Bettina Burger

MicroRNA expression differs in cutaneous squamous cell carcinomas and healthy skin of immunocompetent individuals

Cutaneous squamous cell carcinoma (cSCC) is one of the most common skin cancers, but the influence of microRNA (miRNA) expression has only been sporadically analysed. We hypothesized that miRNAs are differentially expressed in cSCC and hence influence its development. We therefore isolated total miRNA from well‐differentiated cSCCs and from controls without SCC. Expression analyses of 12 miRNAs showed three significantly differentially expressed miRNAs. We identified a significant upregulation of the miR‐21 and the miR‐31, a proto‐oncogene like miR‐21. While the upregulated expression of miR‐21 has been known for some time, the increased expression of miR‐31 was never shown so clearly. Furthermore, we showed the upregulation of miRNA‐205, which has never been described before. The miR‐205 induces specific keratinocyte migration and could be a characteristic marker for cSCC. It has to be determined in following studies whether these upregulated expressions are specific for cSCC and if so, for which cSCC stages.

Buschke-Ollendorff syndrome in a three-generation family: Influence of a novel LEMD3 mutation to tropoelastin expression

Buschke-Ollendorff syndrome refers to the concomitant occurrence of connective tissue nevi, composed of elastic fibers in most cases, with osteopoikilosis. This autosomal dominant inherited disorder is caused by mutations in the gene LEMD3 on chromosome 12q14, which induces a rather heterogeneous clinical phenotype. Here, we report on the most proximal germline mutation found to date in the LEMD3 gene, p.Val94fs, in a three-generation Swiss family. Quantitative RNA analyses in affected and non-affected skin tissue from the proband demonstrate a comparable nonsense-mediated decay of mutant LEMD3 mRNA in both tissues; however, different levels of tropoelastin expression suggest that additional factors are involved in the development of the cutaneous lesions.

The immigration delay disease: Adermatoglyphia–inherited absence of epidermal ridges

In the digital age, personal identification by fingerprints (epidermal ridges) has become more frequent and is often required for biometric passports. The more fingerprints are analyzed, the more variants in their formation are documented. Individuals completely missing fingerprints as an isolated finding are extremely rare. Only 4 kindreds have been described to date, with additional clinical features in most cases. We describe a female patient with missing epidermal ridges on the fingers, palms, toes, and soles as an isolated feature. Absent fingerprints, or adermatoglyphia, were inherited over 4 generations of her family in an autosomal dominant fashion. We present the clinical features of the index patient, and compare the case with previous reports in the literature. Because of problems in personal identification, this embryologic malformation caused the patient significant difficulties when traveling to other countries, which is why we name it the immigration delay disease.

The Phenotypic and Genotypic Spectra of Ichthyosis With Confetti Plus Novel Genetic Variation in the 3' End of KRT10 From Disease to a Syndrome

IMPORTANCE Ichthyosis with confetti (IWC) is a genodermatosis caused by dominant negative mutations in the gene encoding keratin 10 (KRT10). We investigated clinical and genetic details of a substantial number of patients with IWC in order to define major and minor criteria for diagnosis of this rare disorder. OBSERVATIONS Parallel clinical investigation of 6 patients with IWC revealed a novel spectrum of phenotypes. We found several features that qualify as major criteria for diagnosis, which are clearly and consistently associated with the condition. These included malformation of ears, hypoplasia of mammillae, and dorsal acral hypertrichosis. Genetic analysis of patients revealed several different frameshift mutations in intron 6 or exon 7 of KRT10. Analysis of this locus in 17 unrelated control individuals revealed 2 novel polymorphisms of KRT10. CONCLUSIONS AND RELEVANCE We present for the first time to our knowledge the spectrum of clinical variability of IWC in 6 patients with confirmed mutations in KRT10. From this, we have extracted major and minor criteria to aid early and correct clinical diagnosis. Ectodermal malformations, present in all patients, suggest a novel classification of IWC as a syndrome. There is remarkable genetic variation at the IWC disease locus within control individuals from the general population.

Homozygosity for the c.917A--<T (p.N306l) polymorphism in the EVER2/TMC8 gene of two sisters with epidermodysplasia verruciformis Lewandowsky-Lutz originally described by Wilhelm Lutz

Background: Epidermodysplasia verruciformis Lewandowsky-Lutz (EV) is a rare genodermatosis, characterised by development of numerous verrucous skin lesions caused by specific genotypes of human papillomaviruses belonging to the β-papillomavirus genus. The EV loci were mapped to chromosome 2p21–p24 (EV2) and 17q25 (EV1). On chromosome 17, 2 adjacent related genes – EVER1/TMC6 and EVER2/TMC8 – were identified. We reinvestigated 2 patients originally described by Wilhelm Lutz in 1946 with the aim to document the natural course of the disease and confirm his diagnosis. Methods: PCR fragments specific for exons with short flanking intron sequences of EVER1/TMC6 and EVER2/TMC8 genes from patients’ DNA were amplified using sequence information. The single-nucleotide polymorphism (SNP) rs7208422 was studied, using restriction fragment length polymorphism analysis. Results: In the index patient, we identified a homozygous TT genotype in exon 8 of the EVER2/TMC8 gene (c.917A → T, p.N306I). The same mutation could thereafter be detected in her sister from paraffin-embedded skin. Conclusion: We have followed one of the first patients described with EV in Basel, Switzerland, in 1930 until today and demonstrated the TT genotype (SNP rs7208422) in the EVER2/TMC8 gene in this index patient and her sister. The results underline the possible relevance of SNP rs7208422 by influencing the susceptibility to β-papillomaviruses and their oncogenic potential.

Spontaneous fading of reticular pigmentation in Naegeli-Franceschetti-Jadassohn syndrome.

enamel defects of the second teeth with resulting early caries, and moderate hyperkeratosis of the palms and soles. Diffuse palmoplantar keratoderma may coexist with punctate keratoses that are sometimes accentuated in the creases or exhibit a linear pattern [2] . Reticulate hyperpigmentation starts around the age of 2 years without a preceding inflammatory stage. The pigmentation is brown and gray-brown and is localized on the trunk, proximal extremities, axillae, groins and flexures as well as in the periocular and perioral regions. The pigmentation shows a gradual increase during the first 10 years of life, and fading starts around the age of 15 years. Patients with NFJ syndrome who are older than 70 years only have minimal or no pigmentation left [3] . Although patient history gave this information on fading, no photographic documentation of this natural course has previously been presented in the literature. We describe the natural course of hyperpigmentation in a patient of the original family with NFJ syndrome. Our female patient was born in 1944 with NFJ syndrome. Her mutation in keratin 14 had been confirmed previously [1] . The patient had always had difficulties in hot temperatures because of her limited ability to sweat. A pilocarpine test in this patient had been performed by Franceschetti and Jadassohn and was only weakly positive [4] . She had impressive enamel defects and total prostheses were necessary at the age of 30 years. The patient had moderate diffuse palmoplantar keratoderma but her nails were unaffected.

Mosaic manifestations of monogenic skin diseases

A genetic mosaic is defined as an organism which is composed of genetically different cell lines which originate from a homogeneous zygote. Etiologically, cutaneous mosaics can be divided into two large categories, epigenetic mosaicism and genomic mosaicism. Genomic mosaics which have two or more genetically different cell populations are not inherited with the exception of paradominant inheritance pattern. Epigenetic mosaics have a structurally homogeneous cell population but there are functional differences induced by modifying factors in the form of gene‐steering retroviral elements that can be inherited. We distinguish five different manifestation patterns of mosaicism, including the Blaschko lines pattern, patchy pattern without midline separation, checkerboard pattern, phylloid pattern and lateralization pattern. All forms of epigenetic mosaicism, including the various patterns of X‐inactivation, appear to be caused by the action of retrotransposons. A new concept is functional autosomal mosaicism transmittable through the action of retrotransposons.

Prevalence of Skin Lesions in Familial Adenomatous Polyposis: A Marker for Presymptomatic Diagnosis?

BACKGROUND AND AIMS Benign skin tumors such as lipomas, fibromas, and epidermal cysts are among the extracolonic manifestations of familial adenomatous polyposis (FAP). Readily detectable by inspection, they could serve as presymptomatic diagnostic markers to identify FAP patients. We therefore prospectively determined the prevalence of cutaneous lesions in genetically confirmed adenomatous polyposis coli (APC) mutation carriers and assessed their potential usefulness in the identification of FAP patients. METHODS Whole-skin examination was performed in 56 adult APC mutation carriers, compared with a control group (n = 116). In addition, FAP patients were investigated for the presence of congenital hypertrophy of the retinal pigment epithelium (CHRPE), an established clinical marker for FAP, and a detailed review of medical records was performed. RESULTS Nearly half of all FAP patients (48.2%) had at least one FAP-associated skin lesion, compared with one third (34.5%) of controls. Only multiple lipomas and combined skin lesions were significantly more prevalent in APC mutation carriers. CHRPE was observed in 22 (43.1%) of 51 FAP patients, including 14 (37.8%) of 37 individuals with APC mutations outside the CHRPE-associated region between codons 311 and 1465. CONCLUSIONS Despite a significantly higher prevalence of multiple lipomas, occurring at younger age, and combined skin lesions in APC mutation carriers, the low diagnostic sensitivity of FAP-associated skin lesions precludes their use as markers for FAP in clinical practice. Based on our findings, the common CHRPE-associated region should be extended to APC codons 148-2043.

HIV-positive child with epidermodysplasia verruciformis-like lesions and homozygous mutation in TMC6

First released onto the market in 2008 [1], the HIV-1 integrase inhibitor raltegravir is recommended for the treatment of HIV-1 infection in treatment-naive or experienced patients when combined with other antiretroviral agents. Raltegravir is generally well tolerated, with adverse reactions comparable to placebo [2,3]. Gastrointestinal upset, headaches, transaminase elevation, creatine kinase elevation and pruritis have all been described as occasional side-effects. Rare adverse reactions include myopathy and rhabdomyolysis. There is one case report of raltegravir-induced rhabdomyolysis leading to renal failure [4]. Although central nervous system sideeffects such as dizziness and depression have been observed in patients taking raltegravir, cerebellar ataxia associated with raltegravir has not been previously reported [5].

Epidermodysplasia verruciformis: Inborn errors of immunity to human beta-papillomaviruses

Epidermodysplasia verruciformis (EV) is an autosomal recessive skin disorder with a phenotype conditional on human beta-papillomavirus (beta-HPV) infection. Such infections are common and asymptomatic in the general population, but in individuals with EV, they lead to the development of plane wart-like and red or brownish papules or pityriasis versicolor-like skin lesions, from childhood onwards. Most patients develop non-melanoma skin cancer (NMSC), mostly on areas of UV-exposed skin, from the twenties or thirties onwards. At least half of the cases of typical EV are caused by biallelic loss-of-function mutations of TMC6/EVER1 or TMC8/EVER2. The cellular and molecular basis of disease in TMC/EVER-deficient patients is unknown, but a defect of keratinocyte-intrinsic immunity to beta-HPV is suspected. Indeed, these patients are not susceptible to other infectious diseases and have apparently normal leukocyte development. In contrast, patients with an atypical form of EV due to inborn errors of T-cell immunity invariably develop clinical symptoms of EV in the context of other infectious diseases. The features of the typical and atypical forms of EV thus suggest that the control of beta-HPV infections requires both EVER1/EVER2-dependent keratinocyte-intrinsic immunity and T cell-dependent adaptive immunity.