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.

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.

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.

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.

rAAV2-mediated restoration of LEKTI in LEKTI-deficient cells from Netherton patients.

BACKGROUND: Netherton syndrome (NS, MIM 256500) is a potential live threatening autosomal-recessive skin disorder clinically characterized by the trias of congenital erythroderma, hair shaft anomalies and atopic diathesis. It is caused by mutations in the gene SPINK5 resulting in a deficiency of its processed protein named lympho-epithelial Kazal-type related inhibitor (LEKTI). LEKTI controls the activity of several serine proteases in the skin that are involved in terminal differentiation. Loss of LEKTI results in protease hyperactivity, increased degradation of intercellular junctions, reduced stratum corneum adhesion and impaired skin barrier function. Today NS can only be treated symptomatically. OBJECTIVE: Does gene transfer offer a therapeutic option for NS in the future? METHODS: A recombinant adeno-associated virus type 2 vector was constructed containing the full length cDNA (rAAV2/C-SPINK5) of functional human LEKTI. Infectious virus particles were used for transfection of LEKTI-deficient-keratinocytes of NS patients in vitro. RESULTS: Gene transfer of SPINK5 in NS-keratinocytes led to a five-fold increase in mRNA expression of SPINK5 reaching almost 75% of normal value. The functionality of the expressed LEKTI was proven in a hydrolytic activity assay demonstrating that the activity of LEKTI after gene transfer increased closely to the level seen in keratinocytes of healthy individuals. CONCLUSION: The results provide first evidence that gene transfer of SPINK5 results in increased LEKTI activity in NS-keratinocytes, thus offering a rational to further pursue such a gene therapy approach for NS.

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.

Herpes zoster with progression to acute varicella zoster virus-meningoencephalitis.

BACKGROUND: Acute meningoencephalitis (ME) from varicella zoster virus (VZV) reactivation is a rare and serious complication of herpes zoster (HZ). OBJECTIVES AND METHODS: As early diagnostic detection is mandatory to prevent long-term sequelae, any clinical indication is helpful to identify patients that are at higher risk of the development of VZV-ME. In order to find such risk factors, the clinical data of 38 patients consecutively hospitalized for the treatment of HZ over a 1-year period were analyzed. RESULTS: Four of the 38 patients with HZ developed ME. Of these, three had involvement of the trigeminal nerve branch, one including an ophthalmic affection, and one presented with disseminated HZ. All were women with an average age of 83.5 years, in comparison with patients with HZ but without ME who had an average age of 69.3 years and a female preponderance of 60%. The first clinical signs of ME were rapidly progressing somnolence and meningism. Patients with HZ-ME were treated with intravenous acyclovir, oral glucocorticosteroids, and antiseizure therapy, and recovered almost completely without major residual symptoms. CONCLUSION: Progression of HZ to ME seems to occur more often than normally believed. Female patients above 80 years of age with either ophthalmic involvement or disseminated HZ are at a potentially high risk of the development of ME. The general recommendation of starting oral glucocorticosteroids from day 1 of antiviral treatment in older patients must be questioned, as it may stimulate VZV replication and dissemination.

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.

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.