A X-linked nonsense APOO/MIC26 variant causes a lethal mitochondrial disease with progeria-like phenotypes.

APOO/MIC26 is a subunit of the MICOS complex required for mitochondrial cristae morphology and function. Here, we report a novel variant of the APOO/MIC26 gene that causes a severe mitochondrial disease with overall progeria-like phenotypes in two patients. Both patients developed partial agenesis of the corpus callosum, bilateral congenital cataract, hypothyroidism, and severe immune deficiencies. The patients died at an early age of 12 or 18 months. Exome sequencing revealed a mutation (NM_024122.5): c.532G>T (p.E178*) in the APOO/MIC26 gene that causes a nonsense mutation leading to the loss of 20 C-terminal amino acids. This mutation resulted in a highly unstable and degradation prone MIC26 protein, yet the remaining minute amounts of mutant MIC26 correctly localized to mitochondria and interacted physically with other MICOS subunits. MIC26 KO cells expressing MIC26 harboring the respective APOO/MIC26 mutation showed mitochondria with perturbed cristae architecture and fragmented morphology resembling MIC26 KO cells. We conclude that the novel mutation found in the APOO/MIC26 gene is a loss-of-function mutation impairing mitochondrial morphology and cristae morphogenesis.

Red scrotum syndrome: An update on clinicopathologic features, pathogenesis, diagnosis, and management.

The genital skin may be affected by a variety of dermatoses, be it inflammatory, infectious, malignant, idiopathic, or others. The red scrotum syndrome is characterized by persistent erythema of the scrotum associated with a burning sensation, hyperalgesia, and itching. Its cause is unknown, but proposed mechanisms include rebound vasodilation after prolonged topical corticosteroid use and localized erythromelalgia. The condition is chronic, and treatment is often difficult. Here we review the etiology, the physical and histopathologic findings, and the management of this condition. We also describe related conditions such as red scalp syndrome, red ear syndrome, and red vulva syndrome. Finally, we summarize the different cases reported in the literature and discuss the features that help in the differentiation of red scrotum syndrome from its mimickers.

A Piez-o the jigsaw: the Piezo1 channel in skin biology.

The skin is the largest organ covering the entirety of the body. Its role as a physical barrier to the outside world as well as its endocrinological and immunological functions subject it to continuous internal and external mechanical forces. Thus, mechanotransduction is of the utmost importance for the skin in order to process and leverage mechanical input for its various functions. Piezo1 is a mechanosensitive ion channel that is a primary mediator of mechanotransduction and is highly expressed in the skin. The discovery of Piezo1 earned a Nobel Prize, and has had a profound impact on our understanding of physiology and pathology including paramount contributions in cutaneous biology. This review provides insight into the roles of Piezo1 in the development, physiology and pathology of the skin with a special emphasis on the molecular pathways through which it instigates these various roles. In epidermal homeostasis, Piezo1 mediates cell extrusion in conditions of overcrowding and division in conditions of low cellular density. Piezo1 also aids in orchestrating mechanosensation, DNA protection from mechanical stress and the various components of wound healing. Conversely, Piezo1 is pathologically implicated in melanoma progression, wound healing delay, cutaneous scarring and hair loss. By shedding light on these functions, we aim to unravel the potential diagnostic and therapeutic value Piezo1 might hold in the field of Dermatology.

Genodermatoses with behavioural sequelae.

Children with genodermatoses are at an increased risk of developing behavioural disorders which may impart lasting damage on the individual and their family members. As such, early recognition of childhood mental health disorders via meticulous history taking, thorough physical examination, and disorder-specific testing is of paramount importance for timely and effective intervention. If carried out properly, prompt psychiatric screening and intervention can effectively mitigate, prevent or even reverse, the psychiatric sequela in question. To that end, this review aims to inform the concerned physician of the manifestations and treatment strategies relevant to the psychological sequelae of genodermatoses.

Malar rash in a young child with neurodevelopmental delay: a quiz.

-A 14-month-old boy born to consanguineous parents presented to our Dermatology Department with a 6-month history of a malar eczematous rash that worsens with sun exposure. He had butterfly-shaped, hyperpigmented exfoliating plaques, preceded by blister formation (figure 1). He was also noticed to have enophthalmos, a pinched nose, microcephaly and a cachectic physique. His height and weight were below the first percentile for his age. In addition, the patient was noticed to have motor and psychosocial delay; he does not respond to simple spoken requests, cannot get into sitting position without help or stand/walk with help of furniture. The eye examination was completely normal including the absence of retinal and corneal changes. Complete blood count, liver function tests and a karyotype did not show any abnormal findings. Imaging studies were not done.edpract;107/1/28/F1F1F1Figure 1Clinical image. A hyperpigmented exfoliating plaque distributed over the malar area associated with enophthalmos and a pinched nose. WHAT'S YOUR DIAGNOSIS?: Bloom syndrome.Rothmund Thomson syndrome.Cockayne syndrome.Xeroderma pigmentosum.Trichothiodystrophy. Answers can be found on page 02.

Genodermatoses with hearing impairment.

Hearing loss is a prominent feature in multiple genodermatoses. Underappreciation of auditory deficits can misdirect proper diagnosis by the treating dermatologist. This review reviews the anatomic, developmental, and embryologic aspects that characterize the ear and summarizes genodermatoses that have aberrant auditory findings. The latter are classified into neural crest, metabolic, pigmentary, craniofacial, and a miscellaneous category of disorders lacking specific cutaneous findings. The algorithms provided in this review enable treating dermatologists to better recognize and manage genodermatoses with ear involvement.

Comparative characterization of sun exposed and sun protected skin-derived mesenchymal-like stem cells in variegate porphyria and healthy individuals.

BACKGROUND AND PURPOSE: We hypothesized that upon sun exposure, a sub-population of primary skin-derived mesenchymal-like cells is deleteriously affected and thus contribute to the chronic inflammatory state in autosomal recessive variegate porphyria patients. The aim of this study was to isolate and characterize the mesenchymal-like stem cells from different areas of the skin in a porphyria patient (sun exposed, SE, and sun protected, SP) and to compare them with cells from a healthy individual. METHODS: The proliferation rate and the migration ability of SE and SP cells were evaluated in the presence of an antioxidant compound, N-acetylcysteine. A co-culture of SE-damaged cells with the conditioned medium from the enriched mesenchymal cell-like SP population was performed in order to regenerate the dermal injured tissue after sun exposure in patients. RESULTS: Results showed that the percentage of CD105+ cells varies between 3.9% in SP and 5% in SE of the healthy individual and between 3.6% and 1.4% in SP and SE in the porphyria patient, respectively. The osteogenic differentiation potential was lower in the porphyria patient when compared to the control. Furthermore, the expression of stem cell markers was more pronounced in SE than in SP cells of both control and porphyria. The use of N-acetyl cysteine did not show any beneficial effects on porphyria SE cells. Treatment with SP-conditioned medium slightly increased the expression of stem cell markers in SE of porphyria patient. CONCLUSION: In conclusion, the pool of mesenchymal stem-like SE cells is affected in variegate porphyria patient along with modification of their self-renewal and differentiation properties.

Osteoclast-Like Giant Cells: Focus on Entities Relevant to Dermatopathology and Underlying Pathogenesis.

ABSTRACT: Osteoclast-like giant cells (OLGCs) resemble osteoclasts with their abundant cytoplasm and well-developed organelles. OLGCs are characteristic features of giant cell tumor of the tendon sheath and giant cell tumor of soft tissue but they have also been described in numerous other cutaneous conditions. The diagnostic and prognostic significance of the presence of OLGCs is unknown. Here, we summarize the clinical entities that can exhibit these cells to avoid a histological overlap, affecting diagnosis and management.

Consanguinity rates among Syrian refugees in Lebanon: a study on genetic awareness.

Consanguineous marriage is a deeply rooted tradition in the Arab world. Such marriages are linked to higher rates of recessive genetic diseases. During the Syrian conflict, which started in 2011, around one million Syrian individuals became refugees in Lebanon. This study assessed the consanguinity rates among Syrian refugees living in Lebanon up to three successive consanguineous generations, and examined refugees' awareness of the possible consequences of consanguineous marriage and their attitudes towards consanguinity. Their knowledge of, and access to, premarital screening was also assessed. The study was conducted between January and May 2018. Several study sites representing refugees' distribution within the country were chosen. The study sample included 1008 interviewees from different families. Of those interviewed, 51.9% were in a consanguineous marriage. Interestingly, 23.9% were the product of consanguineous marriages themselves, and 17.9% were consanguineous for three successive generations. The interviewees generally knew about premarital screening, but the majority (61.9%) had not had the screening. The high rates of consanguinity in these Syrian refugees call for immediate action, including raising genetic awareness and providing appropriate genetic counselling. Despite the respondents' familiarity with premarital screening, there was a low rate of uptake of the test, underscoring the importance of providing better education to these refugees.

In Vitro Activity of Beauvericin against All Developmental Stages of Sarcoptes scabiei.

Scabies is a frequent cutaneous infection caused by the mite Sarcoptes scabiei in a large number of mammals, including humans. As the resistance of S. scabiei against several chemical acaricides has been previously documented, the establishment of alternative and effective control molecules is required. In this study, the potential acaricidal activity of beauvericin was assessed against different life stages of S. scabiei var. suis and in comparison with dimpylate and ivermectin, two commercially available molecules used for the treatment of S. scabiei infection in animals and/or humans. The toxicity of beauvericin against cultured human fibroblast skin cells was evaluated using an MTT proliferation assay. In our in vitro model, developmental stages of S. scabiei were placed in petri dishes filled with Columbia agar supplemented with pig serum and different concentrations of the drugs. Cell sensitivity assays demonstrated low toxicity of beauvericin against primary human fibroblast skin cells. At 0.5 and 5 mM, beauvericin showed higher activity against adults and eggs of S. scabiei compared to dimpylate and ivermectin. These results revealed that the use of beauvericin is promising and might be considered for the treatment of S. scabiei infection.

A novel TRAF3IP2 variant causing familial scarring alopecia with mixed features of discoid lupus erythematosus and folliculitis decalvans.

Discoid lupus erythematosus (DLE) is an autoimmune disorder with a poorly defined etiology. Despite epidemiologic gender and ethnic biases, a clear genetic basis for DLE remains elusive. In this study, we used exome and RNA sequencing technologies to characterize a consanguineous Lebanese family with four affected individuals who presented with classical scalp DLE and generalized folliculitis. Our results unraveled a novel biallelic variant c.1313C > A leading to a missense substitution p.(Thr438Asn) in TRAF3IP2(NM_147200.3). Expression studies in cultured cells revealed mis-localization of the mutated protein. Functional characterization of the mutated protein showed significant reduction in the physical interaction with the interleukin 17-A receptor (IL17RA), while interaction with TRAF6 was unaffected. By conducting a differential genome-wide transcriptomics analysis between affected and non-affected individuals, we showed that the hair follicle differentiation pathway is drastically suppressed, whereas cytokine and inflammation responses are significantly upregulated. Furthermore, our results were highly concordant with molecular signatures in patients with DLE from a public dataset. In conclusion, this is the first report on a new putative role for TRAF3IP2 in the etiology of DLE. The identified molecular features associated with this gene could pave the way for better DLE-targeted treatment.

Tissue-resident memory T cells in the skin.

PURPOSE: Tissue-resident memory T (TRM) cells are a newly described subset of memory T cells. The best characterized TRM cells are CD8+ and express CD103 and CD69. These cells are non-recirculating and persist long term in tissues, providing immediate protection against invading pathogens. However, their inappropriate activation might contribute to the pathogenesis of autoimmune and inflammatory disorders. In the skin, these cells have been described in psoriasis, vitiligo, and melanoma among other diseases. METHODS: Literature review was done to highlight what is currently known on the phenotype and function of TRM cells and summarizes the available data describing their role in various cutaneous conditions. RESULTS: Resolved psoriatic skin and disease-naïve non-lesional skin contain a population of IL-17-producing TRM cells with shared receptor sequences that recognize common antigens and likely contribute to disease recurrence after cessation of therapy. In vitiligo, TRM cells produce perforin, granzyme B, and interferon-γ following stimulation by interleukin-15 and collaborate with recirculating memory T cells to maintain disease. In melanoma, increased accumulation of TRM cells was recently shown to correlate with improved survival in patients undergoing therapy with immune checkpoint inhibitors.

SuPAR, a potential inflammatory mediator in psoriasis pathogenesis.

Psoriasis is an inflammatory skin disorder that is strongly associated with the metabolic syndrome. The sole reliance on clinical examination to guide prognostication and treatment is insufficient at best; accurate diagnostic and prognostic psoriatic molecular biomarkers are needed. Soluble urokinase plasminogen activator receptor (suPAR) has been implicated in inflammation. The aim of this study is to determine whether suPAR plays a role in the pathogenesis of psoriasis and whether an association exists between suPAR levels, disease severity, and other variables like insulin, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). This study also compares the pattern of uPAR staining in healthy vs psoriatic skin: 39 psoriatic and 30 control subjects were included. Two biopsies (affected and unaffected skin) and one biopsy were taken from psoriasis patients and healthy controls, respectively, with uPAR staining of all skin biopsies. Blood samples from all subjects were obtained to determine suPAR, ESR, CRP, and fasting insulin levels. uPAR staining was prominent in unaffected skin from psoriasis patients and healthy individuals vs weak/absent uPAR staining in psoriatic skin. CRP, ESR and suPAR levels were not significantly elevated in the mild psoriasis group compared to healthy controls. The loss of epidermal uPAR is suggestive of its tentative role in the pathogenesis of psoriasis. Patients with mild-moderate psoriasis possibly lack the powerful association attributed to metabolic syndrome in psoriatic patients. Further studies on larger cohorts are needed to ascertain the validity of the mentioned conclusions.

Genodermatoses with teeth abnormalities.

Many genodermatoses exhibit abnormal teeth findings. Studies examining these entities are scarce and narrow in their scope. This paper reviews the evolution, development, and structure of the tooth and provides a summary of genodermatoses with aberrant dental findings. The latter are classified according to the abnormal dental findings: periodontal disease, anodontia/oligodontia/hypodontia, polydontia, enamel hypoplasia, natal teeth, dental pits, and others. Finally, we provide an algorithm that dermatologists and dentists can follow to better recognize genodermatoses with dental involvement.

Mutations in SDR9C7 gene encoding an enzyme for vitamin A metabolism underlie autosomal recessive congenital ichthyosis.

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of hereditary skin disorder characterized by an aberrant cornification of the epidermis. ARCI is classified into a total of 11 subtypes (ARCI1-ARCI11) based on their causative genes or loci. Of these, the causative gene for only ARCI7 has not been identified, while it was previously mapped on chromosome 12p11.2-q13.1. In this study, we performed genetic analyses for three Lebanese families with ARCI, and successfully determined the linkage interval to 9.47 Mb region on chromosome 12q13.13-q14.1, which was unexpectedly outside of the ARCI7 locus. Whole-exome sequencing and the subsequent Sanger sequencing led to the identification of missense mutations in short chain dehydrogenase/reductase family 9C, member 7 (SDR9C7) gene on chromosome 12q13.3, i.e. two families shared an identical homozygous mutation c.599T > C (p.Ile200Thr) and one family had another homozygous mutation c.214C > T (p.Arg72Trp). In cultured cells, expression of both the mutant SDR9C7 proteins was markedly reduced as compared to wild-type protein, suggesting that the mutations severely affected a stability of the protein. In normal human skin, the SDR9C7 was abundantly expressed in granular and cornified layers of the epidermis. By contrast, in a patient's skin, its expression in the cornified layer was significantly decreased. It has previously been reported that SDR9C7 is an enzyme to convert retinal into retinol. Therefore, our study not only adds a new gene responsible for ARCI, but also further suggests a potential role of vitamin A metabolism in terminal differentiation of the epidermis in humans.

CHILD syndrome: A modified pathogenesis-targeted therapeutic approach.

Congenital Hemidysplasia with Ichthyosiform nevus and Limb Defects (CHILD syndrome) is a rare X-linked dominant genodermatosis caused by mutations in the NAD(P) dependent steroid dehydrogenase-like protein gene. Its defect leads to accumulation of toxic metabolic intermediates upstream from the pathway block and to the deficiency of bulk cholesterol, probably leading to altered keratinocyte membrane function, resulting in the phenotype seen in CHILD syndrome. Symptomatic treatment using emollients and retinoids to reduce scaling has long been used until recently, whereby new therapeutic means based on the pathogenesis-targeted therapy have been developed. We subsequently chose to use the same pathogenesis-based therapy using a 2% cholesterol and 2% lovastatin cream with or without glycolic acid in two of our patients. Improvement in CHILD skin lesions was seen as early as 4 weeks after initiation. The addition of glycolic acid helped improve the penetrance of the cholesterol and lovastatin cream into the thick waxy scales. Our study confirms the efficacy of the pathogenesis-targeted therapy and introduces the possibility of modifying its formula by adding glycolic acid in order to improve the treatment.

Orf virus infection.

Orf virus (ORFV) is an important pathogen responsible for a highly contagious zoonotic viral infection that threatens those who handle sheep and goats. Orf virus is the prototype of the Parapoxvirus genus, and its resilience in the environment and ability to reinfect its host has contributed to the spread and maintenance of the infection in many species. In healthy humans, the disease usually resolves spontaneously within 3 to 6 weeks. There is no specific treatment and many different approaches such as use of imiquimod, cidofovir, curettage, shave excision, cryotherapy, and electrocautery have all been reported to be successful, without supporting evidence from controlled clinical trials. Throughout its interaction with the different hosts, ORFV has evolved a strategy for immune evasion via the development of an array of virulence factors. The interaction of ORFV with the immune system has been the subject of research for decades. Whole inactivated ORFV has been used as a type of immunomodulating drug; a so called paramunity inducer proposed as both a preventative and a therapeutic immunomodulator across various species. Additional research on the remarkable strategies underlying ORFV infection could lead to improved understanding of skin immunity.

SuPAR, an emerging biomarker in kidney and inflammatory diseases.

Soluble urokinase plasminogen activator receptor (suPAR) is a circulating form of a physiological and pathophysiological important cell surface receptor, implicated in inflammation. Recent studies showed that suPAR is a promising biomarker, useful for diagnosis, assessment and prognosis of several diseases. This review summarises the majority of preliminary studies and analyses the significance and the clinical application of suPAR in various clinical conditions. SuPAR seems to have a significant value in the diagnosis as well as prognosis of many diseases; nonetheless, it merits large-scale studies to set cut-off values that help physicians in following up their patients and accordingly tailor their treatment plans.