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.

Keywords: Myhre syndrome; SMAD4; TGF-beta; losartan; systemic sclerosis.

FIGURE 1

(a) Rodnan score at each skin site in subjects S1, S2, S3, S4 and controls (n = 5). (b) Heatmap for Rodnan score at each skin site and total score in each individual and controls. (c) Joint range of motion (ROM) at the elbow, wrist, knee and ankle in S1, S2, S3, S4 and controls (n = 5). Normal range from Luttgen and Hamilton (Luttgens & Hamilton, 1997) are reported in parenthesis. (d) Heatmap of joint ROM for each patient and controls at different sites. (e) Average global longitudinal systolic peak strain (GLPS). Dashed line indicates average value in controls, that in children corresponds to 20.2 ± 0.7% and in adults to 20.2 ± 1.6%. (f) Heart walls divided into 17 segments and segmental strain measurements were plotted in a bull's eye and left ventricular global longitudinal strain based on all three apical views was calculated. For S4, only average GLPS was available. GLPS, global longitudinal systolic peak strain; GLPS_LAX, long axis view; GLPS_A2C, apical 2 chambers view; GLPS_A4C, apical four chambers view [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

(a) Subjects S1 (blue), S2 (red), S3 (green) were treated with losartan for 12 months and the dose was titrated according to blood pressure levels (numbers in boxes indicate mg per day). (b,c) Modified Rodnan scores evaluated at baseline (T0) and after 6 (T6) and 12 (T12) months of treatment with losartan in subjects S1, S2, and S3. Single sites (b) andglobal (c) scores are shown. Dashed lines (c) indicate average total score detected in controls (n =5). (D,E) Joint ROM in three MS subjects at baseline (T0) and after 6 (T6) and 12 (T12) months of treatment. Single sites (d) and average scores (e) are shown. The dashed line (d, e) indicates average value in controls. (f, g) Apical views (long axis, two chambers, four chambers; f) and average global longitudinal systolic peak strain (GLPS; g) in three subjects after 6 and 12 months of treatment with losartan. The dashed line indicates the average value in controls: GLPS average normal values in children is 20.2 ± 0.7% and in adults is 20.2 ± 1.6%. ANOVA and Kruskal–Wallis rank sum test have been used for significance calculation, *p < .05, **p < .01 [Color figure can be viewed at wileyonlinelibrary.com]