A pilot clinical trial with losartan in Myhre syndrome

Abstract

Introduction Myhre syndrome (MS) is an ultra‐rare disorder due to pathogenic variants in the SMAD4 gene that encodes a protein regulating the TGF‐β pathway and extra‐cellular matrix (ECM) homeostasis. Main clinical features of MS include thickening of skin and joint stiffness. Previous studies showed that losartan improved ECM deposition in MS fibroblasts. Materials and methods Four molecularly confirmed MS subjects (mean age 23.8 ± 17 years) were evaluated for: (a) skin thickness by Rodnan score, (b) joint range of motion (ROM) by goniometry, and (c) speckle‐tracking echocardiogram. Following baseline evaluations, three MS individuals received losartan for 12 months and pre‐defined endpoints were monitored after 6 and 12 months of treatment. Results At baseline, Rodnan scores were increased, joint ROM was reduced, and speckle‐tracking echocardiogram revealed reduced myocardial strain. In three MS subjects, improvements in skin thickness, joint ROM and to a lesser extent of myocardial strain, were observed after 6 and 12 months of losartan treatment. Conclusions Although further long‐term controlled clinical trials with a larger number of affected individuals are needed, the present study suggests that losartan might improve skin, joint and heart abnormalities of MS.

Natural history of Myhre syndrome

“…Recently, Cappuccio et al, lead a pilot clinical trial with losartan on four MS patients and identified clinical endpoints on skin thickness, joints range of motion and speckle-tracking echocardiogram of left ventricular function to evaluate losartan efficacy. Authors suggested that losartan might provide benefit to patient with improvements in skin thickness, joint range of motion and to a lesser extent of myocardial strain in MS [ 41 ]. The natural history of MS provided by our study highlighted the occurrence of life-threatening complications such as vascular stenosis or PH.…”

Expanded cardiovascular phenotype of Myhre syndrome includes tetralogy of Fallot suggesting a role for SMAD4 in human neural crest defects

“…A second cardiac surgery was performed at 2 years of age for correction of the left pulmonary artery. She has been on furosemide and losartan treatment (Cappuccio et al, 2021).…”

“…A second cardiac surgery was performed at 2 years of age for correction of the left pulmonary artery. She has been on furosemide and losartan treatment(Cappuccio et al, 2021).At the age of 2.8 years, the echocardiogram and cardiac catheterization showed moderate RV outflow tract obstruction (right pulmonary artery 6 mm, left pulmonary artery 5 mm, transpulmonary pressure gradient 65 mmHg), pulmonary valve annulus diameter 7 mm (Z score À3.38). Severe tricuspid valve regurgitation with tricuspid annular plane systolic excursion 7-8 mm was diagnosed.…”

Driver Mutations in Pancreatic Cancer and Opportunities for Targeted Therapy

“…Myhre syndrome (MS) is driven by pathogenic variants of Smad4 gene. Losartan improves skin thickness and joint range motion in MS [132]. The beneficial role of losartan in Smad4-deficient diseases like MS suggests that losartan may indirectly remediate aberrant Smad4.…”