Citations 2
Emergence of the natural history of Myhre syndrome: 47 patients evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016–2023)
Lin, Angela E. , Scimone, Eleanor R., Thom, Robyn P. , Kinane, T. Bernard , Moschovis, Peter P. , Tan, Weizhen, Hague, Cole , Dannheim, Katelyn , Levitsky, Lynne L. , Lilly, Evelyn , DiGiacomo, Daniel , Masse, Kara M., Kadzielski, Sarah, Zar‐Kessler, Claire , Ginns, Leo C., Colvin, Mary K. , Elder, Jack S. , Learn, Christopher P. , Mou, Hongmei , Weagle, Kathryn M., Butler, William E. , Alhadid, Kenda , Musolino, Patricia L. , Sultana, Sadia , Chou, Elizabeth L. , Dorfman, Aaron T. , Morris, Shaine A. , Bergin, James D., Rayment, Jonathan H. , Schimmenti, Lisa A. , Lindsay, Mark E. , Group, MGH Myhre Syndrome Study, Kinane, T Bernard , Moschovis, Peter P , Dannheim, Katelyn , Levitsky, Lynne L , Lilly, Evelyn , DiGiacomo, Daniel V , Neumeyer, Ann M , Colvin, Mary K , Elder, Jack S , Alhadid, Kenda , Rapalino, Otto , Dorfman, Aaron T , Morris, Shaine A , Schimmenti, Lisa A , Lindsay, Mark E , Balaguru, Duraisamy , Cohen, Michael S. , Buch, Karen A , Bandyopadhyay, Dhrubajyoti , Peacock, Zachary S. , Heidary, Gena , Group, MGH Myhre Syndrome Study
American Journal of Medical Genetics Part A | May 23, 2024 | Volume: 194 | Issue: 10 | Pages: No page available
AbstractMyhre 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.
Human Airway Basal Cells Undergo Reversible Squamous Differentiation and Reshape Innate Immunity
Black, Katharine E., Phung, Thien‐Khoi N. , Thundivalappil, Sujatha, Xu, Jie , Lapey, Allen , Lerou, Paul H. , Que, Jianwen, Park, Jin‐Ah , Hurley, Bryan P. , Mou, Hongmei , Que, Jianwen , Mou, Hongmei , Park, Jin-Ah , Que, Jianwen , Zhang, Yihan , Lin, Tian , Wang, Wei , Zhang, Cheng , Hariri, Lida P. , Li, Hu , Ai, Xingbin
American Journal of Respiratory Cell and Molecular Biology | February 8, 2023 | Volume: 68 | Issue: 6 | Pages: 664-678
Abstract Histological and lineage immunofluorescence examination revealed that healthy conducting airways of humans and animals harbor sporadic poorly differentiated epithelial patches mostly in the dorsal noncartilage regions that remarkably manifest squamous differentiation. In vitro analysis demonstrated that this squamous phenotype is not due to intrinsic functional change in underlying airway basal cells. Rather, it is a reversible physiological response to persistent Wnt signaling stimulation during de novo differentiation. Squamous epithelial cells have elevated gene signatures of glucose uptake and cellular glycolysis. Inhibition of glycolysis or a decrease in glucose availability suppresses Wnt-induced squamous epithelial differentiation. Compared with pseudostratified airway epithelial cells, a cascade of mucosal protective functions is impaired in squamous epithelial cells, featuring increased epithelial permeability, spontaneous epithelial unjamming, and enhanced inflammatory responses. Our study raises the possibility that the squamous differentiation naturally occurring in healthy airways identified herein may represent “vulnerable spots” within the airway mucosa that are sensitive to damage and inflammation when confronted by infection or injury. Squamous metaplasia and hyperplasia are hallmarks of many airway diseases, thereby expanding these areas of vulnerability with potential pathological consequences. Thus, investigation of physiological and reversible squamous differentiation from healthy airway basal cells may provide critical knowledge to understand pathogenic squamous remodeling, which is often nonreversible, progressive, and hyperinflammatory.