Short anagen hair syndrome: association with mono- and biallelic variants in WNT10A and a genetic overlap with male pattern hair loss.

BACKGROUND: Short anagen hair (SAH) is a rare paediatric hair disorder characterized by a short anagen phase, an inability to grow long scalp hair and a negative psychological impact. The genetic basis of SAH is currently unknown. OBJECTIVES: To perform molecular genetic investigations in 48 individuals with a clinical phenotype suggestive of SAH to identify, if any, the genetic basis of this condition. METHODS: Exome sequencing was performed in 27 patients diagnosed with SAH or with a complaint of short, nongrowing hair. The cohort was screened for variants with a minor allele frequency (MAF) < 5% in the general population and a Combined Annotation Dependent Depletion (CADD) score > 15, to identify genes whose variants were enriched in this cohort. Sanger sequencing was used for variant validation and screening of 21 additional individuals with the same clinical diagnosis and their relatives. Genetic association testing of SAH-related variants for male pattern hair loss (MPHL) was performed using UK Biobank data. RESULTS: Analyses revealed that 20 individuals (42%) carried mono- or biallelic pathogenic variants in WNT10A. Rare WNT10A variants are associated with a phenotypic spectrum ranging from no clinical signs to severe ectodermal dysplasia. A significant association was found between WNT10A and SAH, and this was mostly observed in individuals with light-coloured hair and regression of the frontoparietal hairline. Notably, the most frequent variant in the cohort [c.682T>A;p.(Phe228Ile)] was in linkage disequilibrium with four common WNT10A variants, all of which have a known association with MPHL. Using UK Biobank data, our analyses showed that c.682T>A;p.(Phe228Ile) and one other variant identified in the SAH cohort are also associated with MPHL, and partially explain the known associations between WNT10A and MPHL. CONCLUSIONS: Our results suggest that WNT10A is associated with SAH and that SAH has a genetic overlap with the common phenotype MPHL. The presumed shared biologic effect of WNT10A variants in SAH and MPHL is a shortening of the anagen phase. Other factors, such as modifier genes and sex, may also play a role in the clinical manifestation of hair phenotypes associated with the WNT10A locus.

Huriez syndrome: Additional pathogenic variants supporting allelism to SMARCAD syndrome.

Huriez syndrome (HRZ, OMIM181600) is a rare genodermatosis characterized by scleroatrophic hands and feet, hypoplastic nails, palmoplantar keratoderma, and predisposition to cutaneous squamous cell carcinoma (cSCC). We report herein three HRZ families from Croatia, the Netherlands, and Germany. Deep sequencing followed by Sanger validation, confirmed the presence of germline causative SMARCAD1 heterozygous pathogenic variants. All seven HRZ patients displayed hypohidrosis, adermatoglyphia, and one patient developed cSCC at 32 years of age. Two novel monoallelic germline mutations were identified which are predicted to disrupt the first exon-intron boundary of the skin-specific SMARCAD1 isoform. On the basis of phenotypic and genotypic convergence with Adermatoglyphia (OMIM136000) and Basan syndrome (OMIM129200), our results lend credence to the notion that these three Mendelian disorders are allelic. We propose adding Huriez syndrome to the previously suggested SMARCAD syndrome designation, which was originally invoked to describe the spectrum of monogenic disorders between Adermatoglyphia and Basan syndrome.

Recurrent Alterations in the MAPK pathway in Sporadic Pyogenic Granuloma of Childhood.

Pyogenic granuloma is one of the most common vascular tumours. The cause of pyogenic granuloma was previously thought to be an inflammatory reaction with consecutive stimulation of endothelial cell proliferation. However, recent studies suggest that pyogenic granuloma may be driven by constitutive activation of the mitogen-activated protein kinase pathway. The aim of this study was to investigate the molecular profile of sporadic pyogenic granuloma of childhood, using a systematic approach scrutinizing potential aberrations within different oncogenic pathways. Within a retrospective setting pyogenic granuloma of 15 patients was analysed by targeted next generation sequencing using the Oncomine Focus Assay, which includes genes of key tumorigenic signalling pathways. Activating mutations were found in 4 out of 15 cases (27%). Two HRAS hotspot mutations (p.Gly13Arg, p.Ala59Thr), 1 BRAF (p.Val600Glu) mutation and a novel, previously not reported, MAP2K1 hotspot mutation (p.Glu203Lys) were identified. It is notable that all of these genes are involved in constitutive mitogen- activated protein kinase signalling. This study increases the range of underlying genetic alterations in pyogenic granuloma by identifying novel oncogenic mutations in crucial mitogen-activated protein kinase pathway genes. The results provide supporting evidence that activated mitogen-activated protein kinase signalling is a key driver in the pathogenesis of pyogenic granuloma, which might be exploited by targeted treatment approaches for selected cases.

[Wound therapy with cold atmospheric plasma in severe recessive dystrophic epidermolysis bullosa : A pilot study]. / Wundtherapie mit kaltem Plasma bei Epidermolysis bullosa dystrophica : Eine Pilotuntersuchung.

BACKGROUND: Cold atmospheric pressure plasma (CAP) has antimicrobial and wound-healing properties. Patients affected by severe autosomal recessive dystrophic epidermolysis bullosa (RDEB) suffer from widespread, difficult-to-treat wounds, which require complex wound management. OBJECTIVE: In a pilot project, we investigated over a period of 5 months the response and tolerability of a CAP wound therapy in a 21-year-old and a 28-year-old female patient with severe generalized RDEB and following cutaneous squamous cell cancer (cSSC) in the older patient. MATERIALS AND METHODS: In both patients, diagnosis of RDEB was confirmed by molecular genetics. Individual- and patient-specific wound therapy was continued during the study period, and additionally CAP therapy with a dielectric barrier discharge (DBE) device was initiated. CAP treatment was performed for 90 s per wound and could be applied every day or every other day. Clinical evaluation included photographic documentation and regular interviews of patients and parents. RESULTS: CAP-treated wounds largely demonstrated improved wound healing and signs of a reduced bacterial contamination. Furthermore, CAP proved to prevent wound chronification. When applied on a polyester mesh, it was well-tolerated on most body sites. CONCLUSION: The introduction of CAP could improve the wound management of EB patients and should be evaluated in clinical studies. The effect of CAP on cSSC development should be particularly studied.

Porokeratosis Plantaris, Palmaris et Disseminata Caused by Con- genital Pathogenic Variants in the MVD Gene and Loss of Hetero-zygosity in Affected Skin.

Porokeratoses are a heterogeneous group of keratinization disorders. For linear porokeratosis and disseminated superficial actinic porokeratosis, a heterozygous pathogenic germline variant in a mevalonate pathway gene and a postzygotic second hit mutation present in affected skin have been shown to be the patho-genetic mechanism for the development of the lesions. However, the molecular mechanism leading to development of porokeratosis plantaris, palmaris et disseminata is not known. This study analysed a cohort of 4 patients with linear porokeratosis and 3 patients with porokeratosis plantaris, palmaris et disseminata, and performed mutation analyses of DNA extracted from blood samples and skin biopsies. All of the study patients carried the heterozygous germline variant c.70+5G>A in the MVD gene. Loss of heterozygosity due to a second hit mutation was found in affected skin of 3 patients with linear porokeratosis and 2 patients with porokeratosis plantaris, palmaris et disseminata. These results suggest that porokeratosis plantaris, palmaris et disseminata shares the same pathogenetic mechanism as other porokeratosis subtypes and belongs to the phenotypic spectrum of MVD-associated porokeratosis.

Darier and Hailey-Hailey disease: update 2021.

The autosomal-dominant genodermatoses Darier disease and Hailey-Hailey disease present special challenges to dermatologists. Despite their similar pathogenesis featuring impaired adhesion of suprabasal keratinocytes as a result of defective ATPases in epidermal calcium channels, the two diseases differ considerably in clinical presentation and therapeutic options. Darier disease is characterized by reddish brown, keratotic papules in seborrheic and intertriginous areas, which may coalesce into extensive lesions. Individuals affected with Hailey-Hailey disease primarily develop intertriginous papulovesicles and small blisters, which often evolve into erythematous plaques with erosions and painful fissures. Quality of life is significantly reduced because of complaints (itch, burning sensation, pain), body malodor and chronicity. Therapeutic options remain limited. Antiseptics and intermittent topical corticosteroids are a cornerstone of therapy, and systemic anti-infective treatment is often required in cases of superinfection. Ablative surgical interventions such as dermabrasion and CO2 laser surgery can lead to long-term remissions in intertriginous Hailey-Hailey disease, while temporary relief may also be achieved by intralesional injections of botulinum toxin. Of the systemic medications available for Darier disease, acitretin, which is approved for this purpose, has the best supporting evidence. The efficacy of immunosuppressants and immune modulators is inconsistent. Low-dose naltrexone produces more satisfactory results in Hailey-Hailey than Darier disease. The present CME article summarizes current knowledge of the two dermatoses, taking recent developments into account.

Long-standing morphea and the risk of squamous cell carcinoma of the skin.

Scleroderma is a heterogeneous group of fibrosing connective tissue disorders of unknown etiology. Morphea is a localized form of scleroderma that occasionally leads to chronic erosions and ulcerations of the skin. Fibrosis, inflammation and chronic ulcerations may eventually promote skin neoplasms; morphea is therefore a rare but established risk factor for cutaneous squamous cell carcinoma (cSCC). We present a review of 16 scleroderma patients: 15 case reports from the literature (identified by a PubMed search) and one case from our clinic of a patient who had developed cSCC, and we discuss potential underlying mechanisms. Statistical analysis revealed that the lower extremities were the body site most commonly affected by cSCC in these scleroderma patients. The mean time interval between the onset of scleroderma and the development of cSCC was ten to twenty years. In patients with morphea, we recommend checking for skin tumors during follow-up examinations as well as a careful risk-benefit analysis when considering the application of immunosuppressants or phototherapy in view of their potential carcinogenic side effects.

Genetical, clinical, and functional analysis of a large international cohort of patients with autosomal recessive congenital ichthyosis due to mutations in NIPAL4.

Autosomal recessive congenital ichthyosis (ARCI) belongs to a heterogeneous group of disorders of keratinization. To date, 10 genes have been identified to be causative for ARCI. NIPAL4 (Nipa-Like Domain-Containing 4) is the second most commonly mutated gene in ARCI. In this study, we present a large cohort of 101 families affected with ARCI carrying mutations in NIPAL4. We identified 16 novel mutations and increase the total number of pathogenic mutations in NIPAL4 to 34. Ultrastructural analysis of biopsies from six patients showed morphological abnormalities consistent with an ARCI EM type III. One patient with a homozygous splice site mutation, which leads to a loss of NIPAL4 mRNA, showed additional ultrastructural aberrations together with a more severe clinical phenotype. Our study gives insights into the frequency of mutations, a potential hot spot for mutations, and genotype-phenotype correlations.

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.

Zinc and skin: an update.

The essential trace element zinc (Zn) plays a key role in the development, differentiation and growth of various human tissues. Zinc homeostasis is primarily regulated by two zinc transporter families (solute-linked carrier families, SLC). Disturbances in zinc metabolism may give rise to disorders that typically manifest themselves on the skin. An autosomal recessive zinc deficiency disorder, acrodermatitis enteropathica is caused by a mutation in the gene coding for the ZIP4 transporter. Due to intestinal malabsorption, affected infants develop clinical signs and symptoms shortly after weaning. Acquired zinc deficiency is a rare but underdiagnosed disorder associated with various etiologies and variable clinical manifestations. Depending on the patient's age, a multitude of causes have to be considered. Given the characteristic periorificial and acral lesions, the clinical diagnosis is usually made by dermatologists. Laboratory confirmation includes measurement of plasma zinc levels and - as a supplementary measure - zinc-dependent enzymes such as alkaline phosphatase. Oral zinc replacement therapy frequently leads to clinical remission within a few days. Depending on the cause, disease management should include cooperation with pediatricians and gastroenterologists in order to guarantee optimal patient care.

Increase of scabies in Germany and development of resistant mites? Evidence and consequences.

Scabies has been diagnosed surprisingly frequently in Germany in recent years, and the use of acaricides has risen markedly. Present figures indicate an increase in the prevalence/incidence of scabies, but do not prove or quantify it for the following reasons: (a) scabies is not a notifiable disease in Germany; (b) the diagnosis is not always confirmed lege artis by means of light microscopy or dermatoscopy (which may lead to a comparatively high proportion of false­positive diagnoses due to the low overall prevalence of scabies); (c) repeated treatments of the same patient and treatment of contact persons are included in the total number of prescriptions. Therefore, there are no valid data on disease occurrence, either in the current situation or from previous periods. Observations of ineffective treatment with permethrin have led to speculations that Sarcoptes mites are developing resistance to this drug. However, there is little evidence for this assumption. We discuss risk groups (children, elderly people in need of care, migrant health personnel in nursing institutions, refugees, sexually active young adults) and evaluate their possible contribution, albeit in the absence of evidence. None of the groups would be solely responsible for an increased frequency. We have compiled recommendations on how the management of scabies could be improved, and present a way of differentiating permethrin resistance from application errors and/or lack of compliance. The goal is to solve the epidemiological and parasitological questions mentioned above.

S2k guidelines for the treatment of psoriasis in children and adolescents - Short version part 1.

The present guidelines are aimed at residents and board-certified physicians in the fields of dermatology, pediatrics, pediatric dermatology and pediatric rheumatology as well as policymakers and insurance funds. They were developed by dermatologists and pediatric dermatologists in collaboration with pediatric rheumatologists using a formal consensus process (S2k). The guidelines highlight topics such as disease severity, quality of life, treatment goals as well as problems associated with off-label drug therapy in children. Trigger factors and diagnostic aspects are discussed. The primary focus is on the various topical, systemic and UV-based treatment options available and includes recommendations for use and treatment algorithms. Other aspects addressed herein include vaccinations in children and adolescents with psoriasis as well as various disease subtypes such as guttate psoriasis, diaper psoriasis, pustular psoriasis and psoriatic arthritis. Finally, we also provide recommendations for imaging studies and the diagnostic workup to rule out tuberculosis prior to initiating systemic treatment. Note: This article constitutes part 1 of the Sk2 guidelines for the treatment of psoriasis in children and adolescents. Part 2 will be published in the next issue. It contains chapters on UV therapy, systemic treatment, tonsillectomy and antibiotics, vaccinations, guttate psoriasis, psoriatic arthritis, complementary medicine, as well as imaging studies and diagnostic workup to rule out tuberculosis prior to systemic treatment.

S2k guidelines for the treatment of psoriasis in children and adolescents - Short version part 2.

The present guidelines are aimed at residents and board-certified physicians in the fields of dermatology, pediatrics, pediatric dermatology and pediatric rheumatology as well as policymakers and insurance funds. They were developed by dermatologists and pediatric dermatologists in collaboration with pediatric rheumatologists using a formal consensus process (S2k). The guidelines highlight topics such as disease severity, quality of life, treatment goals as well as problems associated with off-label drug therapy in children. Trigger factors and diagnostic aspects are discussed. The primary focus is on the various topical, systemic and UV-based treatment options available and includes recommendations for use and treatment algorithms. Other aspects addressed herein include vaccinations in children and adolescents with psoriasis as well as various disease subtypes such as guttate psoriasis, diaper psoriasis, pustular psoriasis and psoriatic arthritis. Finally, we also provide recommendations for imaging studies and the diagnostic workup to rule out tuberculosis prior to initiating systemic treatment. Note: This article constitutes part 2 of the Sk2 guidelines for the treatment of psoriasis in children and adolescents. Part 1 was published in last month's issue. It contained introductory remarks and addressed aspects of diagnosis and topical treatment.

[Scabies in old age]. / Skabies im Alter.

Scabies is a frequent ectoparasitosis the prevalence of which also seems to increase in older patients. Correct and timely diagnosis of scabies in older age is hampered by atypical clinical manifestations, the potential lack of pruritus and a variety of differential diagnoses. Scabies crustosa, a highly contagious subtype due to the presence of innumerable mites, is of particular importance. It predominantly occurs in immunosuppressed patients as well as in mentally or physically disabled persons and is the most important source of scabies outbreaks in residential and nursing homes. This article reviews the diagnosis and treatment of scabies and the strategies for managing outbreaks with special reference to older patients.

Becker Naevus Syndrome of the Lower Body: One Case and Review of the Literature.

Becker naevus syndrome is a rare epidermal naevus syndrome defined by the co-occurrence of a Becker naevus with various cutaneous, muscular and skeletal anomalies. In the majority of cases, abnormalities exclusively consist of ipsilateral hypoplasia of the breast, areola and/or nipple in addition to the naevus. Here, we report on a 42-year-old woman with an extensive Becker naevus reaching from the left buttock to the left calf verified on histological examination. In addition, there was marked hypoplasia of the fatty tissue of the left thigh confirmed by magnetic resonance imaging in contrast to hyperplasia of the fatty tissue of the left gluteal area. Underlying muscles and bones were not affected. There was no difference in leg lengths. In addition, we review and discuss the features of Becker naevus syndrome with emphasis on 10 reported cases with involvement of the lower body.

S1 guidelines for the diagnosis and treatment of ichthyoses - update.

Ichthyoses are a group of rare genetic skin disorders that pose numerous clinical challenges, in particular with respect to the correct diagnosis and appropriate management. The present update of the German ichthyosis guidelines addresses recent diagnostic advances that have resulted in the Sorèze consensus classification. In this context, we provide an updated diagnostic algorithm, taking into account clinical features as well as the molecular genetic basis of these disorders. Moreover, we highlight current therapeutic approaches such as psychosocial support, balneotherapy, mechanical scale removal, topical therapy, and systemic retinoid therapy. General aspects such as the indication for physical therapy, ergotherapy, or genetic counseling are also discussed. The present update was consented by an interdisciplinary consensus conference that included dermatologists, pediatricians, human geneticists, and natural scientists as well as representatives of the German patient support organization Selbsthilfe Ichthyose e. V.

Disease Manifestation and Inflammatory Activity as Modulators of Th17/Treg Balance and RORC/FoxP3 Methylation in Systemic Sclerosis.

BACKGROUND: There is much evidence that T cells are strongly involved in the pathogenesis of localized and systemic forms of scleroderma (SSc). A dysbalance between FoxP3+ regulatory CD4+ T cells (Tregs) and inflammatory T-helper (Th) 17 cells has been suggested. METHODS: The study aimed (1) to investigate the phenotypical and functional characteristics of Th17 and Tregs in SSc patients depending on disease manifestation (limited vs. diffuse cutaneous SSc, dcSSc) and activity, and (2) the transcriptional level and methylation status of Th17- and Treg-specific transcription factors. RESULTS: There was a concurrent accumulation of circulating peripheral IL-17-producing CCR6+ Th cells and FoxP3+ Tregs in patients with dcSSc. At the transcriptional level, Th17- and Treg-associated transcription factors were elevated in SSc. A strong association with high circulating Th17 and Tregs was seen with early, active, and severe disease presentation. However, a diminished suppressive function on autologous lymphocytes was found in SSc-derived Tregs. Significant relative hypermethylation was seen at the gene level for RORC1 and RORC2 in SSc, particularly in patients with high inflammatory activity. CONCLUSIONS: Besides the high transcriptional activity of T cells, attributed to Treg or Th17 phenotype, in active SSc disease, Tregs may be insufficient to produce high amounts of IL-10 or to control proliferative activity of effector T cells in SSc. Our results suggest a high plasticity of Tregs strongly associated with the Th17 phenotype. Future directions may focus on enhancing Treg functions and stabilization of the Treg phenotype.

Botulinum Toxin Treatment of Autonomic Disorders: Focal Hyperhidrosis and Sialorrhea.

Primary focal hyperhidrosis is a common autonomic disorder that significantly impacts quality of life. It is characterized by excessive sweating confined to circumscribed areas, such as the axillae, palms, soles, and face. Less frequent types of focal hyperhidrosis secondary to underlying causes include gustatory sweating in Frey's syndrome and compensatory sweating in Ross' syndrome and after sympathectomy. Approval of onabotulinumtoxinA for severe primary axillary hyperhidrosis in 2004 has revolutionized the treatment of this indication. Meanwhile further type A botulinum neurotoxins like abobotulinumtoxinA and incobotulinumtoxinA, as well as the type B botulinum neurotoxin rimabotulinumtoxinB are successfully used off-label for axillary and various other types of focal hyperhidrosis. For unexplained reasons, the duration of effect differs considerably at different sites. Beside hyperhidrosis, botulinum neurotoxin is also highly valued for the treatment of sialorrhea affecting patients with Parkinson's disease, cerebral palsy, amyotrophic lateral sclerosis, motor neuron disease, and other neurologic conditions. With correct dosing and application, side effects are manageable and transient.

S1 guidelines on the diagnosis and treatment of scabies - short version.

The goals of this German guideline are the improvement of diagnosis and therapy of scabies, the implementation of a coordinated action in outbreaks of scabies, and the control of this infestation in large migration or refugee flows.Sarcoptes scabiei var. hominis is transmitted by direct skin-to-skin contact of sufficient duration. The infectivity of female mites when removed from patients does not exceed 48 hours at room temperature (21°C) and relative humidity of 40-80%. The risk of infection rises proportionally to the number of mites on the skin and is particularly high in crusted scabies. As elderly persons tend to develop crusted scabies due to disease- or medication-related immunosuppression, there is an increased risk for outbreaks of scabies at nursing homes and extended-care facilities. The guideline contains detailed recommendations for management of such outbreaks. In refugees the prevalence of scabies is higher than in the general population in Germany, but the risk for outbreaks is not high. Scabies infestation should be considered when a recent onset of itching is associated with eczema and presence of burrows or comma-like papules at predilection sites. It is confirmed by dermatoscopic detection of mites or by microscopic identification of mites, mite eggs or fecal matter (scybala) from skin scrapings.The treatment of choice for common scabies is topical permethrin 5% cream applied for 8-12 hours. Permethrin can be considered for off-label use also in infants of less than 3 months of age and pregnant women. For this group crotamiton is another option, which, besides benzyl benzoate, presents a good second line therapy for the other indications. Indications for oral ivermectin, which has just been licensed in Germany, include patients with immunosuppression, severe dermatitis, and low adherence.Crusted scabies is preferentially treated by a combination of topical permethrin and oral ivermectin. Affected patients should be isolated, and all contact persons should be treated. The guideline contains lists for additional measures, including possible treatment of contact persons, clothes, linen and other possibly infested articles.