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Autosomal recessive congenital ichthyoses (ARCI) is a genetically heterogeneous condition that can be caused by pathogenic variants in at least 12 genes, including ABCA12. ARCI mainly consists of congenital ichthyosiform erythroderma (CIE), lamellar ichthyosis (LI) and harlequin ichthyosis (HI). The objective was to determine previously unreported pathogenic variants in ABCA12 and to update genotype-phenotype correlations for patients with pathogenic ABCA12 variants. Pathogenic variants in ABCA12 were detected using Sanger sequencing or a combination of Sanger sequencing and whole-exome sequencing. To verify the pathogenicity of a previously unreported large deletion and intron variant, cDNA analysis was performed using total RNA extracted from hair roots. Genetic analyses were performed on the patients with CIE, LI, HI and non-congenital ichthyosis with unusual phenotypes (NIUP), and 11 previously unreported ABCA12 variants were identified. Sequencing of cDNA confirmed the aberrant splicing of the variant ABCA12 in the patients with the previously unreported large deletion and intron variant. Our findings expand the phenotype spectrum of ichthyosis patients with ABCA12 pathogenic variants. The present missense variants in ABCA12 are considered to be heterogenous in pathogenicity, and they lead to varying disease severities in patients with ARCI and non-congenital ichthyosis with unusual phenotypes (NIUP)., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A 50-year-old man developed a sterile cavernosal abscess followed by prominent features of necrotizing neutrophilic dermatosis. We conducted a literature review, which revealed that aseptic abscesses in the corpus cavernosum occur in association with neutrophilic dermatosis. Patients with this condition frequently receive unnecessary antibiotic treatment and surgical interventions. Although this condition responds to systemic corticosteroids, the functional prognosis of the penis is poor. Abscess formation may be the initial presentation of neutrophilic dermatoses, and underlying conditions may even be absent. Clinicians need to be aware of this condition to distinguish it from bacterial infection and initiate early disease-specific treatments.

Merkel cell carcinoma (MCC), an aggressive skin cancer with neuroendocrine features, has been found to be associated with a new type of human polyomavirus called Merkel cell polyomavirus (MCV). Patients diagnosed with MCC have a significantly increased risk of a second primary cancer. We report here the first case of two primary MCCs arising on the face at different times, associated with MCV infection. The tumour on the patient's right cheek was surgically removed, followed by chemoradiation. After a 10-year tumour-free period, a new tumour developed on the patient's left cheek. Histological and immunohistochemical findings were consistent with MCC. The tumours had high MCV copy numbers and expressed large T antigen, which may play a major role in MCV-mediated carcinogenesis. This case highlights the close links between MCC and MCV.

We present herein the case of an 80-year-old woman with a keratotic plaque measuring 1.4x1.3 cm on the left popliteal fossa. The plaque was resected and diagnosed on microscopic examination as low-grade sebaceous carcinoma. Sebaceous carcinoma on the leg seems extremely rare.

Melanonychia, which is characterized by brown or black pigmentation within the nail plate, includes heterogeneous conditions such as pigmented nevus, subungual melanoma and lentigo. We treated two cases of subungual melanoma in situ. One case was a 58-year-old woman who suffered from a malignant melanoma in situ of the left third fingernail, who had also suffered from melanonychia of the fingers for more than 30 years. She had a past history of carcinoma of the uterine cervix. The other patient was a 42-year-old man, who suffered from a malignant melanoma in situ of the right fifth fingernail. He had a past history of carcinoma of the stomach for which he had undergone surgery 2 years earlier. Both cases were accompanied by Hutchinson's sign on the fingertip skin, and the presence of this sign led to the correct diagnosis of subungual melanoma in situ. Judging from previously reported cases, it is unlikely that patients with malignant melanoma have an increased risk of carcinoma of the uterine cervix or of the stomach.

Muckle-Wells syndrome is a rare autosomally dominant disorder belonging to the group of periodic fever syndromes. Three main features of the disease are: (i) urticarial eruptions; (ii) progressive perceptive deafness; and (iii) amyloid nephropathy. A 26-year-old Japanese woman had suffered at birth from an urticarial rash and episodic fever. The fever was frequently associated with chills and ill-defined malaise. There was no familial history of urticarial rash or fever. Although she did not recognize hearing loss, audiometry revealed perceptive deafness. She also had hepatosplenomegaly and hyperimmunoglobulinemia, but did not have persistent arthritis, or any neurological or gastrointestinal disorder. No growth retardation was observed. Skin biopsy specimens from her buttock showed a sparse perivascular and interstitial infiltrate of neutrophils in the papillary dermis. Periodic fever syndrome was diagnosed. Muckle-Wells syndrome was most likely, although no amyloid nephropathy was observed and no gene mutations of CIAS1 (T785C, C778T, G907A, G1315A, G1075C) were detected. We treated her with prednisolone, which had a partial effect. Previous treatment with colchicines, antihistamines, dapsone, clarithromycin, minocycline hydrochloride and loxoprofen sodium had been unsuccessful. Muckle-Wells syndrome may go undiagnosed for many years or be misdiagnosed as refractory urticaria. Therefore, we should consider the possibility of periodic fever syndrome when we see patients with refractory urticaria and episodic fever.

Transcription factor Nrf2 (encoded by Nfe2l2) regulates a battery of detoxifying and antioxidant genes, and Keap1 represses Nrf2 function. When we ablated Keap1, Keap1-deficient mice died postnatally, probably from malnutrition resulting from hyperkeratosis in the esophagus and forestomach. Nrf2 activity affects the expression levels of several squamous epithelial genes. Biochemical data show that, without Keap1, Nrf2 constitutively accumulates in the nucleus to stimulate transcription of cytoprotective genes. Breeding to Nrf2-deficient mice reversed the phenotypic Keap1 deficiencies. These experiments show that Keap1 acts upstream of Nrf2 in the cellular response to oxidative and xenobiotic stress.

We studied the expression of angiogenic factors (vascular endothelial growth factor, basic fibroblast growth factor, platelet-derived growth factor and hepatocyte growth factor) in cutaneous neurofibroma samples from patients with neurofibromatosis-1. Immunohistochemical staining and the reverse transcribed polymerase chain reaction (RT-PCR) method demonstrated that vascular endothelial and basic fibroblast growths factor are highly expressed in neurofibroma cells at both the protein and mRNA level. These data suggest that vascular endothelial and basic fibroblast growth factors may contribute to both the angiogenesis and hypervascularity of neurofibromas.

Neurofibromas of neurofibromatosis 1 (NF1) are highly vascular. Because the number of PDGF beta receptors in neurofibroma-derived cultured cells (NF-derived cells) has been reported to be increased, we tested whether platelet-derived growth factor BB (PDGF-BB) could induce expression of vascular endothelial growth factor (VEGF) in NF-derived cells. When analysed by reverse transcription-polymerase chain reaction, VEGF mRNA expression was found to be stimulated by PDGF-BB and TGF-beta1. Those growth factors stimulated the secretion of VEGF from NF-derived cells. PDGF-BB furthermore induced the mitogen-activated protein kinase phosphorylation in NF-derived cells from patients with NF1. In conclusion, PDGF-BB stimulated VEGF secretion in NF-derived cells, and this stimulation is probably important in neurofibroma hypervascularization.

We described a 19-year old Japanese female with bullous congenital ichthyosiform erythroderma (BCIE) and examined the keratin gene mutation. Physical examination disclosed generalized erythema, ichthyosiform skin with scales, and erosions without palmoplantar keratoderma. Histological examination revealed hyperkeratosis with vacuolar degeneration in the granular layer of the epidermis. Sequence analysis demonstrated a C to G transition at the first position of codon 156 in the keratin 10 gene. The amino acid at codon 156 was deduced to have changed from arginine to cystine. Substitution from arginine to cysteine at codon 156 of the K 10 gene is assumed to be fatal for keratin filament assembly regardless of racial or ethnic difference.

A 33-year-old man (Case 1) developed scaling and erythema on the extensor side of his extremities, head, and back, 3 years before his first visit to our hospital. The lesions spread out to form several plaques and became persistent (Fig. 1a). Serum antistreptolysin O (ASO) was within the normal range and a pharyngeal culture showed normal flora. Histologic findings were compatible with psoriasis vulgaris (Fig. 1b). Topical steroid therapy was effective; however, scaling and erythema persisted. The 8-year-old daughter (Case 2) of Case 1 had suffered severe tonsillitis 2 months prior to the skin eruptions. Numerous rain drop-like scaly papules appeared on her legs and generalized rapidly (Fig. 2a). Her tonsils were swollen and reddish. Streptococcus pyogenes was detected by pharyngeal smear. The ASO value was at a high level. Histologic examination showed slightly elongated rete ridges, focal lack of the granular layer, parakeratosis, mild spongiosis, and exostosis of neutrophils (Fig. 2b). She was diagnosed with acute guttate psoriasis. Administration of oral antimicrobials reduced the ASO value and led to remission of the disease. After 1 month of antimicrobial treatment, the erythematous papules disappeared. The human leukocyte antigen (HLA) typing of the father was HLA-A24, A31, B7, B39, and Cw7, and that of the daughter was HLA-A24, A31, B39, and Cw7. Both possessed HLA-A24, B39, and Cw7. The HLA typing of other family members was also studied. The mother had HLA-A11, A24, B39, B62, Cw4, and Cw7, and her son had HLA-A11, A24, B7, B62, Cw4, and Cw7. The result of HLA typing is shown in Table 1. Lymphocyte stimulating test was performed using heat-killed S. pyogenes which were boiled at 70 degrees C for 10 min and sonicated. The stimulation index was twofold higher in the daughter than in the father (Fig. 3).

Background: Pustulosis palmaris et plantaris (PPP) is a chronic inflammatory disease consisting of polymorphonuclear leukocyte infiltration, and is often exacerbated by focal infections such as tonsillitis. In some cases, metal allergy has been reported., Objective: The purpose of this study was to evaluate (1) the significance of metal allergy in the formation of pustules, and (2) the participation of leukotriene (LT) B(4) in the formation of pustules of PPP., Methods: Patch tests with metals were performed on 7 patients with PPP, and both pustular and plasma levels of LTB(4) were measured in these 7 patients before and 48 hours after metal patch tests., Results: Palmoplantar pustules were exacerbated after the metal patch tests in all 7 patients. The mean levels of LTB(4) in plasma and pustules of the volar surface at 48 hours after the metal patch tests were significantly higher than those before the metal patch tests., Conclusion: Metals can be important in the pathogenesis of PPP by contributing to the induction of high LTB(4) concentration in the pustules.

Mouse keratin 6a (MK6a) is constitutively expressed in a single cell layer of the outer root sheath (ORS) of hair follicles, but its synthesis can be induced in interfollicular epidermis including the basal cell layer in response to perturbing stimuli. A basally inducible human K6 (HK6) isoform has not been described, and it is not clear which of the known HK6 isoforms is expressed in the ORS. In this study we show that expression of a dominant-negative MK6a construct (Delta2B-P) in the interfollicular epidermis caused severe blistering and neonatal lethality, suggesting that mutations in a yet to be identified basally expressed HK6 isoform might result in a severe blistering phenotype. Surviving Delta2B-P animals showed transgene expression only in isolated epidermal cells and not in all cells of the ORS, but nevertheless developed severe alopecia. Expression of two different C-terminal mutant transgenes also caused alopecia while a third C-terminal mutant had no phenotypic conse- quences. Electron microscopy revealed that Delta2B-P expression resulted in the collapse of keratin filaments, while destruction of hair follicles in the two phenotypic C-terminal mutant lines occurred in the absence of filament abnormalities. The latter finding indicates that the innermost ORS cells are uniquely sensitive to expression of even slightly altered K6 proteins, suggesting that mutations affecting an HK6 isoform expressed in this cell layer could result in alopecia in humans as well.

We report a case of histiocytic necrotizing lymphadenitis in a 28-year-old woman. The biopsy specimen of the enlarged lymph node showed lymphocytes, histiocytes, and a large amount of nuclear debris as well as marked eosinophilic deposits. We found DNA fragments by means of the modified TUNEL method, especially in the transitional area between intact cells and the foci of eosinophilic deposits and the cells positive for anti-Fas antibody in the biopsied lymph node. Therefore, the necrotic appearance of the lymph node was thought to be caused by apoptosis induced by the Fas-Fas ligand system. We hypothesize that the apoptosis was strongly related to the pathogenesis of this disease.

We report a case of papillary tubular adenoma, arising on the knee joint. The overall histologic structure of the tumor is consistent with that of papillary tubular adenoma with slight interluminal papillary changes, but most of the tumor cells present vacuolization outlined by carcinoembryonic antigen staining, suggesting that this adenoma may have resulted from microlumen formation. This is, to our knowledge, the first reported case of a papillary tubular adenoma with marked tubular vacuolization.

To explore the role of retinoids in epidermal development, we recently targeted expression of a dominant-negative, retinoic acid receptor mutant (RAR alpha403) in the epidermis of transgenic mice and observed an unexpected loss of barrier function. In this paper, we demonstrate that transgenic mice expressing the RAR alpha403 transgene show attenuated responsiveness to topical application of all-trans retinoic acid, in agreement with our previous in vitro data. We also show that the vitamin D3 receptor is unaffected in its ability to transactivate in the presence of the dominant-negative RAR alpha403 transgene, indicating that the RAR alpha403 is unlikely to be functioning through a global sequestration of retinoid X receptors. Additionally, we show that the disruption of epidermal barrier function results in a dramatic 4 C drop in mean body surface temperature, probably accounting for the extremely high incidence of neonatal mortality in severely phenotypic pups. Some severely affected pups do survive and show a pronounced hyperkeratosis at postpartum day 4, consistent with previously documented effects of vitamin A deficiency. Biochemical analysis of the severely phenotypic neonates indicates elevated phospholipids and glycosylceramides in the stratum comeum, which results from altered lipid processing. Taken together with previous studies, these data provide strong evidence linking the retinoid-signaling pathway with modulation of lipid processing required for formation of epidermal barrier function.

In order to determine the transactivation domain(s) of the rat estrogen receptor (rat ER), we made a number of rat ER deletion mutants and transfected the mutant plasmids into COS7 cells together with an estrogen-responsive reporter plasmid, ERE-tk(197)-CAT, which contained the estrogen response element of Xenopus vitellogenin A2 gene. We have identified and localized the N-terminal transactivation domain of the rat ER to a hydrophobic region extending from Ala 59 to Glu 140.

Immunohistochemical and ultrastructural studies were conducted to elucidate the nature and origin of osteosarcomatous changes in malignant melanoma in a 43-year-old Japanese man. Immunohistochemical studies with the use of antisera against human S-100 protein and neuron-specific enolase demonstrated positive reactions in the tumor cells within the osteosarcomatous area. Ultrastructurally, the neoplastic cells showed marked similarities to those from osteosarcomas. Additionally, occasional neoplastic cells contained round or ellipsoidal osmiophilic organelles, presumably melanosomes. These findings indicate that osteosarcomatous changes in malignant melanoma are produced by the dedifferentiated melanoma cells.