Assessment of the Genetic Spectrum of Uncombable Hair Syndrome in a Cohort of 107 Individuals.

Importance: Uncombable hair syndrome (UHS) is a rare hair shaft anomaly that manifests during infancy and is characterized by dry, frizzy, and wiry hair that cannot be combed flat. Only about 100 known cases have been reported so far. Objective: To elucidate the genetic spectrum of UHS. Design, Setting, and Participants: This cohort study includes 107 unrelated index patients with a suspected diagnosis of UHS and family members who were recruited worldwide from January 2013 to December 2021. Participants of all ages, races, and ethnicities were recruited at referral centers or were enrolled on their own initiative following personal contact with the authors. Genetic analyses were conducted in Germany from January 2014 to December 2021. Main Outcomes and Measures: Clinical photographs, Sanger or whole-exome sequencing and array-based genotyping of DNA extracted from blood or saliva samples, and 3-dimensional protein modeling. Descriptive statistics, such as frequency counts, were used to describe the distribution of identified pathogenic variants and genotypes. Results: The genetic characteristics of patients with UHS were established in 80 of 107 (74.8%) index patients (82 [76.6%] female) who carried biallelic pathogenic variants in PADI3, TGM3, or TCHH (ie, genes that encode functionally related hair shaft proteins). Molecular genetic findings from 11 of these 80 individuals were previously published. In 76 (71.0%) individuals, the UHS phenotype were associated with pathogenic variants in PADI3. The 2 most commonly observed PADI3 variants account for 73 (48.0%) and 57 (37.5%) of the 152 variant PADI3 alleles in total, respectively. Two individuals carried pathogenic variants in TGM3, and 2 others carried pathogenic variants in TCHH. Haplotype analyses suggested a founder effect for the 4 most commonly observed pathogenic variants in the PADI3 gene. Conclusions and Relevance: This cohort study extends and gives an overview of the genetic variant spectrum of UHS based on molecular genetic analyses of the largest worldwide collective of affected individuals, to our knowledge. Formerly, a diagnosis of UHS could only be made by physical examination of the patient and confirmed by microscopical examination of the hair shaft. The discovery of pathogenic variants in PADI3, TCHH, and TGM3 may open a new avenue for clinicians and affected individuals by introducing molecular diagnostics for UHS.

Genome-Wide MicroRNA Analysis Implicates miR-30b/d in the Etiology of Alopecia Areata.

Alopecia areata (AA) is one of the most common forms of human hair loss. Although genetic studies have implicated autoimmune processes in AA etiology, understanding of the etiopathogenesis is incomplete. Recent research has implicated microRNAs, a class of small noncoding RNAs, in diverse autoimmune diseases. To our knowledge, no study has investigated the role of microRNAs in AA. In this study, gene-based analyses were performed for microRNAs using data of the largest genome-wide association meta-analysis of AA to date. Nominally, significant P-values were obtained for 78 of the 617 investigated microRNAs. After correction for multiple testing, three of the 78 microRNAs remained significant. Of these, miR-30b/d was the most significant microRNA for the follow-up analyses, which also showed lower expression in the hair follicle of AA patients. Target gene analyses for the three microRNAs showed 42 significantly associated target genes. These included IL2RA, TNXB, and ERBB3, which had been identified as susceptibility loci in previous genome-wide association studies. Using luciferase assay, site-specific miR-30b regulation of the AA risk genes IL2RA, STX17, and TNXB was validated. This study implicates microRNAs in the pathogenesis of AA. This finding may facilitate the development of future treatment strategies.

Prevalence and associated factors of skin diseases in aged nursing home residents: a multicentre prevalence study.

OBJECTIVES: The aim of this study was to measure the prevalence of skin diseases in aged nursing home residents and to explore possible associations with demographic and medical characteristics. DESIGN: Descriptive multicentre prevalence study. SETTING AND PARTICIPANTS: The study was conducted in a random sample of ten institutional long-term care facilities in the federal state of Berlin, Germany. In total, n=223 residents were included. RESULTS: In total, 60 dermatological diseases were diagnosed. The most frequently diagnosed skin disease was xerosis cutis (99.1%, 95% CI 97.7% to 100.0%) followed by tinea ungium (62.3%, 95% CI 56.0% to 69.1%) and seborrheic keratosis (56.5%, 95% CI 50.2% to 63.0%). Only few bivariate associations have been detected between skin diseases and demographic and medical characteristics. CONCLUSION: Study results indicate that almost every resident living in residential care has at least one dermatological diagnosis. Dermatological findings range from highly prevalent xerosis and cutaneous infection up to skin cancer. Not all conditions require immediate dermatological treatment and can be managed by targeted skin care interventions. Caregivers need knowledge and diagnostic skills to make appropriate clinical decisions. It is unlikely that specialised dermatological care will be delivered widely in the growing long-term care sector. TRIAL REGISTRATION NUMBER: This study is registered at https://clinicaltrials.gov/ct2/show/NCT02216526.

The effectiveness of standardized skin care regimens on skin dryness in nursing home residents: A randomized controlled parallel-group pragmatic trial.

BACKGROUND: Aged residents of institutional long-term care facilities are at high risk for developing skin and tissue diseases. Besides various common skin problems, dry skin (xerosis cutis) is one of the most frequent skin conditions in this setting. OBJECTIVES: To investigate the effectiveness of two structured skin care regimens in comparison to routine skin care on xerosis cutis in nursing home residents. DESIGN: A multi-center, pragmatic, randomized, controlled, investigator blinded study with three parallel groups. SETTINGS: The study was conducted in a random sample of ten out of 291 institutional long-term care facilities of the federal state of Berlin, Germany. PARTICIPANTS: Long-term care residents being 65+ years affected by dry skin were included. METHODS: The residents were allocated into one of three study groups. Two interventional groups used standardized skin care regimens, consisting of a body wash and twice daily applications of leave-on products for eight weeks. The third control group performed skin care as usual. All participating residents were examined at baseline and after 4 and 8 weeks. Xerosis cutis was measured with the Overall Dry Skin score. Instrumental skin barrier measurements were performed at baseline and after 8 weeks. Diaries were used to document washing and skin care frequencies. RESULTS: In total, 133 residents were included and allocated to one of the three groups. Mean age was 83.8 (SD 8.3) years, 65.4% were female and most residents had care levels I (42.9%) or II (42.9%) according to the German Social Code Book XI. Mean Barthel score was 46.8 (SD 24.2) and mean Braden score was 17.6 (SD 3.7). Leg skin areas were drier compared to arms and trunk areas. At the end of the study the Overall Dry Skin scores in the intervention groups were lower compared to the control group. There were statistically significant improvements of skin dryness in both intervention groups compared to the control group over time. CONCLUSIONS: The results of this pragmatic trial indicate that structured skin care regimens are effective in reducing skin dryness in aged nursing home residents within eight weeks. TRIAL REGISTRATION: The study is registered at https://clinicaltrials.gov/ct2/show/NCT02216526.

Influence of sunflower seed oil or baby lotion on the skin barrier function of newborns: A pilot study.

BACKGROUND: Skin care influences skin barrier function during the first postnatal weeks. Although the use of natural oils in preterms has been investigated, there are currently no data comparing the effect of sunflower oil to an emollient on barrier development in healthy term newborns. METHODS: In a prospective, randomized clinical study, 50 healthy full-term newborns aged ≤72 h were randomly assigned to two groups: group baby lotion (L, n=22) and sunflower seed oil (SSO, n=24). The skin barrier function was evaluated in three anatomical areas (front, abdomen, and thigh) by noninvasive assessment of transepidermal water loss (TEWL), stratum corneum hydration (SCH), sebum, and skin pH at inclusion and after five weeks. RESULTS: In both groups, skin pH decreased and SCH increased statistically significantly in all measured areas at W5 compared to baseline. TEWL decreased statistically significantly on the forearm in both groups, on the upper leg in group L, and on the abdomen in group SSO. CONCLUSIONS: Both skin care regimes did not harm skin barrier function adaptation in healthy term neonates during the first five weeks of life.

Genomewide analysis of copy number variants in alopecia areata in a Central European cohort reveals association with MCHR2.

Alopecia areata (AA) is a common hair loss disorder of autoimmune aetiology, which often results in pronounced psychological distress. Understanding of the pathophysiology of AA is increasing, due in part to recent genetic findings implicating common variants at several genetic loci. To date, no study has investigated the contribution of copy number variants (CNVs) to AA, a prominent class of genomic variants involved in other autoimmune disorders. Here, we report a genomewide- and a candidate gene-focused CNV analysis performed in a cohort of 585 patients with AA and 1340 controls of Central European origin. A nominally significant association with AA was found for CNVs in the following five chromosomal regions: 4q35.2, 6q16.3, 9p23, 16p12.1 and 20p12.1. The most promising finding was a 342.5-kb associated region in 6q16.3 (duplications in 4/585 patients; 0/1340 controls). The duplications spanned the genes MCHR2 and MCHR2-AS1, implicated in melanin-concentrating hormone (MCH) signalling. These genes have not been implicated in previous studies of AA pathogenesis. However, previous research has shown that MCHR2 affects the scale colour of barfin flounder fish via the induction of melanin aggregation. AA preferentially affects pigmented hairs, and the hair of patients with AA frequently shows a change in colour when it regrows following an acute episode of AA. This might indicate a relationship between AA, pigmentation and MCH signalling. In conclusion, the present results provide suggestive evidence for the involvement of duplications in MCHR2 in AA pathogenesis.

Mutations in Three Genes Encoding Proteins Involved in Hair Shaft Formation Cause Uncombable Hair Syndrome.

Uncombable hair syndrome (UHS), also known as "spun glass hair syndrome," "pili trianguli et canaliculi," or "cheveux incoiffables" is a rare anomaly of the hair shaft that occurs in children and improves with age. UHS is characterized by dry, frizzy, spangly, and often fair hair that is resistant to being combed flat. Until now, both simplex and familial UHS-affected case subjects with autosomal-dominant as well as -recessive inheritance have been reported. However, none of these case subjects were linked to a molecular genetic cause. Here, we report the identification of UHS-causative mutations located in the three genes PADI3 (peptidylarginine deiminase 3), TGM3 (transglutaminase 3), and TCHH (trichohyalin) in a total of 11 children. All of these individuals carry homozygous or compound heterozygous mutations in one of these three genes, indicating an autosomal-recessive inheritance pattern in the majority of UHS case subjects. The two enzymes PADI3 and TGM3, responsible for posttranslational protein modifications, and their target structural protein TCHH are all involved in hair shaft formation. Elucidation of the molecular outcomes of the disease-causing mutations by cell culture experiments and tridimensional protein models demonstrated clear differences in the structural organization and activity of mutant and wild-type proteins. Scanning electron microscopy observations revealed morphological alterations in hair coat of Padi3 knockout mice. All together, these findings elucidate the molecular genetic causes of UHS and shed light on its pathophysiology and hair physiology in general.

Children with Dry Skin and Atopic Predisposition: Outcome Measurement with Validated Scores for Atopic Dermatitis.

BACKGROUND: Dry skin is a common skin condition in childhood. Few studies exist investigating the influence of daily skin care on dry skin in infants at risk of developing atopic dermatitis (AD). We aimed to assess the effect of skin care on dry skin in this special cohort using validated scores for AD and analysis of skin microtopography. METHODS: 43 children were randomized to group 1 (G1) and group 2 (G2) and 22 infants to group 3 (G3). During 16 weeks, G1 and G3 applied daily a plant-based emollient and G2 a petrolatum-based emollient. The core outcome was assessed by Severity Scoring of Atopic Dermatitis (SCORAD) and Patient-Oriented SCORing Atopic Dermatitis (PO-SCORAD). The influence on the parents' life was evaluated by a questionnaire and microtopography by Visioscan® VC 98. RESULTS: The SCORAD index declined significantly until week (W) 16 in all groups (p ≤ 0.041). The sleeplessness score analyzed by PO-SCORAD was highly reduced after W12 in G1 and after W16 in G2 (p ≤ 0.030). The influence on the parents' anxiety was reduced in G3 at W12 and W16 (p = 0.016). The Visioscan parameter scaliness strongly diminished at W4 (p ≤ 0.049) and W16 (p ≤ 0.013) in all groups. CONCLUSIONS: This trial demonstrates improved skin conditions and sleep following daily emollient application in infants and children having dry skin and being at risk of AD. Especially parents of infants showed a reduced fear that their children might develop AD. Further studies are required to investigate the preventive effect of daily emollient therapy in this special cohort evaluating the outcome measures used in this trial.

A Single-Centre, Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Investigate the Efficacy and Safety of Minoxidil Topical Foam in Frontotemporal and Vertex Androgenetic Alopecia in Men.

BACKGROUND: 5% minoxidil formulations twice daily are effective in treating vertex male androgenetic alopecia (AGA); however, efficacy and safety data in frontotemporal regions are lacking. OBJECTIVES: To assess the efficacy of 5% minoxidil topical foam (5% MTF) in the frontotemporal region of male AGA patients after 24 weeks of treatment compared to placebo treatment and to the vertex region. METHODS: Seventy males with moderate AGA applied 5% MTF or placebo foam (plaTF) twice daily for 24 weeks in frontotemporal and vertex regions. Target area non-vellus hair count (TAHC) was the primary end point. RESULTS: Frontotemporal and vertex TAHC and target area cumulative non-vellus hair width (TAHW) showed similar responses to 5% MTF with significant increases up to week 16 compared to baseline (p < 0.001). After 24 weeks of treatment, frontotemporal TAHW increased significantly in the 5% MTF group compared to the plaTF group (p = 0.017), while TAHC showed a similar non-significant increase from baseline in both regions. At 24 weeks, 5% MTF users rated a significant improvement in scalp coverage for the frontotemporal (p = 0.016) and vertex areas (p = 0.027). CONCLUSIONS: 5% MTF twice a day promotes hair density and width in both frontotemporal and vertex regions in men with moderate stages of AGA. © 2015 S. Karger AG, Basel.

Effect of diaper cream and wet wipes on skin barrier properties in infants: a prospective randomized controlled trial.

The effect of different diaper care procedures on skin barrier function in infants has been minimally investigated and may be assessed using objective methods. In a single-center, prospective trial, 89 healthy 9-month-old infants (±8 wks) were randomly assigned to three diaper care regimens: group I used water-moistened washcloths at diaper changes (n = 30), group II additionally applied diaper cream twice daily (n = 28), and group III used wet wipes and diaper cream twice daily (n = 31). Transepidermal water loss (TEWL), skin hydration (SCH), skin pH, interleukin 1α (IL-1α) levels, and microbiologic colonization were measured in diapered skin (upper outer quadrant of the buttocks), nondiapered skin (upper leg), and if diaper dermatitis (DD) occurred, using the most affected skin area at day 1 and weeks 4 and 8. Skin condition was assessed utilizing a neonatal skin condition score and diaper rash grade. On diapered skin, SCH decreased in groups II and III, whereas TEWL values were reduced in group II only. Skin pH increased in groups II and III. In general, SCH, skin pH, and IL-1α levels were higher in healthy diapered skin than in nondiapered skin. The incidence and course of DD was comparable in all groups. Areas with DD had greater TEWL and skin pH than unaffected skin areas. Infants who received diaper cream had lower SCH and TEWL and higher pH levels in the diapered area than on nondiapered skin. No correlation with the occurrence of DD was found.

Influence of sunflower seed oil on the skin barrier function of preterm infants: a randomized controlled trial.

BACKGROUND: Inadequate skin care may increase morbidity in preterm infants. Skin care practices that support skin maturation have barely been investigated. OBJECTIVES: To investigate the effect of sunflower seed oil (SSO) on skin barrier development in low-birth-weight premature infants. METHODS: 22 preterm infants (<48 h after birth, 1,500-2,500 g) were randomized into group C (control) and group SSO, receiving daily SSO application during the first 10 postnatal days, followed by no intervention. Transepidermal water loss (TEWL), stratum corneum hydration (SCH), skin pH and sebum were measured <48 h after birth and on postnatal days 5, 11 and 21 on the forehead, abdomen, thigh and buttock. RESULTS: Skin pH decreased, while sebum remained stable in both groups. In group C, TEWL remained stable; in group SSO, TEWL increased significantly on the abdomen, leg and buttock until day 11, followed by a decrease after SSO application had been stopped. Abdomen SCH remained stable in group C, but continuously decreased in group SSO until day 21. CONCLUSION: SSO application may retard postnatal skin barrier maturation in preterm infants.

Prevention of diaper dermatitis in infants--a literature review.

Diaper dermatitis (DD) is one of the most common skin conditions in neonates and infants, with a peak between the ages of 9 and 12 months. Appropriate skin care practices that support skin barrier function and protect the buttocks skin from urine and feces are supposed to be effective in the prevention of DD. Despite many recommendations for parents and caregivers on proper diaper skin care, there is no up-to-date synthesis of the available evidence to develop recommendations for DD prevention practice. Therefore we performed a systematic literature review on the efficacy of nonmedical skin care practices on the diapered area of healthy, full-term infants ages 0 to 24 months. We identified 13 studies covering skin care practices such as cleansing, bathing, and application of topical products. DD prevalence and incidence and physiologic skin parameters were used as efficacy parameters. The results of this review indicate that cleansing of the diaper area using baby wipes or water and a washcloth have comparable effects on diapered skin. Bathing with a liquid baby cleanser twice weekly seems comparable with water alone. The application of ointments containing zinc oxide or petrolatum with or without vitamin A seems to have comparable effects on DD severity. There seems to be no information on whether single skin care practices such as cleansing, bathing, and application of topical preparations can prevent DD. High-quality randomized clinical trials are needed to show the effectiveness of skin care practices for controlling and preventing DD.

Children with dry skin and atopic predisposition: daily use of emollients in a participant-blinded, randomized, prospective trial.

BACKGROUND: Dry skin reflects a skin barrier defect which can lead to atopic dermatitis. Little is known about the distinct effects of emollient use in children with dry skin and atopic predisposition. OBJECTIVES: We investigated the effects of daily application of pressed ice plant juice (PIPJ)-based emollients and petrolatum-based emollients. METHODS: Children aged 2-6 years with dry skin and atopic predisposition were randomized into 2 groups: group 1 received emollients containing PIPJ and natural lipids, while group 2 received petrolatum-based emollients. Skin condition and biophysical properties of the skin barrier were assessed at inclusion and weeks 4, 12 and 16. RESULTS: Skin condition improved significantly in all children. Comparing the groups, children treated with emollients containing PIPJ showed significantly higher stratum corneum hydration values and significantly lower transepidermal water loss values at week 16 on the forearm and forehead. A significant decrease in skin pH was noted in group 2 on the forearm and forehead; group 1 showed a stable course. CONCLUSION: Early intervention with emollients in children with dry skin condition and atopic predisposition may improve their skin condition during daily emollient application. PIPJ-based formulations may be helpful to maintain skin barrier integrity.

Skin barrier function in infancy: a systematic review.

The skin of neonates and infants exhibits distinct anatomical and functional properties that might be clinically reflected by its characteristic susceptibility to skin barrier disruption. In this systematic review, we aimed to characterize skin barrier maturation as reflected by transepidermal water loss (TEWL) and skin surface pH during the first 2 years of life. We systematically searched MEDLINE and EMBASE via OVID from 1975 to 2013 to identify primary studies reporting TEWL and/or skin surface pH values in healthy full-term infants aged 0-24 months without any cutaneous diseases. After full text assessment, 36 studies reporting n = 8,483 TEWL measurements for 26 anatomical areas and n = 6,437 skin surface pH measurements for 14 anatomical areas were included. The mean age of the subjects ranged from 1.4 h to 1.2 years. The lowest pH of 4.63 was identified on the forehead at the age of 25.6 weeks, whereas the highest of 7.31 was on the volar forearm at 0.0 weeks. The lowest TEWL value of 3.1 g/m(2)/h was reported for the back at 0.6 weeks and the highest of 43.1 g/m(2)/h for the upper leg at 58.7 weeks. The skin surface pH reveals a steep decline during the first postnatal week, succeeded by a further gradual site-specific acidification process during the first month. A competent permeability barrier in most anatomical areas is indicated by TEWL, which does not exhibit a time-dependent development during the first 2 years of life.

Investigation of four novel male androgenetic alopecia susceptibility loci: no association with female pattern hair loss.

Female pattern hair loss (FPHL) is a common hair loss disorder in women and has a complex mode of inheritance. The etiopathogenesis of FPHL is largely unknown; however, it is hypothesized that FPHL and male pattern baldness [androgenetic alopecia (AGA)] share common genetic susceptibility alleles. Our recent findings indicate that the major AGA locus, an X-chromosome region containing the androgen receptor and the ectodysplasin A2 receptor (EDA2R) genes, may represent a common genetic factor underlying both early-onset FPHL and AGA. This gives further support for the widespread assumption of shared susceptibility loci for FPHL and AGA. However, we could not demonstrate association of further AGA risk loci, including 20p11, 1p36.22, 2q37.3, 7p21.1, 7q11.22, 17q21.31, and 18q21.1, with FPHL. Interestingly, a recent study identified four novel AGA risk loci in chromosomal regions 2q35, 3q25.1, 5q33.3, and 12p12.1. In particular, the 2q35 locus and its gene WNT10A point to an as-yet unknown involvement of the WNT signaling pathway in AGA. We hypothesized that the novel loci and thus also the WNT signaling may have a role in the etiopathogenesis of FPHL and therefore examined the role of these novel AGA risk loci in our FPHL samples comprising 440 German and 145 UK affected patients, 500 German unselected controls (blood donors), and 179 UK supercontrols. Patients and controls were genotyped for the top two single nucleotide polymorphisms at each of the four AGA loci. However, none of the genotyped variants displayed any significant association. In conclusion, the results of this study provide no support for the hypothesis that the novel AGA loci influence susceptibility to FPHL.

Do repeated skin barrier measurements influence each other's results? An explorative study.

BACKGROUND: Biophysical skin measurement techniques are widely used to quantify the skin barrier function. In clinical research usually several parameters are subsequently measured in the same skin areas. In this study, possible interfering effects of subsequent measurement procedures on transepidermal water loss (TEWL), stratum corneum hydration (SCH) and skin surface pH were investigated. METHODS: An exploratory study was conducted. Twelve young (mean age 32.9 ± 7.2 years) and 12 elderly (mean age 68.3 ± 2.5 years) subjects without any skin diseases were enrolled. The parameters TEWL, skin surface pH, SCH, sebum content, and surface evaluation of living skin were obtained successively in pairs from 4 contralateral volar forearm skin areas. RESULTS: SCH and skin surface pH seemed to be unaffected by previous measurement procedures. TEWL was systematically increased after pH and systematically decreased after stratum corneum measurements. CONCLUSIONS: Measurements per se might interact with the skin, thus changing its characteristics. If several skin barrier function parameters need to be assessed subsequently in the same skin areas, we recommend that TEWL should be measured first followed by all others.