A case of Myhre syndrome mimicking juvenile scleroderma.

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.

Clinical features and management of erythromelalgia: long term follow-up of 46 cases.

OBJECTIVES: To review our clinical experience of this rare condition and describe the clinical features and response to therapy in a cohort of patients with erythromelalgia (EM), a rare condition, characterised by paroxysmal hyperthermia of the extremities with erythema, pain and intense burning. METHODS: A review was made of the electronic and paper medical records of patients with the diagnosis of EM, with a telephone interview to verify and complete clinical information relating treatment and outcome. RESULTS: 46 patients (41 females) were included in this study. Mean age was 57 years and mean duration of symptoms was 16 years. Raynaud's phenomenon was present in 36 patients (80%) and 4 patients (9%) had systemic sclerosis. Smoking (current or previous) was identified as a possible risk factor in 26 cases and exposure to chronic vibration in 3 cases. Overall, the effect on quality of life was mild in 15% of cases, moderate in 30% and severe in 48%. The most common symptoms were burning (96%), heat (93%), pain (87%), and redness (83%). Symptoms affected the lower limbs in 98% of cases, upper limbs in 76%, face in 20% and trunk in 11%. Triggers included heat (85%), exercise (78%) and time of day (76%). Various medications were tried, showing poor effect in most cases. Intravenous iloprost was given to 27 patients, with benefit in 17 patients (63%). CONCLUSIONS: Erythromelalgia is a rare chronic debilitating condition. Exercise, heat and night time are common triggers. Current medical therapies are seldom effective and further research is sorely needed.

Novel mutations mapping to the fourth sodium channel domain of Nav1.7 result in variable clinical manifestations of primary erythromelalgia.

We identified and clinically investigated two patients with primary erythromelalgia mutations (PEM), which are the first reported to map to the fourth domain of Nav1.7 (DIV). The identified mutations (A1746G and W1538R) were cloned and transfected to cell cultures followed by electrophysiological analysis in whole-cell configuration. The investigated patients presented with PEM, while age of onset was very different (3 vs. 61 years of age). Electrophysiological characterization revealed that the early onset A1746G mutation leads to a marked hyperpolarizing shift in voltage dependence of steady-state activation, larger window currents, faster activation kinetics (time-to-peak current) and recovery from steady-state inactivation compared to wild-type Nav1.7, indicating a pronounced gain-of-function. Furthermore, we found a hyperpolarizing shift in voltage dependence of slow inactivation, which is another feature commonly found in Nav1.7 mutations associated with PEM. In silico neuron simulation revealed reduced firing thresholds and increased repetitive firing, both indicating hyperexcitability. The late-onset W1538R mutation also revealed gain-of-function properties, although to a lesser extent. Our findings demonstrate that mutations encoding for DIV of Nav1.7 can not only be linked to congenital insensitivity to pain or paroxysmal extreme pain disorder but can also be causative of PEM, if voltage dependency of channel activation is affected. This supports the view that the degree of biophysical property changes caused by a mutation may have an impact on age of clinical manifestation of PEM. In summary, these findings extent the genotype-phenotype correlation profile for SCN9A and highlight a new region of Nav1.7 that is implicated in PEM.

Validation of a protocol for the assessment of skin temperature and blood flow in childhood localised scleroderma.

BACKGROUND/PURPOSE: Localised scleroderma (LS) is the most common form of scleroderma seen in children, and usually presents unilaterally. Infrared thermography (IRT) and laser Doppler (LD) have both been reported to be useful in assessing the active, inflammatory stage of LS. We developed and validated a protocol using these techniques for the assessment of unilateral LS activity in children. METHOD: We investigated the spatial variability and repeatability of LD measurements from adult control forearm skin, and the inter- and intra-operator reproducibility of both LD blood flow trace analysis and IRT skin temperature analysis. Software was developed to produce overlay images of thermograms onto digital photographs of skin sites. In a group of seven adult control subjects, we established the normal range for skin temperature and LD blood flow at six standardised sites (forehead, cheek, abdomen, back, arm and leg), and measured contralateral differences in readings. In a group of 34 children with LS, we investigated the skin temperature and LD blood flow in unaffected skin at the same six sites. RESULTS: In adults, physiological variability in LD blood flow and skin temperature between the two sides of the body was found to be greater than the uncertainty introduced into the measurements by (inter alia) limited intra- or inter-operator reproducibility. The cheek displayed the highest mean asymmetry in both skin temperature (0.5 degrees C) and LD blood flow (40%). CONCLUSION: Our protocol combines IRT, LD and photography for LS assessment in children, and establishes a normal range of readings in line with other authors.

Laser Doppler flowmetry for assessing localized scleroderma in children.

OBJECTIVE: Assessment of disease activity is a major challenge in the management of children with localized scleroderma. The aim of this study was to evaluate the role of laser Doppler flowmetry (LDF) in comparison with infrared thermography in the detection of scleroderma disease activity. METHODS: In 41 children with localized scleroderma, 111 lesions were assessed on 2 separate occasions, by clinical examination, LDF, and thermography. Measurements from contralateral areas of unaffected skin served as intrapatient controls, and differences in blood flow and temperature were calculated between the corresponding sites. The sensitivity and specificity to detect clinically active lesions were compared between LDF and thermography. RESULTS: Seventy-five active lesions (34%) and 147 inactive lesions (66%) were identified clinically. The median relative increase in blood flow measured by LDF was +89% (range -69% to +449%) for clinically active lesions and +11% (range -46% to +302%) for clinically inactive lesions (P < 0.001). Thermography showed a median difference in temperature of +0.5 degrees C (range -0.1 degrees C to +4.1 degrees C) and +0.3 degrees C (range -1.9 degrees C to +2.7 degrees C) for clinically active lesions and clinically inactive lesions, respectively (P = 0.024). Using a cutoff level of 39% to indicate increase in blood flow, a sensitivity of 80% and specificity of 77% to detect clinically active lesions were observed; for thermography, no useful cutoff level was identified. The correlation between differences in blood flow and differences in temperature was small, but significant (r2 = 0.120, P < 0.001). CONCLUSION: LDF is a helpful, noninvasive diagnostic technique that can be used to discriminate disease activity in children with localized scleroderma, and is more accurate than thermography for this purpose.

Use of thermographic criteria to identify Raynaud's phenomenon in a population setting.

OBJECTIVE: To assess the value of thermographic measurements of digital skin temperature after cold challenge in classifying Raynaud's phenomenon (RP) in a healthy population. METHODS: One hundred seventy-five patients with RP and 404 controls were subjected to a 15 degrees C, 60 s cold challenge test. All participants were women. Digital temperature measurements were taken at baseline, immediately postimmersion, and 10 min after immersion using a portable radiometer. RESULTS: Baseline skin temperature was a significant predictor of RP; however, the fall in temperature on immersion and the subsequent rewarming rate provided no additional information. CONCLUSION: Baseline skin temperature can help to predict the occurrence of RP in patients drawn from the general population, but has relatively low discriminatory power. The cold challenge test itself is of limited additional value for classification. Although objective temperature measurements show little power overall to discriminate between RP and non-RP patients, detecting low baseline digital temperature may be a useful adjunct to clinical history in classifying the disease.