Hideaki Tanizaki

Analysis of clinical symptoms and ABCC6 mutations in 76 Japanese patients with pseudoxanthoma elasticum

Pseudoxanthoma elasticum (PXE) is a hereditary disease, causing calcification and degeneration of elastic fibers, which affects the skin, eye, cardiovascular systems and gastrointestinal tract. PXE is caused by mutations in the ABCC6 gene. Neither detailed nor large‐scale analyses have been accomplished in Japanese patients with PXE. We, therefore, investigated clinical symptoms and ABCC6 gene mutations in 76 Japanese patients. Japanese PXE patients (n = 76) had a significantly lower incidence of vascular lesions than 505 PXE patients in the Leiden Open Variation Database (LOVD) (38.7% vs 65.1%, respectively; P = 1.34E‐06); however, the incidences of the skin, eye, cardiac and gastrointestinal lesion symptoms were not significantly different. Symptom severity scores for skin, eye and vascular lesions, calculated using the Phenodex™ system, were significantly lower in Japanese PXE patients than in LOVD PXE patients. Genetic analysis revealed three nonsense, four frame‐shift, one exon deletion and 13 missense mutations in ABCC6 in 73 patients; however, we were unable to detect pathogenic mutations in three patients. Frequent mutations differed between Japanese and LOVD PXE patients. In Japanese PXE patients, the top five mutations accounted for more than 60% of all pathogenic changes, suggesting the presence of founder effects. Consistent with previous reports, no obvious correlations between genotypes and phenotypes were identified in this study. In conclusion, we consider that the milder clinical phenotypes, observed even in older Japanese PXE patients, could be attributed to environmental factors such as dietary habits and lifestyle, as well as genetic background.

Case of xeroderma pigmentosum group A with West syndrome

80 mg fortnightly for her psoriatic disease. Over 3 months, her psoriatic arthritis flared and she was switched to etanercept 50 mg weekly. Her ulcerative colitis flared after 4 months of etanercept treatment, requiring hospital admission. She was started on 100 mg of i.v. hydrocortisone daily and on discharge commenced induction of infliximab (5 mg/kg) and maintenance with 2-monthly infusions. She continues to have reasonable control of her ulcerative colitis, psoriatic disease (0% surface area involvement; Dermatological Life Quality Index 1/30). Our case highlights the importance of obtaining a full medical history when switching biologic agents. We hypothesize that previous treatment with adalimumab maintained remission of ulcerative colitis. Her flare whilst on ustekinumab most likely represents suboptimal dosing as treatment of IBD employs higher doses than for this patient (90 mg vs 45 mg). There have been concerns regarding ixekizumab and risk of exacerbation of IBD, but this was not observed. Switching to etanercept might have caused dysregulation to her adaptive and innate immune defenses. There have been three documented cases of de novo ulcerative colitis associated with etanercept, with a further five cases associated with etanercept indicated for treatment of psoriatic arthropathy, and a single case related to treatment of psoriatic arthritis, psoriasis and uveitis. Etanercept has been shown to block lymphotoxin like adalimumab and infliximab, but it differs in that it is the only agent consisting of an immunoglobulin G1 fusion protein that binds to transmembrane tumor necrosis factor. Therefore, there is only antibody-dependent cell-mediated cytotoxicity, without activities of complement-dependent cytotoxicity. Thus, this mechanism may allow activation of downstream messenger pathways, causing increased gut permeability and augmentation of mucosal inflammation, producing relapse or in some instances de novo ulcerative colitis.

An adolescent case of xeroderma pigmentosum variant confirmed by the onset of sun exposure-related skin cancer during Crohn's disease treatment

The patient was a 16‐year‐old boy who was diagnosed with Crohns disease at 13 years of age, who was treated with mesalazine, azathioprine, and infliximab. Concurrently, the patient developed small freckle‐like pigmented spots on sun‐exposed areas, which gradually increased in number. At 14 and 16 years of age, a blue‐gray macule and a nodule appeared on his face, respectively. A histopathological examination revealed that the macule had only postinflammatory pigmentation, while the nodule was basal cell carcinoma. The sensitivity to UV‐killing by colony formation of the patients cells was normal but was enhanced by caffeine treatment. In addition, a pathologic mutation in the POLH gene was identified and a diagnosis of xeroderma pigmentosum variant (XP‐V) was established. XP‐V is a cutaneous type of XP that is commonly diagnosed from middle age after the induction of skin cancer on sun‐exposed areas. Our patient had a genetically sensitive background (XP‐V), and we considered that immunosuppressive agents for Crohns disease may have enhanced the photocarcinogenesis at a young age. This finding implies that we should be careful about a skin cancer production and that protection from UV may be essential when pediatric patients with a genetic background of UV sensitivity take immunosuppressive agents.

Acrodermatitis continua of Hallopeau successfully treated only with infliximab: A case report

A 22‐year‐old man presented with a 2‐month history of rapidly progressing pustular eruptions on the accrual regions of his fingers and toes with local arthralgia and severe nail destruction. A histological examination revealed parakeratosis, hyperkeratosis and elongation of the rete ridges of the epidermis with exocytosis of neutrophils forming spongiform pustules of Kogoj. Based on these findings, we diagnosed this case as acrodermatitis continua of Hallopeau (ACH). ACH, a variant of pustular psoriasis, is often resistant to various topical treatments, and the patient experienced prominent decline in his quality of life. Therefore, we decided to use infliximab in the present case. After the fourth administration of infliximab alone, the patients digital arthralgia and pustular eruptions disappeared completely, and the long‐term administration of infliximab drastically reduced all of the patients symptoms of ACH, including the nail lesions without any adverse events or recurrence. Our findings suggest that ACH shares a disease spectrum with plaque‐type and pustular psoriasis. In addition, biologic agents such as a tumor necrosis factor‐α inhibitor are useful for treating patients with ACH just as those with psoriasis and may even be used alone.

Localized involutional lipoatrophy at the site of an influenza vaccination: A case report.

Dear Editor, Localized involutional lipoatrophy (LIL) is a rare non-inflammatory form of localized lipodystrophy characterized by diminutive fat lobules that contain small adipocytes. Although most LIL cases are idiopathic, the s.c. administration of medicines has been known to occasionally induce this condition. A 31-year-old woman received an influenza vaccination on her upper left arm 10 months prior to her presentation and a concave lesion appeared at the inoculation site 6 months later. She presented with a spotty, concave, light reddish-purple lesion 1.8 cm in diameter on her upper left arm (Fig. 1a,b). Blood samples contained no abnormal findings including antidsDNA and anti-Sm antibody. There were no other abnormal findings in the blood or urine. A histopathological examination revealed unremarkable change in the epidermis and dermis, but the subcutaneous tissue contained irregularly-sized adipocytes and a small number of infiltrating inflammatory cells (Fig. 1c,d). Few normal adipocytes were noted, and small adipocytes and surrounding capillary hyperplasia were prominent (Fig. 1d). Immunohistochemistry verified the scattered infiltration of CD68 cells, which were assumed to be macrophages, among the adipocytes (Fig. 1e). Based on these findings, the patient was diagnosed with LIL. She has been managed by observation alone for 1 year without any change of the lesion. Lipoatrophy is classified based on its clinical features as total, partial or localized. Localized lipoatrophy is further classified as two distinctive subsets, involutional or inflammatory, depending on its histology. In the involutional subtype, the adipocytes are small, the surrounding capillaries are hyperplastic and inflammatory cell infiltration is minimal, while in the inflammatory type, the adipocytes are normal sized, inflammatory cell infiltration is pronounced and no capillary hyperplasia is observed. To our knowledge, there have been 41 reported Japanese cases of LIL from subjects aged 5–67 years (mean, 32), in which the extremities were predominant. Most patients

Lichen planus-like keratosis emerging in a pediatric case of xeroderma pigmentosum group A

Dear Editor, A 10-year-old Japanese schoolgirl was referred to our clinic complaining of an asymptomatic scaly erythema on her right cheek (Fig. 1a,b). At 2 months of age of the patient, her mother had noticed severe sunburn following half-hour sun exposure even under cloudy winter weather. At 3 months of age, we diagnosed the patient as having xeroderma pigmentosum group A (XP-A) by using the patient’s cultured fibroblasts, as post-ultraviolet (UV) unscheduled synthesis was decreased (1% of normal), DNA repair capacity was elevated by transfecting an XPA gene and the homozygous IVS3-1G>C founder mutation was detected in the XPA gene. After the diagnosis of XP-A, she had been visiting us every 6 months and was instructed to strictly avoid sun exposure by wearing protective clothing and using high-grade, broad-spectrum protective, physical sunscreen every 3 h when she went out in the sun; however, freckle-like small pigmented spots gradually developed on her face. At the present visit, we clinically suspected actinic keratosis because of her genetic background, which predisposed her to develop UV-induced skin carcinogenesis. A 3-mm punch biopsy specimen histologically revealed liquefaction degeneration, subepidermal blister formation, a band-like infiltrate of mononuclear cells (mainly CD8 T lymphocytes) and scattered dyskeratotic cells without cell atypia in the epidermis (Fig. 1c). Solar elastosis was absent in the dermis. We diagnosed the lesion as lichen planus-like keratosis (LPLK) appearing in a pediatric XP-A case. Six months later, the LPLK lesion had completely disappeared without any treatment (Fig. 1d). Xeroderma pigmentosum is an autosomal recessive photosensitive disease with deficient post-UV DNA repair and patients with XP have an extremely high frequency of developing UV-induced skin cancer. XP-A is the severest form of XP among the eight genetically different groups and skin cancers easily occur on sun-exposed areas of the patients in their childhood if they do not strictly avoid sun exposure. LPLK (or lichenoid keratosis) is a benign keratotic change with inflammation, which is generally observed in middle aged and older adults with a slight preference in males. LPLK is thought to be

X-linked dominant protoporphyria: The first reported Japanese case

A 12‐year‐old boy with photosensitivity since 3 years of age presented with small concavities on both cheeks, the nasal root and the dorsal surface of both hands. According to the clinical features, erythropoietic protoporphyria (EPP) was suspected. Urine and blood samples were tested for porphyrin derivatives, which revealed a markedly elevated level of erythrocyte protoporphyrin (EP) and a diagnosis of EPP was made. The patients mother had no photosensitivity, however, lesions appearing slightly as small scars were found on the dorsum of her right hand; his elder sister and father showed no rash. The EP levels were elevated in samples from his mother and mildly elevated in those from his elder sister and father. To obtain a definitive diagnosis, genetic analyses were performed using samples from all family members, which revealed no mutations in the ferrochelatase‐encoding gene (FECH), which is responsible for EPP. Instead, a pathological mutation of the 5‐aminolevulinic acid synthase‐encoding gene (ALAS2) was identified in samples from the patient, his mother and his elder sister, confirming a definitive diagnosis of X‐linked dominant protoporphyria (XLDPP). This is the first Japanese family reported to have XLDPP, demonstrating evidence of the condition in Japan. In addition, because XLDPP is very similar to EPP in its clinical aspects and laboratory findings, a genetic analysis is required for the differential diagnosis.