点状掌跖角化病遗传学研究进展

点状掌跖角化病是一种以掌跖部不规则分布、进行性加重的角化性丘疹为特征的常染色体显性遗传性皮肤病.目前已报道AAGAB基因和COL14A1基因是点状掌跖角化病致病基因,除此之外,可能还存在其他致病基因.迄今为止,在多个种族或民族点状掌跖角化病家系中已发现39种AAGAB基因突变和1个COL14A1基因突变位点.AAGAB基因突变导致其编码的p34蛋白功能缺失或不足,使表皮生长因子受体再循环发生障碍,角质形成细胞发生过度增殖,导致点状掌跖角化病发生.COL14A1基因突变的致病性有待于蛋白质功能学研究、体外细胞实验以及该基因突变在其他点状掌跖角化病家系内重复性验证等进一步证实.     

Low‐dose etretinate shows promise in management of punctate palmoplantar keratoderma type 1: Case report and review of the published work

Punctate palmoplantar keratoderma type 1 (PPKP1) is a rare autosomal dominant disorder of keratinization, clinically characterized by punctate keratotic papules affecting the palmoplantar skin. Loss‐of‐function mutations in AAGAB have recently been reported as a cause of PPKP1. Despite the discovery of the genetic cause of PPKP1, pathogenesis‐based therapies are still unavailable. Moreover, little is known about the effectiveness of treatments for PPKP1. In this study, we analyzed a Japanese woman with PPKP1 and identified a novel frame‐shift mutation c.195_198del4 (p.Lys66Phefs*43) in AAGAB. Moreover, low‐dose etretinate was effective in improving the PPKP1 lesions in our patient. Our published work review identified only eight cases of PPKP1 with successful response to topical or systemic treatments. Notably, six of the cases were successfully treated with systemic retinoids. Thus, this study clearly provides further evidence that PPKP1 is caused by AAGAB mutations and that systemic retinoids are the most promising current treatment for PPKP1.     

点状掌跖角化病3家系AAGAB致病基因突变位点检测

目的:检测点状掌跖角化病家系中AAGAB基因的突变。方法:分别对来自3个家系的3例患者应用聚合酶链反应(PCR)扩增外周血基因组AAGAB基因的10个外显子及邻近内含子区域,对其产物直接测序和序列分析。结果:3例患者的AAGAB基因编码区均未发现突变位点。结论:AAGAB基因与本研究中的点状掌跖角化病患者发病无关联,提示可能存在其它致病基因。     

Case of punctate palmoplantar keratoderma type I treated with combination of low‐dose oral acitretin and topical salicylic acid and steroid

Palmoplantar keratodermas (PPK) are heterogeneous disorders characterized by abnormal keratinization. Especially, punctate PPK (PPPK), one of the subtypes of hereditary PPK, is a rare punctate keratoderma characterized by tiny “raindrop” keratoses having a tendency to coalesce on the edge of soles, which are exposed to sustained pressure. If typical punctate lesions are confined to the palms and soles and the patient has a family history and late onset, it can be considered as PPPK type I (PPKP1), also called Buschke–Fisher–Brauer disease. The exact etiology of PPPK has not been fully understood. Furthermore, no standardized treatment for PPPK has been established and treatment options are limited. Above all, traditional systemic retinoids have been used in several cases, but dose‐related adverse effects are common. Therefore, combination of low‐dose systemic retinoids and adjuvant topical therapy can be an alternative treatment option for PPPK. Herein, we report a case of PPKP1 treated with combination of low‐dose oral acitretin (10 mg/day) and topical salicylic acid and steroid. Despite low capacity, low‐dose acitretin showed excellent regression of the lesions by combined use of topical ointments. The supplementary topical therapy may be useful in reducing the dose of systemic retinoids and preventing potential toxicity.     

TICK BITES IN KOREA

Background. Tick bites are dermatoses not commonly encountered in Korea. Recognizing their clinical signs as well as their histopathologic findings is important In making a diagnosis of tick-related dermatoses. The incidence and causative species are different depending on the geographic areas. The histopathologic findings of tick bites are known to be a variable depending on the species of ticks involved and the duration of their bloodsucking. Methods. Five ticks were collected from five patients and three of them were identified as Ixodes (/.) nipponensis. Results. Histopathologic findings of panniculitis were prominent in four of five cases; septal panniculitis in two cases, and lobular panniculitis in the other cases. Conclusions. Ixodes nipponensis was the most common causative species of ticks responsible for tick bites in Korea, and tick bite panniculitis must be considered in the differential diagnosis of panniculitis which is mainly composed of neutrophils.     

Punctate Palmoplantar Keratoderma

Punctate palmoplantar keratoderma (PPPK) is a rare entity with an estimated prevalence rate of about 1.17 per 100,000. The exact etiology of the disorder is not known but a dual influence of genetic and environmental factors may trigger the disease. We report the case of a 70-year-old male patient with punctate palmoplantar keratodermic lesions for more than 40 years. Histopathologic examination revealed a hyperkeratotic epidermis without columns of parakeratosis or elastorhexis. On electron microscopy, the basal cells of the epidermis were found to have enlarged nucleoli and abundant tonofilaments, with keratohyalin-like granules confined to the upper part of the stratum spinosum, findings that were consistent with PPPK. Topical keratolytic agents were used with little success. Patients with PPPK and their next of kin should be investigated for possible associated malignancies.     

PERSISTENT VIABILITY OF THE MEDLAR BODY

Background. The Medlar body represents an adaptive tissue form of the fungi known to cause cutaneous chromomycosis. This study was designed to determine the in vitro viability of Medlar bodies that are found in profusion within lesional epidermis. Methods. Epidermal scrapings of three indigenous cases from Texas of chromomycosis due to Fonsecaea pedrosoi were collected and periodically cultured to determine the duration of fungal viability. Results. The causative organism could be recovered 11, 15, and 18 months, respectively, after epidermal scrapings were obtained from the three patients. Conclusions. This simple but important experiment indicates that Medlar bodies are quite hardy. Thus, clinical lesions may appear after long incubation periods subsequent to traumatic implantation of etiologic fungi. The robust adaptability of the tissue form may also account for the difficulty in achieving a “cure” in cases of chromomycosis.     

Molecular typing using polymorphisms of the polyketide synthase gene (PKS1) of strains in Japan morphologically identified as Fonsecaea pedrosoi

Fonsecaea pedrosoi sensu lato is a major causative agent of dematiaceous fungal infection in Japan. Recent sequence analysis of the internal transcribed spacer (ITS) regions of the ribosomal RNA gene has shown that this species can be separated into three species: F. pedrosoi sensu stricto, F. monophora and F. nubica. The cell walls of dematiaceous fungi including the genus Fonsecaea contain melanin, which is important for their virulence. Polyketide synthase (PKS1) is an enzyme required for melanin synthesis. This study analyzed the phylogeny of strains of F. pedrosoi sensu lato isolated in Japan by sequencing the PKS1 gene and ITS regions and identifying molecular polymorphism. Sixty strains morphologically identified as F. pedrosoi isolated worldwide, including 37 strains isolated in Japan, were analyzed. ITS regions of the ribosomal RNA gene and part of the PKS1 gene region were amplified, yielding sequences of approximately 600 and 450 bp, respectively. Polymerase chain reaction products were sequenced, and cluster analysis was performed. The proposed phylogenetic tree based on PKS1 sequences closely matched that based on the ITS regions. Sequencing of both regions showed that the isolates from Japan belonged to the clade of F. monophora. Molecular variations of these Japanese strains were evaluated by assessing both ITS and PKS1 sequences. The 37 isolates could be divided into at least seven molecular subtypes. The combination of these two molecular markers provides a most robust method for intraspecies subtyping and further epidemiological study of F. monophora.     

MULTIPLE GIANT DISSEMINATED PYOGENIC GRANULOMA IN THREE PATIENTS BURNED BY BOILING MILK

Background. Pyogenic granuloma is a common benign skin tumor. The multiple disseminated form of the disease is relatively rare. Methods. We examined three patients who developed giant pyogenic granuloma after burns from boiling milk. The patients were a 1.5-year-old boy, a 5-year-old girl, and a 35-year-old woman, All three patients had second-degree burns over their face and trunk. Results. In these patients, pyogenic granuloma had developed over the previously burned areas 2–3 weeks after exposure. The general condition of the patients remained good and all lesions involuted spontaneously. In a 6-month follow-up period no relapse of the lesions was seen. Conclusions. The cause for development of multiple giant pyogenic granulomas after burns from milk remains unknown, but milk proteins or other components of milk, microorganisms, or the burn itself may be causative factors.     

Fixed drug eruption caused by mefenamic acid: a case series and diagnostic algorithms

Background: Fixed drug eruption is a fairly common drug‐induced hypersensitivity reaction of the skin and the mucous membranes, which is characterized by the re‐occurrence of the lesion(s) exactly on the previously involved sites after repeated administration. The pathogenetic mechanisms of this site‐specificity are not fully elucidated. Patients and Methods: We report on three cases of fixed drug eruption, including a non‐pigmenting generalized bullous fixed drug eruption, caused by mefenamic acid in its pure form. Results and Conclusion: Provocation tests with the assumed causative drug represent the gold standard for establishing the diagnosis and for identifying the culprit. Advantages and pitfalls of topical and systemic provocation tests as diagnostic approaches are discussed.     

Dietary supplement product composed of natural ingredients as a suspected cause of erythema multiforme: A case report and identification for the confident false positivity of lymphocyte transformation test

Growing and sustainable consumption of health‐care products raises a controversial issue underlying the reliability of an in vitro diagnostic approach for adverse skin reaction. This report aimed to: (i) discuss the causative nature of a commercial dietary supplement composed of natural ingredients, particularly an Euglena‐containing product, suspicious for erythema multiforme in our exemplified case; and (ii) to address the assay suitability of the lymphocyte transformation test (LTT) for identifying allergic reaction to any ingredient(s) of the product. A Japanese elderly man developed erythema multiforme after intake of a commercially available natural dietary product, whose LTT was positive. His clinical course and positive LTT suggested a provisional diagnosis of natural dietary product‐induced eruption. We conducted an inquiry survey for the standard LTT with any commercial products containing Euglena in three major Japanese laboratory services and identified 22 subjects, almost all of whom (21/22, 95.6%) showed a positive LTT for any Euglena‐containing products as a suspected causative. Seven normal healthy volunteers who had no intake history of Euglena‐containing products showed an equivalent LTT positivity rate with the same product taken by our case; culprit components of the product included Euglena, Angelica keiskei, Barley grass and Chlorella. A cell‐free culture system and enzyme‐linked immunoassay suggest that the high LTT positivity relies on the non‐specific lymphoproliferative activity, and not contamination of uncharacterized microorganisms and endotoxins. Because of the constitutive false positivity of LTT, this assay is unreliable for in vitro supportive diagnosis of adverse skin events caused by dietary products containing particular natural ingredients, as well as herbal materials.     

Two novel missense mutations of ATP2A2 in two Chinese patients with sporadic Darier Disease

Darier disease (DD) is a rare autosomal dominant skin disorder with characteristic abnormal keratinization and acantholysis. The causative gene, ATP2A2, is located on chromosome 12, and encodes a sarco/endoplasmic reticulum calcium pump ATPase (SERCA2). Two Chinese patients with sporadic DD participated in this study. Genomic sequence analysis identified two novel missense mutations (c.742C>A and c.2098A>G) in the ATP2A2 gene. Our findings provide an additional ATP2A2 mutation causative for DD development, and new lines of evidences for the understanding of genotype–phenotype correlations.     

A rapid and definitive diagnosis of kerosene dermatitis by an analysis of detached lesional epidermis using gas chromatography–mass spectrometry

A 73-year-old woman, who suffered from erythema with bullae and pustules on her abdomen and anterior right thigh, visited our hospital without an awareness of the causative agents. The lesions appeared like first and second degree burns. The small amount of detached roof of bulla was sampled without skin biopsy before the ointment treatment. The sample was sonicated in an ultrasonic bath for 1 min in n-pentane, and then 1 μl of the extract was analyzed by gas chromatography-mass spectrometry (GC–MS). The causative agent was determined to be kerosene. An examination of blood samples collected at the first visit failed to detect kerosene, though traces of trimethylbenzene were detected. A GC–MS analysis of the small sample of lesional epidermis was very useful to identify kerosene as a causative agent.     

Causative agents of onychomycosis — a retrospective study

Background: Dermatophytes, yeasts and moulds all are potential causative agents of onychomycosis.The aim of this study was to determine the percentage of cases of onychomycoses caused by each group. In addition, the responsible genus and species was identified for each nail infection. Patients and Methods: In a retrospective study performed at the Department of Dermatology of the Leipzig University, 5 077 nail samples from 4 177 patients – 2 240 women and 1 937 men – with a variety of nail changes – not just onychomycosis – were investigated. 75% were toenails, 23% fingernails, and 2% from both sites. Results: Both microscopic and/or cultural detection of fungi (dermatophytes, yeasts and moulds) were successful in 54% of samples.Causative fungal agents were: 68% dermatophytes, 29% yeast, and 3% moulds. The most frequently detected dermatophyte species were T. rubrum (91%), and T. mentagrophytes (7.7%).Among yeasts, C. parapsilosis (42%) was most common,followed by C. guilliermondii (20.1%), C. albicans (14.2%), and Trichosporon spp. (10%).Scopulariopsis brevicaularis (43%) was the most frequent mould. The percentage of mixed fungal infections was 22%. Conclusions: Dermatophytes, in particular T.rubrum, but also T. mentagrophytes, are the most frequently isolated causative agents in onychomycosis. In addition, yeasts may be isolated relatively frequently, while moulds are uncommon.     

Update of recent findings in genetic hair disorders

Genetic hair disorders, although unusual, are not very rare, and dermatologists often have opportunities to see patients. Significant advances in molecular genetics have led to identifying many causative genes for genetic hair disorders, including the recently identified causative genes, such as LSS and C3ORF52. Many patients have been detected with autosomal recessive woolly hair/hypotrichosis in the Japanese population caused by founder mutations in the LIPH gene. Additionally, many patients with genetic hair disorders caused by other genes have been reported in East Asia including Japan. Understanding genetic hair disorders is essential for dermatologists, and the findings obtained from analyzing these diseases will contribute to revealing the mechanisms of hair follicle morphogenesis and development in humans.     

Mutations in the drug resistance‐determining region of Mycobacterium lepromatosis isolated from leprosy patients in Mexico

Mycobacterium lepromatosis, an independent species from Mycobacterium leprae, has been found to be a causative agent for diffuse lepromatous leprosy (DLL) in Mexico, but remains poorly studied. Here, the drug resistance‐determining regions (DRDR) of folP1, rpoB and gyrA (conferring resistance to dapsone, rifampicin and quinolone, respectively) in M. lepromatosis from leprosy patients in Mexico were characterized. No mutations or silent mutations were found at previously characterized major sites in DRDR of M. lepromatosis. However, a non‐synonymous mutation was found in codon 54 between two major sites of the folP1 DRDR in M. lepromatosis sequences. All M. lepromatosis isolates showed CAG sequence in codon 54 of folP1. Because the next codons 53 and 55 are known as major mutation sites for drug resistance, more detailed analysis using more samples is needed to determine whether it influences susceptibility to dapsone and/or efficiency of folate biosynthesis in M. lepromatosis or not.     

PAPULAR-PURPURIC GLOVES-AND-SOCKS SYNDROME

Background and Objective. Papular-purpuric gloves-and-socks syndrome (PPGSS) is a recently described dermatosis in which human parvovirus B19 (HPV B19) has been implicated as etiologic agent; however, it is suspected that PPGSS may be caused by various agents. This study was designed to survey the general characteristics of PPGSS and to determine the role of HPV B19 in its etiology. Methods. We analyzed data from 21 patients and examined serum samples from three new cases for various viruses. Results. The PPGSS displays a striking uniform clinical pattern. Histologic and immunofluorescence findings are nonspecific. Seroconversion of HPV B19 was reported in six cases and confirmed in two of our patients. In only one case was a possible causative role of Coxsackie virus B6 suggested consistently. Conclusions. The PPGSS represents a distinctive dermatosis and a manifestation of HPV B19 infection. Unlike erythema infectiosum, anti-HPV B19 antibodies seem to develop later after onset of the skin eruption and while viremia is still present.     

Marie Unna hereditary hypotrichosis accompanied by multiple familial trichoepithelioma in a Chinese family

Marie Unna hereditary hypotrichosis (MUHH) and multiple familial trichoepithelioma (MFT) are both autosomal dominant disorders. Recently, certain genes (HR and EPS8L3) have been found to be responsible for MUHH, while CYLD has been demonstrated to be the main pathogenic gene in MFT patients. However, there exist a number of CYLD mutation‐negative MFT cases, for which the causative gene has been unknown. Here, we identified a large, five‐generation Han Chinese family with several patients presenting with MUHH and MFT. Sanger sequencing of three genes in 13 family members was performed. We found that the c.1A>G mutation in an inhibitory upstream open‐reading frame of HR (U2HR) was present in all MUHH patients, while no pathogenic variants were found in the 3?‐ or 5?‐untranslated regions, exons or flanking intronic sequences of EPS8L3 or CYLD in any family members. Subsequently, whole‐genome sequencing was performed for five affected and one unaffected family member. We found no CYLD variants but identified an FABP12 variant (rs536105592 G>A) in the patients with both MUHH and MFT. These results suggest that the U2HR mutation was responsible for MUHH and the FABP12 variant may be coincidental in the accompanying MFT in this unique pedigree. This report deepens our understanding of the genetic basis of hair follicle diseases.     

Intractable ulcer caused by Mycobacterium shinshuense: successful identification of mycobacterium strain by 16S ribosomal RNA 3′‐end sequencing

An extremely rare case of intractable ulcer caused by Mycobacterium shinshuense is described. A 59‐year‐old Japanese woman developed an ulcerated subcutaneous induration on the upper arm. Ziehl–Neelsen staining revealed positive bacilli. Tissue culture isolated Mycobacterium species, but standard identification techniques (including molecular biological approaches such as DNA–DNA hybridization) could not distinguish the precise causative pathogen, although it was narrowed down to three possibilities: Mycobacterium marinum, Mycobacterium ulcerans and M. shinshuense. Finally, a novel 16S rRNA sequencing method enabled the diagnosis of M. shinshuense infection. The epidemiology of the cutaneous infection caused by this mycobacterium has yet to be elucidated, but a review of reported cases indicated that ulcers having some resemblance to those caused by M. ulcerans infection were found in nonendemic areas and that M. shinshuense could be considered as the cause. The approach introduced in this report could provide a powerful tool for the identification of this organism.