Guidelines for clinical trials of frontal fibrosing alopecia: consensus recommendations from the International FFA Cooperative Group (IFFACG).

BACKGROUND: Frontal fibrosing alopecia (FFA) has become one of the most common causes of cicatricial alopecia worldwide. However, there is a lack of clear aetiology and robust clinical trial evidence for the efficacy and safety of agents currently used for treatment. OBJECTIVES: To enable data to be collected worldwide on FFA using common criteria and assessment methods. METHODS: A multicentre, international group of experts in hair loss was convened by email to create consensus recommendations for clinical trials. Consensus was defined at > 90% agreement on each recommended part of these guidelines. RESULTS: Standardized diagnostic criteria, severity rating, staging, and investigator and patient assessment of scalp hair loss and other clinical features of FFA were created. CONCLUSIONS: These guidelines should allow the collection of reliable aggregate data on FFA and advance efforts in both clinical and basic research to close knowledge gaps in this condition.

Dermatology today and tomorrow: from symptom control to targeted therapy.

For many decades and until recently, medical approach to dermatologic diseases has been based on the physician's ability to recognize and treat symptoms. Nowadays, advances in the understanding of the biology of diseases and in technologies for intervening against them have allowed physicians to diagnose and treat underlying disease processes rather than simply addressing the symptoms. This means that rather than addressing 'the disease in humans', physicians can now address the particular pathologic (biologic, molecular) disturbance as it presents in the individual patient, i.e., physicians now can practice something much closer to 'personalized medicine', leading to greater benefits for the patients and the health of society in general. The deeper understanding of ultraviolet radiation, the importance of photoprotection and increased knowledge about signalling pathways of melanoma and carcinoma have led to more complete care for the dermatologic patient. The current popularity for excessive exposure to the sun, without adequate application of the appropriate photoprotection remedies, is the origin of melanoma, but also for the weakening of the structure and functions of the skin. Indeed, fragility of the skin can affect humans around the world. In the senior population, this skin fragility is accompanied by pruritus, whereas atopic dermatitis is an inflammatory disease with highest prevalence in children and adolescents. Acne, the number one reason for dermatologic consultations worldwide, increases its prevalence in adolescents and in females. Senescent alopecia affects humans after menopause and andropause. The articles in this publication present an overview of the current advanced understanding of the diagnosis and therapeutic approaches in 6 fields of dermatology - dermatopaediatry and gerontodermatology, oncodermatology, hair loss, atopic dermatitis, photoprotection and acne - and thereby serve as a useful compendium of updated information and references for all healthcare professionals who see patients with presentations of the symptoms of these diseases.

Darier disease in Israel: combined evaluation of genetic and neuropsychiatric aspects.

BACKGROUND: Darier disease (DD) is a rare genodermatosis caused by heterozygous mutations in the ATP2A2 gene. It has been associated with neuropsychiatric manifestations. OBJECTIVES: To investigate the genetic basis of Israeli patients with DD, and its association with the neuropsychiatric phenotype. METHODS: A cohort of 32 families comprising 74 affected individuals and 13 unaffected family members was recruited from the Haemek Dermatology Department and other dermatology clinics in Israel. The individuals were evaluated by detailed questionnaires, physical examination and genetic analysis. The main outcome measures were genetic mutations, psychiatric profile and their association. RESULTS: Twenty-three mutations in ATP2A2 were scattered over the entire gene, 14 of them novel. Two families shared the same mutation. Twenty-one patients (28%) had a history of psychiatric disorders, most of them mood disorders. Another seven patients (9%) were highly suspected of having a psychiatric disorder; 21 (28%) reported suicidal thoughts and five (7%) had attempted suicide. The psychiatric phenotype demonstrated inter- and intrafamilial variability, and was not associated with disease severity, family history of psychiatric disease or mutation location. CONCLUSIONS: The cohort demonstrated genetic heterogeneity with no mutation cluster along the gene, and a high prevalence of psychiatric disorders. Although no clear genotype-phenotype correlation was found, the results point to a major effect of genetic background on psychiatric phenotype, together with other modifiers.

Learning disabilities in Darier's disease patients.

BACKGROUND: Neuropsychiatric features and intellectual difficulties have been reported in studies of Darier's disease. Learning disabilities have never been reported or evaluated systematically in these patients. OBJECTIVE: To assess the prevalence of learning disabilities in 76 patients with Darier's disease, and cognitive functioning in 19 of them. METHODS: The data were collected by two methods: a questionnaire, as part of a larger study on the clinical characteristics of 76 patients; and neuropsychological measures for the assessment of learning disabilities in 19 of them. RESULTS: Thirty-one of the 76 patients reported learning disabilities (41%) and 56 (74%) reported a family history of learning disabilities. Significant differences were found between the 19 patients evaluated on cognitive tasks and a control group of 42 skilled learners on subtraction and multiplication tasks. Six (32%) of the 19 were identified as having reading difficulties and five (26%) exhibited low performance on the Concentration Performance Test. All patients had general cognitive ability in the average range. CONCLUSIONS: Findings suggest an association between Darier's disease and learning disabilities, a heretofore unreported association, pointing to the need to obtain personal and family history of such disabilities in order to refer cases of clinical concern for further study.

What causes alopecia areata?

The pathobiology of alopecia areata (AA), one of the most frequent autoimmune diseases and a major unsolved clinical problem, has intrigued dermatologists, hair biologists and immunologists for decades. Simultaneously, both affected patients and the physicians who take care of them are increasingly frustrated that there is still no fully satisfactory treatment. Much of this frustration results from the fact that the pathobiology of AA remains unclear, and no single AA pathogenesis concept can claim to be universally accepted. In fact, some investigators still harbour doubts whether this even is an autoimmune disease, and the relative importance of CD8(+) T cells, CD4(+) T cells and NKGD2(+) NK or NKT cells and the exact role of genetic factors in AA pathogenesis remain bones of contention. Also, is AA one disease, a spectrum of distinct disease entities or only a response pattern of normal hair follicles to immunologically mediated damage? During the past decade, substantial progress has been made in basic AA-related research, in the development of new models for translationally relevant AA research and in the identification of new therapeutic agents and targets for future AA management. This calls for a re-evaluation and public debate of currently prevalent AA pathobiology concepts. The present Controversies feature takes on this challenge, hoping to attract more skin biologists, immunologists and professional autoimmunity experts to this biologically fascinating and clinically important model disease.

Health-related quality of life among Darier's disease patients.

BACKGROUND: Darier's disease (DD) is an autosomal dominant skin disorder characterized by persistent eruption of hyperkeratotic papules. The effect of DD on quality of life (QOL) has been assessed in only one study, which found no correlation between the Dermatology Life Quality Index (DLQI) score and clinical severity of the disease. The correlation between health-related quality of life (HRQL) and other diseases and patient characteristics has not been studied. OBJECTIVES: To examine the HRQL of patients with DD and to evaluate the association between HRQL scores and disease and patient characteristics. METHODS: A total of 74 DD patients completed three QOL questionnaires: DLQI, EQ-5D, and one specially designed for the study. The data reported in this study were collected as part of a larger study on the clinical characteristics of DD; the socio-demographic and clinical data were used in the statistical analysis of the current study. RESULTS: Mean DLQI was 5.41 ± 5.57 and the mean EQ-Visual Analogue Scale (VAS), was 70.84 ± 19.25. DLQI and EQ-VAS were significantly associated with skin area affected, disease severity, age at onset of DD and a seborrhoeic distribution pattern of DD. Stepwise linear regression showed skin area affected to be the most significant variable in the predication of DLQI (beta = 0.183; SE = 0.04; P < 0.001), and disease severity the most significant variable in the predication of EQ-VAS (beta = -9.15; SE = 3.21; P < 0.006). CONCLUSIONS: Darier's disease has a negative impact on HRQL of patients and the HRQL is associated with various disease characteristics, mainly skin area affected and clinical severity.

Bacteriological aspects of Darier's disease.

BACKGROUND: There are no established data on the prevalence of bacterial colonization of lesional skin, nares and perineum in Darier's disease (DD), or its contribution to the clinical manifestations of the disease. OBJECTIVE: To determine the prevalence of bacterial colonization of lesional skin and Staphylococcus aureus (S. aureus) in nares and perineum in 75 patients with DD, the association of these parameters with disease and patient characteristics, and the features of the bacterial skin infection in this group. METHODS: Medical interviews and physical examinations were performed. Bacteria were isolated from swabs taken from lesional skin, nares and perineum. RESULTS: S. aureus was isolated in 68%, 47% and 22% of lesional skin, nares and perineum cultures respectively. Subjects with positive S. aureus culture from lesional skin and/or nares had a statistically significant higher percentage of skin area affected and a more severe disease than patients with negative culture. Thirty of the 75 patients (40%) recalled bacterial skin infection, most often on the chest. CONCLUSIONS: Patients with DD have high prevalence of S. aureus colonization in lesional skin and nares, with a correlation between disease severity and extent of the colonization. Further studies examining the consequences of S. aureus eradication in those sites may establish the need for S. aureus lesional skin and nares colonization screening and eradication as part of the treatment of DD exacerbations.

Erythema ab igne of shins: a kerosene stove-induced prototype in diabetics.

A patient with erythema ab igne of shins is presented, caused by repeated thermal injury induced by a heating stove placed between the knees. This injury pattern has been repeatedly identified in diabetic patients involved in similar heating practice, underscoring a possible predisposition related to diabetic neuropathy.

A novel monilethrix mutation in coil 2A of KRT86 causing autosomal dominant monilethrix with incomplete penetrance.

BACKGROUND: Monilethrix is a genetic hair shaft disorder that causes a dystrophic alopecia. Mutations causing autosomal dominant monilethrix have been found in the helix initiation and helix termination motifs of the type II hair keratins KRT81, KRT83 and KRT86. Mutations in DSG4 are linked to recessive transmission. OBJECTIVES: We investigated a large Tasmanian family demonstrating autosomal dominant monilethrix with incomplete penetrance in order to identify the responsible genetic mutation. As only some affected hairs were moniliform, analysis was undertaken to demonstrate a deficit in the tensile strength of nonmoniliform hairs. METHODS: One hundred and twenty family members were examined. Light microscopy of hair samples was used to support clinical diagnoses. Linkage and gene sequencing studies were then undertaken. Nonbeaded fibres were analysed using the Single Fibre Analyser 3 (SIFAN 3). RESULTS: We identified a novel A280V (c.839C > T substitution) mutation in the coil 2A region of KRT86. This is the first mutation located in a region other than the helix initiation or termination motifs. The A280V mutation was identified in both affected and clinically unaffected family members. Nonmoniliform hairs demonstrated reduced elasticity among both affected and unaffected individuals carrying the A280V mutation. CONCLUSIONS: This is the first mutation located in a region other than the helix initiation or termination motifs, thus expanding the spectrum of mutations and highlighting the importance of molecular diagnosis in monilethrix.

H syndrome: novel and recurrent mutations in SLC29A3.

The H syndrome (OMIM 612391) is a recently described autosomal recessive disorder characterized by cutaneous hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, short stature (low height), hyperglycaemia/diabetes mellitus, hallux valgus, and fixed flexion contractures of the toe and finger joints.(1,2) Histologically, there is an inflammatory infiltrate consisting mainly of histiocytes, later replaced by fibrosis of the deep dermis and subcutis.(3) In total, 31 patients have been reported in the literature with the clinical phenotype characteristic of this syndrome.(1-7)

Identification of a locus for type I punctate palmoplantar keratoderma on chromosome 15q22-q24.

BACKGROUND: The identification of the molecular basis of disorders of keratinisation has significantly advanced our understanding of skin biology, revealing new information on key structures in the skin, such as the intermediate filaments, desmosomes, and gap junctions. Among these disorders, there is an extraordinarily heterogeneous group known as palmoplantar keratodermas (PPK), for which only a few molecular defects have been described. A particular form of PPK, known as punctate PPK, has been described in a few large autosomal dominant pedigrees, but its genetic basis has yet to be identified. AIM: Identification of the gene for punctate PPK. METHODS: Clinical examination and linkage analysis in three families with punctate PPK. RESULTS: A genomewide scan was performed on an extended autosomal dominant pedigree, and linkage to chromosome 15q22-q24 was identified. With the addition of two new families with the same phenotype, we confirmed the mapping of the locus for punctate PPK to a 9.98 cM interval, flanked by markers D15S534 and D15S818 (maximum two point lod score of 4.93 at theta = 0 for marker D15S988). CONCLUSIONS: We report the clinical and genetic findings in three pedigrees with the punctate form of PPK. We have mapped a genetic locus for this phenotype to chromosome 15q22-q24, which indicates the identification of a new gene involved in skin integrity.

Clinical and molecular diagnostic criteria of congenital atrichia with papular lesions.

Congenital atrichia with papular lesions is a rare, autosomal recessive form of total alopecia and mutations in the hairless (hir) gene have been implicated in this disorder. Published estimates of the prevalence of this disorder remain surprisingly low considering pathogenetic mutations in hir have been found in distinct ethnicities around the world. Therefore, it is likely that congenital atrichia with papular lesions is far more common than previously thought and is often mistaken for its phenocopy, the putative autoimmune form of alopecia universalis. To clarify this discrepancy, we propose criteria for the clinical diagnosis of congenital atrichia with papular lesions. Among these is the novel report of the consistent observation of hypopigmented whitish streaks on the scalp surface of affected individuals. Additionally, we report the identification of a novel missense mutation in hir from a family of Arab Palestinian origin that exhibits the pathognomonic features of atrichia with papular lesions. Collectively, we anticipate that an increased recognition of this disorder will result in more accurate diagnosis and the sparing of unnecessarily treatment to patients.

Two p16 (CDKN2A) germline mutations in 30 Israeli melanoma families.

Germline mutations in the p16 (CDKN2A) tumour suppressor gene have been linked to inherited predisposition to malignant melanoma (MM). Variable frequencies of p16 germline mutations were reported in different collections of melanoma families but it can be as high as 50%. Here we describe the results of p16 mutation screening in 30 melanoma kindreds in Israel. The entire coding region of the p16 gene, including exons 1, 2 and 3, flanking exon/intron junctions, and a portion of the 3' untranslated (UTR) region of the gene were examined by single-stranded conformation polymorphism (SSCP) analysis and direct sequencing. Two p16 germline mutations were identified: G101W, which has been previously observed in a number of melanoma kindreds, and G122V, a novel missense mutation. Thus, the frequency of mutations identified in this collection of Israeli families was 7%. Functional analysis indicated that the novel G122V variant retained some capacity to interact with cyclin dependent kinases (CDKs) in vitro, yet it was significantly impaired in its ability to cause a G1 cell cycle arrest in human diploid fibroblasts. This partial loss of function is consistent with the predicted impact of G122V substitution on the 3-dimensional structure of the p16 protein.

Generalized granuloma annulare post autologous bone marrow transplantation in a Hodgkin's disease patient.

A case of generalized granuloma annulare is described in a patient with Hodgkin's disease 3 weeks after autologous bone marrow transplantation (BMT). This is, to our knowledge, the first report of generalized granuloma annulare post-BMT. Immunological pathogenesis is suggested and the association with delayed-type hypersensitivity reaction is discussed.