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A case of Myhre syndrome mimicking juvenile scleroderma



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.


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.


Myhre syndrome is a genetic disorder often presenting in infancy, caused by a gain of function mutation in the SMAD family member 4 (SMAD4) gene causing progressive, proliferative fibrosis, occurring spontaneously or following trauma, in addition to a unique set of clinical phenotypic features described below [1,2,3,4]. Clinical manifestations of Myhre syndrome include: cardiovascular involvement in up to 70% of patients (congenital heart defects, long- and short-segment stenosis of the aorta and peripheral arteries, pericardial effusion, constrictive pericarditis, restrictive cardiomyopathy, and arterial hypertension); respiratory manifestations (choanal stenosis, laryngotracheal narrowing, obstructive airway disease, or restrictive pulmonary disease); gastrointestinal symptoms (pyloric stenosis, duodenal strictures, severe constipation); hearing loss, mild to moderate development delay, dysmorphic features and skin involvement (skin sclerosis, particularly involving the hands and extensor surfaces) leading to joint contractures [1, 5,6,7,8,9,10,11,12]. Patients presenting with predominantly skin sclerosis and contractures, cardiovascular involvement may be misdiagnosed as a having systemic sclerosis (SSc) despite the presence of other atypical features for SSc such as hearing loss and developmental delay thus causing unnecessary exposure to immunosuppression. Herein, we present a case of a 13 year-old female considered as having diffuse cutaneous systemic sclerosis, who was subsequently identified to have Myhre syndrome caused by a previously well described heterozygous c.1499 T > C variant in SMAD4. We discuss the therapeutic implications of establishing a genetic diagnosis in this case and provide an overview of genetic mimics of scleroderma.

Case presentation

A 13 year-old girl of Black African decent was referred to the scleroderma services of the rheumatology department at Great Ormond Street Hospital for Children NHS Foundation Trust, London for a second opinion with history of extensive skin thickening and widespread joint contractures, which started in infancy at the age of 9 months (Fig. 1). The skin changes started in her lower limps and over the course of 2 years spread to the arms and trunk. The joint contractures were noted approximately 2 years after the initial skin changes were observed. There was history suggestive of mild Raynaud’s phenomenon, but no digital ulceration, gastrointestinal, or respiratory symptoms of note. She was born at term with no neonatal complications. She had a past medical history of: valvar and supravalvar pulmonary artery stenosis requiring serial balloon dilatation; mild developmental delay; and conductive hearing loss. Microarray-based comparative genomic hybridization was used to exclude chromosomal abnormalities that could explain her presentation and was normal. There was no history of cancer in the immediate family.

Fig. 1

Cutaneous and skeletal manifestations of the 13 year old patient with Myhre syndrome we describe in this report. a-b Multiple joint contractures and clinodactyly. c Extensive skin thickening and muscle wasting of lower limbs in same patient

Clinical examination revealed diffusely thickened skin affecting the full length of her limbs and trunk, but sparing her face; weight 41 kg (25th centile for age), height 139 cm (2nd centile for age). She was normotensive at time of review. Delayed puberty was noted and the patient had no menarche at the age of 13 years old. There were multiple joint contractures, but no active arthritis. Cutaneous telangiectasia, fingertip ulceration and calcinosis were absent. She was also noted to have mild dysmorphic features: small eyes and ears, a broad nasal tip, a long and prominent chin, bilateral clinodactyly and mild two-three toe syndactyly. Nailfold capillaroscopy was abnormal, with evidence of dilated capillary loops, tortuosity, micro-bleeding, and widespread dropout in a pattern compatible with scleroderma-spectrum connective tissue disease (Fig. 2). Digital thermography demonstrated cold baseline cutaneous temperature of the peripheries, with some of the fingers remaining cool long after cold challenge. She tested weakly positive for antinuclear antibodies (ANA at 1:160, homogenous pattern); negative for dsDNA antibodies, rheumatoid factor and extranuclear antibodies. Complement function (alternate and classical pathways) was normal, as were levels of C3, C4, and C1q. Erythrocyte sedimentation rate and C-reactive protein were repeatedly within normal limits. Echocardiography revealed mild persistent pulmonary stenosis, a small left pulmonary artery, mild coarctation of the aorta, mild biventricular hypertrophy, but no evidence of pulmonary hypertension. Barium swallow was normal. A skeletal survey revealed advanced bone age, but no evidence of skeletal dysplasia. A skin biopsy was performed, with histology revealing hyperkeratotic epidermis, and fibrotic dermis with areas of hyalinization; adnexal structures were sparse with absence of pilosebaceous units (Fig. 3). These histological features are typically encountered in scleroderma histopathology with the exception of the hyperkeratotic epidermis, which is less often seen [11, 13, 14]. She was diagnosed with diffuse cutaneous systemic sclerosis, and treatment with oral prednisolone 2 mg/kg/day for 6 weeks, and subcutaneous methotrexate (15 mg/m2/week) started. There was deterioration in joint contractures (further loss of range of movement) and spreading of skin changes observed despite treatment. When reviewed for a second opinion at GOSH, a genetic diagnosis was suspected and genetic testing via Sanger sequencing was undertaken for some conditions that cause skin thickening, dysmorphic features and congenital heart disease. Genetic testing revealed a previously well described rare heterozygous c.1499 T > C (p.lle500Thr) class 5 variant in SMAD4 [12], suggesting a diagnosis of Myhre syndrome. Testing for variants in other relevant genes pertinent to phenotype (including PTPN11, LMNA, and MMP14) revealed no other pathogenic variants [15,16,17,18,19,20,21,22,23,24,25,26]. Parental testing confirmed this variant arose de novo in the proband. All immunosuppression was subsequently stopped, genetic counselling was provided, and the prognosis of Myhre syndrome was discussed with the patient and family.

Fig. 2

Nailfold capillaroscopy of the 13 year old patient with Myhre syndrome we describe in this report. a-b Abnormal nailfold capillary patterns with small microbleeds, very tortuous loops and mild dilatation in a patient with Myhre syndrome suggesting an evolving microangiopathy

Fig. 3

Skin histology of the 13 year old patient with Myhre syndrome mimicking juvenile scleroderma we describe in this report. a-b Photomicrographs of skin punch biopsy containing epidermis, dermis and superficial subcutis. There is no significant lichenoid reaction or inflammatory infiltrate (L) but the dermis shows marked replacement by hypocellular, hyalinised areas of bland collagen(R). There are no other specific features and the adnexal structures remain in this biopsy. (H&E, original magnifications Lx40 and Rx100)


We present the case of a 13 year-old with a scleroderma-like condition, ultimately diagnosed with Myhre syndrome, a genetic disorder that may mimic juvenile scleroderma (Supplemental Table 1). Securing a molecular diagnosis in this case allowed the cessation of immunosuppression thus reducing the burden of unnecessary toxic exposure to glucocorticoids, and other ineffective immunosuppressive treatments; and facilitated genetic counselling, and prognostication. This also had implications for long term follow up as patients with Myhre syndrome require close surveillance for detection of any malignancy in view of increased risk of cancer reported in these patients [5, 12, 27]. We therefore highlight this case to raise awareness of a growing number of monogenic fibrotic disorders mimicking juvenile scleroderma which need to be considered in patients with cutaneous fibrosis beginning early in life (Table 1).

Table 1 Monogenic disorders with a scleroderma-like phenotype. The clinical features have been summarised as described by the Online Mendelian Inheritance in Man (OMIM) [28] and Genetics Home Reference databases [29]

Myhre syndrome is caused by mutations in SMAD encoding for SMAD4 protein, a transducer mediating transforming growth factor β (TGF-β) signalling [2,3,4]. Skin fibroblasts from patients with Myhre syndrome show increased SMAD4 expression, impaired matrix deposition, and altered expression of genes encoding matrix metalloproteinases and related inhibitors. Losartan, an angiotensin-II type 1 receptor blocker but also a (lesser-known) TGF-β antagonist has been shown in vitro to normalize metalloproteinase and related inhibitor transcript levels, and to correct the extracellular matrix (ECM) deposition defect in fibroblasts from these patients [30]. Some patients with aortic pathology associated with Myhre syndrome have already been treated with losartan, with reports of stabilisation of their vasculopathy; but the effect on skin fibrosis has never been described [30,31,32,33,34]. We suggest that further studies could explore losartan (or other therapies acting on the SMAD4 pathway) as a potential targeted therapeutic option for cutaneous fibrosis associated with this rare genetic disease. At the time of writing this report losartan therapy is being considered for the patient described herein.

Several other conditions may also mimic juvenile scleroderma (Table 1). Skin thickening is common to all of these disorders, and may be localized (morphoea-like), or widespread (like diffuse scleroderma) [35,36,37,38,39,40,41,42,43,44,45]. Vasculopathy is frequently observed and should be actively screened for. We highlight for the first time in this case the abnormal nailfold capillaroscopy with similar findings to those observed in SSc. Degenerative cardiac or pulmonary manifestations may also exhibit a secondary inflammatory component, thus posing considerable diagnostic challenges and making it more likely that such patients could be exposed to ineffective but toxic immunosuppression, as illustrated by our case [1, 2, 4, 46,47,48,49]. On occasions, autoimmunity has also been described [50,51,52,53]. The management and long term outcome of these genetic scleroderma mimics is, however, entirely different and immunosuppression may not be required or may in fact be harmful in some cases [54, 55]. We therefore suggest that genetic testing should be considered in all patients with sclerodermatous skin disease of very young onset (infancy) and recommend screening for vasculopathy (including congenital heart disease and aortopathy) with echocardiography, and non-invasive angiography. Genetic screening for monogenic diseases should also be considered in older patients with scleroderma with atypical clinical course; and in those not responding to conventional immunosuppression.

Regarding the methodology of genetic screening, our case again illustrates the importance of next-generation sequencing (NGS) methodologies in this context. Mainly due to lack of routine NGS methods, initial routine genetic testing of candidate genes by Sanger was performed for this patient. This was a time consuming, costly, and mainly “clinician best guess” driven approach, which resulted in diagnostic delay of several months. Whole exome and genome sequencing and targeted gene panels now allow rapid, simultaneous detection of multiple genes, and are increasingly being used as diagnostic tools and to explore the pathogenesis of monogenic diseases [56,57,58,59,60,61]. These techniques are particularly useful for screening diseases with overlapping phenotypes. For instance, we (and many others) have used NGS to extensively study monogenic systemic inflammation, with significant diagnostic and therapeutic impact [60, 61]. Similarly, we anticipate that application of NGS genetic screening to cohorts of patients with juvenile scleroderma (in all its forms) may identify a proportion with monogenic disease, and that evidence of tissue inflammation and autoimmunity should not preclude the possibility of a genetic diagnosis for the reasons discussed above.

Understanding the genetic basis of these genetic diseases with sclerodermatous features is not only crucial to secure diagnoses, improve prognostication and to facilitate genetic counselling but may also provide clues to the pathogenesis of sporadic cases. For instance, several of the genetic mimics of scleroderma involve the TGF-β pathway [2, 62,63,64]. At the cellular level, TGF-β plays potent roles in proliferation, differentiation and apoptosis of many cell types, and therefore unsurprisingly germline mutations in the TGF-β signalling pathway cause various phenotypes affecting the skeletal, muscular, and/or cardiovascular systems [2, 62,63,64,65]. TGF-β has also been identified as a regulator of pathological fibrogenesis in juvenile and adult onset systemic sclerosis [64,65,66,67,68]. A wide range of drugs targeting the TGF-β signalling pathways are now available [69,70,71,72,73], and need to be tested for their ability to modulate the phenotypes of both these inherited scleroderma mimics but possibly also for efficacy in addition to anti-inflammatory medication in sporadic systemic sclerosis, given their overlapping pathomechanisms.


Myhre syndrome is a rare genetic disorder that causes skin thickening and joint contractures, and may be misdiagnosed as juvenile scleroderma (systemic sclerosis). Many other genetic conditions can similarly mimic the clinical manifestations of juvenile scleroderma and should be considered in the differential diagnosis of juvenile scleroderma. Onset in infancy and comorbidities such as structural heart disease, large vessel vasculopathy, dysmorphic features, developmental delay, and hearing loss are important clues to a genetic diagnosis. Clinical application of NGS is likely to transform the genetic diagnostic approach to young patients with scleroderma-like diseases and suggest targeted therapies for some cases. Therapeutic targets for sporadic cases of juvenile scleroderma are also likely to emerge, given the overlapping disease mechanisms for all these conditions leading to vasculopathy, skin and organ fibrosis.

Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated or analysed.



Anti-nuclear antibodies


Extracellular Matrix


Double-stranded DNA


Next generation sequencing


Systemic sclerosis


Transforming growth factor type beta


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Dr. Eleftheriou, Professor Sebire and Professor Brogan acknowledge the National Institute of Health Research (NIHR) Biomedical Research Centre at GOSH.


The views expressed are those of the authors and not necessarily those of the NHS, NIHR, or Department of Health.


No funding sources. Dr. Jensen was supported by GOSH Children’s Charity Grant (CP_RSRCH_003) and Rosetrees Trust Grant (A2584) Dr. Eleftheriou and Dr. Hong were supported by Versus Arthritis (grants 20164, 21593, and 21791). Professor Brogan is supported by the Great Ormond Street Hospital (GOSH) Children’s Charity.

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BJ, RJ, PB and DE conceived the study, obtained and analysed data and drafted the manuscript. YH, EO, CP, NS and KH obtained and analysed data and drafted the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Barbara Jensen.

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Supplementary information

Additional file 1 Supplemental Table

 1. Features of juvenile localised scleroderma, juvenile systemic sclerosis and Myhre syndrome.

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Jensen, B., James, R., Hong, Y. et al. A case of Myhre syndrome mimicking juvenile scleroderma. Pediatr Rheumatol 18, 72 (2020).

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  • Scleroderma
  • Myhre syndrome
  • SMAD4