Variant PADI3 in Central Centrifugal Cicatricial Alopecia.

BACKGROUND: Central centrifugal cicatricial alopecia (CCCA) is the most common form of scarring alopecia among women of African ancestry. The disease is occasionally observed to affect women in families in a manner that suggests an autosomal dominant trait and usually manifests clinically after intense hair grooming. We sought to determine whether there exists a genetic basis of CCCA and, if so, what it is. METHODS: We used exome sequencing in a group of women with alopecia (discovery set), compared the results with those in a public repository, and applied other filtering criteria to identify candidate genes. We then performed direct sequencing to identify disease-associated DNA variations and RNA sequencing, protein modeling, immunofluorescence staining, immunoblotting, and an enzymatic assay to evaluate the consequences of potential etiologic mutations. We used a replication set that consisted of women with CCCA to confirm the data obtained with the discovery set. RESULTS: In the discovery set, which included 16 patients, we identified one splice site and three heterozygous missense mutations in PADI3 in 5 patients (31%). (The approximate prevalence of the disease is up to 5.6%.) PADI3 encodes peptidyl arginine deiminase, type III (PADI3), an enzyme that post-translationally modifies other proteins that are essential to hair-shaft formation. All three CCCA-associated missense mutations in PADI3 affect highly conserved residues and are predicted to be pathogenic; protein modeling suggests that they result in protein misfolding. These mutations were found to result in reduced PADI3 expression, abnormal intracellular localization of the protein, and decreased enzymatic activity - findings that support their pathogenicity. Immunofluorescence staining showed decreased expression of PADI3 in biopsy samples of scalp skin obtained from patients with CCCA. We then directly sequenced PADI3 in an additional 42 patients (replication set) and observed genetic variants in 9 of them. A post hoc analysis of the combined data sets showed that the prevalence of PADI3 mutation was higher among patients with CCCA than in a control cohort of women of African ancestry (P = 0.002 by the chi-square test; P = 0.006 by Fisher's exact test; and after adjustment for relatedness of persons, P = 0.03 and P = 0.04, respectively). CONCLUSIONS: Mutations in PADI3, which encodes a protein that is essential to proper hair-shaft formation, were associated with CCCA. (Funded by the Ram Family Foundation and others.).

Synthetic hair extensions causing irritant contact dermatitis in patients with a history of atopy: A report of 10 cases.

BACKGROUND: We present a case series of 10, atopic, African women who developed irritant contact dermatitis (ICD) from synthetic hair extensions. METHODS: Ten consecutive African female patients who presented with a pruritic cutaneous eruption on the neck over a period of 2 years are described. Patients underwent skin patch testing using both standard and hair commercial patch test panels and samples of their own hair extensions. Hair care products were not tested. RESULTS: All 10 patients used synthetic hair extensions. A strong history of atopy was documented for all the patients and examination was significant for eczematous, lichenified plaques at the location of contact with the free end of the hair extension. Patch test results yielded no relevant reactivity and a diagnosis of ICD was made for all patients. The lesions resolved completely on removal of the hair extensions and the use of topical steroids and emollients, dependent on eczema severity. CONCLUSIONS: Artificial hair extensions should be considered as a potential irritant, resulting in ICD. Patients with a history of atopy are at risk of developing ICD from synthetic hair extensions.

Epidermal barrier function in healthy black South African infants compared with adults.

A cross-sectional observational study of 43 infants and 60 adult women was performed in South Africa to assess skin barrier (SB) function through noninvasive quantification of transepidermal water loss (TEWL) and skin surface hydration (SSH). TEWL and SSH improved with age and in anatomic locations with chronic environmental exposure in keeping with reported trends in other ethnicities.

Central Centrifugal Cicatricial Alopecia: New Insights and a Call for Action.

Central centrifugal cicatricial alopecia (CCCA) is a common and progressive form of lymphocyte predominant scarring alopecia which impacts negatively on the quality of life of those affected. It is seen more commonly in women of African descent with prevalence ranging from 2.7% to 5.7%. Current postulates include genetic inheritance, with traction inducing hairstyling practices and hair chemicals as aggravating factors. Histology reveals a perifollicular lymphocytic inflammation of the lower infundibulum, premature desquamation of the inner root sheath, and fibrous connective tissue. Treatment remains challenging and is directed at suppressing and preventing the inflammation, thus aborting scarring, with surgical intervention reserved for those who have stable disease or absence of histological inflammation. Future research with more patient numbers, focusing on the genetics of CCCA may prove useful in order to fully understand the etiology, thus providing more effective treatments for CCCA.

Central Centrifugal Cicatricial Alopecia in Children: A Case Series and Review of the Literature.

BACKGROUND/OBJECTIVES: Central centrifugal cicatricial alopecia (CCCA) is a form of scarring hair loss most commonly seen in middle-aged African and African American women. It is rarely reported in children. The objective of the current study was to document the presence of CCCA in children and to encourage physicians to recognize early signs of CCCA in children of affected adults. METHODS: Six children presented with biopsy-proven CCCA to the Department of Dermatology at Wake Forest Baptist Health and the Nelson R. Mandela School of Medicine from 2012 to 2015. Demographic characteristics, hair styling history, and family history of CCCA were noted. Examination included complete history, skin and scalp examination, photographs of the scalp, and scalp biopsies. RESULTS: Patient ages ranged from 14 to 19 years (mean age at onset 14 years). Five patients reported scalp symptoms such as tender papules, pruritus, and scaling. Four patients reported appreciable hair loss on the vertex of the scalp. One patient had used chemical relaxers and hair dyes in the past. Five patients had a known family history of CCCA. CONCLUSION: Because CCCA is not typically seen or suspected in children, it is likely to be misdiagnosed or underreported. The findings in these cases add weight to the concept that genetic susceptibility rather than hair care practices may play a significant role in causing CCCA.

Autosomal dominant inheritance of central centrifugal cicatricial alopecia in black South Africans.

BACKGROUND: Central centrifugal cicatricial alopecia (CCCA) is the commonest type of primary scarring alopecia in women of African descent. Little is currently known about the disease genetics. OBJECTIVE: We sought to investigate patterns of inheritance in CCCA and ascertain the contribution of nongenetic factors such as hair-grooming habits to the pathogenesis of the disease. METHODS: Affected individuals with at least 1 available family member were recruited from 2005 through 2012 inclusive for pedigree analysis. CCCA was diagnosed on clinical and histopathological grounds. RESULTS: Fourteen index African families with 31 immediate family members participated in the initial screening. The female to male ratio was 29:2 with an average age of 50.4 years. All patients displayed histologic features typical for CCCA. Pedigree analysis suggested an autosomal dominant mode of inheritance. Hair-grooming habits were found to markedly influence disease expression. LIMITATIONS: Small number of patients is a limitation. CONCLUSION: CCCA can be inherited in an autosomal dominant fashion, with partial penetrance and a strong modifying effect of hairstyling and gender.

Integrated sun protection advice for the South African population.

Exposure to solar ultraviolet radiation (UVR) is associated with several cutaneous adverse effects. However, to the best of our knowledge, in South Africa there are no formal guidelines on sun protection. A group of South African dermatologists and researchers convened over the course of 1 year to deliberate on integrated advice for sun protection among the multi-ethnic South African population. For people with light skin and those with genetic skin disorders (e.g., oculocutaneous albinism), sun protection was identified as critical to prevent sunburn, skin cancer, and photoaging. The evidence is less clear for people with medium and darker skin types, especially the latter, in whom melanin may confer a degree of protection against some parts of the solar spectrum. Recent studies have demonstrated that visible light can cause pigmentary changes in individuals with darker skin types in particular. Sun protection for people of all skin colors is beneficial to protect against photoaging and ocular damage. Herein sun protection advice is suggested for South Africans of all skin colors to reduce morbidity and mortality from sun exposure, particularly relating to skin cancer. Several knowledge gaps are identified as future research priorities.

Chemical analysis and in vitro†UV-protection characteristics of clays traditionally used for sun protection in South Africa.

Clays have been used in southern Africa as photoprotectants by the indigenous people. Typically, two types of clay are used: one white in colour and the other red. In this work, the two clays were identified and characterized, and their in vitro SPF values measured. The clays afford a low SPF but offer broad-spectrum protection. No cutaneous side effects from the use of these clays are known. Further consideration should be given to the potential use of clays in sunscreen preparations.

Bartonella quintana-induced vulval bacillary angiomatosis.

Bacillary angiomatosis (BA) is an increasingly reported infection, mainly in patients with acquired immunodeficiency syndrome. Different epidemiological risk factors are associated with the transmission of the causative agents, Bartonella henselae and B. quintana. Vulval BA is described rarely. Two patients presented with a vulval mass (Patient 1) and a verrucous vulval growth (Patient 2), which were diagnosed clinically as tuberculosis and carcinoma, respectively. Patient 1 also had pulmonary tuberculosis and Kaposi sarcoma. Biopsy of the vulval lesions confirmed BA, characterized by a multilobular proliferation of blood vessels that were lined by epithelioid endothelial cells. There were prominent intervascular neutrophils, karyorrhectic debris, and clumps of paravascular argyrophilic organisms. The biopsy from Patient 1 was deep dermal/subcutaneous in location and displayed foci of confluent suppuration. There was florid pseudoepitheliomatous hyperplasia in the biopsy from Patient 2. Molecular investigations confirmed intralesional B. quintana, hitherto unreported in vulval BA, as the causative agent in both biopsies. On follow-up, Patient 2 had developed additional lesions in the vulva and thigh, but all her lesions and the vulval mass (Patient 1) responded to erythromycin treatment. Patient 1 succumbed to tuberculosis. Heightened recognition of BA underpins rapid and optimal clinicopathological diagnosis, even in uncommon locations. Identification of the causative Bartonella species is important for appropriate, interventive social management.

Epidermal barrier function in human immunodeficiency virus-infected South African infants compared with uninfected.

BACKGROUND AND OBJECTIVE: Infant human immunodeficiency virus (HIV) infection remains a problem in different parts of the world. Early signs of disease manifestation often involve infant skin. This study compared the skin barrier properties of HIV infected with uninfected infants. METHODS: A cross-sectional descriptive study was undertaken with HIV positive and HIV negative unexposed African infants (6 weeks-12 months). Both had normal birth weight for age, no pre-existing dermatoses or co-infections, and received all their vaccinations timeously. The HIV positive infants were on antiretroviral (ARV) therapy. The skin barrier quality was assessed by measuring the transepidermal water loss (TEWL) and skin surface hydration (SSH) on the dorsal arm (1) and the inner forearm (2). RESULTS: Eighty-six HIV negative and 43 HIV positive African children were recruited. There were significant differences between the two groups based on the presence of HIV infection. In both sites, measured TEWL rates were significantly higher for the HIV positive children. There was a nonsignificant difference between the SSH values for site 1 and a marginally significant difference for site 2, with the average values higher in the HIV positive group. In both groups, TEWL rates and SSH values were significantly lower on site 1 compared to site 2. CONCLUSION: Differences in skin barrier properties of HIV infected and uninfected children may exist. The altered skin barrier in infected children may be one of the factors that predisposes them to various inflammatory and infectious dermatoses. Improving the skin barrier may assist in preventing these conditions.

Mucocutaneous diseases in the combined antiretroviral therapy era: prevalence and spectrum in HIV seropositive children and adolescents in Durban, South Africa.

BACKGROUND: Mucocutaneous diseases (MCD) have been commonly described among human immunodeficiency virus (HIV) infected patients before the combined antiretroviral therapy (cART) era. There is limited data on the frequency and type of MCD in the cART era in African children and adolescents. This study aimed to describe the prevalence and spectrum of MCD in South African children and adolescents seropositive for HIV on cART. METHODS: A cross-sectional study of 310 participants aged 0-19 years attending a public sector ART clinic at King Edward VIII Hospital, Durban, South Africa, was conducted. Demographic, clinical, and laboratory information was obtained from the participants and hospital records. Participants were examined. Data were collated and analyzed with SPSS version 23. RESULTS: MCD were observed in 77.4% of HIV-infected children. The prevalence was higher among males and adolescents above 16 years old (83.9%). Infectious skin disorders (44.7%) were less common than noninfectious dermatoses (55.3%). More common disorders encountered included generalized pruritus (32.6%), fungal infections (20.9%), and inflammatory (20.4%) and pigmentary (20.4%) skin disorders. Tinea capitis and pedis were the most prevalent fungal infections, while oral candidiasis (0.2%) was the least. Inflammatory skin disorders and dyschromia appeared to be more common than in the pre-cART era. CONCLUSIONS: While MCD are still common in HIV-infected children and adolescents in the cART era, the pattern and types of disorders have changed to a predominance of non-infectious dermatoses.

Systemic Therapy for Atopic Dermatitis in Older Adults and Adults With Comorbidities: A Scoping Review and International Eczema Council Survey.

BACKGROUND: Clinical trials of systemic therapies for atopic dermatitis (AD) often exclude patients based on age and comorbidities. OBJECTIVES: We conducted a scoping review of observational studies and survey of International Eczema Council (IEC) members on the treatment of AD in patients with liver disease, renal disease, viral hepatitis, HIV, or history of malignancy. METHODS: We searched MEDLINE via Ovid, Embase via Ovid, and Web of Science from inception to September 14, 2020. We mapped the available evidence on the use of cyclosporine, methotrexate, azathioprine, mycophenolate, systemic corticosteroids, and dupilumab for AD in older adults (≥65 years) and adults with the previously mentioned comorbidities. We surveyed IEC members on their preferred systemic medications for each patient population. RESULTS: We identified 25 studies on the use of systemic medications in special populations of adults with AD. Although IEC members preferred dupilumab as the first-line systemic agent across all special populations, many could not identify viable third-line systemic therapy options for some populations. CONCLUSIONS: Data on systemic therapy for AD for older adults and adults with comorbidities are limited. Although IEC members' access to systemic therapies differs geographically, expert opinion suggests that dupilumab is preferred for those patients.

The impact of basic dermatology education and training on primary healthcare providers in KwaZulu-Natal, South Africa.

BACKGROUND: Dermatological diseases are amongst the commonest reasons for consultation at primary care level. Yet, dermatology teaching in medical and nursing curricula is inconsistent and often insufficient to enable medical and nursing professionals to manage these conditions effectively. METHODS: We tested the knowledge of 100 doctors and 195 nurses who attended dermatology training sessions held in three health districts in the province of KwaZulu-Natal (KZN), South Africa, by using a quasi-experimental uncontrolled before-and-after study design. At the start of the session, participants were exposed to 15 slides representing common dermatological conditions; this was followed by a test. The participants then attended a series of short lectures followed by the same test. Pre- and post-intervention test scores were compared, and the results were analysed by professional status, health district and type of facility. RESULTS: The mean (standard deviation [SD]) pre-intervention test score was 40.6% (20.5%). Doctors scored significantly higher than nurses (p 0.0001). There were significant differences in performance by district (p 0.001) and type of facility (p 0.001). The mean (SD) post-intervention score improved to 68.7% (22.5%). CONCLUSION: Doctors and nurses working in the primary care sector appear to be insufficiently trained in the management of common dermatological conditions. A short period of in-service training resulted in an immediate, significant improvement in knowledge, although we did not study long-term retention beyond this. We recommend improved prequalification training in dermatology in medical and nursing schools and an expansion of continuing professional development as well as in-service training opportunities for primary care practitioners.

The Essential Role of Dermatology Publications in Enhancing Professional Diversity, Equity, and Inclusion.

Dermatology publications have substantial untapped potential to improve patient care for all patients and communities. The leadership role of both editors and editorial boards of these journals, books, and digital media provides an important opportunity to support professional diversity, equity, and inclusion (DEI) plus democratization of knowledge.1 Multiple events in many countries in recent times have revealed the need to work harder at DEI to ensure a level playing field for all patients, clinicians, and researchers.

The effect of isolates from Cassipourea flanaganii (Schinz) alston, a plant used as a skin lightning agent, on melanin production and tyrosinase inhibition.

ETHNOPHARMACOLOGICAL RELEVANCE: The Zulu and Xhosa people of South Africa use the stem bark of Cassipourea flanaganii as a skin-lightning cosmetic. AIM OF THE STUDY: To isolate and identify compounds responsible for the skin lightning properties from the stem bark of Cassipourea flanaganii and to evaluate their cytotoxicity towards skin cells. MATERIALS AND METHODS: Extracts from the stem bark of Cassipourea flanaganii were isolated using chromatographic methods and structures were determined using NMR, IR and MS analysis. The tyrosinase inhibitory activity and the ability to inhibit the production of melanin were determined using human primary epidermal melanocyte cells. Cytoxicity was established using the same melanocytes and a neutral red assay. RESULTS: One previously undescribed compound, ent-atis-16-en-19-al (1) along with the known ent-atis-16-en-19-oic acid (2), ent-atis-16-en-19-ol (3), ent-kaur-16-en-19-oic acid (4), ent-kaur-16-en-19-al (5), ent-manoyl oxide (6), guinesine A (7), guinesine B (8), guinesine C (9), lichenxanthone (10), 2,4-dihydroxy-3,6-dimethyl benzoic acid methyl ester (11), lynoside (12), lupeol (13), ß-amyrin (14), docosyl ferulate (15), stigmasterol, sitosterol and sitosterol-O-glucoside were isolated in this investigation. An impure fraction containing compound 3 was acetylated to obtain 19-acetoxy-ent-atis-16-ene (3a). Compounds 10 and 11 are usually isolated from lichen, hence they are possible contaminants of lichen harvested with the bark. Compounds 1, 3a, 5-14 were not significantly cytotoxic to the primary epidermal melanocyte cells (P > 0.05) when compared to the negative and positive controls (DMSO, 0.1% and hydrogen peroxide, 30 wt% in water). Inhibition of tyrosinase was significantly greater with respect to the negative control (P < 0.001) for compounds 3a, 5-8 and 9-10 at 10 µM and for compounds 5-8 and 9-10 at 100 µM. Compared to hydroquinone (the positive control) at 10 µM, the level of inhibition was comparable or to that of compounds 3a, 5, 6, and 8-10 at 10 µM, with 9 and 10 showing a greater level of inhibition. Inhibition of melanin was both concentration and time dependent for all compounds tested with higher melanin content at 24 h compared to 48 h s and at 10 mM compared to100 mM at both time points; melanin content was significantly lower for hydroquinone at both time points and concentrations. CONCLUSIONS: Compounds 1, 5-14, isolated from Cassipourea flanaganii and the derivative 3a showed low cytotoxicity. All compounds had a clear time and concentration dependent effect on melanin content which did not appear to be dependent on their inhibition of tyrosinase.

Lupus Masquerading as a Drug Reaction in HIV Infection.

An HIV-positive female on antiretroviral therapy (ART) presented with an annular eruption diagnosed as a drug reaction based on histology of a lichenoid dermatitis. She responded to oral steroid therapy and discontinuation, but progressed to develop features in keeping with cutaneous lupus. Although the antinuclear factor remained negative, her low serum complement levels, histology, and clinical features pointed to a diagnosis of subacute lupus in the setting of HIV infection. She responded well to antimalarial therapy and recommenced ART.

Outcomes of Stevens-Johnson syndrome and toxic epidermal necrolysis in HIV-infected patients when using systemic steroids and/or intravenous immunoglobulins in Pietermaritzburg, South Africa.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe life-threatening mucocutaneous reactions. There is an ongoing controversy regarding the use of systemic corticosteroids and intravenous immunoglobulin (IVIG) in SJS/TEN and their utility in HIV-infected patients. OBJECTIVES: The objective was to assess the outcome of a combination of intensive supportive care with oral corticosteroids in SJS and a combination of systemic steroids and IVIG for 3 consecutive days in HIV-infected patients with TEN. In addition, we assessed management in a general dermatology ward without implementing wound debridement. METHODS: This was a retrospective cohort study of 36 HIV-infected adults with SJS/TEN admitted to a tertiary dermatology unit between 1st January 2010 and 31st July 2011. Standard-of-care protocols included identification and elimination of the possible causative drug, meticulous wound care without debridement, initiation of oral prednisone (1 mg/kg/day) on admission for 3 consecutive days, and the addition of IVIG (1 g/kg/day) for 3 consecutive days to those with TEN. RESULTS: Of the 36 patients in the study, 32 were female. Nevirapine was the commonest drug implicated. A diagnosis of tuberculosis did not increase the case fatality rate. Complications included infections, anaemia, drug-induced hepatitis, ocular involvement, renal impairment, deep vein thrombosis, respiratory distress, Leucopenia, gastritis and hypernatremia. The overall survival rate was 97%. CONCLUSION: HIV-infected SJS and TEN patients were treated in a tertiary dermatology ward with a treatment plan of skin care, and a combination of systemic corticosteroids and IVIG respectively had a survival rate of 97%.

Prevalence of pigmentary disorders: A cross-sectional study in public hospitals in Durban, South Africa.

BACKGROUND: Pigmentary disorders are common in patients with skin of color and one of the top five most common dermatologic diagnoses in individuals of African descent. Little is known about the spectrum of pigmentary disorders in South Africa's second largest province, KwaZulu Natal. OBJECTIVE: This study aimed to determine the profile of pigmentary disorders in patients at five outpatient public hospital skin clinics in Durban, South Africa. METHODS: We collected data related to age, sex, ethnicity, and skin dyspigmentation diagnosis in a cross-sectional descriptive study of all dermatology patients at five public hospitals in Durban, South Africa between January 1 and March 31, 2015. The diagnosis was made on the basis of clinical grounds, supported by relevant laboratory investigations or histopathology where necessary. Only data relating to patients' first visit were recorded and captured using a Microsoft Excel 2007 spreadsheet. RESULTS: A total of 304 patients, the majority of whom were African women (n = 230; 75.8%), were included in the study. The three most common pigmentary diagnoses included vitiligo, postinflammatory hyperpigmentation, and melasma. CONCLUSION: Dyschromias are the third most common dermatologic diagnosis in Durban, KwaZulu-Natal province, South Africa. The most common subtypes of pigmentary disorders include (in order of frequency) vitiligo, postinflammatory hyperpigmentation, and melasma.