Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis.

Osteopoikilosis, Buschke-Ollendorff syndrome (BOS) and melorheostosis are disorders characterized by increased bone density. The occurrence of one or more of these phenotypes in the same individual or family suggests that these entities might be allelic. We collected data from three families in which affected individuals had osteopoikilosis with or without manifestations of BOS or melorheostosis. A genome-wide linkage analysis in these families, followed by the identification of a microdeletion in an unrelated individual with these diseases, allowed us to map the gene that is mutated in osteopoikilosis. All the affected individuals that we investigated were heterozygous with respect to a loss-of-function mutation in LEMD3 (also called MAN1), which encodes an inner nuclear membrane protein. A somatic mutation in the second allele of LEMD3 could not be identified in fibroblasts from affected skin of an individual with BOS and an individual with melorheostosis. XMAN1, the Xenopus laevis ortholog, antagonizes BMP signaling during embryogenesis. In this study, LEMD3 interacted with BMP and activin-TGFbeta receptor-activated Smads and antagonized both signaling pathways in human cells.

Acanthosis nigricans in a child with mild osteochondrodysplasia and K650Q mutation in the FGFR3 gene.

A girl with a mild sporadic osteochondrodysplasia (OCD) similar to hypochondroplasia but with significant short stature is reported. She has been followed clinically between the ages of 9 months and 14 years. Growth remained normal throughout childhood with stature evolving about 3.5 SDs under the mean for age. By 8 years of age gradually appearing acanthosis nigricans (AN) in the neck and flanks was histopathologically confirmed. It provided the new incentive to search for specific FGFR3 mutations associated with this dermatologic abnormality. This resulted in the identification of the 1948A > C transversion predicting the K650Q missense substitution in the FGFR3 protein. Besides the expansion of the phenotypic spectrum of FGFR3-related OCDs to HCH with AN, this observation underscores the continuing adverse effect of this specific mutation upon the normal inhibitory signaling of the receptor at least in epidermal cells.

Origin, clinical presentation, and diagnosis of hypomelanotic skin disorders.

Hypomelanotic skin disorders are cutaneous pigmentary disorders characterized by a reduced melanin content in the skin that results in a lightening of the skin. Establishing the correct diagnosis for hypomelanotic skin disorders requires a good history, a detailed physical examination, the use of special lighting techniques, such as Wood's light, and sometimes a biopsy of the abnormally pigmented skin and the normally pigmented skin. This article focuses on the origin, clinical presentation, and diagnosis of acquired hypomelanotic skin disorders. An algorithm for the diagnostic approach to these hypomelanoses is given.

Topical pimecrolimus in the treatment of vitiligo.

Although the treatment of vitiligo has improved during the last decade, therapy is still not satisfactory for many patients. Recently topical calcineurin inhibitors were introduced in the treatment of atopic dermatitis. Considering the autoimmune hypothesis of vitiligo pathogenesis, the use of these topical calcineurin inhibitors seems reasonable. Most clinical vitiligo trials have been performed with tacrolimus and show beneficial effects. Concerning the value of pimecrolimus in the treatment of vitiligo only few data are available. Therefore we performed an open pilot study in 26 patients to evaluate the efficacy and safety of 1% pimecrolimus in the treatment of vitiliginous lesions in the head and neck region. In 13 of 26 (50%) evaluated target lesions, repigmentation was noted after a 6 month treatment period with a median percentage of repigmentation of 72.9% (interquartile range: 30.5-98.3%). Duration of vitiligo and total affected body surface area tended to be inversely correlated with the success rate of treatment. Side effects were mainly limited to a burning sensation at the application site. Despite the promising results of topical immunomodulators in the treatment of vitiligo, prudence is in order, as long-term follow up studies are still lacking.

Neurofibromatosis type 1 protein and amyloid precursor protein interact in normal human melanocytes and colocalize with melanosomes.

The neurofibromatosis type 1 (NF1) gene product, neurofibromin, is known to interact with Ras, thereby negatively regulating its growth-promoting function. Although this is a well-established interaction, the discovery of other neurofibromin interacting partners could reveal new functional properties of this large protein. Using yeast two-hybrid analysis against a brain cDNA library, we identified a novel interaction between the amyloid precursor protein and the GTPase activating protein-related domain of neurofibromin. This interaction was further analyzed in human melanocytes and confirmed by immunoprecipitation and colocalization studies. In addition, we observed a colocalization of amyloid precursor protein and neurofibromin with melanosomes. Amyloid precursor protein has been proposed to function as a vesicle cargo receptor for the motor protein kinesin-1 in neurons. This colocalization of amyloid precursor protein and neurofibromin with melanosomes was lost in melanocytes obtained from normal skin of a NF1 patient. We suggest that a complex between amyloid precursor protein, neurofibromin, and melanosomes might be important in melanosome transport, which could shed a new light on the etiopathogenesis of pigment-cell-related manifestations in NF1.

Consistent cutaneous imaging with commercial digital cameras.

OBJECTIVE: To demonstrate how to improve the reproducibility and accuracy of digital images of the skin taken with commercially available digital cameras by transforming them to a standard color space, sRGB. METHODS: Our computer algorithm transforms digital images to the standard sRGB color space. It is based on a card with a number of color squares with known colorimetric properties that is included in the image, thereby removing any ambiguity about the color information in the image. Reproducibility and accuracy of the method were assessed by comparing images of color squares with known colorimetric properties taken with different digital cameras at different exposures and zoom settings. RESULTS: Although calibrated images exhibit markedly improved precision and accuracy compared with noncalibrated images, all variability of the imaging process cannot be eliminated. CONCLUSION: With a little care and effort, a calibrated color chart, and computer software, it is possible to greatly improve the quality of clinical imaging in dermatology and possibly other fields of medicine.

Use of calcipotriene cream (Dovonex cream) following acute treatment of psoriasis vulgaris with the calcipotriene/betamethasone dipropionate two-compound product (Taclonex): a randomized, parallel-group clinical trial.

INTRODUCTION: A calcipotriene/betamethasone dipropionate two-compound product (Taclonex ointment) has been shown to be safe and effective in the treatment of psoriasis over 4 weeks. Since treatment of psoriasis is generally long-term, the objective of this study was to investigate the efficacy and safety of transferring patients to maintenance treatment with calcipotriene cream (Dovonex cream) following a 4-week treatment period with the two-compound product. METHODS: Patients with psoriasis were randomized to one of the following three treatment groups: 4 weeks of the two-compound product followed by 8 weeks of calcipotriene cream (calcipotriene cream group); 4 weeks of the two-compound product followed by 8 weeks of calcipotriene cream on weekdays and the two-compound product on weekends (alternating group); 4 weeks of the two-compound product followed by 8 weeks of vehicle of calcipotriene cream (vehicle group). All medications were applied once daily. RESULTS: A total of 1136 patients were randomized: 383 to the calcipotriene cream group, 377 to the alternating group, and 376 to the vehicle group. The mean percentage change in the Psoriasis Area and Severity Index from baseline to the end of the trial was -44.5% in the calcipotriene cream group, -58.4% in the alternating group, and -33.1% in the vehicle group. The mean difference between the calcipotriene cream and vehicle groups (primary treatment comparison) was -11.7% (95% CI -17.9, -5.5), which was statistically significant (p<0.001), and the mean difference between the alternating and vehicle groups was -24.7% (95% CI -30.9, -18.5), which was also statistically significant (p<0.001). For the investigators' global assessment of disease severity at the end of the trial, the differences between the calcipotriene cream and vehicle groups, and between the alternating and vehicle groups, were statistically significant (p<0.001), showing superior efficacy in the nonvehicle groups. The results were similar for the patients' global assessment of response to treatment. There were 43 patients (11.3%) with adverse drug reactions in the calcipotriene cream group, 28 (7.6%) in the alternating group, and 32 (8.6%) in the vehicle group. There were no statistically significant differences in the incidence of adverse drug reactions in the calcipotriene cream group relative to the vehicle group (odds ratio 1.36; 95% CI 0.84, 2.21; p=0.21), or in the alternating group relative to the vehicle group (odds ratio 0.87; 95% CI 0.51, 1.48; p=0.61). CONCLUSION: Four weeks of treatment with the calcipotriene/betamethasone dipropionate two-compound product followed by 8 weeks of maintenance treatment with calcipotriene cream is effective and safe. As an alternative maintenance regimen, treatment with calcipotriene cream on weekdays and the two-compound product on weekends is also effective and safe.

Café-au-lait spots in neurofibromatosis type 1 and in healthy control individuals: hyperpigmentation of a different kind?

Solitary café-au-lait spots are quite common in the general population but multiple café-au-lait macules (CALM) are often indicative of an underlying genetic disorder. The frequency of having more than five CALM is rare in normal individuals and is therefore considered as a cut-off for the diagnosis of neurofibromatosis type 1 (NF1). The etiopathogenesis of these macules is still very obscure. In this study we compared epidermal melanocyte and dermal mast cell numbers between four groups: control normal and control CALM skin, and NF1 normal and NF1 CALM skin and elaborated a possible role for stem cell factor (SCF) in CALM formation. The groups were analyzed by immunohistochemistry for numerical analysis of the melanocyte and mast cell population and by ELISA, western blot analysis and real-time quantitative PCR for further determination of the role of SCF. We found a significant increase in melanocyte density in NF1 CALM skin compared with the isolated CALM in control individuals. However, both groups displayed a similar increase in mast cell density. In addition, we found increased levels of soluble SCF in NF1 CALM and in NF1 normal fibroblast supernatant. We conclude that SCF is an important cytokine in NF1 skin, but that additional (growth) factors and/or genetic mechanisms are needed to induce NF1-specific CALM hyperpigmentation.

Method to measure force required to remove Pediculus humanus capitis (Phthiraptera: Pediculidae) eggs from human hair.

Head lice are very common and mainly affect children between 3 and 12 yr old. Little is known about the way nits, the eggs of the head louse, are attached to the hair. In this report, an objective measurement procedure for the ease with which nits can be removed is presented. The first peak force, associated with the start of nit movement, and the average and maximal force during the sliding of the nit were measured. The three force variables correlated with the length of the cylinder by which the nit was attached to the hair. A negative correlation was found between the maximum force exerted and the distance of the nit from the scalp. The method described in this report can be used to determine the in vitro efficacy of various products to remove nits.

Knowledge and management of scabies in general practitioners and dermatologists.

Scabies is an infectious skin disease with an increasing incidence during the past decade. A survey was conducted among general practitioners (GPs) and dermatologists in the region of Ghent, Belgium, to explore their knowledge on scabies. Information on the treatment advice given and the frequency of reporting scabies to the Health Inspection was also collected. The scores on the knowledge test were of an acceptable level in both GPs and dermatologists (median score 59% and 79% respectively). We found that profession (dermatologist versus GP), the number of years of experience and the estimated number of scabies patients per year had a significant effect on this score. Permethrin cream, currently regarded as the standard treatment, is prescribed as the only treatment for scabies by half of the GPs and dermatologists. Almost 50% of the GPs and dermatologists indicated they rarely or never report scabies to the Health Inspection. As a result the correct incidence of scabies in Belgium, as in many other countries, is not known.

The importance of socio-economic status and individual characteristics on the prevalence of head lice in schoolchildren.

Pediculosis is a common infestation in schoolchildren but little is known about the factors influencing its prevalence. The aim of this study was to determine the prevalence of head lice in schoolchildren in Ghent and to investigate the independent association between individual characteristics of the child, socio-economic status (SES) of the family and head lice. The prevalence of head lice at baseline and 14 days after treatment advice was determined by the wet combing method in a total of 6,169 schoolchildren age 2.5 to 12 years from Ghent (Belgium). Age, sex, educational level and hair characteristics of the child, SES of the family, and number of children in the family was collected by the school health department. The prevalence of head lice was 8.9%. The only statistically significant factors at the child level are SES, the number of children in the family, hair length and hair colour. Treatment failure was recorded in 41% of the children positive at baseline screening and was significantly related to hair colour and SES. This study demonstrated that the prevalence of head lice is determined by clustering of children rather than by characteristics of the child. The management of head lice should take a community-based approach equally involving families, schools, health care professionals and the government.

Interactions of human Myosin Va isoforms, endogenously expressed in human melanocytes, are tightly regulated by the tail domain.

Primary human epidermal melanocytes express six endogenous isoforms of the human actin-associated myosin Va motor protein, involved in organelle transport. As isoforms containing exon F are most abundant in melanocytes, we hypothesized that these isoforms probably have a melanocyte-specific function. To uncover the biologic role of the six isoforms we introduced enhanced green fluorescent protein (eGFP)-myosin Va tail constructs in human melanocytes. We found that the medial tail, undergoing alternative splicing, has to be expressed in combination with the globular tail in order to obtain clear colocalization with organelles. Our data show that isoforms lacking exon F but containing exon D are associated with vesicles near the Golgi area. Myosin Va isoforms containing exon F are able to colocalize with and influence melanosome distribution by indirect interaction with rab27a and direct interaction with melanophilin. These results indicate that the myosin Va medial tail domain provides the globular tail domain with organelle-interacting specificity.

Double-blind placebo-controlled study of autologous transplanted epidermal cell suspensions for repigmenting vitiligo.

OBJECTIVES: To investigate the efficacy of epidermal noncultured cellular grafting in patients with vitiligo and the role of postinflammatory, spontaneous, or UV-induced pigmentation in obtaining repigmentation. DESIGN: A prospective, randomized, double-blind, placebo-controlled study. SETTING: Ambulatory patients in an institutional practice. Patients were followed up for 3 to 12 months. PATIENTS: A total of 33 paired, symmetrically distributed leukodermic lesions, all resistant to therapy, were observed in 28 patients. Nineteen patients appeared to have a stable vitiligo (group 1), whereas there was doubt about the stability of the disease in 9 patients (group 2). INTERVENTION: After laser ablation, a hyaluronic acid-enriched cellular graft was applied to 1 lesion while the paired lesion received placebo. Three weeks later all lesions were exposed to UV irradiation twice per week for approximately 2 months. MAIN OUTCOME MEASURES: Primarily, the percentage of repigmentation was assessed after 3, 6, and 12 months using a digital image analysis system. The repigmentation pattern was also evaluated after 1 and 3 months. RESULTS: A strongly significant difference between cellular grafts and placebo was observed after 3, 6, and 12 months (P<.001, P = .002, and P = .002, respectively). In group 1, repigmentation of at least 70% of the treated area was achieved in 55%, 57%, and 77% of the actively treated lesions 3, 6, and 12 months after treatment, whereas in group 2 repigmentation of at least 70% of the treated area was not observed at any time point. The repigmentation pattern was diffuse in 94% of the responding patients. CONCLUSIONS: After a strict preoperative selection for disease stability, transplantation resulted in repigmentation of at least 70% of the treated area in most actively treated vitiligo lesions. Repigmentation was primarily caused by the transplanted melanocytes.

A new digital image analysis system useful for surface assessment of vitiligo lesions in transplantation studies.

So far there is no uniformity in the evaluation methods used in the assessment of treatment outcome in vitiligo studies. The ability to objectively measure surfaces of vitiligo lesions is important for both clinical practice and research. Our objective was to assess the reproducibility, accuracy, user-friendliness and time effectiveness of a new digital image analysis system for surface measurement of vitiligo lesions. Three different observers performed both a visual estimation and a digital image analysis on 30 images of 10 vitiligo lesions. Inter- and intra-observer variation were evaluated and results were compared with the 2D gold standard measurements and a 3D measurement. A high inter- and intra-observer variability was observed for the visual estimation of surfaces. With the digital image analysis system a significant improvement of the reproducibility was achieved (p = 0.01). Moreover, results were accurate and the measurement procedure was user-friendly. Importantly, a systematic underestimation was demonstrated when comparing the 2D with the 3D measurements. We introduced an objective measurement method that might be useful in the future for consistently measuring surfaces of selected vitiligo lesions both before and after different therapeutic modalities.

Cutis laxa of the autosomal recessive type in a consanguineous family.

Cutis laxa comprises a group of uncommon disorders of elastin fibers first described by Graf in the early 19th century. The main characteristic is a redundant, loose skin with deep wrinkling or sagging combined with a variable systemic involvement. Histopathologic examination presents various abnormalities of the elastin fibers. We distinguish congenital as well as acquired forms of generalized or localized cutis laxa. The mode of inheritance shows great heterogeneity: autosomal dominant, autosomal recessive and X-linked recessive inheritance have all been described. We present a severe case of autosomal recessive type 1 cutis laxa in a female patient, born in a large, consanguineous Turkish family, where three other family members had already died of the disease. A missense mutation of fibulin-5 was identified in this patient.

Management of vitiligo patients and attitude of dermatologists towards vitiligo.

As vitiligo does not cause any physical impairment, it is often considered unimportant by physicians. Vitiligo patients repeatedly experience disinterest from the medical world regarding their skin problem. A questionnaire survey was used to assess the management of vitiligo patients and the attitude of dermatologists towards vitiligo in Belgium. Vitiligo patients (n = 244) visiting an academic affiliated dermatology department were included and 454 out of 558 Belgian dermatologists returned a mailed questionnaire. Vitiligo patients do not often visit a doctor concerning their disease and do not often treat their disease. Disease severity as reported by the patient is correlated with the number of doctor visits (p = 0.001) but not to treatment of the disease. Information about the treatment and physician's encouragement to treat seem important in motivating patients to treat their vitiligo, but 50% of the patients were not adequately informed about their disease and its treatment during their first doctor visit. Today, nearly all the dermatologists report widely informing their patients, but only 36% of them encourage their patients to treat their disease, being pessimistic concerning expected treatment results. Interestingly, two thirds of the patients who ever treated their disease find it worthwhile.

End-stage disease of native kidneys in a patient with biopsy-proven Arndt-Gottron scleromyxoedema and recurrence in the transplanted kidney.

End-stage renal disease-stage 5 chronic kidney disease (CKD)-of the native kidneys, related to biopsy-proven Arndt-Gottron scleromyxoedema, developed in a male patient. From 1998 until 2001, the patient was treated by haemodialysis. In June 2001, cadaveric kidney transplantation was performed. In January 2004, a kidney biopsy was performed because of deteriorating renal function revealing relapse of scleromyxoedema with typical concentric narrowing of the arterioles due to accumulation of mucopolysaccharides with severe glomerular ischaemia. Arndt-Gottron scleromyxoedema is an as yet unsuspected cause of stage 5 CKD of the native kidneys. Moreover, the disease can relapse in the transplanted kidney, again leading to intractable transplant stage 5 CKD.

The quest for the mechanism of melanin transfer.

Skin pigmentation is accomplished by production of melanin in specialized membrane-bound organelles termed melanosomes and by transfer of these organelles from melanocytes to surrounding keratinocytes. The mechanism by which these cells transfer melanin is yet unknown. A central role has been established for the protease-activated receptor-2 of the keratinocyte which effectuates melanin transfer via phagocytosis. What exactly is being phagocytosed - naked melanin, melanosomes or melanocytic cell parts - remains to be defined. Analogy of melanocytes to neuronal cells and cells of the haemopoietic lineage suggests exocytosis of melanosomes and subsequent phagocytosis of naked melanin. Otherwise, microscopy studies demonstrate cytophagocytosis of melanocytic dendrites. Other plausible mechanisms are transfer via melanosome-containing vesicles shed by the melanocyte or transfer via fusion of keratinocyte and melanocyte plasma membranes with formation of tunnelling nanotubes. Molecules involved in transfer are being identified. Transfer is influenced by the interactions of lectins and glycoproteins and, probably, by the action of E-cadherin, SNAREs, Rab and Rho GTPases. Further clues as to what mechanism and molecular machinery will arise with the identification of the function of specific genes which are mutated in diseases that affect transfer.

Subjective and objective evaluation of noncultured epidermal cellular grafting for repigmenting vitiligo.

BACKGROUND: Noncultured epidermal cell transplantation in vitiligo permits the coverage of relatively large areas without culturing cells. OBJECTIVE: To investigate the effectiveness of noncultured epidermal cell transplantation in treating stabilized vitiligo using objective and subjective evaluation methods. METHODS: Noncultured autologous melanocytes and keratinocytes were grafted in a hyaluronic-acid-enriched suspension on superficially laser-abraded vitiligo lesions in 40 patients with refractory stable vitiligo (30 with generalized and 10 with localized vitiligo). The repigmentation was evaluated 3-12 months after grafting using a digital image analysis system. Furthermore the treatment was evaluated from the patients' point of view with the DLQI (Dermatology Life Quality Index) and a 'global assessment'. RESULTS: The mean percentage of repigmentation, evaluated at the last follow-up visit, was 72% (median 84%), and a repigmentation of >or=70% was observed in 62% of patients. The best results were achieved in the neck and the presternal region. A subjective evaluation was performed in half of the subjects. The mean DLQI score at inclusion (6.95, SD = 6.68, n = 20) was significantly decreased after treatment (p = 0.013, mean 3.85, SD = 4.13, n = 20). The patients were satisfied with the achieved result, found it worthwhile to undergo the treatment and would choose it again. CONCLUSION: According to both subjective and objective evaluation methods, noncultured epidermal cell transplantation is promising in patients with stable vitiligo.