Myhre syndrome

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]

  1. ^ 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. ^ 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.