Journal of Autism and Developmental Disorders

, Volume 49, Issue 7, pp 3031–3035 | Cite as

Autism Spectrum Disorder and Psychiatric Comorbidity in a Patient with Myhre Syndrome

  • Pehlivanidis ArtemiosEmail author
  • Spyropoulou Areti
  • Papanikolaou Katerina
  • Fryssira Helen
  • Tsoytsoy Eirini
  • Papageorgiou Charalambos
Letter to the Editor


Myhre syndrome (MS) is a connective tissue disorder with multisystem involvement with or without intellectual disability. In most cases SMAD4 mutations are reported. To date, 55 individuals have been molecularly confirmed. Autism has been proposed among associate clinical features of MS but no standardized diagnosis was available in previous cases. We report a case of a 25-year-old man with a pathogenic heterozygous SMAD4 missense mutation affecting residue Arg496 (SMAD4:p.Arg496Cys). Clinical findings are consistent with MS, commorbid with affective disorder and High Functioning Autism Spectrum Disorder confirmed by a standardized assessment procedure. The thorough clinical assessment of cases with syndromes such as MS can extend our knowledge on both the phenotypic characteristics of the syndrome and the genetic basis of autism.


Myhre syndrome SMAD4 mutation High functioning autism spectrum disorder Affective disorder 



We need to acknowledge the patient and his family as well as Dr A. Anastasakis Cardiologist and Dr K. Markoglou Gastroenterologist for their kind contribution to the collection of data.

Authors’ contributions

PA conceived of the study, drafted the manuscript, SA conceived of the study, helped to draft the manuscript, PK conceived of the study, drafted the manuscript, FH conceived of the study, helped to draft the manuscript, TE conceived of the study, helped to draft the manuscript and PC conceived of the study, helped to draft the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

Additional informed consent was obtained from the participant for whom identifying information is included in this article.


  1. American Psychiatric Association (APA). (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: APA.CrossRefGoogle Scholar
  2. Burglen, L., Héron, D., Moerman, A., Dieux-Coeslier, A., Bourguignon, J.-P., Bachy, A., et al. (2003). Myhre syndrome: new reports, review, and differential diagnosis. Journal of Medical Genetics, 40, 546–551.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Caputo, V., Bocchinfuso, G., Castori, M., Traversa, A., Pizzuti, A., Stella, L., et al. (2014). Novel SMAD4 mutation causing Myhre syndrome. American Journal of Medical Genetics, 164A, 1835–1840.CrossRefPubMedGoogle Scholar
  4. Caputo, V., Cianetti, L., Niceta, M., Carta, C., Ciolfi, A., Bocchinfuso, G., et al. (2012). A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene underlies Myhre syndrome. American Journal of Human Genetics, 90, 161–169.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Geisheker, R. M., Heymann, G., Wang, T., Coe, B. P., TurneT, N., HollyA, F., et al. (2017). Hotspots of missense mutation identify novel neurodevelopmental disorder genes and functional domains. Nature Neuroscience, 20(8), 1043–1051.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Le Couteur, A., Lord, C., & Rutter, M. (2003). The autism diagnostic interview—revised (ADI-R). Los Angeles, CA: Western Psychological Services.Google Scholar
  7. Le Goff, C., Mahaut, C., Abhyankar, A., Le Goff, W., Serre, V., Afenjar, A., et al. (2012). Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome. Nature Genetics, 44, 85–88.CrossRefGoogle Scholar
  8. Lelieveld, S. H., Wiel, L., Venselaar, H., Pfundt, R., Vriend, G., Veltman, J. A., et al. (2017). Spatial clustering of de Novo Missense mutations identifies candidate neurodevelopmental disorder-associated genes. American Journal of Human Genetics, 101(3), 478–487.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Lin, E., Michot, A. C., Cormier-Daire, V., L’Ecuyer, T. J., MatherneG, P., BarnesH, B., et al. (2016). Gain of function mutations in SMAD4 cause a distinctive repertoire of cardiovascular phenotypes in patients with Myhre syndrome. American Journal of Medical Genetics, 170A, 2617–2631.CrossRefGoogle Scholar
  10. Lord, C., Rutter, M., DiLavore, P. C., Risi, S., Gotham, K., Bishop, S. L., et al. (2012). Autism diagnostic observation schedule (2nd ed.). Torrance, CA: Western Psychological Services.Google Scholar
  11. Michot, C., Le Goff, C., Mahaut, C., Afenjar, A., Brooks, A., Campeau, M. P., et al. (2014). Myhre and LAPS syndromes: clinical and molecular review of 32 patients. European Journal of Human Genetics, 22, 1272–1277.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Millat, G., Bouvagnet, P., Chevalier, P., Sebbag, L., Dulac, A., Dauphin, C., et al. (2011). Clinical and mutational spectrum in a cohort of 105 unrelated patients with dilated cardiomyopathy. European Journal of Medical Genetics, 54(6), e570–e575.CrossRefPubMedGoogle Scholar
  13. Moss, P., Howlin, P., Savage, S., Bolton, P., & Rutter, M. (2015). Self and informant reports of mental health difficulties among adults with autism findings from a long-term follow-up study. Autism., 19(7), 832–841.CrossRefPubMedGoogle Scholar
  14. Myhre, S. A., RuvalcabaR, H., & Graham, C. B. (1981). A new growth deficiency syndrome. Clinical Genetics, 20, 1–5.CrossRefPubMedGoogle Scholar
  15. Niemi, E. M., Martin, C. H., Rice, L. D., Gallone, G., Gordon, S., Kelemen, M., et al. (2018). Common genetic variants contribute to risk of rare severe neurodevelopmental disorders. Nature, 562(7726), 268–271.CrossRefPubMedGoogle Scholar
  16. Papanikolaou, K., Paliokosta, E., Houliaras, G., Vgenopoulou, S., Giouroukou, E., Pehlivanidis, A., et al. (2009). Using the autism diagnostic interview: Revised and the autism diagnostic observation schedule-generic for the diagnosis of autism spectrum disorders in a Greek sample with a wide range of intellectual abilities. Journal of Autism and Developmental Disorders, 39(4), 414–420.CrossRefPubMedGoogle Scholar
  17. Piccolo, P., Mithbaokar, P., Sabatino, V., Tolmie, J., Melis, D., Schiaffino, M. C., et al. (2014). SMAD4 mutations causing Myhre syndrome result in disorganization of extracellular matrix improved by losartan. European Journal of Human Genetics, 22, 988–994.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Starr, L. J., Lindor, N. M., & Lin, A. E. (2017). Myhre syndrome. Seattle: University of Washington.Google Scholar
  19. Titomanlio, L., Marzano, M. G., Rossi, E., D’Armiento, M., De Brasi, D., Vega, G. R., et al. (2001). Case of Myhre syndrome with autism and peculiar skin histological findings. American Journal of Human Genetics, 103, 163–165.Google Scholar
  20. Watkins, H., McKenna, W. J., Thierfelder, L., Suk, H. J., Anan, R., O’Donoghue, A., et al. (1995). Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. New England Journal of Medicine, 332(16), 1058–1064.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.1st Department of PsychiatryNational and Kapodistrian University of Athens Medical School, “Eginition” HospitalAthensGreece
  2. 2.Department of Child PsychiatryNational and Kapodistrian University of Athens Medical School, “Agia Sophia” Children’s HospitalAthensGreece
  3. 3.Medical Genetics Choremio Research LaboratoryNational and Kapodistrian University of Athens Medical School, “Agia Sophia” Children’s HospitalAthensGreece

Personalised recommendations