Myhre syndrome

{{Infobox medical condition

| synonyms = LAPS syndrome, Laryngotracheal stenosis, Arthropathy, Prognathism, and Short stature syndromeLindor 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.

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| field = Medical genetics

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Myhre syndrome (MS) is an ultrarare genetic disorder caused by dominant gain-of-function (GOF) mutations in the SMAD4 gene.{{Cite journal |last1=Caputo |first1=Viviana |last2=Bocchinfuso |first2=Gianfranco |last3=Castori |first3=Marco |last4=Traversa |first4=Alice |last5=Pizzuti |first5=Antonio |last6=Stella |first6=Lorenzo |last7=Grammatico |first7=Paola |last8=Tartaglia |first8=Marco |date=2014 |title=Novel SMAD4 mutation causing Myhre syndrome |journal=American Journal of Medical Genetics Part A |language=en |volume=164 |issue=7 |pages=1835–1840 |doi=10.1002/ajmg.a.36544|pmid=24715504 }} MS mutations are missense heterozygous mutations affecting only Ile500 or Arg496 residues of the SMAD4 protein.{{Citation |last1=Lin |first1=Angela E. |title=Myhre Syndrome |date=1993 |work=GeneReviews® |editor-last=Adam |editor-first=Margaret P. |url=http://www.ncbi.nlm.nih.gov/books/NBK425723/ |access-date=2024-12-23 |place=Seattle (WA) |publisher=University of Washington, Seattle |pmid=28406602 |last2=Brunetti-Pierri |first2=Nicola |last3=Lindsay |first3=Mark E. |last4=Schimmenti |first4=Lisa A. |last5=Starr |first5=Lois J. |editor2-last=Feldman |editor2-first=Jerry |editor3-last=Mirzaa |editor3-first=Ghayda M. |editor4-last=Pagon |editor4-first=Roberta A.}} 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.{{Cite journal |last1=Starr |first1=Lois J. |last2=Lindsay |first2=Mark E. |last3=Perry |first3=Deborah |last4=Gheewalla |first4=Gregory |last5=VanderLaan |first5=Paul A. |last6=Majid |first6=Adnan |last7=Strange |first7=Charlie |last8=Costea |first8=George-Claudiu |last9=Lungu |first9=Adrian |last10=Lin |first10=Angela E. |date=2022 |title=Review of the Pathologic Characteristics in Myhre Syndrome: Gain-of-Function Pathogenic Variants in SMAD4 cause a Multisystem Fibroproliferative Response |journal=Pediatric and Developmental Pathology |volume=25 |issue=6 |pages=611–623 |doi=10.1177/10935266221079569 |pmid=36120950}} 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.{{Cite journal |last1=Starr |first1=Lois J. |last2=Grange |first2=Dorothy K. |last3=Delaney |first3=Jeffrey W. |last4=Yetman |first4=Anji T. |last5=Hammel |first5=James M. |last6=Sanmann |first6=Jennifer N. |last7=Perry |first7=Deborah A. |last8=Schaefer |first8=G. Bradley |last9=Olney |first9=Ann Haskins |date=2015 |title=Myhre syndrome: Clinical features and restrictive cardiopulmonary complications |journal=American Journal of Medical Genetics Part A |volume=167 |issue=12 |pages=2893–2901 |doi=10.1002/ajmg.a.37273|pmid=26420300 }} Consistent with these clinical observations, cells isolated from patients with MS demonstrate increased TGF-β signaling.{{Cite journal |last1=Lindsay |first1=Mark E. |last2=Scimone |first2=Eleanor R. |last3=Lawton |first3=Joseph |last4=Richa |first4=Rashmi |last5=Yonker |first5=Lael M. |last6=Di |first6=Yuanpu P. |last7=Buch |first7=Karen |last8=Ouyang |first8=Wukun |last9=Mo |first9=Xiulei |last10=Lin |first10=Angela E. |last11=Mou |first11=Hongmei |date=2024 |title=Gain-of-function variants in SMAD4 compromise respiratory epithelial function |journal=The Journal of Allergy and Clinical Immunology |pages=S0091–6749(24)00908–4 |doi=10.1016/j.jaci.2024.08.024 |pmid=39243984}}

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).{{Cite journal |last1=Gallione |first1=Carol |last2=Aylsworth |first2=Arthur S. |last3=Beis |first3=Jill |last4=Berk |first4=Terri |last5=Bernhardt |first5=Barbara |last6=Clark |first6=Robin D. |last7=Clericuzio |first7=Carol |last8=Danesino |first8=Cesare |last9=Drautz |first9=Joanne |last10=Fahl |first10=Jeffrey |last11=Fan |first11=Zheng |last12=Faughnan |first12=Marie E. |last13=Ganguly |first13=Arupa |last14=Garvie |first14=John |last15=Henderson |first15=Katharine |date=2010 |title=Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome |journal=American Journal of Medical Genetics. Part A |volume=152A |issue=2 |pages=333–339 |doi=10.1002/ajmg.a.33206 |pmid=20101697}} Patients also have external phenotypes similar to Marfan syndrome.{{Cite journal |last1=Gheewalla |first1=Gregory M. |last2=Luther |first2=Jay |last3=Das |first3=Saumya |last4=Kreher |first4=Jeffrey B. |last5=Scimone |first5=Eleanor R. |last6=Wong |first6=Ashley W. |last7=Lindsay |first7=Mark E. |last8=Lin |first8=Angela E. |date=2022 |title=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 |journal=American Journal of Medical Genetics. Part A |volume=188 |issue=10 |pages=3084–3088 |doi=10.1002/ajmg.a.62915 |pmid=35869926}}

Biologically, SMAD4 plays a prominent role in both canonical TGF-β and other TGF-β superfamily signaling.{{Cite journal |last1=Heldin |first1=Carl-Henrik |last2=Miyazono |first2=Kohei |last3=ten Dijke |first3=Peter |date=1997 |title=TGF-β signalling from cell membrane to nucleus through SMAD proteins |journal=Nature |volume=390 |issue=6659 |pages=465–471 |doi=10.1038/37284|pmid=9393997 |bibcode=1997Natur.390..465H }} 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).

Signs and symptoms

The clinical presentation is variable but includes:{{Cite journal |last1=Lin |first1=Angela E. |last2=Scimone |first2=Eleanor R. |last3=Thom |first3=Robyn P. |last4=Balaguru |first4=Duraisamy |last5=Kinane |first5=T. Bernard |last6=Moschovis |first6=Peter P. |last7=Cohen |first7=Michael S. |last8=Tan |first8=Weizhen |last9=Hague |first9=Cole D. |last10=Dannheim |first10=Katelyn |last11=Levitsky |first11=Lynne L. |last12=Lilly |first12=Evelyn |last13=DiGiacomo |first13=Daniel V. |last14=Masse |first14=Kara M. |last15=Kadzielski |first15=Sarah M. |date=2024 |title=Emergence of the natural history of Myhre syndrome: 47 patients evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016–2023) |journal=American Journal of Medical Genetics Part A |volume=194 |issue=10 |pages=e63638 |doi=10.1002/ajmg.a.63638|pmid=38779990 |pmc=11586855 }}{{Cite journal |last1=Cappuccio |first1=Gerarda |last2=Brunetti-Pierri |first2=Nicola |last3=Clift |first3=Paul |last4=Learn |first4=Christopher |last5=Dykes |first5=John C. |last6=Mercer |first6=Catherine L. |last7=Callewaert |first7=Bert |last8=Meerschaut |first8=Ilse |last9=Spinelli |first9=Alessandro Mauro |last10=Bruno |first10=Irene |last11=Gillespie |first11=Matthew J. |last12=Dorfman |first12=Aaron T. |last13=Grimberg |first13=Adda |last14=Lindsay |first14=Mark E. |last15=Lin |first15=Angela E. |date=2022 |title=Expanded cardiovascular phenotype of Myhre syndrome includes tetralogy of Fallot suggesting a role for in human neural crest defects |journal=American Journal of Medical Genetics Part A |language=en |volume=188 |issue=5 |pages=1384–1395 |doi=10.1002/ajmg.a.62645|pmid=35025139 }}{{Cite journal |last1=Le Goff |first1=C. |last2=Michot |first2=C. |last3=Cormier-Daire |first3=V. |date=2014 |title=Myhre syndrome |journal=Clinical Genetics |volume=85 |issue=6 |pages=503–513 |doi=10.1111/cge.12365 |pmid=24580733}}{{Cite journal |last1=Alape |first1=Daniel |last2=Singh |first2=Rani |last3=Folch |first3=Erik |last4=Fernandez Bussy |first4=Sebastian |last5=Agnew |first5=Alexis |last6=Majid |first6=Adnan |date=2020 |title=Life-Threatening Multilevel Airway Stenosis Due to Myhre Syndrome |journal=American Journal of Respiratory and Critical Care Medicine |volume=201 |issue=6 |pages=731–732 |doi=10.1164/rccm.201905-0922im|pmid=31539271 }}{{Cite journal |last1=Yang |first1=David Dawei |last2=Rio |first2=Marlene |last3=Michot |first3=Caroline |last4=Boddaert |first4=Nathalie |last5=Yacoub |first5=Wael |last6=Garcelon |first6=Nicolas |last7=Thierry |first7=Briac |last8=Bonnet |first8=Damien |last9=Rondeau |first9=Sophie |last10=Herve |first10=Dominique |last11=Guey |first11=Stephanie |last12=Angoulvant |first12=Francois |last13=Cormier-Daire |first13=Valerie |date=2022 |title=Natural history of Myhre syndrome |journal=Orphanet Journal of Rare Diseases |volume=17 |issue=1 |pages=304 |doi=10.1186/s13023-022-02447-x|doi-access=free |pmid=35907855 |pmc=9338657 }}{{Cite journal |last1=Vanbelleghem |first1=Eva |last2=Van Damme |first2=Tim |last3=Beyens |first3=Aude |last4=Symoens |first4=Sofie |last5=Claes |first5=Kathleen |last6=De Backer |first6=Julie |last7=Meerschaut |first7=Ilse |last8=Vanommeslaeghe |first8=Floris |last9=Delanghe |first9=Sigurd E. |last10=van den Ende |first10=Jenneke |last11=Beyltjens |first11=Tessi |last12=Scimone |first12=Eleanor R. |last13=Lindsay |first13=Mark E. |last14=Schimmenti |first14=Lisa A. |last15=Hinze |first15=Alicia M. |date=2024 |title=Myhre syndrome in adulthood: clinical variability and emerging genotype-phenotype correlations |journal=European Journal of Human Genetics |volume=32 |issue=9 |pages=1086–1094 |doi=10.1038/s41431-024-01664-1 |pmc=11369149 |pmc-embargo-date=2025-09-01 |pmid=38997468}}

Small at birth
Developmental and growth delays
Firm skin
Keratosis pilaris
“Athletic” muscular build
Characteristic facial appearance
Deafness
Hyperopia
Variable cognitive deficits
Autism spectrum disorders/social disability
Tracheal stenosis
Premature puberty
Heavy menses in females
Aortic stenosis
Pyloric stenosis

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:

Short stature
Stiff joints/stiff gait
Scoliosis
Straight spine
Square body shape
Broad ribs
Iliac hypoplasia
Brachydactyly
Flattened vertebrae
Thickened calvaria

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

Myhre syndrome is due to mutations in the SMAD4 gene. 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.{{Cite journal |last1=Shi |first1=Yigong |last2=Massagué |first2=Joan |date=2003 |title=Mechanisms of TGF-β Signaling from Cell Membrane to the Nucleus |journal=Cell |volume=113 |issue=6 |pages=685–700 |doi=10.1016/s0092-8674(03)00432-x|pmid=12809600 }}{{cite journal|last1=Le Goff|first1=Carine|last2=Mahaut|first2=Clémentine|last3=Abhyankar|first3=Avinash|last4=Le Goff|first4=Wilfried|last5=Serre|first5=Valérie|last6=Afenjar|first6=Alexandra|last7=Destrée|first7=Anne|last8=di Rocco|first8=Maja|last9=Héron|first9=Delphine|last10=Jacquemont|first10=Sébastien|last11=Marlin|first11=Sandrine|last12=Simon|first12=Marleen|last13=Tolmie|first13=John|last14=Verloes|first14=Alain|last15=Casanova|first15=Jean-Laurent|last16=Munnich|first16=Arnold|last17=Cormier-Daire|first17=Valérie|title=Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome|journal=Nature Genetics|date=December 2011|volume=44|issue=1|pages=85–88|doi=10.1038/ng.1016|url=https://www.researchgate.net/publication/51868517|accessdate=11 July 2015|pmid=22158539|s2cid=13042633}}

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.

Diagnosis

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. 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). Rarely, the family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations).{{Cite journal |last1=Meerschaut |first1=Ilse |last2=Beyens |first2=Aude |last3=Steyaert |first3=Wouter |last4=De Rycke |first4=Riet |last5=Bonte |first5=Katrien |last6=De Backer |first6=Tine |last7=Janssens |first7=Sandra |last8=Panzer |first8=Joseph |last9=Plasschaert |first9=Frank |last10=De Wolf |first10=Daniël |last11=Callewaert |first11=Bert |date=2019 |title=Myhre syndrome: A first familial recurrence and broadening of the phenotypic spectrum |journal=American Journal of Medical Genetics Part A |language=en |volume=179 |issue=12 |pages=2494–2499 |doi=10.1002/ajmg.a.61377|pmid=31595668 }}

Treatment

There are currently no disease specific therapies, although the use of losartan has been suggested to prevent fibrosis.{{Cite journal |last1=Cappuccio |first1=Gerarda |last2=Caiazza |first2=Martina |last3=Roca |first3=Alessandro |last4=Melis |first4=Daniela |last5=Iuliano |first5=Antonella |last6=Matyas |first6=Gabor |last7=Rubino |first7=Marta |last8=Limongelli |first8=Giuseppe |last9=Brunetti-Pierri |first9=Nicola |date=2021 |title=A pilot clinical trial with losartan in Myhre syndrome |journal=American Journal of Medical Genetics Part A |language=en |volume=185 |issue=3 |pages=702–709 |doi=10.1002/ajmg.a.62019 |pmc=7898344 |pmid=33369056}}

History

This disorder was first reported in 1981.{{Cite journal |last1=Myhre |first1=Selma A. |last2=Ruvalcaba |first2=Rogelio H. A. |last3=Graham |first3=C. Benjamin |date=1981 |title=A new growth deficiency syndrome |journal=Clinical Genetics |volume=20 |issue=1 |pages=1–5 |doi=10.1111/j.1399-0004.1981.tb01798.x|pmid=7296942 }}

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.