Developmental and family history-based analysis of congenital fused labia phenotype in the captive common marmoset (Callithrix jacchus).

BACKGROUND: Congenital fused labia (CFL) is defined as a failure or significant delay in the opening of the juvenile sealed labia majora. This phenotype is known to be variably common in adult captive female marmosets but has never been investigated in detail before. MATERIALS AND METHODS: Here, we define, describe and quantify the variations in the degree of closure of the vulva in 122 captive marmosets (Callithrix jacchus) from 1.2 to 42 months old and include colony analysis. RESULTS: There was a negative correlation between the degree of labial fusion and animal age after prepubertal period (P < 0.05). CFL females had higher number CFL relatives (4.3 ± 0.6 vs 2.4 ± 0.5 for non-CFL, P < 0.05) and more external ancestors compared to non-CFL (P < 0.05). CONCLUSIONS: Our results therefore suggest that CFL phenotype is most likely associated with epigenetic effects induced by the captive environment and colony management strategy of extensive crossing of family lines to promote heterozygosity.

Different DNA damage and cell cycle checkpoint control in low- and high-risk human papillomavirus infections of the vulva.

Human papillomavirus (HPV) infections may result in benign hyperplasia, caused by low-risk HPV types, or (pre)malignant lesions caused by high-risk HPV types. The molecular basis of this difference in malignant potential is not completely understood. Here, we performed gene profiling of different HPV infected vulvar tissues (condylomata acuminata (n = 5), usual type vulvar intraepithelial neoplasia (uVIN) (n = 9)) and control samples (n = 14) using Affymetrix Human U133A plus 2 GeneChips. Data were analyzed using OmniViz®, Partek® and Ingenuity® Software. Results were validated by real-time RT-PCR and immunostaining. Although similarities were observed between gene expression profiles of low- and high-risk HPV infected tissues (e.g., absence of estrogen receptor in condylomata and uVIN), high-risk HPV infected tissues showed more proliferation and displayed more DNA damage than tissues infected with low-risk HPV. These observations were confirmed by differential regulation of cell cycle checkpoints and by increased expression of DNA damage-biomarkers p53 and γH2AX. Furthermore, FANCA, FANCD2, BRCA1 and RAD51, key players in the DNA damage response, were significantly upregulated (p < 0.05). In addition, we compared our results with publicly available gene expression profiles of various other HPV-induced cancers (vulva, cervix and head-and-neck). This showed p16(INK4a) was the most significant marker to detect a high-risk HPV infection, but no other markers could be found. In conclusion, this study provides insight into the molecular basis of low- and high-risk HPV infections and indicates two main pathways (cell cycle and DNA damage response) that are much stronger affected by high-risk HPV as compared to low-risk HPV.

The high rate of familial lichen sclerosus suggests a genetic contribution: an observational cohort study.

BACKGROUND: Familial lichen sclerosus (LS) has been described in only 37 families. We feel that the association is under-reported. OBJECTIVES: To determine the percentage of patients with LS who have a positive family history. METHOD: A large observational-cohort study of a total of 1052 females at vulval clinics within a University Hospital with a diagnosis of LS of the vulva (clinical diagnosis was confirmed in 80% of cases by histology). Patients were questioned as to family history of LS or balanitis xerotica obliterans; male circumcision for medical reasons; vulval cancer; and routine medical and family history. The outcome was the presence or absence of personal or family history of LS, autoimmune disorder or vulval cancer. RESULTS: In total 1052 patients were investigated. Of these, 126 (12%) had a positive family history of LS. These patients belonged to 95 families. Vulval cancer was significantly increased in those with a family history of LS compared with those without (4.1% vs. 1.2%, P < 0.05). There was more associated autoimmune disease in familial LS than in sporadic LS, although this was not statistically significant. (7% vs. 5%, P > 0.2). CONCLUSION: Our data from a large cohort of patients with LS provide evidence of an increased risk for family members to develop LS. This indicates a likely genetic component in the aetiology of LS.

Analysis of clonality and HPV infection in benign, hyperplastic, premalignant, and malignant lesions of the vulvar mucosa.

To elucidate the pathogenesis of vulvar carcinomas, we studied clonality and human papillomavirus (HPV) infection in vulvar epithelial diseases. Monoclonal composition was demonstrated in all 9 invasive tumors (squamous cell carcinoma [SCC], 6; basal cell carcinoma, 1; malignant melanoma, 2), 15 of 20 cases of vulvar intraepithelial neoplasia (VIN), 7 of 9 cases of Paget disease, 2 of 6 cases of lichen sclerosus (LS), and 2 of 3 cases of squamous cell hyperplasia (SCH); high-risk type HPV was revealed in 5 of 6 SCCs and 17 of 20 VINs. These observations might imply that a subset of cases of LS and SCH result from a neoplastic proliferation, similar to VINs but not related to infection with high-risk type HPV. In 1 case of SCC with concurrent VIN 3 in an adjacent lesion, both lesions showed the same pattern of X chromosome inactivation and the presence of HPV-16 in episomal and integrated forms, suggesting that monoclonal expansion triggered by high-risk type HPV integration is an early event for carcinogenesis of HPV-associated SCC.

Impact of genetic variation in interleukin-1 receptor antagonist and melanocortin-1 receptor genes on vulvar vestibulitis syndrome.

OBJECTIVE: To investigate the risk of vulvar vestibulitis syndrome (VVS) in the presence of specific genetic variants (polymorphisms) that affect chronic inflammation, pain and skin color. STUDY DESIGN: For a retrospective, case-control study performed at a university-based ambulatory gynecologic service, 36 consecutive VVS cases and 69 consecutive pain-free controls were selected. Polymerase chain reaction products containing genetic variants of 2 genes, the interleukin-1 receptor antagonist (IL1RN) and melanocortin-1 receptor (MC1R), were analyzed by 2 independent techniques, gel electrophoresis and direct sequencing. RESULTS: VVS cases were significantly more likely to be homozygous (+/+) for allele 2 of IL1RN as compared to controls (OR=4.4, 95% CI 1.11-17.14, P=.032). VVS cases were more likely to carry at least 1 of 6 loss-of-function polymorphisms of the MC1R gene as compared to controls, overall (OR=3.5, 95% CI 1.45-8.37, P=.005) and adjusted for race (OR=2.6, 95% CI 1.06-6.51, P=.037). The combined presence of allele 2 (+/+) IL1RN and at least 1 of the 6 MC1R polymorphisms resulted in an additive risk for VVS (OR=8.5; additive risk for VVS (OR=8.5; P=.046). CONCLUSION: The risk of VVS is increased with proinflammatory genetic variants of IL1RN and MC1R, and combined genetic effects are associated with additive risk. This study supports a genetic contribution to VVS, suggests an increased risk of VVS in women withfair skin and indicates potential new treatment and primary prevention options.

p73 is over-expressed in vulval cancer principally as the Delta 2 isoform.

p73 was studied in squamous cancers and precursor lesions of the vulva. Over-expression of p73 occurred commonly in both human papillomavirus (HPV)-positive and -negative squamous cell cancers (SCC) and high-grade premalignant lesions. Whereas expression in normal vulval epithelium was detected only in the basal and supra-basal layers, expression in neoplastic epithelium increased with grade of neoplasia, being maximal at both protein and RNA levels in SCC. p73 Delta 2 was the principal over-expressed isoform in the majority of cases of vulval SCC and often the sole form expressed in SCC. Over-expression of p73 was associated with expression of HPV-encoded E7 or with hypermethylation or mutation of p16(INK4a) in HPV-negative cases. There was a close correlation between expression of p73 and p14(ARF) in cancers with loss of p53 function. The frequent over-expression of p73 Delta 2 in neoplastic but not normal vulval epithelium, and its co-ordinate deregulation with other E2F-1 responsive genes suggests a role in the oncogenic process.

Lichen sclerosus premenarche: autoimmunity and immunogenetics.

Lichen sclerosus is among the most frequently seen paediatric vulval disorders. In adults a strong association between lichen sclerosus and autoimmune diseases, and also with HLA class II locus DQ7, has been well demonstrated in women and a weaker association in men. These associations have not previously been studied in children, although in other autoimmune diseases, the HLA associations have been strongest in children. We performed HLA tissue typing and looked for autoimmune associations in a group of 30 children with vulval lichen sclerosus. HLA DQ7 was present in 66% of female children with lichen sclerosus compared with 31% in controls. Previous studies reported DQ7 in 51% of adult female patients and 45% of male patients. Sixteen per cent of the children were homozygous for DQ7 as opposed to 5% of controls. In the childhood group, only 4% had another autoimmune disease, but 56% of their parents or grandparents did. Age differences make comparison difficult, but the family history of autoimmunity appears to be strong in the early-onset group, in addition to the stronger association with DQ7.

[Localized reticulate hyperpigmentation]. / Umschriebene retikuläre Hyperpigmentierungen--ein weites klinisches Spektrum.

34 year-old pregnant woman presented with reticulate pigmentation of the flexures, the dorsum of the hands and the genitoperianal region. She was in good health and her family history was unremarkable. Histologic examination of the hyperpigmented patches revealed pigmented filiform downgrowths of the interfollicular epidermis and follicular infundibula, as well as small epithelial cysts. Upon immunohistochemical and ultrastructural studies, the number of melanocytes appeared normal. The elongated dendritic processes of the melanocytes contained many mature melanosomes. In the adjacent keratinocytes large melanosomes did not aggregate into complexes. The diagnosis of localized reticulate pigmentary disorder was established. The knowledge of the broad clinical spectrum of localized reticulate hyperpigmentations with its favorable prognosis is of practical importance. Genital or flexural pigmented lesions have to be differentiated from melanosis of the vulva or acanthosis nigricans. The presented case gives further evidence that many of the proposed entities characterized clinically by reticulate pigmented macules and hyperkeratotic follicular lesions are different phenotypic expressions of the same autosomal dominant genodermatosis.

Vulvar lichen sclerosus and squamous cell carcinoma: a cohort, case control, and investigational study with historical perspective; implications for chronic inflammation and sclerosis in the development of neoplasia.

The histological changes of lichen sclerosus (LS) are frequently found in association with vulvar squamous cell carcinoma (SCC). The importance of chronic inflammation and scarring in oncogenesis is well recognized. Thirty-two patients with symptomatic vulvar LS and 60 with vulvar SCC were studied. Paraffin sections of vulvar LS, and three controls groups (acute scars, normal vulva, and vulvar lichen simplex chronicus [LSC]) were investigated with a panel of seven tissue markers and for DNA content in areas without vulvar intraepithelial neoplasia (VIN). All published cases to date of vulvar LS associated with SCC were reviewed. Of the cohort of symptomatic vulvar LS patients (mean/median age, 60 years), 9% developed VIN lesions and 21% invasive SCC; symptomatic LS preceded the carcinoma by a mean of 4 years (range, 1 to 23 years). Second and third primary tumors developed in three of these patients. Of the series of 60 patients presenting with vulvar SCCa, the clinical setting and histological features of SCCs associated with LS were significantly distinctive compared with SCCas without LS: SCCs associated with LS occurred in an older age-group (74 v 65 years; P = .01), were located on the clitoris (41% v 5%; P = .003), were of conventional SCCa type (85% v 57%; P = .02), were associated with a prominent fibromyxoid stromal response (46% v 10%; P = .004), were not associated with VIN 3 (SCC in situ) (5% v 67%; P = .02) and diffusely expressed tumor suppressor gene product p53 (43% v 19%; P = .01) and cytokine TGF-beta (33% v 9%; P = .05). The epidermis of vulvar LS was similar to that of acute scars and differed significantly compared with normal vulva with respect to keratinocytic expression of markers to keratin AE 1, involucrin and filaggrin, epidermal thickness (0.13 mm [LS] v 0.05 mm [normal]; P < .03), and proliferative index by PCNA and Mib-1 labeling (53/60 [LS] v 15/19 [normal] per 200 basal cells [bc]; P < .003). Vulvar LS showed significantly higher expression of p53 than all three control groups (80 [LS] v 3 [normal]/44 [acute scar]/28 [LSC] per 200 bc; P < .008), and aneuploidy (33% v diploid controls) in the absence of VIN. Comparing LS with and without associated SCCa found significant increases in age of patients (74 v 66 years; P = .001), and DNA aneuploidy (52% v 11%; P = .0001) and no differences in epidermal thickness, sclerotic thickness, proliferative index, or p53 expression. However, those cases of LS with an aneuploid DNA content showed significantly elevated p53 expression (88 v 60/200 bc; P = .01) and epidermal thickness (0.16 v 0.11 mm; P = .005) compared with LS with a diploid DNA content. Review of published cases supports an association between LS and vulvar SCC. The phenomenon of chronic inflammation and scarring giving rise to carcinoma has been well documented. Vulvar lichen sclerosus (LS) is an inflammatory dermatosis characterized by clinicopathologic persistence and hypocellular fibrosis (sclerosis). A subset of vulvar SCCs is significantly associated with the presence of LS and diffusely express the p53 gene product. Keratinocytes affected by LS show a proliferative phenotype and can exhibit markers of neoplastic progression such as increased p53 expression and DNA aneuploidy. As a chronic scarring inflammatory dermatosis, vulvar LS could act as both "initiator and promoter" of carcinogenesis, explaining the frequent coexistence of these diseases. Because keratinocytes of LS significantly express tumor suppressor gene p53 protein, the p53 gene may be involved early in this proposed pathway of carcinogenesis.

Familial lichen sclerosus et atrophicus in childhood.

Lichen sclerosus et atrophicus (LSA) is uncommonly reported in family members and is seen occasionally in young children. We report genital LSA in two young sisters who were diagnosed a year apart. The English language literature on familial LSA in childhood is reviewed and discussed.

[Hailey-Hailey pemphigus--one only sees what one recognizes]. / Pemphigus Hailey-Hailey--man sieht nur was man kennt.

A diagnosis of Pemphigus Hailey-Hailey was made by histopathology after more than 20 years of suffering and medical treatment. The lesion had almost exclusively affected the vulvar region of a 44-year-old woman. A case like this confronts the gynecologists with the necessity of including a rare disease into particular consideration and investigation.

[Dowling-Degos disease with exclusively genital manifestations]. / Morbus Dowling-Degos mit ausschliesslich genitaler Manifestation.

We report on two women with pigmented lesions of the vulva. The histopathology (filiform downgrowth of pigmented epithelial strands two to four cells wide, extending from the interfollicular epidermis and from follicular infundibula; no increased numbers of melanocytes; horn pseudocysts) was specific for Dowling-Degos disease. One patient also had acne inversa, and the other patient had been treated surgically for a pilonidal sinus some years before. The spectrum of conditions that should be considered in the differential diagnosis of genital pigmented lesions is discussed. Vulvar melanosis, genital lentigo, malignant melanoma, acanthosis nigricans maligna and benigna and syndromes occurring concomitantly with pigmentation of the mucosa need to be excluded. The association of Dowling-Degos disease with acne inversa, which was recently described for the first time, is discussed.

Normal histology and nomenclature of the vulva, and malignant neoplasms, including VIN.

In this article, vulvar anatomy and histology are reviewed, and nonneoplastic and neoplastic epithelial disorders are presented. Included are lichen sclerosus, squamous cell hyperplasia, vulvar intraepithelial neoplasia, vulvar Paget's disease, and squamous cell carcinoma. Current terminology, tumor measurements, and staging for vulvar carcinoma are reviewed.

Search for herpes simplex virus 2 and human papillomavirus genetic expression in vulvar neoplasia.

Specimens from vulvar carcinomas and vulvar intraepithelial neoplasia (VIN) of various degrees were analyzed for the presence of herpes simplex virus 2 (HSV 2) and human papillomavirus (HPV) genetic information. A search for the HPV 16 E6 protein as well as the HSV 2 antigenic determinant LA1 and ICSP 11/12 protein was carried out with an immunoperoxidase assay on 12 vulvar carcinomas and 6 VINs. Seven invasive cancers and four VINs were screened for the presence of homology to HPV 16 DNA and HSV 2 DNA transforming sequences with Southern blot hybridization. We used specimens from labial tumors and from normal vulvas and cervixes as controls. The preliminary results showed that one vulvar carcinoma and two VINs contained HPV 16 DNA. Four vulvar carcinomas expressed the E6 protein, while all the VINs were negative. Homology to HSV 2 DNA transforming sequences was detected in one vulvar cancer but not in any VIN cases. Positivity to HSV 2 ICSP 11/12 was observed in 33.3% of VIN cases and 75% of invasive cancers. HSV 2 LA1 antigenic determinant was expressed in 33.3% of VIN and 66.6% of cancer cases.

[Genital vulvar lichen sclerosis in 2 siblings]. / Genitaler vulvärer Lichen sclerosus bei Geschwistern.

Lichen sclerosus of the vulva mainly occurs in older women, but shows another peak of incidence at the age just before puberty. The etiology of the disease, which is characterized by firm atrophy, is not known. There are some hints for a genetic disposition, such as a certain constellation of HLA and familial incidence. Our present case report is concerned with the clinical course of vulval lichen sclerosus in sisters, which had almost simultaneously developed. In both cases, the disease was successfully treated with a cream containing thyme extract; there were no side effects.

Juvenile laryngeal papillomatosis.

From the records of 23 patients with juvenile laryngeal papillomatosis, various aspects of the aetiology, natural history and treatment of the condition have been presented. The lesions are thought to be viral in origin, they are notoriously unpredictable in their behaviour, and treatment can often be prolonged and frustrating. Tracheostomy should be avoided, if possible, owing to the risk of further dissemination down the trachea and bronchi. The CO2 laser now seems to be the surgical treatment of choice, and early reports of adjuvant interferon therapy are encouraging. However, the laser is only available in certain centres, and interferon supplies are limited at present.

The development of lichen sclerosus et atrophicus in monozygotic twin girls.

The development of vulval lichen sclerosus et atrophicus in monozygotic twins is described. This is the first report of the occurrence of lichen sclerosus et atrophicus in two genetically identical individuals, and is considered to provide further evidence that inherited factors are of relevance in the aetiology of this disorder.