Efficacy and safety of fumaric acid esters in young patients aged 10-17 years with moderate-to-severe plaque psoriasis: a randomized, double-blinded, placebo-controlled trial.

BACKGROUND: Apart from biologics, no systemic drugs are approved in Europe for children with moderate-to-severe psoriasis. Retrospective observational studies have shown promising results for fumaric acid esters (FAE) in this setting. OBJECTIVES: To show superiority of FAE over placebo in terms of treatment response after 20 weeks in children and adolescents aged 10-17 years. METHODS: In a multicentre, randomized, double-blind, placebo-controlled phase IIIb study, patients aged 10-17 years with moderate-to-severe plaque psoriasis requiring systemic therapy were randomized 2 : 1 to receive FAE (n = 91) or placebo (n = 43) over 20 weeks, followed by an open-label FAE treatment phase. The coprimary endpoints were ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) and Physician's Global Assessment (PGA) score of 0 or 1 (clear or almost clear) at week 20. The study was registered with EudraCT number 2012-000035-82. RESULTS: At week 20, 55% [95% confidence interval (CI) 0·44-0·65] of FAE-treated patients achieved a PASI 75 response vs. 19% (95% CI 0·08-0·33) in the placebo group (absolute difference 36%, 95% CI 0·20-0·53; P < 0·001). In total, 42% (95% CI 0·32-0·53) in the FAE group vs. 7% (95% CI 0·01-0·19) in the placebo group achieved a PGA score of 0 or 1 at week 20 (absolute difference 35%, 95% CI 0·21-0·49; P < 0·001). During the double-blind period, drug-related adverse events occurred more frequently in patients receiving FAE compared with placebo (76% vs. 47%). Gastrointestinal disorders were the most common adverse events. CONCLUSIONS: FAE administered over a period of 20 weeks demonstrated a better response than placebo; the difference was statistically significant and clinically meaningful. Application up to 40 weeks was generally well tolerated. However, further studies are required.

Secukinumab demonstrates high efficacy and a favourable safety profile in paediatric patients with severe chronic plaque psoriasis: 52-week results from a Phase 3 double-blind randomized, controlled trial.

BACKGROUND: Secukinumab has demonstrated sustained long-term efficacy with a favourable safety profile in various psoriatic disease manifestations in adults. OBJECTIVES: Here, the efficacy and safety of two secukinumab dosing regimens [low dose (LD) and high dose (HD)] in paediatric patients with severe chronic plaque psoriasis over one year are reported. METHODS: In this multicentre, double-blind study (NCT02471144), patients aged 6 to <18 years with severe chronic plaque psoriasis were stratified and randomized by weight (<25 kg, 25 to <50 kg, ≥50 kg) and age (6 to <12 years, 12 to <18 years) to receive low-dose (LD: 75/75/150 mg) or high-dose (HD: 75/150/300 mg) subcutaneous secukinumab or placebo or etanercept 0.8 mg/kg (up to a max of 50 mg). RESULTS: Overall, 162 patients were randomized to receive secukinumab LD (n = 40) or HD (n = 40), etanercept (n = 41) or placebo (n = 41). The co-primary objectives of the study were met with both secukinumab doses (LD and HD) showing superior efficacy compared to placebo (P < 0.0001) with respect to PASI 75 response (80.0%, 77.5% vs. 14.6%) and IGA mod 2011, 0 or 1 response (70%, 60% vs. 4.9%) at Week 12. Both secukinumab doses were superior to placebo (P < 0.0001) with respect to PASI 90 response at Week 12 (72.5%, 67.5% vs. 2.4%). The efficacy of both doses was sustained to Week 52 with secukinumab achieving higher responses vs. etanercept (PASI 75/90/100: LD, 87.5%/75.0%/40.0% and HD, 87.5%/80.0%/47.5.% vs. etanercept, 68.3%/51.2%/22.0% and IGA 0 or 1: LD, 72.5% and HD, 75.0% vs. etanercept, 56.1%). The safety profile of secukinumab was consistent with the adult Phase 3 studies, with no new safety signals identified. CONCLUSIONS: Both doses of secukinumab demonstrated high and sustained efficacy up to Week 52 with a favourable safety profile in paediatric patients with severe chronic plaque psoriasis.

[Rheumatoid arthritis : These dermatoses lead you to the diagnosis]. / Rheumatoide Arthritis : Bei welchen Hautveränderungen sollte man daran denken?

BACKGROUND: Rheumatoid arthritis is one of the most common autoimmune disorders. In addition to chronic arthritis, rheumatoid arthritis may present a variety of extra-articular manifestations, most commonly of the skin. OBJECTIVES: Cutaneous manifestations associated with rheumatoid arthritis can be diverse, both specific and nonspecific. Which dermatoses should lead you to the diagnosis of an underlying rheumatoid arthritis? METHODS: Evaluation of exemplary overviews, case presentations and relevant textbook articles. RESULTS: Rheumatoid arthritis presents various specific and nonspecific skin manifestations. Besides visual diagnosis like classic rheumatoid nodules a histopathologic correlation or an interdisciplinary approach is often needed, such as for diagnosis of pyoderma gangrenosum. CONCLUSIONS: The early detection and correct classification of cutaneous manifestations associated with rheumatoid arthritis can be groundbreaking for a successful therapy and a consequently better prognosis for patients with rheumatoid arthritis. Therefore dermatologists bear responsibility in the patient-centered care.

Secukinumab dosing optimization in patients with moderate-to-severe plaque psoriasis: results from the randomized, open-label OPTIMISE study.

BACKGROUND: Secukinumab is a fully human monoclonal antibody that selectively binds to and neutralizes interleukin-17A. OBJECTIVES: To assess the efficacy and safety of different maintenance dosing regimens of secukinumab 300 mg based on Psoriasis Area and Severity Index (PASI) response at week 24 in patients with moderate-to-severe plaque psoriasis. METHODS: OPTIMISE was a randomized, open-label, rater-blinded phase IIIb study. Patients (n = 1647) received secukinumab 300 mg at baseline; weeks 1, 2, 3 and 4; and every 4 weeks (q4w) to week 24. At week 24, PASI 90 responders (≥ 90% improvement in PASI; n = 1306) were randomized to secukinumab 300 mg q4w (n = 644) or q6w (n = 662) to week 52, and PASI ≥ 75 to < 90 responders (n = 206) were randomized to secukinumab 300 mg q4w (n = 114) or q2w (n = 92) to week 52. RESULTS: PASI 90 response was maintained at week 52 by 85·7% of patients with q4w dosing vs. 74·9% with q6w dosing (odds ratio 1·91, 95% confidence interval 1·44-2·55). The primary end point, noninferiority of q6w vs. q4w dosing, was not met. In PASI ≥ 75 to < 90 responders, the proportion of patients with PASI 90 response at week 52 was numerically higher in the q2w vs. the q4w group (57% vs. 46·5%, respectively, P = 0·10). Heavier patients (≥ 90 kg) demonstrated numerically higher PASI 90 response with the q2w (57·1%) vs. the q4w regimen (40%, P = 0·11). CONCLUSIONS: Standard q4w dosing of secukinumab 300 mg is the optimal dosing regimen to achieve and maintain clear or almost clear skin. Patients with body weight ≥ 90 kg not achieving PASI 90 at week 24 may benefit from the q2w dosing regimen. What's already known about this topic? Individual responses to biologics in patients with psoriasis vary considerably and there may be a need to individualize treatment. Dose optimization strategies of currently available biologic drugs have been investigated mainly in rheumatic disorders. Secukinumab has shown long-term PASI 90/100 responses (percentage improvement in Psoriasis Area and Severity Index) to year 5 in patients with moderate-to-severe plaque psoriasis when used at the dose of 300 mg every 4 weeks. What does this study add? Standard every 4 week (q4w) dosing of secukinumab 300 mg is the optimal regimen to achieve and maintain clear or almost clear skin at week 52; the majority of the patients (85·7%) maintain PASI 90 at week 52. Superiority of intensified (q2w) dosing over the q4w regimen could not be claimed. However, patients with a higher body weight (≥ 90 kg) not achieving PASI 90 response at week 24 may benefit from q2w dosing.

Dupilumab treatment improves quality of life in adult patients with moderate-to-severe atopic dermatitis: results from a randomized, placebo-controlled clinical trial.

BACKGROUND: Dupilumab, a human anti-interleukin-4 receptor alpha monoclonal antibody, significantly improved clinical signs and symptoms in adults with moderate-to-severe atopic dermatitis in a randomized, double-blind, placebo-controlled, phase IIa trial. OBJECTIVES: We evaluate health-related quality of life (HRQoL) and correlation of HRQoL with secondary clinical and patient-reported outcomes in a subset of patients from this trial of dupilumab. METHODS: Patients were randomized to 300 mg weekly subcutaneous dupilumab or placebo for 12 weeks (trial registration: NCT01548404). The Quality of Life Index of Atopic Dermatitis (QoLIAD) score (exploratory outcome) and its correlation with efficacy outcomes [Eczema Area and Severity Index (EASI); primary end point; SCORing Atopic Dermatitis (SCORAD), SCORAD visual analogue scale (VAS) scores for sleep and pruritus, pruritus numerical rating scale (NRS) and 5-dimensional pruritus] were assessed in 64 adults with moderate-to-severe atopic dermatitis. RESULTS: Mean QoLIAD scores at baseline ± standard error (SE) were 13·3 ± 1·34 and 11·3 ± 1·09 for the placebo and dupilumab groups, respectively. Dupilumab significantly improved QoLIAD score after 12 weeks of treatment vs. placebo (mean % change from baseline in QoLIAD score ± SE: -64·0 ± 6·91 vs. -11·1 ± 9·31). Least squares mean % difference from baseline vs. placebo in QoLIAD score ±SE was -52·0 ± 11·43, P < 0·001). QoLIAD scores significantly correlated with changes in efficacy outcomes, including EASI (r = 0·44), 5-dimensional pruritus (r = 0·49), pruritus NRS (r = 0·41), total SCORAD (r = 0·56) and SCORAD VAS scores for sleep (r = 0·47) and pruritus (r = 0·54); all P < 0·05. CONCLUSIONS: Dupilumab improved QoLIAD scores in adults with atopic dermatitis and was significantly associated with improvements in study outcomes.

Dose-escalation study evaluating pegylated interferon alpha-2a in patients with cutaneous T-cell lymphoma.

BACKGROUND: This open-label, multicenter, dose-escalation study evaluated the safety, tolerability, and efficacy of subcutaneous pegylated (40 kD) interferon α-2a (PEG-IFN α-2a) in patients with cutaneous T-cell lymphoma (CTCL). PATIENTS AND METHODS: PEG-IFN α-2a was administered subcutaneously at 180 (n = 4), 270 (n = 6), or 360 µg (n = 3) once weekly for 12 weeks. Efficacy was assessed by the proportion of patients with complete response (CR) or partial response (PR). RESULTS: PEG-IFN α-2a was generally well tolerated, with a moderate number of reductions or withholding of doses because of adverse events (AEs) (25% (n = 1), 66% (n = 4), and 0% (n = 0) in the 180-, 270-, and 360-µg/week groups, respectively). The only dose-limiting toxicity was a grade 3 elevation of liver enzymes in the 270-µg dose group. The most common AEs were fatigue, acute flu-like symptoms, and hepatic toxicity. The major response rate (CR or PR) was 50% in the 180-µg group (CR, 50%; PR, 0%), 83% in the 270-µg group (CR, 67%; PR, 17%), and 66% in the 360-µg group (CR, 33%; PR, 33%). CONCLUSION: PEG-IFN α-2a at doses up to 360 µg once weekly was well tolerated in patients with CTCL up to the highest dose group and showed good response rates. Due to their good tolerance even in high doses, they might be an option for patients not tolerating standard IFN-α preparations. However, for this purpose and to evaluate comparability between standard and PEG-IFN larger clinical trials are needed, alone and in combination with oral photochemotherapy (PUVA).

Fumaric acid ester treatment in cutaneous lupus erythematosus (CLE): a prospective, open-label, phase II pilot study.

OBJECTIVE: The aim of the study was to assess the efficacy and safety of fumaric acid esters (FAEs) in patients with cutaneous lupus erythematosus (CLE). METHODS: In this 24-week, prospective, open-label, phase II pilot study, 11 patients with CLE, refractory to topical corticosteroids, were included. The primary endpoint of the study was the evaluation of the efficacy of FAEs after 24 weeks of treatment as assessed by the Revised Cutaneous Lupus Disease Area and Severity Index (RCLASI). RESULTS: Compared to baseline, significant improvement in the mean total RCLASI activity score and the mean RCLASI activity score for skin lesions was observed in week 12 (p = 0.002, p = 0.002, respectively) and in week 24 (p = 0.009, p = 0.009, respectively). Most common adverse events included abdominal cramps and headache. CONCLUSIONS: FAEs could be an alternative and safe treatment in patients with therapy-refractory CLE; however, randomized controlled trials are warranted to evaluate the efficacy and safety of FAEs in this disease.

[Pruritus in psoriasis : Profile and therapy]. / Pruritus bei Psoriasis : Profil und Therapie.

Psoriasis is a common chronic inflammatory disease with an incidence of about 0.5-3 %. Previously psoriasis was not primarily regarded to be associated with pruritus; however, this perception has changed in recent years. Meanwhile data conclusively show that between 64 and 97 % of patients report about pruritus that can be severe in a number of cases. Apart from suffering from psoriasis, the presence of pruritus causes additional stress and leads to a significant impairment of health-related quality of life. Neurogenic inflammation at least in part contributes to the development of pruritus in psoriasis skin lesions. A number of neuropeptides including substance P and calcitonin gene related peptide can act as pro-inflammatory mediators. There is evidence for a dysbalance between κ­ and µ­opioid receptors in lesional skin favoring inflammation and pruritus. After clearing of psoriasis lesions, pruritus is relieved as well. Therefore, specific treatment of pruritus is not necessary in general. In cases where severe pruritus is a prominent symptom, targeted therapy with mirtazapin or doxepin or neuroleptic compounds such as pregabalin or gabapentin or drugs affecting the κ­ und µ­opioid receptor balance can be administered. Today the importance of pruritus as a prominent symptom of psoriasis lesions has been widely accepted. In recent and running clinical trials with new drugs, pruritus at baseline and the effect of these drugs on pruritus is always assessed. This awareness also fuels basic research about pruritus in psoriasis.

Daylight photodynamic therapy with methyl aminolevulinate cream is effective and nearly painless in treating actinic keratoses: a randomised, investigator-blinded, controlled, phase III study throughout Europe.

BACKGROUND: Unmet needs exist in actinic keratosis (AK) treatment. Daylight photodynamic therapy (DL-PDT) has shown good efficacy and safety results compared to conventional PDT (c-PDT) in a recent Phase III multi-centre randomised controlled trial in Australia among 100 subjects with AKs. OBJECTIVES: Demonstrate non-inferior efficacy and superior safety of DL-PDT compared to c-PDT in treating multiple mild and/or moderate facial/scalp AKs. METHODS: Phase III, 12 week, multi-centre, randomised, investigator-blinded, controlled, intra-individual study conducted at different latitudes in Europe. AKs of adult subjects were treated once with methyl aminolevulinate (MAL) DL-PDT on one side of the face and MAL c-PDT contralaterally. Endpoints for DL-PDT concerned efficacy (non-inferiority regarding complete lesion response at week 12) and safety (superiority regarding subject's assessment of pain after treatment, on an 11-point numeric rating scale). Safety evaluation also included incidence of adverse events. Subject satisfaction was described using a questionnaire at baseline and last visit. RESULTS: At week 12, the total lesion complete response rate with DL-PDT was similar (non-inferior) to c-PDT (70% vs. 74%, respectively; 95% CI [-9.5; 2.4] in PP analysis, confirmed in ITT analysis). In addition, efficacy of DL-PDT was demonstrated regardless of weather conditions (sunny or cloudy). DL-PDT was nearly painless compared to c-PDT (0.7 vs. 4.4, respectively; P < 0.001), better tolerated and resulted in higher subject satisfaction. CONCLUSION: DL-PDT in comparison with c-PDT was as effective, better tolerated and nearly painless with high patient satisfaction, and may be considered a treatment of choice to meet needs of patients with mild or moderate facial/scalp AKs.

[Medical rehabilitation in dermatology : Goals, program content, and application process]. / Medizinische Rehabilitation in der Dermatologie : Ziele, Inhalte und Antragstellung.

BACKGROUND: Medical rehabilitation plays an important role in the management of patients with chronic dermatoses and dermato-oncological diseases. OBJECTIVES: Which dermatological indications qualify for a medical rehabilitation? What forms need to be completed for a successful application? Which treatments are provided and what are goals to be accomplished during dermatological rehabilitation? MATERIALS AND METHODS: Evaluation of current guidelines, directives, and recommendations as well as exemplary reviews. RESULTS: Dermato-oncological diseases and every chronic dermatological disease that is associated with a limitation of body functions and structures, activity and participation is eligible for medical rehabilitation. They include need, ability to absolve a rehabilitation, and a favorable prognosis. Treatments range from therapy of the underlying dermatological condition to interdisciplinary treatment of comorbidities with the aim of restoring functional health. CONCLUSIONS: Medical rehabilitation follows a holistic approach and represents a significant addition to outpatient and acute inpatient care, often leading to a long-term improvement in clinical outcome, participation, and activity.

Skin metastases in metastatic uveal melanoma: GNAQ/GNA11 mutational analysis as a valuable tool.

BACKGROUND: Uveal melanomas represent 3.1% of all melanomas, with a high potential of metastatic disease of up to 50%, where the median survival time is 6 months. Though liver metastases dominate as the primary site for metastasis, the existence of primary skin metastases is still under discussion but has been reported in only a few studies. OBJECTIVES: We present two cases in which patients with a known history of uveal melanoma developed melanoma skin metastases. METHODS: Mutational analysis was performed to clarify the origin of the metastases (uvea or skin). RESULTS: The analyses revealed GNA11 mutations, which are typical for uveal melanoma. These cases strongly suggest the skin to be the primary site of uveal melanoma. CONCLUSIONS: Knowledge about the mutational status of uveal melanomas opens the opportunity for future targeted therapies that directly interact with the mutation and its activated signal cascades. First trials in uveal melanoma have shown promising results with MEK inhibitors.

Comparison of pegylated interferon α-2b plus psoralen PUVA versus standard interferon α-2a plus PUVA in patients with cutaneous T-cell lymphoma.

OBJECTIVE: The aim of this study was to evaluate the safety and efficacy profile of pegylated interferon α-2b (PEG-IFN α-2b) in combination with photochemotherapy (PUVA) in the treatment of cutaneous T-cell lymphoma (CTCL) in comparison with standard IFN α plus PUVA. DESIGN: Retrospective cohort study over a period of 7 years. PATIENTS AND INTERVENTIONS: A total of 17 consecutive CTCL patients (stage IA-IV) were retrospectively analysed for toxicity and response rates associated with PEG-IFN α-2b (1.5 µg/kg weekly) plus PUVA (n = 9) or standard IFN α-2a (9 MIU 3×/week) plus PUVA (n = 8). MAIN OUTCOME MEASURES: Differences of response rates (complete/partial remission), progression-free survival, discontinuation of therapy, safety and toxicity profiles according to World Health Organization - Common Terminology Criteria of Adverse Events (WHO-CTCAE). RESULTS: Myelosuppression and liver toxicity occured more frequently during PEG-IFN α-2b plus PUVA treatment than during standard IFN α-2a plus PUVA therapy [77.8 vs. 50% (odds ratio 1.477) and 77.8 vs. 50% (odds ratio 1.692), respectively]. By contrast, the occurence of constitutional side-effects (mainly fatigue) [100 vs.77.8% (odds ratio 0.889)] and more adverse events leading to study discontinuation was considerably higher in the standard IFN α-2a plus PUVA group. The overall response rate in the PEG-IFN α-2b plus PUVA group (89%) was significantly superior. CONCLUSIONS: In patients with cutaneous T-cell lymphoma PEG-IFN α-2b plus PUVA might become a promising treatment alternative as its higher rate of myelosuppression and liver toxicity is outweighed by its lower percentage of constitutional side-effects, and its significantly higher overall response. Due to the small number of participants at this retrospective study, a larger prospective study is essential to verify our results.

Infantile-onset cutaneous T-cell lymphoma.

BACKGROUND: Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL), is mainly a disease of the elderly. OBJECTIVES: To review paediatric CTCL cases reported in the literature, with a focus on the time between onset of symptoms and establishment of a correct diagnosis. METHODS: A review of the literature was carried out and a case reported. RESULTS: A total of 254 cases of CTCL have been reported in children aged<16 years, 13 cases (<1% of all reported cases) in children below the age of 2 years, and only seven cases (including ours) during the first year of life. CTCL was most prevalent in children aged 10-12 years. The delay between age of onset and establishment of diagnosis was largest in the youngest age group (0-3 years), and declined steadily thereafter, thus reflecting the increasing likelihood that CTCL is considered in the differential diagnosis of skin disorders with increasing age of the patient. CONCLUSIONS: The diagnosis of CTCL is frequently delayed in young children. It needs to be considered in chronic 'eczematous' skin lesions irrespective of the patient's age, and including infants.

The anti-IL-4 receptor alpha antibody dupilumab: facing a new era in treating atopic dermatitis.

INTRODUCTION: Atopic dermatitis is the most common chronic inflammatory skin disease with high prevalence rates in adults and even higher among children. For the numerous patients suffering from moderate to severe disease, standard systemic treatment regimens such as cyclosporine A, methotrexate or azathioprine are not suited for long-term treatment due to their unfavorable safety profile. A promising alternative would be the newly developed IL-4 receptor alpha antibody dupilumab which has been investigated in several clinical trials during the last years. AREAS COVERED: Recently, four phase I and II studies have been published providing a favorable efficacy and safety profile. Clinical scores such as EASI were reduced by 74% after 12 weeks of treatment with early onset of first improvement after already one week. Safety data showed no evidence of drug-related serious adverse events and no organ toxicity. EXPERT OPINION: First clinical data of treating AD with dupilumab provided strong evidence for a highly significant efficacy and safety. In the case, future phase III studies will confirm these findings, dupilumab has the potential to become a new first line standard treatment for patients with severe AD.

[Werner's syndrome]. / Werner-Syndrom.

HISTORY AND CLINICAL FINDINGS: A 49-year-old man of German parentage with Werner's syndrome (including insulin-dependent type 2 diabetes mellitus) was treated in our department for extensive ulcers on his lower legs. GENETICS: Genetic analysis detected a novel compound heterozygous defect (1396delA and 2334delAC) of the WRN gene. TREATMENT AND FURTHER COURSE: The ulcer clearly decreased in size on local and antibiotic treatment as well as autologous fibroplast transplantation. The most severely affected right small finger required amputation with exarticulation. The severe pain caused by the ulcer was successfully treated with temporary blockage of the stellate ganglion and permanent sympathetic blockage at the level of the 2nd thoracic and lumbar vertebrae. CONCLUSION: Werner's syndrome is a rare form of progeria with an autosomal recessive mode of inheritance mimicking the symptoms of accelerated aging. The reduced life expectancy is caused by the increased incidence and early onset of atherosclerosis and malignant tumors. The detection of underlying molecular mechanisms will have an important impact in the field of anti-aging research.

Transition of pityriasis lichenoides et varioliformis acuta to febrile ulceronecrotic Mucha-Habermann disease is associated with elevated serum tumour necrosis factor-alpha.

Febrile ulceronecrotic Mucha-Habermann disease (FUMHD) represents a fulminant and potentially lethal variant of pityriasis lichenoides. Only 24 cases have been described so far. We report a 9-year-old boy who initially presented with classical pityriasis lichenoides et varioliformis acuta (PLEVA) following a mild enteritis. Three weeks later, his skin lesions started to ulcerate progressively, involving > 90% of his body surface, accompanied by high fever, normal C-reactive protein, but highly elevated serum levels of tumour necrosis factor (TNF)-alpha. Methotrexate 10 mg m(-2) weekly was required to halt disease progression, while oral steroids (initial dose 2.8 mg kg(-1) daily) alone proved insufficient. Sequential histology revealed progressively dense perivascular and intramural lymphocytic inflammation as well as keratinocyte necrosis. Our case demonstrates the clinical and histological continuum between 'classical' PLEVA and FUMHD and points to the potentially pathogenic significance of TNF-alpha. We hypothesize that in future cases, treatment with TNF-alpha antagonists might represent a reasonable alternative to high-dose immunosuppressive therapy.

A novel compound heterozygous mutation in Werner syndrome results in WRN transcript decay.

BACKGROUND: Werner syndrome (WS) is a rare autosomal recessive progeroid disorder caused by mutations of the WRN gene encoding a protein of the RecQ-type family of DNA helicases. OBJECTIVES: To develop a rapid and simple reverse transcription-polymerase chain reaction (RT-PCR) strategy for mutation analysis of the WRN gene, to identify pathogenic mutations in a German patient with WS and to determine the effects of the pathogenic mutations on WRN mRNA stability. METHODS: Allele-specific RT-PCR, semiquantitative RT-PCR, DNA sequencing. RESULTS: We describe a novel and rapid RT-PCR-based method for mutation analysis in WS and report a German patient with WS carrying a previously reported (1396delA) as well as a novel nonsense mutation (2334delAC) of the WRN gene. By semiquantitative RT-PCR analysis we demonstrate that this compound heterozygous genotype leads to WRN transcript decay. CONCLUSIONS: In previous studies WS was primarily attributed to a loss of function of stable truncated WRN gene products. Our findings indicate that mutations can also lead to markedly decreased WRN transcript stability.