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Emergence of the natural history of Myhre syndrome: 47 patients evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016-2023)
Journal article   Peer reviewed

Emergence of the natural history of Myhre syndrome: 47 patients evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016-2023)

Angela E Lin, Eleanor R Scimone, Robyn P Thom, Duraisamy Balaguru, T Bernard Kinane, Peter P Moschovis, Michael S Cohen, Weizhen Tan, Cole D Hague, Katelyn Dannheim, …
American journal of medical genetics. Part A, Vol.194(10), pp.e63638-n/a
10/2024
DOI: 10.1002/ajmg.a.63638
PMCID: PMC11586855
PMID: 38779990

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Abstract

Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016-2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence-based guidelines in anticipation of disease-specific therapies.
 Phenotype Adolescent Adult Child Child, Preschool Clubfoot - epidemiology Clubfoot - genetics Clubfoot - pathology Cryptorchidism - genetics Cryptorchidism - pathology Facies Female Genotype Growth Disorders - epidemiology Growth Disorders - genetics Growth Disorders - pathology Hand Deformities, Congenital Hospitals, General Humans Infant Intellectual Disability - genetics Intellectual Disability - pathology Male Massachusetts - epidemiology Mutation - genetics Smad4 Protein - genetics Young Adult

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