Skip to main content

Advertisement

SpringerLink
Log in

Natural history and life-threatening complications in Myhre syndrome and review of the literature

  • Original Article
  • Published:
European Journal of Pediatrics Aims and scope Submit manuscript

Abstract

Myhre syndrome (OMIM 139210) is a rare developmental disorder inherited as an autosomal dominant trait and caused by a narrow spectrum of missense mutations in the SMAD4 gene. The condition features characteristic face, short stature, skeletal anomalies, muscle pseudohypertrophy, restricted joint mobility, stiff and thick skin, and variable intellectual disability. While most of the clinical features manifest during childhood, the diagnosis may be challenging during the first years of life. We report on the evolution of the clinical features of Myhre syndrome during childhood in a subject with molecularly confirmed diagnosis. The clinical records of 48 affected patients were retrospectively analysed to identify any early clinical signs characterizing this disorder and to better delineate its natural history. We also note that pericarditis and laryngotracheal involvement represent important life-threatening complications of Myhre syndrome that justify the recommendation for cardiological and ENT follow-up for these patients.

Conclusion: Short length/stature, short palpebral fissures, and brachydactyly with hyperconvex nails represent signs/features that might lead to the correct diagnosis in the first years of life and direct to the proper molecular analysis. We underline the clinical relevance of pericarditis and laryngotracheal stenosis as life-threatening complications of this disorder and the need for careful monitoring, in relation to their severity.

What is Known:

• The clinical and radiological signs of the disease in children older than 7–8 years.

• Pericarditis, sometimes occurring with constrictive pericardium requiring pericardiectomy, has been reported as a recurrent feature but has not been adequately stressed in previous literature.

What is New:

• Short length/stature, short palpebral fissures, brachydactyly with hyperconvex nails represent clinical signs that might lead to diagnosis in the first years of life.

• Review of the literature showed that pericarditis and laryngotracheal complications represent major recurrent issues in patients with Myhre syndrome.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

BMI:

Body mass index

CT:

Computerized tomography

ENT:

Ear nose throat

FISH:

Fluorescence in situ hybridization

MRI:

Magnetic resonance imaging

MYHRS:

Myhre syndrome

SMAD4:

SMA- and MAD-related protein 4

References

  1. Al Ageeli E, Mignot C, Afenjar A, Whalen S, Dorison N, Mayer M, Esteva B, Dubern B, Momtchilova M, Le Gargasson JF, Bursztyn J, Héron D (2012) Retinal involvement in two unrelated patients with Myhre syndrome. Eur J Med Genet 55:541–547

    Article  PubMed  Google Scholar 

  2. Asakura Y, Muroya K, Sato T, Kurosawa K, Nishimura G, Adachi M (2012) First case of a Japanese girl with Myhre syndrome due to a heterozygous SMAD4 mutation. Am J Med Genet A 158:1982–1986

    Article  CAS  Google Scholar 

  3. Burglen L, Héron D, Moerman A, Dieux- Coeslier A, Bourguiognon JP, Bachy A, Carel JC, Cormier-Daire V, Monouvrier S, Verloes A (2003) Myhre syndrome new reports, review, and differential diagnosis. J Med Genet 40:546–551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Caputo V, Bocchinfuso G, Castori M, Traversa A, Pizzuti A, Stella L, Grammatico P, Tartaglia M (2014) Novel SMAD4 mutation causing Myhre syndrome. Am J Med Genet A 164(7):1835–1840

    Article  CAS  Google Scholar 

  5. Caputo V, Cianetti L, Niceta M, Carta C, Ciolfi A, Bocchinfuso G, Carrani E, Dentici ML, Biamino E, Belligni E, Garavelli L, Boccone L, Melis D, Andria G, Gelb BD, Stella L, Silengo M, Dallapiccola B, Tartaglia M (2012) A restricted Spectrum of mutations in the SMAD4 tumor-suppressor Gene underlines Myhre syndrome. Am J Hum Genet 90:161–169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Garcia-Cruz D, Figuera LE, Feria-Velazco A, Sánchez-Corona J, Garcia-Cruz MO, Ramirez-Duenãs RM, Hernandez-Córdova A, Ruiz MX, Bitar-Alatorre WE, Ramirez-Dueñas ML, Cantù JM (1993) The Myhre syndrome: report of two cases. Clin Genet 44:203–207

    Article  CAS  PubMed  Google Scholar 

  7. Hawkes L, Kini U (2015) Myhre syndrome with facial paralysis and branch pulmonary stenosis. Clin Dysmorphol 24:84–85

    Article  PubMed  Google Scholar 

  8. Hopkin RJ, Cotton R, Langer LO, Saal HM (1998) Progressive laryngotracheal stenosis with short stature and arthropathy. Am J Med Genet 80:241–246

    Article  CAS  PubMed  Google Scholar 

  9. Kenis C, Verstreken M, Gieraerts K, De Foer B, Van der Aa N, Offeciers EF, Casselman JW (2014) Bilateral otospongiosis and uniteral vestibular schwannoma in a patient with Myhre syndrome. Otol & Neurol 35(9):e253–e255

    Article  Google Scholar 

  10. Le Goff CL, Cormier-Daire V (2012) The role of TGFβ signalling in growth and its disorders. Am J Med Genet C 160:145–153

    Article  CAS  Google Scholar 

  11. Le Goff C, Mahaut C, Abhyankar A, Le Goff W, Serre V, Afenjar A, Destrée A, Di Rocco M, Héron D, Jacquemont S, Marlin S, Simon M, Tolmie J, Verloes A, Casanova JL, Munnich A, Cormier-Daire V (2012) Mutations at a single codon in mad homology 2 domain of SMAD4 cause Myhre syndrome. Nat Genet 44:85–88

    Article  CAS  Google Scholar 

  12. Le Goff C, Michot C, Cormier-Daire V (2014) Myhre syndrome. Clin Genet 85:503–513

    Article  CAS  PubMed  Google Scholar 

  13. Lindor NM, Kasperbauer JL, Hoffman AD, Parisi JE, Wang H, Warman M (2002) Confirmation of existence of a new syndrome: LAPS syndrome. Am J Med Genet 109:93–99

    Article  PubMed  Google Scholar 

  14. Lindor NM (2009) LAPS syndrome and Myhre syndrome: two disorders or one? Am J Med Genet A 149:798–799

    Article  Google Scholar 

  15. Lindor NM, Gunawardena SR, Thibodeau SN (2012) Mutations of SMAD4 account for both LAPS and Myhre syndromes. Am J Med Genet A 158:1520–1521

    Article  CAS  Google Scholar 

  16. Lopez-Cardona MG, Garzia-Cruz D, Garcia Ortiz JE, Davalos NO, Feria-Velasco A, Rodriguez-Rojas LX, Garcia-Cruz MO, Figuera-Villanueva LE, Stephens A, Larios-Arceo F, Sanchez-Corona J (2004) Second female case of Myhre syndrome. Clin Dysmorphol 13:91–94

    Article  CAS  PubMed  Google Scholar 

  17. McGowan R, Gulati R, McHenry P, Cooke A, Butler S, Keng WT, Murday V, Witheford M, Dikkers FG, Sikkema-Raddatz B, van Essen T, Tolmie G (2011) Clinical features and respiratory complications in Myhre syndrome. Eur J Med Genet 54(6):e553–e559

    PubMed  Google Scholar 

  18. Michot C, Le Goff C, Mahaut C, Afenjar A, Brooks AS, Campeau PM, Destree A, Di Rocco M, Donnai D, Hennekam R, Heron D, Jacquemont S, Kannu P, Lin AE, Manouvrier-Hanu S, Mansour S, Marlin S, McGowan R, Murphy H, Raas-Rothschild A, Rio M, Simon M, Stolte-Dijkstra I, Stone JR, Sznajer Y, Tolmie J, Touraine R, van den Ende J, Van der Aa N, van Essen T, Verloes A, Munnich A, Cormier-Daire V (2014) Myhre and LAPS syndromes: clinical and molecular review of 32 patients. Eur J Hum Genet 22:1272–1277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Myhre SA, Ruvalcaba RHA, Graham CB (1981) A new growth deficiency syndrome. Clin Genet 20:1–5

    Article  CAS  PubMed  Google Scholar 

  20. Picco P, Naselli A, Pala G, Marsciani A, Buoncompagni A, Martini A (2013) Recurrent pericarditis in Myhre syndrome. Am J Med Genet A 161:1164–1166

    Article  Google Scholar 

  21. Piccolo P, Mithbaokar P, Sabatino V, Tolmie J, Melis D, Schiaffino MC, Filocamo M, Andria G, Brunetti-Pierri N (2014) SMAD4 mutations causing Myhre syndrome result in disorganization of extracellular matrix improved by losartan. Eu. J Hum Genet 22:988–994

    Article  CAS  Google Scholar 

  22. Rahman MS, Akhtar N, Jamil HM, Banik RS, Asaduzzaman SM (2015) TGF-β/BMP signaling and other molecular events: regulation of osteoblastogenesis and bone formation. Bone Res 3:15005. doi:10.1038/boneres.2015.5 eCollection 2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Starr LJ, Grange DK, Delaney JW, Yetman AT, Hammel JM, Sanmann JN, Perry DA, Schaefer GB, Olney AH (2015) Myhre syndrome: clinical features and restrictive cardiopulmonary complications. Am J Med Genet A 167:2893–2901

    Article  Google Scholar 

  24. Van Steensel MAM, Vreeburg M, Steijlen PM, de Die-Smulders C (2005) Myhre syndrome in a female with previously undescribed symptoms: further delineation of the phenotype. Am J Med Genet A 139:127–130

    Article  Google Scholar 

  25. Whiteford ML, Doig WB, Raine PA, Hollman AS, Tolmie JL (2001) A new case of Myhre syndrome. Clin Dysmorphol 10:135–140

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors wish to thank the co-operating family members for the necessary medical data and photographs for publication, Dr.Viviana Caputo Dr. Alessandro De Fanti, Dr. Chiara Gelmini, and Dr. Anita Wischmeijer for their cooperation and their valuable help in the study of this clinical case, as well as the photographers Marco Bonazzi and Luca Valcavi. The technical assistance of Dorothea Bornholdt is gratefully acknowledged.

Author’s contribution

Livia Garavelli1 made the clinical diagnosis of Myhre syndrome, and conceived, and wrote the manuscript;

Ilenia Maini1, examined the child in the follow-up, wrote the manuscript, and contributed to data collection and analysis;

Federica Baccilieri1, examined the child in the follow-up and contributed to the manuscript;

Ivan Ivanovski1,2, examined the child in the follow-up and contributed to the manuscript, and data collection and analysis;

Marzia Pollazzon1, examined the child in the follow-up in the last 2 years for the connective tissue problems and carried out the genetic counselling for the parents;

Simonetta Rosato1 collected all the auxological data;

Lorenzo Iughetti3 examined the child in the follow-up for growth retardation;

Sheila Unger4 confirmed the clinical diagnosis on the basis of the clinical and radiological features and contributed to the manuscript and data analysis;

Andrea Superti-Furga5 confirmed the clinical diagnosis on the basis of the clinical and radiological features and contributed to the manuscript and data analysis;

Marco Tartaglia6 carried out the molecular analysis together with his group, discussed the case with clinicians, and contributed to the manuscript and data analysis.

Author information

Authors and Affiliations

  1. Clinical Genetics Unit, Department of Obstetrics and Paediatrics, IRCCS, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy

    Livia Garavelli, Ilenia Maini, Federica Baccilieri, Ivan Ivanovski, Marzia Pollazzon & Simonetta Rosato

  2. Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy

    Ivan Ivanovski

  3. Department of Medical and Surgical Sciences of Childhood and Adult, University of Modena and Reggio Emilia, Modena, Italy

    Lorenzo Iughetti

  4. Medical Genetics Service, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

    Sheila Unger

  5. Department of Paediatrics, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland

    Andrea Superti-Furga

  6. Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy

    Marco Tartaglia

Authors
  1. Livia Garavelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ilenia Maini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Federica Baccilieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ivan Ivanovski
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marzia Pollazzon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Simonetta Rosato
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lorenzo Iughetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sheila Unger
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Andrea Superti-Furga
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Marco Tartaglia
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Livia Garavelli.

Ethics declarations

Funding

This study was supported in part by intramural funding by Ospedale Pediatrico Bambino Gesù (GeneRare to M.T.) and by Fondazione Cassa di Risparmio di Reggio Emilia Pietro Manodori.

Conflict of interest

The authors declare that they have no competing interests.

Ethics approval and consent to participate

All procedures performed in study involving the patient were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Written informed consent to publish the photographs was obtained from the parents.

Additional information

Communicated by Beat Steinmann

Revisions received: 14 July 2016; 9 August 2016

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Garavelli, L., Maini, I., Baccilieri, F. et al. Natural history and life-threatening complications in Myhre syndrome and review of the literature. Eur J Pediatr 175, 1307–1315 (2016). https://doi.org/10.1007/s00431-016-2761-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00431-016-2761-3

Keywords

Search

Navigation