Biomedical subjects
Publications and source records attributed to E I Grussendorf-Conen.
Shortly after birth, a five-week-old female infant developed small blisters and erythema that followed the lines of Blaschko on the upper and lower extremities as well as the abdomen. Histological examination confirmed the clinical presumptive diagnosis of incontinentia pigmenti. We discuss the dinical features, diagnosis, and the molecular genetic basis of this rare inherited skin disorder.
A 9-year-old female developed facial papules and pustules since four years. Clinically, perioral dermatitis was suspected. Different topical therapy regimens and systemic anibiotics had been unsuccessful and a skin biopsy showed granulomatous (lupoid) rosacea. Only systemic antibiotic treatment with minocyclin led to healing of the skin lesions. While granulomatous rosacea-like dermatitis is more frequently diagnosed in adults, it is only rarely encountered in children where, in most of the cases, it represents a therapeutic challenge.
We describe the case of a 53-year-old man in whom pigmented bowenoid papulosis developed on the skin of the neck. By polymerase chain reaction with general primers for genital human papillomaviruses (HPV) and subsequent restriction enzyme cleavage we could demonstrate HPV 18-related DNA in two biopsy specimens of the pigmented papules. To our knowledge, this report represents the first case of HPV 18-induced extragenital bowenoid papulosis of the neck.
Human papillomavirus types 2 (HPV-2), HPV-27, and HPV-57, are three closely related viruses within the phylogenetic supergroup formed by the remotely related genital papillomaviruses. In contrast to this phylogenetic association, these three viruses are most often found in common warts at nongenital sites, but also occasionally in genital warts and mucosal lesions of the nasopharyngeal cavity. We studied the genomic diversity of HPV sequences in skin warts presumably caused by these viruses. These biopsies were sampled from 75 patients living in Germany, Japan, or Singapore. Among 27 warts with HPV-2, we found seven new genomic variants and among 32 with HPV-57, eight new variants. In both cases, we did not detect the original prototype genomes. In contrast, 13 of 16 warts with HPV-27 contained the prototype genome, and only one new variant was found in three patients. We did not find variants clearly intermediate between any two types, although HPV-2 and HPV-27 are among the most closely related of the extent HPV types. We also did not detect novel HPV types, although the samples were examined with polymerase chain reaction protocols that would have detected remotely related HPVs. So we propose that the phylogenetic group formed by HPV-2, HPV-27, and HPV-57 has no or only very are additional members. One of the HPV-57 variants found, HPV-57-G44, was most likely identical to the subtype HPV-57b, previously proposed to be associated with nasal neoplasia, but found here frequently in common skin warts. Our publication establishes a foundation for pathological and phylogenetic comparisons of HPV types in skin warts.
The morphology of common warts depends on the inducing human papillomavirus (HPV) type. In order to assess the impact of the virus type on wart epidemiology we determined the virus type by PCR and recorded anamnestic data of 238 patients with common warts. Warts induced by the related HPV types 2, 27 and 57 predominated in the study population (n = 202). These warts mostly occurred as multiple verrucae vulgares, mosaic warts or endophytic warts. Patients aged between 10 and 30 years were most affected and they typically displayed a long disease history (mean duration of warts at the time of first clinical examination, 22 months). A different age distribution was observed in HPV 1-induced warts, most of which occurred in children 6-10 years of age. HPV 2-related warts responded only modestly to treatment, as they persisted in approximately 50% of all patients for more than 6 additional months. No sex preference was detected, but an association with atopic diseases was noted as 39.8% of patients with warts containing HPV 2-related viruses showed a history of atopic eczema, pollinosis or asthma as compared with 20.6% of the control population without a history of warts or with short-duration wart disease. Thus, our results indicate that the epidemiology, as well as morphology, of common warts is closely linked to the virus type.
The differential diagnosis of herpes simplex and zoster may require virological confirmation, yet virus typing is not regarded as necessary in routine dermatological assessment. In an attempt to evaluate the clinical benefits of the routine detection of herpes simplex virus (HSV) and varicella zoster virus (VZV), we analysed skin swabs from 110 patients who were diagnosed at the first clinical visit as having herpes simplex (n = 45) or zoster (n = 65). Viruses were typed using the polymerase chain reaction (PCR) with the general primer pair GPHV-RU. PCR analysis showed that at the initial clinical presentation, herpes simplex in these patients was not mistaken for zoster but that zoster was incorrectly diagnosed as herpes simplex in nine cases. Thus these results suggest that initial zoster often mimics herpes simplex, hence routine PCR diagnosis of HSV and VZV or alternative rapid diagnostic approaches may be beneficial in these cases.
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The polymerase chain reaction (PCR) enables rapid and sensitive detection of VZV and HSV DNA and its efficiency depends mainly on the choice of the primers. Primers should hybridize to conserved DNA sequences within the viral genomes in order to avoid unreliable amplification due to DNA sequence variation between different strains. The aim of the study was to design and to evaluate a general primer pair which permits fast and reliable detection of HSV and VZV. The genes UL 15 of HSV and UL 42 of VZV share the highest degree of homology within the two genomes. We designed a primer pair (GPHV-RU) which hybridizes to these genes. The genetic variability of amplified sequences from clinical specimens was analyzed by restriction enzyme cleavage analysis and by temperature gradient SSCP analysis (TG-SSCP). PCR with GPHV-RU amplified viral sequences from all analyzed specimens (25 x VZV, 10 x HSV-1, 5 x HSV-2) obtained from patients with clinical evidence of HSV or VZV infection. Restriction enzyme cleavage analysis with Hpa II further permitted reliable distinction between VZV, HSV-1, and HSV-2. Analysis of the heterogeneity of the amplified sequences by restriction enzyme cleavage and by TG-SSCP demonstrated no variability between the analyzed clinical specimens of VZ and of HSV-2 and only one differing TG-SSCP-pattern within the HSV-1 isolates. The results suggest that detection of HSV and VZV using the new primer pair GPHV-RU should give reliable results as the amplified sequences show little genetic variability within clinical isolates of HSV-1/2 and VZV.
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A modified non-radioactive single strand conformation polymorphism analysis incorporating a temperature gradient (TG-SSCP) and temperature gradient gel electrophoresis (TGGE) were evaluated for the detection of human papillomavirus type 6 (HPV 6)-variants in 41 condylomata acuminata and 5 Buschke-Loewenstein tumours. TG-SSCP and TGGE analysed part of the transforming ORF E6 of HPV 6 spanning nucleotides 10 to 495. TG-SSCP distinguished between 8 HPV 6-variants whereas TGGE demonstrated 6 different DNA-species. HPV 6-strains found in Buschke-Loewenstein tumours did not vary in the analysed portion of the E6 ORF as compared to ordinary condylomata acuminata. TG-SSCP and TGGE further showed absence of double infection with different HPV 6-strains in the analysed samples. Our results demonstrated that both methods may be successfully used for the detection of different strains of microbiological agents, although TG-SSCP seemed to provide easier execution and to confer a higher degree of flexibility than TGGE.
The value of DNA single cell cytometry for the detection of aneuploidy was assessed in 100 specimens of actinic keratoses and 39 specimens of Bowen's disease. Ten seborrhoeic keratoses and 10 samples of normal epidermis served as negative control groups. Monolayer smears, prepared from formalin-fixed, paraffin-embedded tissues, were Feulgen-stained and used for interactive DNA-cytometry. In each specimen, the DNA content of 150 randomly chosen squamous epithelial cells was measured, using a TV-image analysis system (TAS-plus, Leica, Germany). Aneuploidy was diagnosed if at least three nuclei with a DNA content above 5c (5cEE > or = 3) were found. The aneuploidy rate in actinic keratosis was 69% (69 of 100) and in Bowen's disease was 95% (37 of 39). Another 20 specimens of actinic keratoses and the remaining two specimens of Bowen's disease were diagnosed as suspicious for aneuploidy (0 < 5cEE < 3). The 20 specimens of seborrhoeic keratoses and normal epidermis did not show any nuclei above the 5c level, and were classified as non-aneuploid. This indicates a sensitivity of 76% (106 of 139) and a specificity of 100% (20 of 20). The frequent occurrence of aneuploidy in actinic keratoses and Bowen's disease underlines the character of the lesions as epidermal carcinomas in situ, but does not explain the long-term low incidence of invasive growth.
Human papillomavirus type 6 (HPV 6) induces condylomata acuminata and laryngeal papillomas. Occasionally, HPV 6 may also be found in low-grade verrucous carcinomas. In some tumours, genetic analysis revealed the presence of HPV 6 variants with rearrangements, mostly DNA duplications, within the upstream regulatory region (URR). In this study, we analysed 98 formalin-fixed, paraffin-embedded condylomata acuminata obtained from 54 patients for the presence of URR-duplication variants of HPV 6. HPV 6 DNA could be amplified by polymerase chain reaction (PCR) from 40 samples. One condyloma acuminatum contained a HPV 6 genome with rearranged URR. Analysis using restriction enzyme cleavage suggested a DNA duplication within the URR of approximately 200 bp, spanning the Hpa II site at nt 7863 and the Dde I site at nt 7843 but not involving the Rsa I site at nt 7633. In addition, we analysed the distribution of the already characterized URR-duplication variant HPV 6AC1B within different paraffin-embedded tissue sections of a Buschke-Loewenstein tumour. No correlation could be demonstrated between the presence of the rearranged genome and malignant histological changes. This result and the demonstration of an URR-duplication variant in a typical condyloma acuminatum suggest that duplications within the URR of HPV 6 are not directly related to malignant progression of HPV 6-induced tumours.
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We studied the papillomaviruses (HPV) found in 131 common warts from 111 immunocompetent patients by amplification of viral DNA sequences with the general-primer-mediated polymerase chain reaction (PCR). The virus types were determined by restriction-enzyme cleavage and reverse-blot analysis. Results were confirmed by using the Southern blot technique. Forty patients harboured HPV 2a, 25 individuals showed HPV 2c and 13 yielded HPV 57. Common warts from 16 patients were induced by a variant of HPV 57. HPV 7 was found in four patients. HPV 1 was identified in two patients, and there was evidence for HPV 4 in only one case. One individual yielded an HPV type which was only weakly related to HPV 2. Three patients were infected by more than one HPV type. PCR did not demonstrate HPV-DNA in warts from six individuals. The distribution and variation of HPV types found in the common warts of immunocompetent patients were similar to the findings in immunocompromised patients reported by other authors.
During recent years, advances have been made in understanding the functions of the viral oncoproteins E6 and E7. E6 und E7 code for proteins forming complexes with cellular proteins, which regulate the cell cycle. This leads to a disturbance of the physiological control mechanism and to increased proliferation of the infected cells. Enhanced expression of viral oncogenes in cells infected by genital "high risk" HPV types results in chromosomal instability and in an accumulation of mutational events. Cutaneous HPV types apparently follow other strategies to transform their host cells.
We report on a 33-year-old patient with unusually extensive and predominantly cutaneous condylomata acuminata spreading from the penis over the mons pubis to the entire lower abdominal wall but almost completely sparing the genital mucous membranes. Single lesions were found on the left arm and on the buttocks. Southern blot hybridization detected HPV-6a DNA sequences within the fibroepithelial tumours. Carbon dioxide laser treatment resulted is cosmetically acceptable healing without recurrence.
Clinically malignant Buschke-Löwenstein tumours and benign condylomata acuminata are caused by human papillomaviruses (HPVs), predominantly HPV-6 and -11. In some cases, the HPV-6 genomes found in Buschke-Löwenstein tumours and in verrucous carcinomas differ from HPV-6b isolated from a benign genital wart, by rearrangements of the upstream regulatory region (URR). To evaluate the frequency and role of mutations of the URR of HPV-6 we analysed 42 condylomata acuminata and four Buschke-Löwenstein tumours by the polymerase chain reaction and restriction enzyme cleavage. Using only four different restriction enzymes we could demonstrate four distinct restriction patterns, indicating that naturally occurring HPV-6 isolates display a high degree of DNA polymorphism within the URR. One Buschke-Löwenstein tumour and two condylomata acuminata yielded rearranged URRs with DNA duplications. All three lesions harboured multiple HPV-6 variants, suggesting that cellular or environmental factors facilitate the development of rearrangements. Therefore, rearrangements of the URR may represent only secondary events in condylomata acuminata and Buschke-Löwenstein tumours which do not necessarily confer a higher malignant potential to the infected cell.
A 39-year-old woman with cutis marmorata telangiectatica congenita (CMTC) on the back presented with a 5-year history of pain in the involved area which initially occurred only on touch and cold exposure but was ultimately virtually constant. Histological examination of a skin biopsy specimen revealed an increased number of nerve fibres. The phlebectatic subcutaneous veins were demonstrable by NIR (near infrared) venoscopy.