Updated mutational spectrum and genotype-phenotype correlations in ichthyosis patients with ABCA12 pathogenic variants.

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).

Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation.

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.

Metachronous Merkel cell carcinoma on both cheeks.

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.

Aseptic Cavernosal Abscess: An Unrecognized Feature of Neutrophilic Dermatosis.

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.

Low-grade sebaceous carcinoma presenting on the leg.

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.

Two cases of subungual melanoma in situ.

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.

Toxic Epidermal Necrolysis in a Patient with Autoimmune Limbic Encephalitis with Anti-Glutamate Receptor Antibodies.

We report on a 44-year-old woman who was diagnosed with toxic epidermal necrolysis (TEN) during the recovery phase from autoimmune limbic encephalitis with anti-glutamate receptor antibodies. Both, autoimmune limbic encephalitis and TEN are very rare diseases. The co-existence of the two diseases has not yet been reported. We speculate that the total of 18 drugs needed for the treatment of encephalitis might have increased the risk of TEN. Similar reports would be required to elucidate the pathophysiology of the co-existence.

A probable case of Muckle-Wells syndrome.

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.

PDGF-BB induces MAP kinase phosphorylation and VEGF expression in neurofibroma-derived cultured cells from patients with neurofibromatosis 1.

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.

A keratin 10 gene mutation (Arg156Cys) in a Japanese patient with bullous congenital ichthyosiform erythroderma.

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 case of carcinoma of the male breast mimicking a mucinous carcinoma of the skin.

The authors report a case of mucinous carcinoma of the male breast firstly diagnosed as a mucinous carcinoma of the skin. The immunohistochemical results of this tumor were as follows: cytokeratin7 (-), gross cystic disease fluid protein 15 (-), p63 (-), estrogen receptor (+), and progesterone receptor (+) for the primary nodule; cytokeratin7 (-), thyroid transcription factor-1 (-), gross cystic disease fluid protein 15 (-), p63 (-), cytokeratin8 (+), cytokeratin18 (+), and cytokeratin20 (+) for the recurrent nodule. The tumor cells had cytokeratin7 (-)/ cytokeratin20 (+) phenotype and it was very unusual for mucinous carcinoma of the breast.

Subcutaneous antihistamine injection is effective to control a local allergic reaction to human insulin.

A 31-year-old woman, having a type-1 diabetes and an insulin allergy, was successfully treated with a subcutaneous antihistamine injection to the next continuous subcutaneous insulin infusion site.

Expression of angiogenic factors in neurofibromas.

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.