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Phenotypes
Original research
Weill-Marchesani syndrome: natural history and genotype-phenotype correlations from 18 news cases and review of literature
  1. Pauline Marzin1,2,
  2. Sophie Rondeau1,2,
  3. Jean-Luc Alessandri3,
  4. Klaus Dieterich4,
  5. Carine le Goff5,
  6. Clémentine Mahaut2,
  7. Sandra Mercier6,
  8. Caroline Michot1,2,
  9. Oana Moldovan7,
  10. Gianmaria Miolo8,
  11. Massimiliano Rossi9,
  12. Julien Van-Gils10,
  13. Christine Francannet11,
  14. Matthieu P Robert12,13,
  15. Jean-Philippe Jaïs14,15,16,
  16. Céline Huber2,
  17. Valerie Cormier-Daire1,2
  1. 1Centre de Référence pour les Maladies Osseuses Constitutionnelles, Fédération de médecine génomique des maladies rares, APHP, Hôpital Necker-Enfants Malades, F-75015 Paris, France
  2. 2Université Paris Cité, INSERM UMR1163, Institut Imagine, F-75 015, Paris, France
  3. 3Service de génétique médicale, CHU de la Réunion - Hôpital Félix Guyon, Bellepierre, 97405 Saint-Denis, France
  4. 4Univ. Grenoble Alpes, Inserm, U1209, CHU Grenoble Alpes, Medical Genetics, Institute for Advanced Biosciences, 38000 Grenoble, France
  5. 5Université Paris Cité and Université Sorbonne Paris Nord, INSERM U1148, Laboratory of Vascular Translational Science, Bichat Hospital, Paris, France
  6. 6Service de génétique médicale - Unité de Génétique clinique, CHU de Nantes - Hôtel Dieu, 1 place Alexis Ricordeau, 44093 Nantes, France
  7. 7Serviço de Genética Médica, Departamento de Pediatria, Hospital de Santa Maria, Centro Hospitalar Universitário de Lisboa Norte, Lisbon, Portugal
  8. 8: S.S.D. di Citogenetica e Genetica Molecolare, Dipartimento di Medicina di Laboratorio, Azienda Ospedaliera Santa Maria degli Angeli, Via Montereale 24, 33170 Porderone, Italy
  9. 9Service de génétique, Hospices Civils de Lyon ; INSERM U1028, CNRS UMR5292, Centre de Recherche en Neurosciences de Lyon, GENDEV Team, Université Claude Bernard Lyon 1, Bron, France
  10. 10Département de Génétique Médicale, Centre de Référence Anomalies du Développement et Syndrome Malformatifs, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
  11. 11Service de génétique médicale, CHU de Clermont-Ferrand, 1 place lucie et raymond Aubrac, 63003 Clermont-fd cedex 1, France
  12. 12Service d'ophtalmologie, Hôpital Universitaire Necker - enfants malades, Paris, France
  13. 13Borelli Centre, UMR 9010 CNRS-SSA-ENS Paris Saclay-Paris University, Paris, France
  14. 14Biostatistic Unit, Necker University Hospital, AP-HP, Paris, France
  15. 15Imagine Institute, Université Paris Cité, Paris, France
  16. 16Human genetics of infectious diseases: Complex predisposition, INSERM UMR1163, Paris, France
  1. Correspondence to Professor Valerie Cormier-Daire, Necker-Enfants Malades Hospitals, Paris, Île-de-France, France; valerie.cormier-daire{at}inserm.fr

Abstract

Background Weill-Marchesani syndrome (WMS) belongs to the group of acromelic dysplasias, defined by short stature, brachydactyly and joint limitations. WMS is characterised by specific ophthalmological abnormalities, although cardiovascular defects have also been reported. Monoallelic variations in FBN1 are associated with a dominant form of WMS, while biallelic variations in ADAMTS10, ADAMTS17 and LTBP2 are responsible for a recessive form of WMS.

Objective Natural history description of WMS and genotype-phenotype correlation establishment.

Materials and methods Retrospective multicentre study and literature review. Inclusion criteria: clinical diagnosis of WMS with identified pathogenic variants.

Results 61 patients were included: 18 individuals from our cohort and 43 patients from literature. 21 had variants in ADAMTS17, 19 in FBN1, 19 in ADAMTS10 and 2 in LTBP2. All individuals presented with eye anomalies, mainly spherophakia (42/61) and ectopia lentis (39/61). Short stature was present in 73% (from −2.2 to −5.5 SD), 10/61 individuals had valvulopathy. Regarding FBN1 variants, patients with a variant located in transforming growth factor (TGF)-β-binding protein-like domain 5 (TB5) domain were significantly smaller than patients with FBN1 variant outside TB5 domain (p=0.0040).

Conclusion Apart from the ophthalmological findings, which are mandatory for the diagnosis, the phenotype of WMS seems to be more variable than initially described, partially explained by genotype-phenotype correlation.

  • phenotype
  • genetics, medical
  • fractures, cartilage
  • human genetics
  • mutation

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

https://doi.org/10.1136/jmg-2023-109288

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information.

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    Footnotes

    • Correction notice This article has been corrected since it was published online first. An author's name has been amended.

    • Contributors VCD designed the whole study and acts as guarantor. PM made acquisition and analysis of data. PM and VC-D drafted the main manuscript. J-LA, KD, SM, CM, OM, GM, MR, JV-G, CF and VC-D contributed to clinical data. SR, CH, ClG and CM made molecular analysis. MR provided an expert opinion about ophthalmologial features. All members revised the manuscript and made comments on the structure, details and grammar of the article.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.