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Myhre syndrome

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Myhre syndrome
Other namesLAPS syndrome, Laryngotracheal stenosis, Arthropathy, Prognathism, and Short stature syndrome[1]
Myhre syndrome is inherited in an autosomal dominant manner[2]
SpecialtyMedical genetics

Myhre syndrome (MS) is an ultrarare genetic disorder caused by dominant gain-of-function (GOF) mutations in the SMAD4 gene.[3] MS mutations are missense heterozygous mutations affecting only Ile500 or Arg496 residues of the SMAD4 protein.[4] MS patients exhibit manifestations of connective tissue disease including dysfunction of the integumentary, cardiovascular, respiratory, gastrointestinal, and musculoskeletal systems and is often characterized by proliferative systemic fibrosis.[5] Some of these features are life threatening, such as airway or arterial narrowing (laryngotracheal stenosis or aortic coarctation) and fibroproliferation of tissues including lung, heart, and liver.[6] Consistent with these clinical observations, cells isolated from patients with MS demonstrate increased TGF-β signaling.[7]

In contrast, loss-of-function (LOF) mutations in SMAD4 predispose individuals to gastrointestinal polyps, a higher risk of colorectal cancer, and a risk of forming arteriovenous malformations (AVM) a hallmark manifestation of hereditary hemorrhagic telangiectasia (HHT).[8] Patients also have external phenotypes similar to Marfan syndrome.[9]

Biologically, SMAD4 plays a prominent role in both canonical TGF-β and other TGF-β superfamily signaling.[10] The systemic manifestations of these two disorders suggest opposite biologic effects, such as the finding of aortic aneurysm in SMAD4-JP-HHT (LOF of SMAD4) versus the aortic hypoplasia seen in Myhre syndrome (GOF in SMAD4).[9]

Signs and symptoms

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The clinical presentation is variable but includes:[11][12][13][14][15][16]

The facial abnormalities include:

  • Short palpebral fissures (opening of the eyes)
  • Maxillary hypoplasia (underdevelopment of the upper jaw)
  • Maxillary hypoplasia (underdevelopment of the upper jaw)
  • Prognathism (prominent lower jaw)
  • Short philtrum
  • Prominent nose

The Musculo-skeletal abnormalities include:

Cardiovascular abnormalities include:

  • Congenital heart defects
  • Atrial septal defect
  • Ventricular septal defect
  • Patent ductus arteriosus
  • Tetralogy of Fallot
  • Aortic coarctation
  • Aortic stenosis
  • Mitral valve stenosis
  • Aortic hypoplasia
  • Pericardial effusion
  • Pericarditis
  • Restrictive cardiomyopathy

Other anomalies

  • Undescended testes in males

Genetics

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Myhre syndrome is due to mutations in the SMAD4 gene.[3] This gene encodes a protein - transducer mediating transforming growth factor beta. Some researchers believe that the SMAD4 gene mutations that cause Myhre syndrome impair the ability of the SMAD4 protein to attach (bind) properly with the other proteins involved in the signaling pathway. Other studies have suggested that these mutations result in an abnormally stable SMAD4 protein that remains active in the cell longer. Changes in SMAD4 binding or availability may result in abnormal signaling in many cell types, which affects development of several body systems and leads to the signs and symptoms of Myhre syndrome.[17][18]

The patients of this disease exhibit hypertrophic phenotype in their muscle tissues. Myostatin target genes are found to be downregulated while bone morphogenetic protein (BMP) target genes display both upregulated and downregulated genotypes.[18]

Diagnosis

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The diagnosis of Myhre syndrome is established in a proband with characteristic clinical findings and a heterozygous pathogenic (or likely pathogenic) variant in SMAD4 detected by molecular genetic testing.[11] Because Myhre syndrome is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family).[11] Rarely, the family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations).[19]

Treatment

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There are currently no disease specific therapies, although the use of losartan has been suggested to prevent fibrosis.[20]

History

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This disorder was first reported in 1981.[21] It has many similarities to LAPS Syndrome and they both arise from the same mutations in the SMAD4 gene. It is believed that they are the same syndrome.[1]

References

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This article incorporates text from the United States National Library of Medicine ([1]), which is in the public domain.

  1. ^ a b Lindor NM, Gunawardena SR, Thibodeau SN. Mutations of SMAD4 account for both LAPS and Myhre syndromes. Am J Med Genet A. 2012;158a(6):1520-1.
  2. ^ RESERVED, INSERM US14 -- ALL RIGHTS. "Orphanet: Myhre syndrome". www.orpha.net. Retrieved 27 December 2017.{{cite web}}: CS1 maint: numeric names: authors list (link)
  3. ^ a b 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 doi: 10.1002/ajmg.a.36544
  4. ^ Lin AE, Brunetti-Pierri N, Lindsay ME, Schimmenti LA, Starr LJ. Myhre Syndrome. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJ, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993 [cited 2024 Mar 18]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK425723/ PMID: 28406602
  5. ^ Starr LJ, Lindsay ME, Perry D, Gheewalla G, VanderLaan PA, Majid A, Strange C, Costea GC, Lungu A, Lin AE. Review of the Pathologic Characteristics in Myhre Syndrome: Gain-of-Function Pathogenic Variants in SMAD4 cause a Multisystem Fibroproliferative Response. Pediatr Dev Pathol. 2022;25(6):611–623. PMID: 36120950
  6. ^ Starr LJ, Grange DK, Delaney JW, Yetman AT, Hammel JM, Sanmann JN, et al. Myhre syndrome: Clinical features and restrictive cardiopulmonary complications. Am J Med Genet A. 2015;167a(12):2893-901.
  7. ^ Lindsay ME, Scimone ER, Lawton J, Richa R, Yonker LM, Di YP, Buch K, Ouyang W, Mo X, Lin AE, Mou H. Gain-of-function variants in SMAD4 compromise respiratory epithelial function. Journal of Allergy and Clinical Immunology. 2024 Sep;S0091674924009084.
  8. ^ Gallione C, Aylsworth AS, Beis J, Berk T, Bernhardt B, Clark RD, Clericuzio C, Danesino C, Drautz J, Fahl J, Fan Z, Faughnan ME, Ganguly A, Garvie J, Henderson K, Kini U, Leedom T, Ludman M, Lux A, Maisenbacher M, Mazzucco S, Olivieri C, Ploos van Amstel JK, Prigoda-Lee N, Pyeritz RE, Reardon W, Vandezande K, Waldman JD, White RI, Williams CA, Marchuk DA. Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome. Am J Med Genet A. 2010 Feb;152A(2):333– 339. PMID: 20101697
  9. ^ a b Gheewalla GM, Luther J, Das S, Kreher JB, Scimone ER, Wong AW, Lindsay ME, Lin AE. An additional patient with SMAD4-Juvenile Polyposis-Hereditary hemorrhagic telangiectasia and connective tissue abnormalities: SMAD4 loss-of-function and gain-of-function pathogenic variants result in contrasting phenotypes. Am J Med Genet A. 2022 Oct;188(10):3084-3088. doi: 10.1002/ajmg.a.62915. Epub 2022 Jul 23. PubMed PMID: 35869926.
  10. ^ Heldin CH, Miyazono K, ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature. 1997 Dec 4;390(6659):465–71.
  11. ^ a b c Lin AE, Scimone ER, Thom RP, Balaguru D, Kinane TB, Moschovis PP, Cohen MS, Tan W, Hague CD, Dannheim K, Levitsky LL, Lilly E, DiGiacomo DV, Masse KM, Kadzielski SM, Zar-Kessler CA, Ginns LC, Neumeyer AM, Colvin MK, Elder JS, Learn CP, Mou H, Weagle KM, Buch KA, Butler WE, Alhadid K, Musolino PL, Sultana S, Bandyopadhyay D, Rapalino O, Peacock ZS, Chou EL, Heidary G, Dorfman AT, Morris SA, Bergin JD, Rayment JH, Schimmenti LA, Lindsay ME, MGH Myhre Syndrome Study Group. Emergence of the natural history of Myhre syndrome: 47 patients evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016–2023). American J of Med Genetics Pt A. 2024 Oct;194(10):e63638.
  12. ^ Expanded cardiovascular phenotype of Myhre syndrome includes tetralogy of Fallot suggesting a role for SMAD4 in human neural crest defects Gerarda Cappuccio, Nicola Brunetti-Pierri, Paul Clift, Christopher Learn, John C. Dykes, Catherine L. Mercer, Bert Callewaert, Ilse Meerschaut, Alessandro Mauro Spinelli, Irene Bruno, Matthew J. Gillespie, Aaron T. Dorfman, Adda Grimberg, Mark E. Lindsay, Angela E. Lin First published: 13 January 2022 https://doi.org/10.1002/ajmg.a.62645
  13. ^ Le Goff C, Michot C, Cormier-Daire V. Myhre syndrome. Clin Genet. 2014 Jun;85(6):503–513. PMID: 24580733
  14. ^ Alape D, Singh R, Folch E, Fernandez Bussy S, Agnew A, Majid A. Life-Threatening Multilevel Airway Stenosis Due to Myhre Syndrome. Am J Respir Crit Care Med. 2020;201(6):731-2.
  15. ^ Yang DD, Rio M, Michot C, Boddaert N, Yacoub W, Garcelon N, et al. Natural history of Myhre syndrome. Orphanet J Rare Dis. 2022;17(1):304.
  16. ^ Myhre syndrome in adulthood: clinical variability and emerging genotype-phenotype correlations Eva Vanbelleghem # 1 2, Tim Van Damme # 1, Aude Beyens 1 2, Sofie Symoens 1 2, Kathleen Claes 1 2, Julie De Backer 1 3, Ilse Meerschaut 4, Floris Vanommeslaeghe 5, Sigurd E Delanghe 5, Jenneke van den Ende 6, Tessi Beyltjens 6, Eleanor R Scimone 7, Mark E Lindsay 8 9, Lisa A Schimmenti 10, Alicia M Hinze 11, Emily Dunn 12, Natalia Gomez-Ospina 12, Isabelle Vandernoot 13, Thomas Delguste 13, Sandra Coppens 13, Valérie Cormier-Daire 14, Marco Tartaglia 15, Livia Garavelli 16, Joseph Shieh 17, Şenol Demir 18, Esra Arslan Ateş 19, Martin Zenker 20, Mersedeh Rohanizadegan 21, Greysha Rivera-Cruz 22, Sofia Douzgou 23; Myhre Syndrome Foundation; Angela E Lin 7, Bert Callewaert 24 25 Collaborators, Affiliations Expand PMID: 38997468 PMCID: PMC11369149 (available on 2025-09-01) DOI: 10.1038/s41431-024-01664-1
  17. ^ Shi, Y. & Massague, J. Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell 113, 685–700 (2003).
  18. ^ a b Le Goff, Carine; Mahaut, Clémentine; Abhyankar, Avinash; Le Goff, Wilfried; Serre, Valérie; Afenjar, Alexandra; Destrée, Anne; di Rocco, Maja; Héron, Delphine; Jacquemont, Sébastien; Marlin, Sandrine; Simon, Marleen; Tolmie, John; Verloes, Alain; Casanova, Jean-Laurent; Munnich, Arnold; Cormier-Daire, Valérie (December 2011). "Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome". Nature Genetics. 44 (1): 85–88. doi:10.1038/ng.1016. PMID 22158539. S2CID 13042633. Retrieved 11 July 2015.
  19. ^ Myhre syndrome: A first familial recurrence and broadening of the phenotypic spectrum Ilse Meerschaut, Aude Beyens, Wouter Steyaert, Riet De Rycke, Katrien Bonte, Tine De Backer, Sandra Janssens, Joseph Panzer, Frank Plasschaert, Daniël De Wolf, Bert Callewaert First published: 09 October 2019 https://doi.org/10.1002/ajmg.a.61377
  20. ^ A pilot clinical trial with losartan in Myhre syndrome Gerarda Cappuccio, Martina Caiazza, Alessandro Roca, Daniela Melis, Antonella Iuliano, Gabor Matyas, Marta Rubino, Giuseppe Limongelli, Nicola Brunetti-Pierri First published: 24 December 2020 https://doi.org/10.1002/ajmg.a.62019
  21. ^ Myhre SA, Ruvalcaba RHA, Graham CB (1981) A new growth deficiency syndrome. Clin Genet 20: 1-5
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