hebrew University of Jerusalem
34 GAD - Génétique des Anomalies du Développement

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.

Mots clés: exome; genome sequencing; frontonasal dysplasia; oculoauriculofrontonasal syndrome; Pai syndrome

Domaines: Sciences du Vivant [q-bio]

D. Lehalle, A. L. Bruel, A. Vitobello, A. S. Denommé-Pichon, Y. Duffourd, et al.. Toward clinical and molecular dissection of frontonasal dysplasia with facial skin polyps: From Pai syndrome to differential diagnosis through a series of 27 patients.. American Journal of Medical Genetics Part A, 2022, American Journal of Medical Genetics Part A, 188 (7), pp.2036-2047. ⟨10.1002/ajmg.a.62739⟩. ⟨hal-04236858⟩