Abstract
Myhre syndrome (MS, MIM 139210) is a rare multisystemic disorder caused by recurrent pathogenic missense variants in SMAD4. The clinical features have been mainly documented in childhood and comprise variable neurocognitive development, recognizable craniofacial features, a short stature with a pseudo-muscular build, hearing loss, thickened skin, joint limitations, diverse cardiovascular and airway manifestations, and increased fibrosis often following trauma or surgery. In contrast, adults with MS are underreported obscuring potential clinical variability. Here, we describe 24 adults with MS, including 17 diagnosed after the age of 18 years old, and we review the literature on adults with MS. Overall, our cohort shows a milder phenotype as well as lower mortality rates compared to what has been published in literature. Individuals with a codon 500 variant in SMAD4 present with a more pronounced neurodevelopmental and systemic phenotype. However, in contrast to the literature, we observe cardiovascular abnormalities in individuals with the p.(Arg496Cys) variant. In addition, we describe scoliosis as a new manifestation and we report fertility in two additional males with the p.(Arg496Cys). In conclusion, our study contributes novel insights into the clinical variability of MS and underscores the importance of variant-specific considerations, and we provide recommendations for the management of MS in adulthood.
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The data generated and/or analyzed during this study can be found within this article and the Supplementary files.
Change history
13 September 2024
There was an error in the labeling of Table 1.
10 September 2024
A Correction to this paper has been published: https://doi.org/10.1038/s41431-024-01690-z
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Acknowledgements
EVB is a predoctoral research fellow of the Special Research Fund of Ghent University. BC is a senior clinical investigator of the Research Foundation—Flanders. The following authors of this publication are member of the European Reference Network for Skin Disorders (ERN-Skin): Ghent University Hospital, University Hospital Brussels, Necker-Enfants Malades Hospital Paris, Bambino Gesù Children’s Hospital Rome), the European Reference Network for Rare Malformation Syndromes, Intellectual and Other Neurodevelopmental Disorders (ERN-ITHACA; Ghent University Hospital, Antwerp University Hospital, University Hospital Brussels, AUSL IRCCS Arcispedale Santa Maria Nuova Reggio Emilia, Bambino Gesù Children’s Hospital Rome, University Hospital Magdeburg, Haukeland University Hospital), the European Reference Network for Rare Multisystemic Vascular Diseases (VascERN; Ghent University Hospital, Antwerp University Hospital, Bambino Gesù Children’s Hospital Rome) and the European Rare Kidney Diseases Reference Network (ERKNet; Ghent University Hospital, Necker-Enfants Malades Hospital Paris, Bambino Gesù Children’s Hospital Rome). This study is within the framework of Project 2629394, “The post-exome clinic: improving the impact of exome sequencing for developmental disorders in Norway”.
Funding
This research was funded by a grant of the Research Foundation—Flanders to BC (G035620N) and a research grant (2022) of the Myhre Syndrome Foundation to BC. Project 2629394, “The post-exome clinic: improving the impact of exome sequencing for developmental disorders in Norway”, is funded by the Norwegian Advisory Unit on Rare Disorders (grant #43066).
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EVB and TVD: data curation, formal analysis, investigation, methodology, writing—original draft. AB, JDB, IM, FV, SED, JVDE, TB, ERS, MEL, LAS, AMH, ED, NGO, IV, TD, SC, VCD, MT, LG, JS, SD, EAA, MZ, MR, GRC, SD, MSF, and AEL: providing clinical data, writing—review & editing. SS and KC providing molecular data. BC: conceptualization, funding acquisition, formal analysis, writing—review & editing.
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The research included in this report was conducted in a manner consistent with the principles of research ethics, such as those described in the Declaration of Helsinki and/or the Belmont Report. In particular, this research was conducted with the voluntary, informed consent of any research participants, free of coercion or coercive circumstances, and received approval by the Ethics Committee of the Ghent University Hospital, Ghent, Belgium (study reference BC-10086), consistent with the principles of research ethics and the legal requirements of the lead authors’ jurisdiction(s). Informed consent was obtained from the individuals and/or legal guardians, including permission for the publication of clinical photographs.
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Vanbelleghem, E., Van Damme, T., Beyens, A. et al. Myhre syndrome in adulthood: clinical variability and emerging genotype-phenotype correlations. Eur J Hum Genet 32, 1086–1094 (2024). https://doi.org/10.1038/s41431-024-01664-1
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DOI: https://doi.org/10.1038/s41431-024-01664-1
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