Naoyuki Kariya

Mutation Analysis of the IL36RN Gene in 14 Japanese Patients with Generalized Pustular Psoriasis

Generalized pustular psoriasis (GPP) is a rare, potentially life threatening, and aggressive form of psoriasis, which is characterized by sudden onset with repeated episodic skin inflammation leading to pustule formation. Familial GPP is known to be caused by recessively inherited mutations in the IL36RN gene, which encodes interleukin 36 receptor antagonist (IL‐36Ra). In this article, we performed mutation analysis of the IL36RN gene in 14 Japanese patients with GPP, and identified mutations in two of these patients analyzed. One patient was compound heterozygous for mutations c.115+6T>C and c.368C>G (p.Thr123Arg), whereas the other carried compound heterozygous mutations c.28C>T (p.Arg10*) and c.115+6T>C in the IL36RN gene. Expression studies using total RNA from the patients’ skin revealed that the mutation c.115+6T>C resulted in skipping of exon 3, leading to a frameshift and a premature termination codon (p.Arg10Argfs*1). The protein structure analysis suggested that the missense mutation p.Thr123Arg caused misfolding and instability of IL‐36Ra protein. In vitro studies in cultured cells showed impaired expression of the p.Thr123Arg mutant IL‐36Ra protein, which failed to antagonize the IL‐36 signaling pathway. Our data further underscore the critical role of IL36RN in pathogenesis of GPP.

Netherton syndrome in two Japanese siblings with a novel mutation in the SPINK5 gene: immunohistochemical studies of LEKTI and other epidermal molecules

Background  Netherton syndrome (NS) is a severe autosomal recessive disorder characterized by ichthyosiform erythroderma, bamboo hair and atopy. The disease is caused by mutations in the SPINK5 gene, which encodes a putative serine protease inhibitor, LEKTI (lymphoepithelial Kazal‐type‐related inhibitor). Previous studies have clearly shown a crucial role for LEKTI in skin barrier formation.

A case of recessive dystrophic epidermolysis bullosa caused by compound heterozygous mutations in the COL7A1 gene

Dystrophic epidermolysis bullosa (DEB) is a severe heritable bullous disease caused by mutations in the COL7A1 gene encoding type VII collagen, the major structural component of anchoring fibrils at the dermal–epidermal junction (DEJ). The disease is inherited in either an autosomal dominant (DDEB) or recessive (RDEB) fashion and exhibits various clinical heterogeneities. We report a Japanese patient affected with DEB showing a moderately severe phenotype. Mutation analysis resulted in the identification of compound heterozygous mutations in the COL7A1 gene of our patient. On the paternal allele is a novel G2088E substitution; on the maternal allele is a recurrent E2857X mutation. Our data will provide important information for future genetic counselling in the family.

Segmental lichen aureus in infancy.

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Skin metastasis of dermatofibrosarcoma protuberans with distinct morphological features, confirmed by COL1A1-PDGFB fusion gene analysis

We discuss a metastatic dermatofibrosarcoma protuberans on the occiput of a 53-year-old man whose initial tumor appeared on his forehead 23 years previously. The pathology of the tumor that recurred at the initial site was fibrosarcomatous dermatofibrosarcoma protuberans, whereas the metastatic tumor was a pigmented dermatofibrosarcoma protuberans, the so-called Bednar tumor. Because both tumors possessed the identical chimeric COL1A1-PDGFB fusion gene, the metastatic nature of the occipital tumor was confirmed.

Novel splice site mutation in the fumarate hydratase (FH) gene is associated with multiple cutaneous leiomyomas in a Japanese patient.

Cutaneous leiomyoma is a benign skin tumor that originates from the smooth muscle, such as the arrector pili muscle of the hair follicles. Familial cases with multiple cutaneous leiomyomas exist, which typically show an autosomal dominant inheritance trait. Most patients with the disease are known to carry heterozygous germ line mutations in the fumarate hydratase (FH) gene and can be complicated by tumors in internal organs, especially uterine leiomyoma and renal cell cancer in high frequency. In this study, we identified a Japanese male patient with multiple cutaneous leiomyomas and found a novel heterozygous splice site mutation, c.738 + 2T>A, in the FH gene of the patient, which was unexpectedly inherited from his unaffected father. Further analysis demonstrated loss of heterozygosity in the tumor tissue, which resulted in a hemizygote state of the mutant allele. Expression studies with the tumor tissue showed that the mutation led to skipping of exon 5 at mRNA levels, which was predicted to cause an in‐frame deletion of FH protein (p.Ser186_Gln246del). The protein structure analysis strongly suggested that the deletion would severely disrupt the conformation of the FH protein including the substrate‐binding domain, and thus would severely affect the expression and the function. Our findings further disclose the molecular basis of multiple cutaneous leiomyomas and also provide precious information to the mutation carriers in the family for an early diagnosis of renal cell cancer in the future.

Case of infantile digital fibromatosis: Observation of its dermoscopic features

by proliferation of the sebaceous glands, milia-like cyst and crown vessels. In our case, dermoscopic findings showed multiple white patches, many white-yellow globules or milia-like cysts, and a delicate pigment network at the periphery (Fig. 1b). Referring to the histopathological findings, these features correspond to the fibrotic areas associated with overlying sebaceous hyperplasia. We speculate that originally a single central white patch was apparently divided into a couple of patches by hyperplasic sebaceous glands with hyperpigmented epidermis, which were induced by possible paracrine factors emanating from the dermal fibrosis. The lack of a central white scar-like patch, cumulus sign or crown vessels may be helpful to distinguish dermatofibroma with overlying sebaceous hyperplasia from typical dermatofibroma or sebaceous hyperplasia. The clinical diagnosis of dermatofibroma is rather easy. However, white-yellow globules or milia-like cysts would be confusable for dermoscopic diagnosis of dermatofibroma, if the presence of overlying sebaceous hyperplasia is not subject to differential diagnosis. Given that milia-like cysts show low disease specificity, multiple white-yellow globules could be useful dermoscopic features for dermatofibroma with overlying sebaceous hyperplasia.

A case of malignant peripheral nerve sheath tumor with lymph node metastasis

70歳, 女性。神経線維腫症1型の既往はない。10年来の左大腿部に多発した皮下腫瘤を切除し, 神経線維腫の診断で経過観察されていた。1年半後, 左鼠径部に自覚症状を伴わない3cm大の皮下腫瘤が出現。生検標本の組織像では皮下に巨大な腫瘍として認められ, 個々の腫瘍細胞は異型性の強い大小さまざまな核を持っており, 細胞密度も高かった。また免疫組織化学染色では, S-100蛋白とビメンチンが腫瘍細胞に陽性であった。組織学的に悪性末梢神経鞘腫 (malignant peripheral nerve sheath tumor, 以下MPNSTと略す) と診断した。拡大切除術およびリンパ節郭清を施行したところ, 摘出したリンパ節に転移を認めた。追加治療として, 局所に合計63Gyの4MeVのX線照射を行った。術後1年の時点で再発・転移は認めていない。MPNSTのリンパ行性転移は極めて稀であり, また, 自験例が神経線維腫症5型である可能性を考えた。