A gain-of-function variant in SREBF1 causes generalized skin hyperpigmentation with congenital cataracts.

BACKGROUND: Lipid metabolism plays essential roles in skin barrier formation and the regulation of skin inflammation. Moreover, lipid homeostasis regulates skin melanogenesis, although the underlying mechanism remains largely unknown. Sterol regulatory element binding protein 1 (SREBP-1) is a key transcription factor essential for cellular lipid metabolism. Loss-of-function variants in SREBF1 are responsible for autosomal-dominant ichthyosis follicularis, alopecia, and photophobia syndrome, emphasizing the significance of lipid homeostasis in skin keratinization. OBJECTIVES: To identify the genetic basis of a new entity featuring diffuse skin hyperpigmentation with congenital cataracts, and to unravel the underlying mechanism for the pathogenesis of the SREBF1 variant. METHODS: Whole-exome sequencing was performed to identify the underlying genetic variants. Quantitative PCR, western blot, and immunofluorescent staining were employed to assess the expression and the subcellular localization of the SREBF1 variant. The transcriptional activity of the mutant SREBP-1 was determined by luciferase reporter assay. A transgenic zebrafish model was constructed. RESULTS: Two patients of different ethnicities presented with generalized skin hyperpigmentation with skin xerosis, congenital cataracts, and extracutaneous symptoms. We identified a de novo nonsense variant c.1289C>A (p.Ser430*) in the SREBF1 gene in both patients. The variant encoded a truncated protein which showed preferential nucleus localization, in contrast to wild-type SREBP-1 which is mainly localized in cytoplasm in sterol-sufficient conditions. Luciferase reporter assay revealed that the Ser430* mutant exhibited an enhanced transcriptional activity. The primary cultured melanocytes from the patient showed increased melanin synthesis compared to those from normal controls. The Ser430* transgenic zebrafish model exhibited more black spots, along with upregulated expression of melanogenic genes at 35 days post-fertilization. CONCLUSIONS: We demonstrated that a gain-of-function variant in SREBF1 caused a previously undescribed disorder characterized by generalized skin hyperpigmentation and congenital cataracts. Our study reveals the involvement of SREBP-1 in melanogenesis and lens development and paves the way for developing novel therapeutic targets for skin dyspigmentation or cataracts.

Hydroa vacciniforme lymphoproliferative disorder: a retrospective study of 42 paediatric cases.

Hydroa vacciniforme lymphoproliferative disorder (HVLPD) is a rare disease related to Epstein-Barr virus (EBV), mainly in children, and is an EBV-associated cutaneous T and natural killer (NK) cell lymphoproliferative disorder. The disorder in some patients may progress to EBV-associated systemic T or NK-cell lymphoma. To summarize the characteristics of HVLPD in Chinese paediatric patients and to examine the risk factors indicating poor prognosis. We performed a retrospective analysis of patients with HVLPD from the Department of Dermatology, Beijing Children's Hospital. Based on diagnosis, medical history, examination results, and immunophenotype, we analysed HVLPD in 42 paediatric cases in order to examine the clinical features, prognoses, and risk factors. Forty-two paediatric patients were enrolled, with a median onset age of five years. All patients presented with papulovesicular lesions, and 32 systemic HVLPD (sHVLPD) patients had systemic symptoms, including fever, lymphadenopathy, hepatomegaly, splenomegaly, and liver dysfunction. Of the sHVLPD cases, 13 also had severe mosquito bite allergy (SMBA). Twenty-five cases were T-type, and nine were CD56+-dominant type. Follow-up data showed that 12 patients had complete remission, and three patients died. SMBA is a risk factor for disease progression in patients with HVLPD, and the pathological CD56+-dominant phenotype is associated with poor prognosis.

Somatic GNA11/GNAQ variants in a cohort of Chinese children with phakomatosis pigmentovascularis.

Importance: Postzygotic mutations in the GNAQ/GNA11 genes, which encode the G-protein nucleotide binding protein alpha subunits, have been identified in patients with phakomatosis pigmentovascularis (PPV). However, little is known about the Chinese population. Objective: To identify pathogenic mutations in pediatric patients with PPV within the Chinese population. Methods: We performed whole-exome sequencing (WES) using skin lesion tissues from pediatric patients diagnosed with PPV. Additionally, ultradeep-targeted sequencing was conducted to validate the somatic mutations. A genotype-phenotype correlation was analyzed by integrating data from previous reports with the findings of the present study. Results: Thirteen patients were enrolled, all diagnosed with the cesioflammea type of PPV, except for one patient with an unclassifiable type. We identified somatic GNA11 c.547C>T (p.R183C) variant in seven patients and GNAQ c.548G>A (p.R183Q) in four patients, with low allelic fractions ranging from 2.1% to 8.6% through ultradeep sequencing. Besides, a GNAQ c.548G>A (p.R183Q) variant was detected through targeted sequencing in one of two patients who did not exhibit detectable variants via WES. The genotype-phenotype correlation analysis, involving 15 patients with a GNA11 variant and 10 with a GNAQ variant, revealed that facial capillary malformation (87% vs. 50%, P = 0.075) and ocular melanocytosis (80% vs. 40%, P = 0.087) appeared to be more frequent in patients with GNA11 mutation compared to those with GNAQ mutations. All four patients diagnosed with cesiomarmorata type or overlapping cesioflammea and cesiomarmorata type PPV carried the GNA11 variant. Interpretation: Our study demonstrated that the majority of PPV patients in the Chinese population carried a postzygotic variant of GNAQ/GNA11, thus further confirming the pathogenic role of GNAQ/GNA11 mosaicism in the development of PPV cesioflammea type.

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

BACKGROUND: 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 small interfering RNA 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 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, TEM revealed an increased number 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 microphthalmia-associated transcription factor and tyrosinase, and downregulation of phosphorylated p70S6 K vs. mock-transfected cells. CONCLUSIONS: We found that 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.

A group of skin conditions known as 'inherited hyperpigmented skin disorders' includes some diseases with different clinical and genetic traits. The genetic basis of the majority of these diseases is not understood. To identify the gene responsible for a disease that causes darker patches of skin (hyperpigmentation) with or without the abnormal growth of blood vessels and the presence of cells named glomus cells (a glomuvenous malformation), we used genetic techniques called whole-exome sequencing and Sanger sequencing in five unrelated families with this disease. We also used a technique called a 'minigene assay' to evaluate genetic alterations in a gene called GLMN, which encodes a protein called glomulin. Immunofluorescence and transmission electron microscopy (TEM) were used to determine the number of pigment-producing cells (called melanocytes) and melanosomes (where the pigment melanin is synthesized, stored and transported) in hyperpigmented skin lesions. We identified five different variants of the GLMN gene in five unrelated families. Although the number of melanocytes remained unchanged in skin lesions, TEM revealed an increased number of melanosomes. By 'switching off' the GLMN gene, we found that skin cells produced more pigment, as well as the proteins MITF and tyrosinase; they also showed a decrease in the phosphorylated protein p-p70S6 K. Overall, we found that loss-of-function mutations in GLMN caused skin hyperpigmentation with or without abnormal blood vessels. The results suggest there could be a potential role of the protein glomulin in human skin colour and blood vessel changes.

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.