Pyoderma gangrenosum, acne, suppurative hidradenitis (PASH) and polycystic ovary syndrome: Coincidentally or aetiologically connected?

The clinical triad of pyoderma gangrenosum, acne conglobata and hidradenitis suppurativa has been named PASH syndrome. Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism and inflammation. Hidradenitis suppurativa, like acne vulgaris, may be a feature of hyperandrogenism. Obesity may be associated with both hidradenitis suppurativa and PCOS. We describe a possible association between PASH syndrome and PCOS.

Eight Novel Mutations Confirm the Role of AAGAB in Punctate Palmoplantar Keratoderma Type 1 (Buschke-Fischer-Brauer) and Show Broad Phenotypic Variability.

Punctate palmoplantar keratoderma (PPKP1; Buschke-Fischer-Brauer) is a rare autosomal dominant inherited skin disease characterized by multiple hyperkeratotic papules involving the palms and soles. Mutations have been found at 2 loci, on chromosomes 15q22-15q24 and 8q24.13-8q24.21. We recently identified mutations in 3 families, in the AAGAB gene on 15q, which encodes the alpha- and gamma-adaptin-binding protein p34. The current study examined 14 additional families, comprising a total of 26 affected individuals and identified 8 novel mutations in 9 families. In one family a mutation that was present only in the affected individuals was found, and in 4 other families, previously reported mutations were found (1, 2). These results confirm the role of AAGAB in PPKP1. Our findings suggest that there is no correlation with age, but with mechanical factors. No additional obvious genotype-phenotype correlation was observed, even when comparing different types of mutations. Rather, identical genotypes presented a very broad interfamilial and intrafamilial variability of phenotypes.

Nonsense mutations in AAGAB cause punctate palmoplantar keratoderma type Buschke-Fischer-Brauer.

Punctate palmoplantar keratodermas (PPKPs) are rare autosomal-dominant inherited skin diseases that are characterized by multiple hyperkeratotic plaques distributed on the palms and soles. To date, two different loci in chromosomal regions 15q22-15q24 and 8q24.13-8q24.21 have been reported. Pathogenic mutations, however, have yet to be identified. In order to elucidate the genetic cause of PPKP type Buschke-Fischer-Brauer (PPKP1), we performed exome sequencing in five affected individuals from three families, and we identified in chromosomal region 15q22.33-q23 two heterozygous nonsense mutations-c.370C>T (p.Arg124(∗)) and c.481C>T (p.Arg161(∗))-in AAGAB in all affected individuals. Using immunoblot analysis, we showed that both mutations result in premature termination of translation and truncated protein products. Analyses of mRNA of affected individuals revealed that the disease allele is either not detectable or only detectable at low levels. To assess the consequences of the mutations in skin, we performed immunofluorescence analyses. Notably, the amount of granular staining in the keratinocytes of affected individuals was lower in the cytoplasm but higher around the nucleus than it was in the keratinocytes of control individuals. AAGAB encodes the alpha-and gamma-adaptin-binding protein p34 and might play a role in membrane traffic as a chaperone. The identification of mutations, along with the results from additional studies, defines the genetic basis of PPKP1 and provides evidence that AAGAB plays an important role in skin integrity.

Aquagenic wrinkling of the palms: morphological changes in reflectance confocal microscopy and high-definition optical coherence tomography.

Aquagenic wrinkling of the palms (AWP) is a rare condition, which is characterized by appearance of whitish papules and plaques, and an excessive wrinkling and swelling of the palmar skin after exposure to water. In most cases, young women are affected, and an association of AWP with cystic fibrosis (CF) has been surmised. We report on two cases of AWP, which were not related to CF, in whom we used two innovative imaging techniques, namely high-definition optical coherence tomography and reflectance confocal microscopy, to show in vivo skin changes occurring after exposure of the skin to tap water in comparison to the findings in a healthy control person.

Successful treatment of nail lichen planus with alitretinoin: report of 2 cases and review of the literature.

BACKGROUND: Treatment of nail lichen planus (LP) is difficult and an optimal therapy is lacking. OBJECTIVE: To report additional cases to the scant existing literature to learn more about therapeutic options for nail LP. METHODS: A regimen of 30 mg alitretinoin daily in 2 cases of nail LP over a period of 9 and 8 months, respectively. RESULTS: In either case, nail changes showed marked improvement under oral alitretinoin therapy within 2 and 4 months, respectively. In both patients, affected nails with end-stage destructive pterygium were resistant to any previously applied therapy. CONCLUSION: Alitretinoin is an effective treatment option for nail LP. We recommend early diagnosis of nail LP and early initiation of systemic therapy with alitretinoin to prevent the development of pterygium and permanent nail damage. However, further clinical studies are needed to establish reliable guidelines for nail LP therapy.

Preradial myxedema in a euthyroid male: A distinct rarity.

Localized or pretibial myxedema is one of the signs of Graves disease (along with goiter, exophthalmus, thyroid acropathy, and high circulating levels of long-acting thyroid-stimulating hormone) and usually tends to occur at a later stage of the disease or even after the patient becomes euthyroid post treatment. Very rarely has it been reported in euthyroid patients. We report a euthyroid man presenting with localized myxedema on the extensor surface of his forearm with clinical and histopathological features consistent with pretibial myxedema. He responded partially to topical clobetasol propionate cream and tacrolimus ointment 0.1 percent for about 7 months. To the best of our knowledge, this is the first case of preradial myxedema in a euthyroid patient in the English international dermatological literature.

Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH)--a new autoinflammatory syndrome distinct from PAPA syndrome.

BACKGROUND: PAPA syndrome is a recently identified hereditary autoinflammatory syndrome clinically characterized by pyogenic arthritis, severe acne, and pyoderma gangrenosum. It is caused by mutations in the PSTPIP1 gene and may be closely linked to the aseptic abscesses syndrome, which has been shown to be associated with CCTG repeat amplification in the promoter region of PSTPIP1. OBJECTIVE: We describe two unrelated patients with a clinical presentation quite similar to, yet distinct from, PAPA syndrome. RESULTS: Both patients had pyoderma gangrenosum and acute or remittent acne conglobata, but, in contrast to PAPA syndrome, lacked any episodes of pyogenic arthritis. Instead, they had suppurative hidradenitis. Mutations in PSTPIP1 exons 1 to 15 were excluded. In the promoter region, an increased repetition of the CCTG microsatellite motif was present on one allele in both patients. Alterations of the most commonly affected exons of the MEFV, NLRP3, and TNFRSF1A genes also were not detectable. One patient was treated with the interleukin (IL)-1 receptor antagonist anakinra and responded well, although without complete remission. This implies that IL-1ß may be of pathogenetic importance. LIMITATIONS: Small number of patients, no gene mutation identified, and unclear efficacy of therapy are limitations. CONCLUSIONS: The clinical triad of pyoderma gangrenosum, acne, and suppurative hidradenitis represents a new disease entity within the spectrum of autoinflammatory syndromes, similar to PAPA and aseptic abscesses syndrome. For this disease, we propose the acronym "PASH" syndrome. PASH syndrome may respond to IL-1ß blockade.

Skin manifestations in autoinflammatory syndromes.

Autoinflammatory diseases encompass a group of inflammatory diseases that are non-infectious, non-allergic, non-autoimmune and non-immunodeficient. The term was initially coined for a small group of familial periodic fever syndromes of which familial Mediterranean fever (FMF) is the most common and best known. Genetic and molecular analyses demonstrated for the majority of these diseases an impairment of inflammasomes to cause an increased activity of an interleukin-1-dependent inflammatory response. Over the last years an increasing number of either rare hereditary syndromes or acquired common diseases could be summarized under the designation of autoinflammatory disease, thus creating an emerging new rubric of inflammatory diseases. Many of them display cutaneous manifestations as both concomitant or more rarely main symptoms. To name some of them like erysipelas-like erythema in FMF; urticaria-like rashes in tumor necrosis factor receptor 1- or cryopyrin-associated periodic syndromes (TRAPS, CAPS), hyperimmunoglobulin D syndrome (HIDS) or Schnitzler syndrome; pyoderma gangrenosum and acne in PAPA syndrome; or behçetoid aphthous ulcerations in HIDS and PFAPA syndrome. Based on the new insights into pathogenesis one increasingly realizes the good response of these diseases to IL-1 antagonist therapies.

Cutaneous metastases from internal malignancies.

Cutaneous metastases of internal malignancies still seem to occur infrequently, although medical publications report an incidence rate of up to 10.4%. Common sense, however, fosters suspicion that we might underdiagnose the problem distracted by harder striking facets of an advanced disease. With contemporary knowledge, morphology and behavior of cutaneous metastases resemble each other regardless of the site of origin. This article itemizes clinical presentations according to organ systems, specific features, and differential diagnoses. In general, the survival turned out to be less than 12 months. But incremental awareness of cutaneous metastases proclaims this paradigm insufficient. Although excision is the local treatment of choice, investigations attempt to propose tumor-specific chemotherapeutic/immunological approaches. This paper endeavors to critically review the state of the art concerning the clinic, prognosis, and therapeutic concepts.

Molecular diagnosis in dermatopathology: what makes sense, and what doesn't.

Molecular techniques have provided us with a wealth of information about biological events in healthy individual, and improved tremendously our understanding about the pathogenesis of a huge variety of cutaneous diseases. Those methods have originally been invented to support basic scientific investigations on a molecular level and are translated increasingly into sophisticated diagnostic tools changing the classic paradigm of diagnostic pathology; among them are immunohistochemistry (IHC), polymerase chain reaction (PCR), G-banding, loss of heterozygosity, fluorescence in situ hybridization (FISH), chromogen in situ hybridization (CISH), comparative genomic hybridization on chromosomes and microarray technology. Some of them such as IHC and PCR have already been standardized to a level that allows its utility in daily routine diagnostics for several dermatological diseases. For others like array-based technologies, their optimal indications await to be fully determined. These ancillary methods have the great potential to contribute important new information to challenging cases, and will help to improve diagnostic accuracy particularly in cases in which conventional histopathology is ambiguous. Thus, they will broaden our armamentarium for diagnostic pathology. Herein, some key techniques will be reviewed and their applicability towards the diagnosis of dermatological diseases critically discussed.

Cutaneous metastases of visceral tumours: a review.

BACKGROUND: Up to 10% of all visceral malignancies develop cutaneous metastases. As cutaneous metastases are underestimated and underdiagnosed they can be a clinical challenge. The clinical appearance and patterns of distribution of cutaneous metastases, the characterisation of clinical outcomes and available therapeutic options are compiled. PATIENTS AND METHODS: Literature (over the last 6 years) MESH in terms of cutaneous metastases was comprehensively evaluated. Characteristics from 92 available cases are elaborated and adjusted with terms (time unlimited) of published epidemiological reviews to single organs. RESULTS: The broad clinical spectrum with differential diagnoses is displayed. An allocation of cutaneous metastases and a particular organ is not reliable. In 22% of all cases cutaneous metastases can lead to the diagnosis of an internal malignoma. The majority of cases reveal cutaneous metastases to emerge in a tumour-free interval in about 36 months, after a successful treatment of the primary tumour, most commonly along with other organ metastases. Probable survival turned out to be less than 12 months. Consistently with this end-stage condition, treatment aligns with rules of palliation. Local treatment of choice is excision. Only a minority of investigators attempted to come up with tumour-specific treatment strategies, and almost no randomised therapy studies can be presented. CONCLUSION: A reference guide of cutaneous metastases is given; the clinical spectrum is adjusted to an actual status; state of the art of the treatment is accomplished. An epidemiological, improved registration and diagnostic work-up for targeted therapies in conjunction with dermatologists are favoured.

Hereditary palmoplantar keratodermas.

Hereditary palmoplantar keratodermas (PPK) comprise a clinically and genetically heterogeneous group of genodermatoses, which share impaired epidermal differentiation resulting in prominent palmoplantar hyperkeratosis. Classically, keratodermas have been separated according to their clinical appearance into diffuse, focal, and as a feature of ectodermal dysplasias and many other syndromes. Since molecular genetic analyses have helped characterize the underlying genetic defects in an increasing number of hereditary PPK over the last two decades, a pathophysiological separation seems more reasonable. Today PPK can be classified based on defects in keratins, loricrin, desmosomes, connexins, and cathepsins. Although these proteins have different structures and functions, all of them influence epidermal differentiation and cornified envelope assembly. Depending on tissue distribution and location of mutation with a certain gene, the clinical spectrum of PPK range from a pure palmoplantar restricted skin abnormality to a complex combination of symptoms with dental anomalies, deafness, progressive cardiomyopathy and even cancer. Solely for those reasons, a correct diagnosis based on molecular genetic analyses is mandatory, although a causal therapy is still not available. Instead, several therapeutic modalities including topical ointments, surgical interventions and systemic retinoids help to reduce the patients' symptoms.

Granular parakeratosis--a clinical-pathological correlation of 10 cases.

BACKGROUND: Granular parakeratosis describes chronic skin lesions within the intertriginous areas that demonstrate microscopically parakeratosis together with retention of keratohyalin granules within a thickened stratum corneum. Granular parakeratosis is rarely diagnosed, since it is still relatively unknown within the differential diagnoses of intertriginous eruptions, and a skin biopsy is required for diagnosis. In order to gain insight into the clinical-histopathologic correlation, we present 10 cases of granular parakeratosis. METHODS: The files of the DermatoHistologisches Labor Dr. H. Laaff, Freiburg, were searched for the diagnosis of granular parakeratosis. Identified cases were evaluated for clinical information and histopathologic characteristics. RESULT: From 2004 to 2007 10 cases (7 women, 3 men) of granular parakeratosis were found corresponding to a frequency of 0.004%. The average age was 62 (33-82). In women lesions occurred in submammary region (4), axillae (2) and popliteal fossa; in men, groin (2) and genital region. Clinically two different patterns are recognized--lichen planus-like red-brown slightly hyperkeratotic or scaly papules, and larger plaques which are either bright red shiny or grey-brown with lichenification. Histologically the typical granular parakeratosis was seen in a prominently thickened stratum corneum. It remains unclear whether granular parakeratosis is a disease entity or whether it reflects a reaction pattern to unknown stimuli.

Perifollicular protrusions--mid-dermal elastolysis.

Mid-dermal elastolysis is a rare peculiar entity clinically characterized by fine wrinkles and perifollicular protrusions that give the skin an aged or peau d'orange appearance. The histopathologic correlate is a bandlike loss of elastic tissue within the mid-dermis.We present a typical case with prominent perifollicular protrusions.

Subepidermal cleft formation as a diagnostic marker for cutaneous malignant melanoma.

Cleft formation has been postulated as a clue to the histopathological diagnosis of malignant melanoma (MM). The frequency and reliability of clefts as a diagnostic criterion remain to be determined. We reviewed 503 cases of histologically proven MM searching for clefting between the epidermal layer and underlying MM. Cleft was defined as a separation of at least 0.3 mm in length. Conspicuous cleft formation was present in 120 (24%) of 503 MMs. The presence of clefts was not associated with age or sex of the patients, but showed a slight predilection for the back, a slightly higher prevalence in superficial spreading type of MM and for tumors with a Breslow thickness between 1 and 2 mm. Morphologically, clefts could be separated in 3 different types: linear (37.5%), single-nest (10.9%), and multi-nest (51.6%). In comparison, among 939 benign melanocytic lesions including 100 Spitz or Reed nevi, only 9 exhibited clefts longer than 0.3 mm (< 1%). One was an atypical compound nevus; all others were Spitz nevi, with the majority exhibiting an arched morphology above 1 or 2 large round nests. The relative frequency of cleft formation allowed a highly significant differentiation between MM and benign melanocytic lesions. Clefts are a reliable diagnostic criterion in favor of MM.

Adeno-associated virus vectors are able to restore fatty aldehyde dehydrogenase-deficiency. Implications for gene therapy in Sjogren-Larsson syndrome.

Sjogren-Larsson Syndrome (SLS) is caused by an autosomal recessive defect in the gene coding for fatty aldehyde dehydrogenase (FALDH), an enzyme necessary for the oxidation of long-chain aliphatic aldehydes to fatty acid as one enzyme of the fatty alcohol:nicotinamide-adenine dinucleotide (NAD+)-oxidoreductase complex (FAO). The impaired activity of FALDH leads to the clinical symptom triad of generalized ichthyosis, mental retardation, and spastic diplegia or tetraplegia. Treatment options are primarily symptomatic. Gene therapy by means of genetic reintroduction of the functional FALDH gene into defective cells has so far not been considered as a therapeutic modality. In order to pursue such an approach for SLS, we constructed a recombinant adeno-associated virus-2 vector containing the human cDNA of functional FALDH and evaluated its capability to restore the enzyme-deficiency in a FALDH-deficient cell line resembling the gene defect of SLS. rAAV-2 transduction of FALDH-deficient cells, usually exhibiting less than 10% of normal FALDH activity, resulted in an increase of FALDH activity within the range of unaffected cells. Moreover, FALDH-transduced cells regained resistance over exposure to long chain aldehydes, which are otherwise toxic to FALDH-deficient cells. These results indicated that rAAV-2 vectors are able to restore FALDH-deficiency in a cell system resembling SLS. The findings give the first support to the concept that gene therapy might be a future option for the treatment of SLS.

Recombinant adeno-associated virus type 2-mediated gene transfer into human keratinocytes is influenced by both the ubiquitin/proteasome pathway and epidermal growth factor receptor tyrosine kinase.

Efficient gene delivery into keratinocytes is a prerequisite for successful skin gene therapy. Vectors based on recombinant adeno-associated virus type 2 (rAAV-2) offer several promising features that make them attractive for cutaneous applications. However, highly efficient gene delivery may be hampered by different cellular factors, including lack of viral receptors, impairment of cytoplasmic trafficking or limitations in viral second-strand synthesis. This study was undertaken to find factors that influence rAAV-2-mediated in vitro gene transfer into human keratinocytes and, consequently, ways to optimize gene delivery. Transduction experiments using rAAV-2 vectors expressing green fluorescent protein (GFP) demonstrated that impaired cellular trafficking of vector particles and high levels of autophosphorylation at epidermal growth factor receptor tyrosine kinase (EGF-R TK) have a negative influence on gene transfer into keratinocytes. Treatment of keratinocytes with proteasome inhibitor MG132 resulted in a transient augmentation of GFP expression in up to 37% of cells. Treatment with EGF-R TK inhibitors (quinazoline type) enhanced transgene expression in 10-14.5% of the cells. Gene expression was stable for more than 10 weeks and persisted until proliferative senescence occurred. This stable gene expression allows speculation that keratinocyte stem cells have initially been transduced. These findings might have relevance for the use of rAAV-2 vectors in skin gene therapy: transient enhancement of rAAV-2 transduction with proteasome inhibitors might be useful for genetic promotion of wound healing or skin-directed vaccination. Treatment with quinazolines may increase rAAV-2 transduction of keratinocyte stem cells, which is important for gene therapy approaches to inherited diseases.