Deep intronic founder mutations identified in the ERCC4/XPF gene are potential therapeutic targets for a high-frequency form of xeroderma pigmentosum.

Xeroderma pigmentosum (XP) is a genodermatosis defined by cutaneous photosensitivity with an increased risk of skin tumors because of DNA repair deficiency. The worldwide prevalence of XP is ~1 to 4 in million, with higher incidence in some countries and regions including Japan (1 in 22,000) and North Africa due to founder mutations and a high degree of consanguinity. Among XP, the complementation group F (XP-F), is a rare form (1% of worldwide XP); however, this is underdiagnosed, because the ERCC4/XPF gene is essential for fetal development and most of previously reported ERCC4/XPF pathogenic variants are hypomorphs causing relatively mild phenotypes. From the largest Japanese XP cohort study, we report 17 XP-F cases bearing two pathogenic variants, both identified in deep intronic regions of the ERCC4/XPF gene. The first variant, located in intron 1, is a Japanese founder mutation, which additionally accounts for ~10% of the entire Japanese XP cases (MAF = 0.00196), causing an aberrant pre-mRNA splicing due to a miss-binding of U1snRNA. The second mutation located in intron eight induces an alternative polyadenylation. Both mutations cause a reduction of the ERCC4/XPF gene expression, resulting in XP clinical manifestations. Most cases developed early-onset skin cancers, indicating that these variants need critical attention. We further demonstrate that antisense oligonucleotides designed for the mutations can restore the XPF protein expression and DNA repair capacity in the patients' cells. Collectively, these pathogenic variants can be potential therapeutic targets for XP.

Genetic profile of thymic epithelial tumors in the Japanese population: an exploratory study examining potential therapeutic targets.

Background: Thymic epithelial tumors (TETs) are prone to developing in East Asian populations. However, little is known about the genomic profile of TETs in East Asian populations, and the genomic aberrations in TETs have not yet been fully clarified. Thus, molecular targeted therapies for patients with TETs have not been established. This prospective study was conducted to explore the genetic abnormalities of surgically resected TETs in a Japanese cohort and to identify clues for carcinogenesis and potential therapeutic targets in TETs. Methods: Genetic profiles of TETs were investigated using fresh-frozen specimens resected from operable cases with TETs. DNA sequencing was performed using a next-generation sequencing (NGS) gene panel test with Ion Reporter™ and CLC Genomics Workbench 11.0. The mutation sites were further confirmed by Sanger sequencing, digital droplet polymerase chain reaction (ddPCR), and TA cloning for validation. Results: Among 43 patients diagnosed with anterior mediastinal tumors between January 2013 and March 2019, NGS and validation analyses were performed in 31 patients [29 thymomas and two thymic cancers (TCs)] who met the study criteria. Of these, 12 cases of thymoma types A, AB, B1, and B2 harbored the general transcription factor 2-I (GTF2I) mutation (L424H). Conversely, the mutation was not detected in type B3 thymoma or TC, suggesting that the GTF2I mutation existed in indolent types of TETs. Rat sarcoma viral oncogene (RAS) mutations were detected in three cases [Harvey RAS (HRAS) in two cases of type AB thymoma and neuroblastoma RAS (NRAS)] in one case of type B1 thymoma), and additional sex combs like 1 (ASXL1) mutation was present in one case of TC. All RAS mutations were observed in GTF2I-mutated cases. Conclusions: The GTF2I mutation (L424H) is the most frequently occurring mutation in the limited histology of thymoma, consistent with those in the non-Asian population. HRAS and NRAS mutations co-occurred in cases harboring the GTF2I mutation. These findings suggest that the existence of the GTF2I mutation might be related to indolent types of TETs, and RAS mutations could be candidates as therapeutic targets in TETs.

Aicardi-Goutières syndrome with SAMHD1 deficiency can be diagnosed by unscheduled DNA synthesis test.

Aicardi-Goutières syndrome (AGS) is a rare genetic disorder characterised by progressive encephalopathy, involving microcephaly, intracranial calcification, and cerebrospinal fluid lymphocytosis with increased interferon-α concentrations. The clinical features of AGS overlap with fetal cerebral anomalies caused by congenital infections, such as TORCH (toxoplasmosis, other, rubella, cytomegalovirus, and herpes), or with those of other genetic disorders showing neonatal microcephaly, including Cockayne syndrome (CS) with transcription-coupled DNA repair deficiency, and Seckel syndrome (SS) showing aberrant cell-cycle checkpoint signaling. Therefore, a differential diagnosis to confirm the genetic cause or a proof of infection should be considered. In this report, we describe an individual who showed primordial dwarfism and encephalopathy, and whose initial diagnosis was CS. First, we conducted conventional DNA repair proficiency tests for the patient derived fibroblast cells. Transcription-coupled nucleotide excision repair (TC-NER) activity, which is mostly compromised in CS cases, was slightly reduced in the patient's cells. However, unscheduled DNA synthesis (UDS) was significantly diminished. These cellular traits were inconsistent with the diagnosis of CS. We further performed whole exome sequencing for the case and identified a compound heterozygous loss-of-function variants in the SAMHD1 gene, mutations in which are known to cause AGS. As SAMHD1 encodes deoxyribonucleoside triphosphate triphosphohydrolase, we reasoned that the deoxyribonucleoside triphosphate (dNTP) pool size in the patient's cells was elevated, and the labeling efficiency of UDS-test was hindered due to the reduced concentration of phosphorylated ethynyl deoxyuridine (EdU), a nucleoside analogue used for the assay. In conclusion, UDS assay may be a useful diagnostic tool to distinguish between AGS with SAMHD1 mutations and other related diseases.

Novel Application of Cultured Epithelial Autografts (CEA) with Expanded Mesh Skin Grafting Over an Artificial Dermis or Dermal Wound Bed Preparation.

Cultured epithelial autografts (CEA) with highly expanded mesh skin grafts were used for extensive adult burns covering more than 30% of the total body surface area. A prospective study on eight patients assessed subjective and objective findings up to a 12-month follow-up. The results of wound healing for over 1:6 mesh plus CEA, gap 1:6 mesh plus CEA, and 1:3 mesh were compared at 3, 6, and 12 months using extensibility, viscoelasticity, color, and transepidermal water loss by a generalized estimating equation (GEE) or generalized linear mixed model (GLMM). No significant differences were observed among the paired treatments at any time point. At 6 and 12 months, over 1:6 mesh plus CEA achieved significantly better expert evaluation scores by the Vancouver and Manchester Scar Scales (p < 0.01). Extended skin grafting plus CEA minimizes donor resources and the quality of scars is equal or similar to that with conventional low extended mesh slit-thickness skin grafting such as 1:3 mesh. A longitudinal analysis of scars may further clarify the molecular changes of scar formation and pathogenesis.

Silver Sulfadiazine-Impregnated Hydrocolloid Dressing Is Beneficial in Split-Thickness Skin-Graft Donor Wound Healing in a Small Randomized Controlled Study.

Donor-site wound healing was tested with a silver sulfadiazine (SSD)-impregnated hydrocolloid dressing and hydrocolloid dressing applied manually by a physician on site. A total of 14 patients, 5 woman and 9 men (23-89 years old, average = 61.6 ± 18.70 years), were enrolled in this prospective controlled study. The degree of bleeding was significantly less with the SSD-impregnated than with the hydrocolloid dressing (P < .01). In the moisture meter analysis, the values of the effective contact coefficient and corneal thickness were significantly smaller with the SSD-impregnated dressing (P < .05). In the color analysis, the clarity was significantly lower with the hydrocolloid dressing after 3 months than that of intact neighboring skin (P < .01). Regarding red-green color, SSD-impregnated and hydrocolloid values were significantly greater than the intact skin value immediately after and at 3 months, and the hydrocolloid value was significantly greater than intact at 6 months (P < .01 immediately; P < .01 at 3 months and intact at 6 months) in redness. Regarding yellow-blue color, the hydrocolloid value was significantly lower than the intact skin value at 3 months (P < .05 and intact) in yellow. The extensibility was significantly lower with the hydrocolloid dressing than in intact skin immediately (P < .01), and viscoelasticity was significantly lower with the hydrocolloid dressing than in intact skin immediately and after 3 and 6 months (P < .01 immediately and at 6 months and P < .05 at 3 months). The SSD-impregnated hydrocolloid dressing led to superior wound healing, decreased the degree of bleeding, and demonstrated better corneal barrier function, clarity, color matching, and viscoelasticity in split-thickness donors.

Reconstruction of lateral forefoot using reversed medial plantar flap with free anterolateral thigh flap.

Skin defects of the heel have frequently been reconstructed using the medial plantar flap; however, forefoot coverage has remained a challenge, because the alternatives for flap coverage have been very limited. We describe a case of malignant melanoma on the lateral forefoot that was radically removed and reconstructed successfully with a distally based medial plantar flap, together with a free anterolateral thigh flap. The advantages of this flap include that it does not reduce the vascular supply to the foot owing to reconstruction of the medial plantar vascular systems, reduces the risk of flap congestion, minimizes donor site morbidity, and enables the transport of structurally similar tissues to the plantar forefoot. We believe this technique is a reasonable reconstructive option for large lateral plantar forefoot defects.

Teledermatology may play a role in reducing severity of pressure ulcers in both rural and urban settings.

INTRODUCTION: Teledermatology is already thought to be a valuable tool for patients in rural areas due to their lack of easy access to specialty care providers. This study explored the benefit of teledermatology for bedridden patients living in both rural and urban areas. METHODS: The following 4 studies were evaluated: 1) evaluation of conditions of 83 patients who had developed pressure ulcers before being admitted to the hospital; 2) evaluation of the circumstances of 53 patients with pressure ulcers who received home care; 3) survey of 321 home care nurses regarding their concerns about wound care; and 4) results of a teledermatology system aiming at early intervention for chronic wound treatment. RESULTS: 1) Sixtythree percent of patients who developed pressure ulcers were over 70 years old, 84% of them were bedridden, and 66% developed at home. 2) Seventy-four percent of patients who received home care and developed pressure ulcers lived alone or with an elderly spouse, and only 19% consulted a specialist. 3) A survey of 321 home care nurses revealed that they have difficulties with consulting a specialist, with their complaints against home care doctors amounting to 70% of their responses. 4) Seventeen consultations were sent to a new teledermatology system, 82% by patients, families, and home care nurses. About half of these patients were bedridden, and 82% were currently living at home. Twelve cases (70.6%) were from urban areas. CONCLUSION: Because of the potential for teledermatology to prevent the worsening of ulcers, teledermatological wound consultations should be utilized by all bedridden patients who have a wound.