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.

[Pigmented macules as possible early signs of genetic syndromes]. / Pigmentierte Flecken als mögliche Frühzeichen genetischer Syndrome.

Solitary congenital or early apparent pigmented macules are usually without relevance; however, when multiple, extensive or in a patterned arrangement, they are not uncommonly the first sign of an underlying genetic syndrome. The present article gives an overview on the clinical significance of multiple café-au-lait macules, multiple lentigines and pigmentary mosaicism and discusses the differential diagnosis of associated syndromes. Early diagnosis with the essential contribution of the dermatologist is not only important for genetic counseling but can also contribute to avoidance of sometimes life-threatening complications.

Tracing the evolution of the heterotrimeric G protein α subunit in Metazoa.

BACKGROUND: Heterotrimeric G proteins are fundamental signaling proteins composed of three subunits, Gα and a Gßγ dimer. The role of Gα as a molecular switch is critical for transmitting and amplifying intracellular signaling cascades initiated by an activated G protein Coupled Receptor (GPCR). Despite their biochemical and therapeutic importance, the study of G protein evolution has been limited to the scope of a few model organisms. Furthermore, of the five primary Gα subfamilies, the underlying gene structure of only two families has been thoroughly investigated outside of Mammalia evolution. Therefore our understanding of Gα emergence and evolution across phylogeny remains incomplete. RESULTS: We have computationally identified the presence and absence of every Gα gene (GNA-) across all major branches of Deuterostomia and evaluated the conservation of the underlying exon-intron structures across these phylogenetic groups. We provide evidence of mutually exclusive exon inclusion through alternative splicing in specific lineages. Variations of splice site conservation and isoforms were found for several paralogs which coincide with conserved, putative motifs of DNA-/RNA-binding proteins. In addition to our curated gene annotations, within Primates, we identified 15 retrotranspositions, many of which have undergone pseudogenization. Most importantly, we find numerous deviations from previous findings regarding the presence and absence of individual GNA- genes, nuanced differences in phyla-specific gene copy numbers, novel paralog duplications and subsequent intron gain and loss events. CONCLUSIONS: Our curated annotations allow us to draw more accurate inferences regarding the emergence of all Gα family members across Metazoa and to present a new, updated theory of Gα evolution. Leveraging this, our results are critical for gaining new insights into the co-evolution of the Gα subunit and its many protein binding partners, especially therapeutically relevant G protein - GPCR signaling pathways which radiated in Vertebrata evolution.

[Lichen nitidus and lichen striatus]. / Lichen nitidus und Lichen striatus.

Lichen nitidus is a rare, chronic dermatosis which occurs more often in children than in adults. It presents with tiny, monomorphous, lichenoid, mostly asymptomatic papules in regional or disseminated distribution which show a pathognomonic histological pattern. The pathogenesis is unclear; however, immunologic phenomena and genetic factors are under discussion. In rare cases, an association with other dermatoses and systemic diseases has been described. Moreover, medical treatments have been incriminated as triggers. Considering the self-limited course in mostly young patients, treatment must be thoroughly weighed. Possible therapeutic options include topical corticosteroids and calcineurin inhibitors as well as oral antihistamines, corticosteroids and narrow-band ultraviolet B phototherapy. Lichen striatus is an acquired, usually asymptomatic dermatosis occurring mostly in preschool children. The characteristic feature is the arrangement of small, flat, light red- to skin-colored papules along the lines of Blaschko. Therefore, a postzygotic mutation of epidermal progenitor cells induced to express new surface antigens by trigger factors as infections, vaccinations or trauma with consecutive immune reaction is assumed. Nail involvement of the affected limb can rarely occur. Lichen striatus usually heals without scarring within several months, so that therapies with severe side effects are obsolete. Mild topical corticosteroids or calcineurin inhibitors may be used, especially if patients exceptionally suffer from pruritus. A postinflammatory hypopigmentation can persist for months to years.

[Staphylococcal Scalded Skin Syndrome in a Very Low Birth Weight Premature Infant]. / Staphylococcal Scalded Skin Syndrome bei einem sehr unreifen Frühgeborenen.

INTRODUCTION: Staphylococcal scalded skin syndrome (SSSS) was often endemic in the past but is nowadays rare. The hematogeneous spread of exfoliative toxins A (ETA) or B (ETB) produced by specific Staphylococcus aureus strains causes a scald-like eruption with disseminated bullous lesions. CASE REPORT: A perioral impetigo lesion occurred on day 14 of life in a preterm male infant (1,065 g, 30 weeks of gestational age). Empiric antibiotic therapy with cefotaxime and vancomycin was given for 6 days and led to complete resolution. A Staphylococcus aureus strain was isolated. After a symptom-free interval a relapse was noted on day 26 of life. Despite restarting the antibiotic therapy immediately the initial lesion expanded, and disseminated flaccid blisters on an erythematous base appeared within a few hours. On histological examination the cleavage was in the level of the granular layer. There was no mucosal involvement, and the Nikolsky I sign was positive. The antibiotic therapy was changed to a combination of cefotaxime, flucloxacillin and clindamycin which rapidly stopped progression of the exfoliation. Supportive therapy included adequate analgesia, parenteral rehydration, and application of local antiseptics. The preterm infant completely recovered. In the primary lesion an ETA-producing Staphylococcus aureus strain was isolated. Nasal microtrauma by a nasogastric tube was assumed to have caused the fulminant disease. At the same time, no other Staphylococcus aureus infections were seen in our Department of Neonatology. DISCUSSION: According to the literature, the incidence of SSSS is higher in premature infants and newborns than in older children. Possible causes include lower antibody levels against exfoliative toxins and renal immaturity. Rapid diagnosis and immediate appropriate antibiotic therapy are essential to prevent secondary infection, dehydration with electrolyte disturbance, death, and endemic spread.

[Differential diagnosis of oral mucosal erosions and ulcers in children]. / Differenzialdiagnose erosiver und ulzeröser Mundschleimhauterkrankungen im Kindesalter.

BACKGROUND: Oral ulcers and erosions are of great clinical importance because they are common in childhood and adolescence and generally painful. They can be related to harmless conditions, such as recurrent aphthous stomatitis. On the other hand, they can be associated with severe systemic diseases making an early diagnosis and initiation of treatment necessary. OBJECTIVES: We herein focus on the systematic presentation of differential diagnoses of oral ulcers and erosions in pediatric patients and present clues in the history and clinical features that are helpful to establish the diagnosis. CONCLUSIONS: Patient's age at the beginning of the symptoms, differentiation between acute and chronic course, distribution of mucosal lesions, additional involvement of the skin, extracutaneous symptoms, general condition of the patient, comorbidities and medication may be determining factors of the correct diagnosis. In children and adolescents aphthous stomatitis, infections and trauma are the most frequent causes of oral ulcerations or erosions of the mucous membranes.

[Psoriasis vulgaris in children and adolescents. Pathogenesis, clinical picture and therapy]. / Psoriasis vulgaris bei Kindern und Jugendlichen. Pathogenese, Klinik und Therapie.

BACKGROUND: The prevalence of psoriasis vulgaris in childhood ranges from 0.12 % in infants to 1.2 % in adolescents. Psoriasis is a polygenic disease triggered by external factors and is influenced by comorbidities such as obesity, metabolic syndrome, chronic inflammatory bowel diseases and rheumatic diseases. CLINICAL FEATURES: Its clinical presentation is variable. Typical complications include erythroderma, disseminated pustulosis and arthropathy. THERAPY: Amongst a wide range of topical or systemic therapeutical options, individualized treatment is based on severity, site and extent of cutaneous involvement, age, potential side-effects and comorbidities.

[Developmental abnormalities and nevi of the scalp]. / Fehlbildungen und Nävi des behaarten Kopfes.

Unusual congenital or early-onset skin lesions on the scalp often pose a diagnostic challenge particularly as the clinical evaluation may be hampered by dense hair growth. Thus, this paper provides a concise review on developmental abnormalities and nevi with exclusive or predominant scalp localization. Aplasia cutis congenita occurs as an isolated finding, in association with genetic syndromes, nevi and anomalies or as a consequence of intrauterine trauma and teratogens. A hairless area with a narrow surrounding rim of hypertrichosis (hair collar sign) may point to occult cranial dysraphism, especially if accompanied by further suggestive signs as port-wine stains, large hemangiomas, dimples, congenital dermoid cysts, and sinuses. Many diverse entities may hide behind cutis verticis gyrata with the primary essential form being rare and representing a diagnosis of exclusion. In contrast to former belief, benign adnexal tumors arise in a nevus sebaceus considerably more often than basal cell carcinomas and other malignant epithelial tumors. Provided that tumor development is not suspected, excision of a nevus sebaceus nevus is indicated primarily for aesthetic-psychosocial reasons. However, surgical treatment is considerably easier in small children. Nevus sebaceus may be a cutaneous marker for several complex syndromes whereas nevus psiloliparus presents almost always in connection with encephalocraniocutaneous lipomatosis. Congenital melanocytic nevi of the scalp tend toward clinical regression, so that surgical intervention in large lesions should be carefully considered. In contrast, the threshold for excision of blue nevi and other conspicuous melanocytic nevi on the scalp should be low, especially since they are difficult to monitor.

[Anetodermic pilomatricoma. Uncommon variant of a common childhood adnexal tumor]. / Anetodermisches Pilomatrikom. Seltene Variante eines häufigen Adnextumors im Kindesalter.

The anetodermic ("bullous") subtype is a rare variant of pilomatricoma which we diagnosed in 2 girls who were 9 and 10 years old. The tumors presented as 3 × 2 and 1.5 × 1.5 cm red dome-shaped nodules with a slightly wrinkled surface on the upper back and on the pretibial region, respectively. Both were superficially soft, but then firm as one palpated deeper. Histology showed an edematous, well-vascularized dermis resembling granulation tissue overlying a deep otherwise typical pilomatricoma. Clinical and histological characteristics of the anetodermic subtype are discussed on the basis of previously published cases.

Efficacy and safety of methantheline bromide (Vagantin(®) ) in axillary and palmar hyperhidrosis: results from a multicenter, randomized, placebo-controlled trial.

BACKGROUND: Focal hyperhidrosis can severely affect quality of life. So far, knowledge on the effect of systemic therapy of focal hyperhidrosis is limited. OBJECTIVE: To assess the efficacy and safety of methantheline bromide (MB) in the treatment of axillary and palmar-axillary hyperhidrosis. METHODS: A multicenter controlled randomized double-blind clinical trial was conducted in patients with axillary or palmar-axillary hyperhidrosis defined by a sweat production >50 mg/5 min. Patients received 3 × 50 mg MB daily or placebo over a period of 28 ± 1 days. Main outcome criterion was the reduction of sweat as measured by gravimetry on day 28 ± 1. Quality of life was assessed by Dermatology Life Quality Index (DLQI) and Hyperhidrosis Disease Severity Score (HDSS). RESULTS: A total of 339 patients were randomly assigned to receive MB or placebo. On day 28 ± 1, the mean axillary sweat production was 99 mg for MB and 130 mg for placebo compared with 168 mg and 161 mg respectively at baseline (P = 0.004). Patient's HDSS score decreased in the MB group from 3.2 to 2.4 compared with 3.2 to 2.7 for placebo (P = 0.002). Similar results could be obtained for the DLQI with 9.7 for MB and 12.2 for placebo, which decreased from 16.4 or 17 respectively (P = 0.003). Tolerability was good for both groups. The most frequent adverse event was dry mouth. CONCLUSION: Fifty milligrams methantheline bromide three times a day is an effective and safe treatment of axillary hyperhidrosis.

[Acquired alopecia in childhood]. / Erworbene alopezien im kindesalter.

Hair loss and alopecia occur frequently in children. The prevalence of the underlying causes and conditions, treatment options and prognosis differ in part significantly from adulthood. This article focuses on frequent forms of acquired alopecia which are not associated with inflammation or scarring of the scalp. Special attention is given to alopecia areata as the most important entity and to trichotillomania as its most difficult differential diagnosis. Significant forms of diffuse hair loss include anagen-dystrophic and telogen effluvium, androgenetic alopecia and loose anagen hair.

Lethal junctional epidermolysis bullosa with pyloric atresia due to compound heterozygosity for two novel mutations in the integrin ß4 gene.

BACKGROUND: Junctional epidermolysis bullosa with pyloric atresia (JEB-PA) is a rare autosomal recessive disease with blister formation within the lamina lucida due to mutations in the integrin ß4 (ITGB4) and α6 (ITGA6) genes. CASE REPORT: A female preterm infant, first child of healthy non-consanguineous parents, was born at 26 + 4 weeks of gestation by caesarean section, following polyhydramnion and abruption of placenta. She presented with extensive areas of denuded skin on both lateral sides of the head, neck and extremities. Auricles were hypoplastic. Abdominal ultrasound and X-ray were suggestive of pyloric atresia which was revised surgically on the 4th day of life. Further course was complicated by progressive skin detachment, sepsis, and renal insufficiency with fatal outcome at 18 days of age. Immunofluorescence mapping of cryopreserved skin showed junctional cleft formation with negative staining for integrin α6 and integrin ß4. Mutational analysis disclosed compound heterozygosity for two novel nonsense mutations in the ITGB4 gene: c.600dupC/p.F201fsX14 and c.2533C>T/p.Q845X. 2 subsequent pregnancies were terminated following prenatal diagnosis disclosing the same ITGB4 mutations, a 4th pregnancy was unaffected. CONCLUSION: We describe a case of lethal JEB-PA with negative immunoreactivity to integrin α6 and integrin ß4 predicting a poor outcome. Identification of compound heterozygosity for two novel ITGB4 mutations in the affected preterm infant permitted prenatal diagnosis and finally birth of a healthy sibling.

[Botulinum toxin in focal hyperhidrosis. An update]. / Botulinumtoxin bei fokaler Hyperhidrose. Ein aktueller Überblick.

Eight years after its approval, intralesional injections of botulinum toxin type A have become established as an easily performed, highly effective and almost complication-free therapeutic option in primary axillary hyperhidrosis. Sweat production is decreased to about a sixth of previous amounts, and the effect persists for 7 months on average. Restoration of the often significantly impaired quality of life has been convincingly documented in large studies. The effect of botulinum toxin is based on the inhibition of the release of acetylcholine into the synaptic cleft. In addition to this approved use, botulinum toxin is also successfully employed in other forms of focal hyperhidrosis, particularly in gustatory sweating. However, its use in palmoplantar hyperhidrosis, the second most common form of primary hyperhidrosis, is limited because of the pain from numerous injections, need for increased doses of the expensive toxin and the relatively short effective period of about 4 months. Botulinum toxin type B appears to be comparably effective as type A products but is more often associated with systemic adverse events.

Heterotrimeric G proteins.

Over the past year, the thrust of work in the field of heterotrimeric G proteins has been primarily in the following areas: first, resolution of their three-dimensional structures by X-ray crystallography; second, elucidation of the effect of lipid modifications on the Galpha and Ggamma subunits; third, understanding the role of the Gbetagamma dimer in stimulation of a variety of effectors following receptor activation; and fourth, identification of the points of contact among the Galpha, Gbeta, and Ggamma subunits, and between these subunits and their cognate receptor or effector molecules.

Segmental multilayered argon plasma coagulation: effective therapy option for perianal and scrotal Hailey-Hailey disease.

AIM: Hailey-Hailey disease (HHD) is a genodermatosis characterized by recurrent chronic weeping plaques at intertriginous sites. In severe cases, topical and systemic treatments are often insufficient. Extensive excisions are traumatic for patients and have a high morbidity. Superficial ablative procedures such as dermabrasion have become established, but are difficult to perform in the perianal region and scrotum. Therefore, alternative therapies are required. METHOD: Four patients with extensive anogenital HHD were treated by argon plasma coagulation (APC). This leads to a controlled coagulation of nearly constant depth. After dividing the affected areas into segments, a multilayered APC was performed in every second segment to the upper corium. The remaining segments were treated in the same way after healing of the initially treated parts. RESULTS: A disease-free period of up to 37 months was observed in all four patients. There was no case of reduced cutaneous sensitivity or extensive scarring. CONCLUSIONS: Argon plasma coagulation is effective and safe for perianal and scrotal HHD. The benefits include the accessibility to difficult anatomic sites and good control of ablation. The risk of anal stenosis is minimized by the segmental two-step procedure. The rapid re-epithelialization occurs from structures not affected by the disease and allows rapid mobilization of patients.

Endothelial cell-surface gp60 activates vesicle formation and trafficking via G(i)-coupled Src kinase signaling pathway.

We tested the hypothesis that the albumin-docking protein gp60, which is localized in caveolae, couples to the heterotrimeric GTP binding protein G(i), and thereby activates plasmalemmal vesicle formation and the directed migration of vesicles in endothelial cells (ECs). We used the water-soluble styryl pyridinium dye N-(3-triethylaminopropyl)-4-(p-dibutylaminostyryl) pyridinium dibromide (FM 1-43) to quantify vesicle trafficking by confocal and digital fluorescence microscopy. FM 1-43 and fluorescently labeled anti-gp60 antibody (Ab) were colocalized in endocytic vesicles within 5 min of gp60 activation. Vesicles migrated to the basolateral surface where they released FM 1-43, the fluid phase styryl probe. FM 1-43 fluorescence disappeared from the basolateral EC surface without the loss of anti-gp60 Ab fluorescence. Activation of cell-surface gp60 by cross-linking (using anti-gp60 Ab and secondary Ab) in EC grown on microporous filters increased transendothelial (125)I-albumin permeability without altering liquid permeability (hydraulic conductivity), thus, indicating the dissociation of hydraulic conductivity from the albumin permeability pathway. The findings that the sterol-binding agent, filipin, prevented gp60-activated vesicle formation and that caveolin-1 and gp60 were colocalized in vesicles suggest the caveolar origin of endocytic vesicles. Pertussis toxin pretreatment and expression of the dominant negative construct encoding an 11-amino acid G(alphai) carboxyl-terminal peptide inhibited endothelial (125)I-albumin endocytosis and vesicle formation induced by gp60 activation. Expression of dominant negative Src (dn-Src) and overexpression of wild-type caveolin-1 also prevented gp60-activated endocytosis. Caveolin-1 overexpression resulted in the sequestration of G(alphai) with the caveolin-1, whereas dn-Src inhibited G(alphai) binding to caveolin-1. Thus, vesicle formation induced by gp60 and migration of vesicles to the basolateral membrane requires the interaction of gp60 with caveolin-1, followed by the activation of the downstream G(i)-coupled Src kinase signaling pathway.