Loss-of-function variants in GLMN are associated with generalized skin hyperpigmentation with or without glomuvenous malformation.

BACKGROUNDS: Inherited hyperpigmented skin disorders comprise a group of entities with considerable clinical and genetic heterogenicity. The genetic basis of a majority of these disorders remains to be elucidated. OBJECTIVES: This study aimed to identify the underlying gene for an unclarified disorder of autosomal-dominant generalized skin hyperpigmentation with or without glomuvenous malformation. METHODS: Whole-exome sequencing was performed in five unrelated families with autosomal-dominant generalized skin hyperpigmentation. Variants were confirmed using Sanger sequencing and a minigene assay was employed to evaluate the splicing alteration. Immunofluorescence and transmission electron microscopy (TEM) were used to determine the quantity of melanocytes and melanosomes in hyperpigmented skin lesions. GLMN knockdown by siRNA assays was performed in human MNT-1 cells to examine melanin concentration and the underlying molecular mechanism. RESULTS: We identified five variants in GLMN in five unrelated families, including c.995_996insAACA(p.Ser333Thrfs*11), c.632 + 4delA, c.1470_1473dup(p.Thr492fs*12), c.1319G > A(p.Trp440*), and c.1613_1614insTA(Thr540*). The minigene assay confirmed that the c.632 + 4delA mutant resulted in an abolishment of the canonical donor splice site. Although the number of melanocytes remained unchanged in skin lesions as demonstrated by immunofluorescent staining of tyrosinase and premelanosome protein (PMEL), TEM revealed an increased quantity of melanosomes in the skin lesion of a patient. The GLMN-knockdown MNT-1 cells demonstrated a higher melanin concentration, a higher proportion of stage III and IV melanosomes, upregulation of MITF and tyrosinase, and downregulation of phosphorylated p70S6 K, compared to mock-transfected cells. CONCLUSIONS: We found loss-of-function variants in GLMN are associated with generalized skin hyperpigmentation with or without glomuvenous malformation. Our study implicates a potential role of glomulin in human skin melanogenesis, in addition to vascular morphogenesis.

Two chromosome-level genomes of Smittia aterrima and Smittia pratorum (Diptera, Chironomidae).

Chironomids are one of the most abundant aquatic insects and are widely distributed in various biological communities. However, the lack of high-quality genomes has hindered our ability to study the evolution and ecology of this group. Here, we used Nanopore long reads and Hi-C data to produce two chromosome-level genomes from mixed genomic data. The genomes of Smittia aterrima (SateA) and Smittia pratorum (SateB) were assembled into three chromosomes, with sizes of 78.45 Mb and 71.56 Mb, scaffold N50 lengths of 25.73 and 23.53 Mb, and BUSCO completeness of 98.5% and 97.8% (n = 1,367), 5.68 Mb (7.24%) and 1.94 Mb (2.72%) of repetitive elements, and predicted 12,330 (97.70% BUSCO completeness) and 11,250 (97.40%) protein-coding genes, respectively. These high-quality genomes will serve as valuable resources for comprehending the evolution and environmental adaptation of chironomids.

Real-World Data on the Use of Sirolimus in Asian Children with Vascular Malformations.

OBJECTIVES: The management of vascular malformations is complex and challenging. This study aimed to explore efficacy, plasma trough concentrations of sirolimus, post-withdrawal conditions, and adverse reactions of sirolimus in treating complex vascular malformations. METHODS: In our center, we analyzed vascular malformations treated with sirolimus (and corticosteroid) from August 2017 to June 2021. Meanwhile, we reviewed the medical records, the efficacy, side effects, and laboratory tests. Patients who had stopped taking sirolimus were followed up by telephone. RESULTS: A total of 25 patients with complicated vascular malformations in our center, including 7 females and 18 males aged 4 months to 15 years, were enrolled. In all, 19 patients (76.0%) responded to sirolimus, and the plasma concentration of sirolimus fluctuated between 0.97 and 27.15 ng/ml. In all, 24 patients (96.0%) were in follow-up. A total of 15 patients (62.5%) stopped taking sirolimus during follow-up, and 2 patients (13.3%) discontinued the sirolimus due to side effects. A total of 3 patients (20.0%) restarted sirolimus treatment. CONCLUSION: Starting dose of 1.5-2 mg/m2 sirolimus is effective and safe in vascular malformation treatment. The best treatment regimen and discontinuation indications needed more investigation. Most should be done about targeted therapy to improve effectiveness and reduce side effects.

A sequential tape stripping approach for the assessment of the impact of personal cleansing products on the stratum corneum surface layers' acid mantle properties and antimicrobial defense.

BACKGROUND: Stratum corneum (SC) plays a critical role in skin barrier function for protection and defense in nature. The acidic skin pH, which is also known as the acid mantle, is very important in fighting against outer environmental threats, especially, bacteria. Furthermore, recent research has shown that the transient bacteria could potentially penetrate into deeper layer of the SC down to a few micrometers while posing an additional threat to the deeper layers of the skin. AIM: To develop a sequential tape stripping method for assessing the impact of personal cleansing product on the SC surface layers' acid mantle properties and antimicrobial defense against transient bacteria. METHODS: Fifty-five subjects were recruited. High pH soap-based Product 1 and low pH synthetic surfactant-based Product 2 were applied on the left and right forearms of each subject. Sequential tape stripping was performed on the same spots to access multiple layers of the skin SC. Both antimicrobial defense property and skin pH of different skin layers were evaluated at baseline and 12 h after treatment. RESULTS: The skin's antimicrobial defense was significantly higher 12 h after treatment of the low pH Product 2 as compared to the treatment of high pH Product 1. In fact, this trend was consistent across all three skin layers (Layer 1 to Layer 3) as measured in this study (p < 0.01). Furthermore, the skin surface pH of Layer 1 and Layer 3 were also lower 12 h after the treatment of low pH Product 2 as compared to that of the high pH Product 1 (p < 0.01). CONCLUSION: The results of this investigation demonstrated the benefits of 12-h long lasting and deeper protection of SC acid mantle properties and antimicrobial defense using a low pH skin cleansing product as compared to a high pH product.

Alectinib In the Treatment of Systemic Juvenile Xanthogranuloma of Infancy With ALK Translocation.

This observational case series examines the diagnosis and treatment of 2 patients with systemic juvenile xanthogranuloma treated with alectinib.

The update of treatment strategies in pediatrics with generalized pustular psoriasis in China.

Generalized pustular psoriasis (GPP) is a severe subtype of psoriasis, commonly combined with systemic inflammation. Gene mutations have been found to be associated with GPP and vary by ethnicity. Systemic treatments are usually required for the severity and potential complications of GPP. However, there is no common consensus in China, especially among pediatric patients, whose data are scarce. Acitretin, methotrexate, and cyclosporine are widely used in pediatrics with GPP, while the adverse effects should be highlighted. The emergence of different biological agents brings us into a new era. This article discusses the genetic background of Chinese patients and demonstrates the evidence of treatment in pediatrics with GPP.

Somatic mutation spectrum of a Chinese cohort of pediatrics with vascular malformations.

BACKGROUND: Somatic mutations of cancer driver genes are found to be responsible for vascular malformations with clinical manifestations ranging from cutaneous birthmarks to life-threatening systemic anomalies. Till now, only a limited number of cases and mutations were reported in Chinese population. The purpose of this study was to describe the somatic mutation spectrum of a cohort of Chinese pediatrics with vascular malformations. METHODS: Pediatrics diagnosed with various vascular malformations were collected between May 2019 and October 2020 from Beijing Children's Hospital. Genomic DNA of skin lesion of each patient was extracted and sequenced by whole-exome sequencing to identify pathogenic somatic mutations. Mutations with variant allele frequency less than 5% were validated by ultra-deep sequencing. RESULTS: A total of 67 pediatrics (33 males, 34 females, age range: 0.1-14.8 years) were analyzed. Exome sequencing identified somatic mutations of corresponding genes in 53 patients, yielding a molecular diagnosis rate of 79.1%. Among 29 PIK3CA mutations, 17 were well-known hotspot p.E542K, p.E545K and p.H1047R/L. Non-hotspot mutations were prevalent in patients with PIK3CA-related overgrowth spectrum, accounting for 50.0% (11/22) of detected mutations. The hotspot GNAQ p.R183Q and TEK p.L914F mutations were responsible for the majority of port-wine stain/Sturge-Weber syndrome and venous malformation, respectively. In addition, we identified a novel AKT1 p.Q79K mutation in Proteus syndrome and MAP3K3 p.E387D mutation in verrucous venous malformation. CONCLUSIONS: The somatic mutation spectrum of vascular malformations in Chinese population is similar to that reported in other populations, but non-hotspot PIK3CA mutations may also be prevalent. Molecular diagnosis may help the clinical diagnosis, treatment and management of these pediatric patients with vascular malformations.

Clinical features of cutaneous infantile hemangioma combined with asymptomatic infantile hepatic hemangioma and efficacy of propranolol treatment.

INTRODUCTION: Infantile hepatic hemangioma (IHH) is a common liver tumor in infants and shares the same characteristics as cutaneous infantile hemangioma (IH). Propranolol is effective for symptomatic IHH. The clinical features between cutaneous IH and IHH, and treatment efficacy of IHH (smaller than 4 cm) is unclear. To evaluate the correlation of clinical features between cutaneous IH and IHH, as well as efficacy of systemic propranolol in the treatment of cutaneous IH combined with IHH. MATERIALS AND METHODS: The clinical data of infants with complicated cutaneous IH combined with IHH treated with systemic propranolol (1.5 ~ 2 mg/(kg d)) from January 2011 to October 2020 were retrospectively analyzed. RESULTS: Forty-five cases with IHH combined with complicated cutaneous IH were reviewed. Single cutaneous IH is more likely to be combined with focal IHH, cutaneous IH greater than 5, more likely to be combined with multiple IHH (Pearson = 0.546, p < 0.01). The mean age of focal and multiple IHH regression was 11.93 ± 14.42 months and 10.20 ± 9.15 months, respectively. CONCLUSIONS: The number of cutaneous IH were correlated with the number of IHH. There was no difference in the age of complete remission for focal and multiple IHH.

Takayasu Arteritis Coexisting with Cutaneous Leishmaniasis.

Takayasu arteritis (TA) is a rare large-vessel vasculitis that can result in significant morbidity and mortality. The coexistence of TA with leishmaniasis infection has not been reported previously. Case description: An 8-year-old girl presented with recurrent skin nodules that heal spontaneously for four years. Her skin biopsy revealed granulomatous inflammation with Leishmania amastigotes identified in the histocyte cytoplasm and the extracellular space. The diagnosis of cutaneous leishmaniasis was made and intralesional sodium antimony gluconate was started. One month later, she experienced dry coughs and fever. The CT angiography of the carotid arteries showed dilation in the right common carotid artery and thickening of artery walls with elevated acute phase reactants. The diagnosis of Takayasu arteritis (TA) was made. Reviewing her chest CT before treatment, a soft-tissue density mass was identified in the right carotid artery region, suggesting a pre-existing aneurysm. The patient was treated with surgical resection of the aneurysm with systemic corticosteroids and immunosuppressants. Her skin nodules resolved with scars after the second cycle of antimony while a new aneurysm arose due to a lack of control of TA. Conclusions: This case highlights that benign as the natural course is for cutaneous leishmaniasis, fatal comorbidities can occur as a consequence of chronic inflammation, and can be aggravated by the treatment.

A controlled forearm washing ex vivo method for assessing the impact of personal cleansing products on skin's acid mantle properties and antimicrobial defence against transient bacteria.

BACKGROUND: An important trend in the personal care industry involves the development of advanced personal cleaning products that not only provide skin mildness but support skin's acid mantle properties and skin's natural antimicrobial defence function. OBJECTIVE: The objective of this study was to develop a controlled forearm washing ex vivo method for assessing the impact of personal cleansing products on skin's acid mantle properties and antimicrobial defence against transient bacteria. METHODS: We developed a controlled forearm washing ex vivo method (ex vivo NET method) to compare the impact of two representative personal cleansing products on skin's acid mantle properties and antimicrobial defence against transient bacteria: one was a low-pH skin cleanser, and the other was high-pH soap cleanser. Skin pH was measured at baseline and 4 h after the product application. Concurrently, D-squame tape stripping procedure was followed to sample the stratum corneum surface layers. Then, two selected transient bacteria, Staphylococcus aureus and Escherichia coli, were inoculated onto the D-squame tapes and incubated under controlled conditions, respectively. The residual bacteria counts can provide an objective measure of skin's acid mantle properties against transient bacteria. Results from the ex vivo NET method were compared with the traditional in vivo cup-scrub RET method. RESULTS: The skin pH was significantly lower 4 h after washing the forearm with the low-pH cleanser versus the high-pH soap, consistent with literatures. Interestingly, the skin surface washed by the low-pH cleanser showed significantly higher hostility against representative transient bacteria as demonstrated by the lower counts of S. aureus by 1.09 log and E. coli by 0.6 log versus the high-pH soap based on the ex vivo NET method. Results from the ex vivo NET method were further supported by the traditional in vivo RET method which also showed the skin washed by the low-pH cleanser had significantly lower counts of S. aureus and E. coli versus the high-pH soap. CONCLUSIONS: The skin's acid mantle properties and antimicrobial defence can be directly impacted by the personal cleansing products. The low-pH skin cleanser works better than the high-pH soap for supporting skin's acid mantle properties and antimicrobial defence against transient bacteria. Results from the ex vivo NET method are consistent with the in vivo RET method. It is important that the ex vivo NET method offers many advantages since it is quicker to run with higher throughput and has better safety without the constraint of inoculating harmful microorganisms onto the human subjects.

CONTEXTE: Une tendance importante du secteur des soins personnels est de développer des produits d'hygiène personnelle sophistiqués qui non seulement rendent la peau plus douce, mais favorisent également les propriétés du manteau acide de la peau et la fonction de défense antimicrobienne naturelle de la peau. OBJECTIF: L'objectif de cette étude était de développer une méthode ex vivo de lavage contrôlé des avant-bras pour évaluer l'impact des produits d'hygiène personnelle sur les propriétés du manteau acide de la peau et la défense antimicrobienne contre les bactéries transitoires. MÉTHODES: Nous avons développé une méthode ex vivo de lavage contrôlé des avant-bras (méthode NET ex vivo) pour comparer l'impact de deux produits d'hygiène personnelle représentatifs sur les propriétés du manteau acide de la peau et la défense antimicrobienne contre les bactéries transitoires: d'une part un nettoyant pour la peau à pH faible, d'autre part un savon nettoyant à pH élevé. Le pH de la peau a été mesuré à l'entrée dans l'étude et quatre heures après l'application du produit. Parallèlement, une procédure de stripping par ruban adhésif D-Squame a été suivie pour prélever des couches de surface de la couche cornée. Ensuite, deux bactéries transitoires sélectionnées, S. aureus et E. coli, ont été inoculées sur les rubans adhésifs D-Squame et incubées dans des conditions contrôlées, respectivement. Le nombre de bactéries résiduelles peut fournir une mesure objective des propriétés du manteau acide de la peau contre les bactéries transitoires. Les résultats de la méthode NET ex vivo ont été comparés à la méthode RET in vivo traditionnelle par coupe-grattage. RÉSULTATS: Le pH de la peau était significativement inférieur quatre heures après le lavage des avant-bras avec le nettoyant à pH faible en comparaison avec le savon à pH élevé, conformément à la littérature. Il est intéressant de noter que la surface de la peau lavée au moyen du nettoyant à pH faible présentait une hostilité significativement plus élevée contre les bactéries transitoires représentatives, comme démontré par le nombre inférieur de S. aureus de 1,09 log et d'E. coli de 0,6 log, en comparaison avec le savon à pH élevé, sur base de la méthode NET ex vivo. Les résultats de la méthode NET ex vivo ont été encore par la méthode RET in vivo traditionnelle, laquelle a également démontré que la peau lavée à l'aide du nettoyant à pH faible présentait des nombres significativement plus faibles de S. aureus et d'E. coli que celle lavée à l'aide du savon à pH élevé. CONCLUSIONS: Les propriétés du manteau acide de la peau et la défense antimicrobienne peuvent être directement affectées par les produits d'hygiène personnelle. Le nettoyant de la peau à pH faible fonctionne mieux que le savon à pH élevé pour ce qui est de favoriser les propriétés du manteau acide de la peau et la défense antimicrobienne contre les bactéries transitoires. Les résultats de la méthode NET ex vivo sont cohérents avec la méthode RET in vivo. Il est important de noter que la méthode NET ex vivo offre de nombreux avantages étant donné qu'elle est plus rapide à exécuter avec une capacité plus élevée et offre une meilleure sécurité sans la contrainte d'inoculer des micro-organismes nocifs à des sujets humains.