A case of Myhre syndrome mimicking juvenile scleroderma

Abstract

Background Myhre syndrome is a genetic disorder caused by gain of function mutations in the SMAD Family Member 4 (SMAD4) gene, resulting in progressive, proliferative skin and organ fibrosis. Skin thickening and joint contractures are often the main presenting features of the disease and may be mistaken for juvenile scleroderma. Case presentation We report a case of a 13 year-old female presenting with widespread skin thickening and joint contractures from infancy. She was diagnosed with diffuse cutaneous systemic sclerosis, and treatment with corticosteroids and subcutaneous methotrexate recommended. There was however disease progression prompting genetic testing. This identified a rare heterozygous pathogenic variant c.1499 T > C (p.Ile500Thr) in the SMAD4 gene, suggesting a diagnosis of Myhre syndrome. Securing a molecular diagnosis in this case allowed the cessation of immunosuppression, thus reducing the burden of unnecessary and potentially harmful treatment, and allowing genetic counselling. Conclusion Myhre Syndrome is a rare genetic mimic of scleroderma that should be considered alongside several other monogenic diseases presenting with pathological fibrosis from early in life. We highlight this case to provide an overview of these genetic mimics of scleroderma, and highlight the molecular pathways that can lead to pathological fibrosis. This may provide clues to the pathogenesis of sporadic juvenile scleroderma, and could suggest novel therapeutic targets.

Review of the Pathologic Characteristics in Myhre Syndrome: Gain-of-Function Pathogenic Variants in SMAD4 cause a Multisystem Fibroproliferative Response

“…1 Subsequently, other authors have further defined the facial, skeletal, respiratory, and upper airway features of the syndrome and have expanded the clinical phenotype (Figure 1) to include variable neurodevelopmental features. [2][3][4][5][6][7][8][9][10][11][12][13] In 2012, the genetic basis for Myhre syndrome was reported by 2 groups as pathogenic variants within a very restricted range of SMAD4 of only two codon positions, 496 and 500. [14][15][16] Currently, Myhre syndrome is defined by these SMAD4 pathologic variants, and gain-of-function changes in SMAD4 are associated only with Myhre syndrome.…”

A pilot clinical trial with losartan in Myhre syndrome

“…MS is part of TGF‐β‐pathies, a group of disorders that includes both genetic and nongenetic conditions, such as acromicric dysplasia (Banka et al, 2015), geleophysic dysplasia (Banka et al, 2015), Weill–Marchesani syndrome (Banka et al, 2015), Leri pleonosteosis (Banka et al, 2015), stiff skin syndrome (Banka et al, 2015), and systemic scleroderma (SSc). TGF‐β‐pathies share ECM abnormalities resulting in progressive fibrosis (Jensen et al, 2020). Rodnan score, joint range of motion (ROM) by goniometry and speckle‐tracking echocardiography have been used for monitoring skin, joint and heart fibrosis in SSc, the most common TGF‐β‐pathy (Khanna et al, 2017; Shima et al, 2015; Spethmann et al, 2014).…”