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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, Viviana; Bocchinfuso, Gianfranco; Castori, Marco; Traversa, Alice; Pizzuti, Antonio; Stella, Lorenzo; Grammatico, Paola; Tartaglia, Marco (2014). "Novel SMAD4 mutation causing Myhre syndrome". American Journal of Medical Genetics Part A. 164 (7): 1835–1840. doi:10.1002/ajmg.a.36544. PMID 24715504.
  4. ^ Lin, Angela E.; Brunetti-Pierri, Nicola; Lindsay, Mark E.; Schimmenti, Lisa A.; Starr, Lois J. (1993), Adam, Margaret P.; Feldman, Jerry; Mirzaa, Ghayda M.; Pagon, Roberta A. (eds.), "Myhre Syndrome", GeneReviews®, Seattle (WA): University of Washington, Seattle, PMID 28406602, retrieved 2024-12-23
  5. ^ Starr, Lois J.; Lindsay, Mark E.; Perry, Deborah; Gheewalla, Gregory; VanderLaan, Paul A.; Majid, Adnan; Strange, Charlie; Costea, George-Claudiu; Lungu, Adrian; Lin, Angela E. (2022). "Review of the Pathologic Characteristics in Myhre Syndrome: Gain-of-Function Pathogenic Variants in SMAD4 cause a Multisystem Fibroproliferative Response". Pediatric and Developmental Pathology. 25 (6): 611–623. doi:10.1177/10935266221079569. PMID 36120950.
  6. ^ Starr, Lois J.; Grange, Dorothy K.; Delaney, Jeffrey W.; Yetman, Anji T.; Hammel, James M.; Sanmann, Jennifer N.; Perry, Deborah A.; Schaefer, G. Bradley; Olney, Ann Haskins (2015). "Myhre syndrome: Clinical features and restrictive cardiopulmonary complications". American Journal of Medical Genetics Part A. 167 (12): 2893–2901. doi:10.1002/ajmg.a.37273. PMID 26420300.
  7. ^ Lindsay, Mark E.; Scimone, Eleanor R.; Lawton, Joseph; Richa, Rashmi; Yonker, Lael M.; Di, Yuanpu P.; Buch, Karen; Ouyang, Wukun; Mo, Xiulei; Lin, Angela E.; Mou, Hongmei (2024). "Gain-of-function variants in SMAD4 compromise respiratory epithelial function". The Journal of Allergy and Clinical Immunology: S0091–6749(24)00908–4. doi:10.1016/j.jaci.2024.08.024. PMID 39243984.
  8. ^ Gallione, Carol; Aylsworth, Arthur S.; Beis, Jill; Berk, Terri; Bernhardt, Barbara; Clark, Robin D.; Clericuzio, Carol; Danesino, Cesare; Drautz, Joanne; Fahl, Jeffrey; Fan, Zheng; Faughnan, Marie E.; Ganguly, Arupa; Garvie, John; Henderson, Katharine (2010). "Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome". American Journal of Medical Genetics. Part A. 152A (2): 333–339. doi:10.1002/ajmg.a.33206. PMID 20101697.
  9. ^ a b Gheewalla, Gregory M.; Luther, Jay; Das, Saumya; Kreher, Jeffrey B.; Scimone, Eleanor R.; Wong, Ashley W.; Lindsay, Mark E.; Lin, Angela E. (2022). "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". American Journal of Medical Genetics. Part A. 188 (10): 3084–3088. doi:10.1002/ajmg.a.62915. PMID 35869926.
  10. ^ Heldin, Carl-Henrik; Miyazono, Kohei; ten Dijke, Peter (1997). "TGF-β signalling from cell membrane to nucleus through SMAD proteins". Nature. 390 (6659): 465–471. Bibcode:1997Natur.390..465H. doi:10.1038/37284. PMID 9393997.
  11. ^ a b c Lin, Angela E.; Scimone, Eleanor R.; Thom, Robyn P.; Balaguru, Duraisamy; Kinane, T. Bernard; Moschovis, Peter P.; Cohen, Michael S.; Tan, Weizhen; Hague, Cole D.; Dannheim, Katelyn; Levitsky, Lynne L.; Lilly, Evelyn; DiGiacomo, Daniel V.; Masse, Kara M.; Kadzielski, Sarah M. (2024). "Emergence of the natural history of Myhre syndrome: 47 patients evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016–2023)". American Journal of Medical Genetics Part A. 194 (10): e63638. doi:10.1002/ajmg.a.63638. PMC 11586855. PMID 38779990.
  12. ^ Cappuccio, Gerarda; Brunetti-Pierri, Nicola; Clift, Paul; Learn, Christopher; Dykes, John C.; Mercer, Catherine L.; Callewaert, Bert; Meerschaut, Ilse; Spinelli, Alessandro Mauro; Bruno, Irene; Gillespie, Matthew J.; Dorfman, Aaron T.; Grimberg, Adda; Lindsay, Mark E.; Lin, Angela E. (2022). "Expanded cardiovascular phenotype of Myhre syndrome includes tetralogy of Fallot suggesting a role for in human neural crest defects". American Journal of Medical Genetics Part A. 188 (5): 1384–1395. doi:10.1002/ajmg.a.62645. PMID 35025139.
  13. ^ Le Goff, C.; Michot, C.; Cormier-Daire, V. (2014). "Myhre syndrome". Clinical Genetics. 85 (6): 503–513. doi:10.1111/cge.12365. PMID 24580733.
  14. ^ Alape, Daniel; Singh, Rani; Folch, Erik; Fernandez Bussy, Sebastian; Agnew, Alexis; Majid, Adnan (2020). "Life-Threatening Multilevel Airway Stenosis Due to Myhre Syndrome". American Journal of Respiratory and Critical Care Medicine. 201 (6): 731–732. doi:10.1164/rccm.201905-0922im. PMID 31539271.
  15. ^ Yang, David Dawei; Rio, Marlene; Michot, Caroline; Boddaert, Nathalie; Yacoub, Wael; Garcelon, Nicolas; Thierry, Briac; Bonnet, Damien; Rondeau, Sophie; Herve, Dominique; Guey, Stephanie; Angoulvant, Francois; Cormier-Daire, Valerie (2022). "Natural history of Myhre syndrome". Orphanet Journal of Rare Diseases. 17 (1): 304. doi:10.1186/s13023-022-02447-x. PMC 9338657. PMID 35907855.
  16. ^ Vanbelleghem, Eva; Van Damme, Tim; Beyens, Aude; Symoens, Sofie; Claes, Kathleen; De Backer, Julie; Meerschaut, Ilse; Vanommeslaeghe, Floris; Delanghe, Sigurd E.; van den Ende, Jenneke; Beyltjens, Tessi; Scimone, Eleanor R.; Lindsay, Mark E.; Schimmenti, Lisa A.; Hinze, Alicia M. (2024). "Myhre syndrome in adulthood: clinical variability and emerging genotype-phenotype correlations". European Journal of Human Genetics: EJHG. 32 (9): 1086–1094. doi:10.1038/s41431-024-01664-1. PMC 11369149. PMID 38997468.
  17. ^ Shi, Yigong; Massagué, Joan (2003). "Mechanisms of TGF-β Signaling from Cell Membrane to the Nucleus". Cell. 113 (6): 685–700. doi:10.1016/s0092-8674(03)00432-x. PMID 12809600.
  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. ^ Meerschaut, Ilse; Beyens, Aude; Steyaert, Wouter; De Rycke, Riet; Bonte, Katrien; De Backer, Tine; Janssens, Sandra; Panzer, Joseph; Plasschaert, Frank; De Wolf, Daniël; Callewaert, Bert (2019). "Myhre syndrome: A first familial recurrence and broadening of the phenotypic spectrum". American Journal of Medical Genetics Part A. 179 (12): 2494–2499. doi:10.1002/ajmg.a.61377. PMID 31595668.
  20. ^ Cappuccio, Gerarda; Caiazza, Martina; Roca, Alessandro; Melis, Daniela; Iuliano, Antonella; Matyas, Gabor; Rubino, Marta; Limongelli, Giuseppe; Brunetti-Pierri, Nicola (2021). "A pilot clinical trial with losartan in Myhre syndrome". American Journal of Medical Genetics Part A. 185 (3): 702–709. doi:10.1002/ajmg.a.62019. PMC 7898344. PMID 33369056.
  21. ^ Myhre, Selma A.; Ruvalcaba, Rogelio H. A.; Graham, C. Benjamin (1981). "A new growth deficiency syndrome". Clinical Genetics. 20 (1): 1–5. doi:10.1111/j.1399-0004.1981.tb01798.x. PMID 7296942.
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