Masaki Uchiyama

Mutations in SERPINB7, Encoding a Member of the Serine Protease Inhibitor Superfamily, Cause Nagashima-type Palmoplantar Keratosis

Nagashima-type palmoplantar keratosis (NPPK) is an autosomal recessive nonsyndromic diffuse palmoplantar keratosis characterized by well-demarcated diffuse hyperkeratosis with redness, expanding on to the dorsal surfaces of the palms and feet and the Achilles tendon area. Hyperkeratosis in NPPK is mild and nonprogressive, differentiating NPPK clinically from Mal de Meleda. We performed whole-exome and/or Sanger sequencing analyses of 13 unrelated NPPK individuals and identified biallelic putative loss-of-function mutations in SERPINB7, which encodes a cytoplasmic member of the serine protease inhibitor superfamily. We identified a major causative mutation of c.796C>T (p.Arg266(∗)) as a founder mutation in Japanese and Chinese populations. SERPINB7 was specifically present in the cytoplasm of the stratum granulosum and the stratum corneum (SC) of the epidermis. All of the identified mutants are predicted to cause premature termination upstream of the reactive site, which inhibits the proteases, suggesting a complete loss of the protease inhibitory activity of SERPINB7 in NPPK skin. On exposure of NPPK lesional skin to water, we observed a whitish spongy change in the SC, suggesting enhanced water permeation into the SC due to overactivation of proteases and a resultant loss of integrity of the SC structure. These findings provide an important framework for developing pathogenesis-based therapies for NPPK.

Oral finasteride improved the quality of life of androgenetic alopecia patients

Although androgenetic alopecia (AGA) is not a systemic disease, some patients suffer from anxiety about the progression of their condition. This study was conducted in order to ascertain whether treatment by oral finasteride can improve the quality of life (QOL) of these patients. Twenty‐seven male AGA patients aged 19–76u2003years (average, 33.8) answered the Visual Analog Scale (VAS), Dermatology Life Quality Index (DLQI), WHO/QOL‐26 and State–Trait Anxiety Inventory (STAI) questionnaires before and after the administration of finasteride (1u2003mg/day) for 6u2003months. Patients assessed by physicians as “excellent” or “good” were defined as “high responders”; those assessed as “moderate” or “no change” were “low responders”. The changes in QOL before and after the treatment were statistically analyzed, and the improved value of each QOL index of the high responders and low responders from baseline were compared. There was a statistical difference in the VAS (Pu2003<u20030.0001) and DLQI (Pu2003<u20030.01) indices before and after the administration of finasteride. No significant changes occurred in the WHO/QOL‐26 and STAI indices. Comparison of the high responders (11 cases) and low responders (16 cases) revealed no statistical difference in the improvement of VAS and DLQI scores. Oral finasteride improves the QOL of these patients, and VAS and DLQI are useful for the evaluation of patients’ QOL because of the high sensitivity of these tests. However, oral finasteride did not alleviate the patients’ anxiety nor did its efficacy correlate with the level of reported anxiety.

Multivariate analysis of prognostic factors in patients with rapidly progressive alopecia areata.

BACKGROUNDnAlopecia areata (AA) is a common acquired hair disorder showing variable hair loss. Although various prognostic factors have been reported, no evident factors for determining prognosis and appropriate treatment are known.nnnOBJECTIVEnTo identify prognostic factors in AA patients, especially those with positive results for the hair-pull test on the first visit or with a history of rapidly progressive AA (RPAA) within 6 months prior to the first visit.nnnMETHODSnOne thousand thirty (1030) patients diagnosed with AA at Tokyo Medical University Hospital were retrospectively examined for 3 years, and their prognosis was assessed on the basis of various indices using multivariate analysis.nnnRESULTSnPatients with regenerated vellus hairs showed a significantly higher improvement or cure rate regardless of severity. Early onset and lengthy duration were significantly associated with lower cure, and higher relapse, rates. RPAA patients tended to show a good prognosis regardless of the treatment employed.nnnLIMITATIONSnThe present study is retrospective, and treatment modalities were chosen according to clinical and social circumstances.nnnCONCLUSIONnRPAA patients tend to show a favorable prognosis regardless of treatment modality. Furthermore, the presence of regenerated vellus hairs may indicate a good prognosis.

Athlete's nodule

Three cases of athlete’s nodule on the feet are reported. In case 1, a 30‐year‐old man, who had been an amateur football player, presented with nodules on the lateral side of the feet and on the right lateral malleolus with a duration of 1u2003year. In case 2, a 22‐year‐old man, who had participated in karate and track‐and‐field, presented with nodules on the lateral side of the feet and on the right lateral malleolus with a duration of 10u2003years. In case 3, a 25‐year‐old man, who had skied, presented with a nodule on the right lateral malleolus with a duration of 4u2003years. The biopsy specimens from the lesion demonstrated hyperkeratosis, acanthosis of the epidermis and thickness of the dermis. In 1991, Cohen et al. proposed the concept of athlete’s nodule which indicated an acquired cutaneous nodule caused by chronic stimuli with sports. Histopathology of the athlete’s nodule shows hypertrophy of the epidermis and dermis. To the best of our knowledge the term “athlete’s nodule” has not been used in Japan, but it is a useful term to refer to the lesion induced by athletics or the use of sporting equipment.

Case of localized scleroderma successfully treated with bath psoralen and ultraviolet A therapy.

The patient was a 12‐year‐old girl with linear scleroderma distributed on the right abdomen, dorsal aspect of the right thigh, lower leg and foot. The initial regimen of oral prednisolone and methotrexate, or i.v. methylprednisolone failed in the treatment of the scleroderma. Then bath psoralen and ultraviolet A therapy (bath‐PUVA) therapy of 0.2u2003J–4.0u2003J/cm2 daily to total doses 62.8u2003J/cm2 combined with oral prednisolone was started. After bath‐PUVA therapy, regression of the skin sclerosis was observed, the possible mobile range of the right ankle was increased and histological examination confirmed improvement of the sclerosis. The successful results of bath‐PUVA therapy in this case suggest its utility for localized scleroderma.

Elderly cases of Churg–Strauss syndrome: Case report and review of Japanese cases

Churg–Strauss syndrome (CSS) is a vasculitis usually thought to affect comparatively young individuals, however, elderly cases of CSS are being reported increasingly. We report two elderly cases of CSS and review 123 cases of CSS reported in Japan between 2003 and 2010. The two patients showed typical features of CSS such as asthma, chronic sinusitis, purpura and mononeuritis multiplex. The biopsy specimens demonstrated leukocytoclastic vasculitis with infiltration of eosinophils. Both patients responded well to oral prednisolone. The age of the CSS cases we reviewed ranged from the teens to the 80s, with 47.2% of the patients aged 60u2003years or older. These patients tended more frequently to have complications such as gastrointestinal involvement, and a higher mortality rate. Elderly cases of CSS are not rare. Correct diagnosis at an earlier stage and careful, long‐term follow up are of particular importance in preventing a fatal outcome.

Lupus miliaris disseminatus faciei involving the scalp resulted in cicatricial alopecia.

malnutrition, and regrowth of the scalp hairs were gradually obtained accompanied by elongated eyelashes and increased lanugo hairs of the forehead. No evidence for HIV infection was detected and no medications associated with hypertrichosis were administrated during the development of eyelash elongation. There was no history of congenital heart diseases or ophthalmologic disorders. The eyelashes were gradually normalized following complete recovery of her scalp hairs. Eyelashes show a much shorter anagen phase (~30 days) than scalp hairs, resulting in almost fixed length. Excessive eyelash elongation is defined as eyelashes of 12 mm or longer, and observed in various conditions, such as congenital disorders, allergic diseases, HIV infection and uveitis. Several drugs, such as epidermal growth factor receptor antagonist and prostaglandin F2a which has been applied as a treatment of eyelash hypotrichosis, are associated with eyelash trichomegaly. The present case had not been related to these conditions or drugs. Eyelash trichomegaly is a rare complication of alopecia areata and malnutrition including anorexia nervosa. In alopecia areata, eyelash trichomegaly may be observed during hair loss of the scalp, but is usually normalized along with complete regrowth of the scalp hairs. Our case showed eyelash elongation following malnutrition-associated diffuse scalp hair loss. Although our case is not associated with alopecia areata, shared factors may play a role in eyelash trichomegaly during recovery from the diffuse scalp hair loss. Although eyelash trichomegaly can be induced by various conditions, the precise pathomechanism remains unknown. However, malnutrition should be included as one of the provoking factors.

Case of Vogt–Koyanagi–Harada disease with psoriasis vulgaris

Dear Editor, Vogt–Koyanagi–Harada disease (VKH) is an autoimmune disorder affecting melanocytes. We report a case of VKH with psoriasis. A 67-year-old Japanese man developed erythematous plaques on the scalp and elbows 5 years prior. He had exhibited vitiligo on the face, trunk and both hands for 10 years. He also noticed blurred vision preceding the vitiligo, and was diagnosed with bilateral uveitis 4 years prior, but had no history of ocular trauma or ocular surgery. When he visited our hospital, areas of symmetrical depigmentation were observed on the scalp, bilateral upper eyelids, neck, bilateral extremities and trunk (Fig. 1). Poliosis and alopecia were noted, but the poliosis was partial and it could not be determined if the alopecia was androgenetic. Erythematous plaques with scales were also observed, completely confined to the vitiligo in the posterior cervical region and bilateral elbows (Fig. 1). Blood tests for syphilis and angiotensin-converting enzyme were negative. The chest X-ray showed no abnormalities. An ophthalmological examination revealed a decrease in visual acuity (right, 0.3; left, 0.4) and bilateral uveitis. A fundoscopy revealed “sunset glow” fundus, characteristic of VKH (Fig. 2). Syphilis, sarcoidosis and Behc et’s disease were ruled out. A biopsy specimen of the vitiligo of the elbow demonstrated absence of melanin and the presence of clear cells in the basal layer. S-100 and Melan-A staining revealed no positive cells. A biopsy specimen of the erythematous plaque on the elbow demonstrated parakeratotic acanthosis with the elongation of the rete ridge, compatible with psoriasis. He was diagnosed with incomplete VKH (i.e. lacking neurological involvement) and psoriasis vulgaris. Topical steroids were effective for the psoriasis. However, treatment with oral prednisolone failed to improve the patient’s vision. The ophthalmological features of VKH are bilateral choroiditis, ocular depigmentation and chronic anterior uveitis in the absence of ocular trauma or surgery. Neurological, auditory or cutaneous findings, including vitiligo with symmetrical distribution, are also listed as diagnostic criteria. Only nine cases of the coexistence of VKH and psoriasis have been reported. Vitiligo was noted in five cases, and in most of these, psoriasis was confined to the vitiliginous areas. Autoimmune diseases were noted in two cases. Interestingly, only our case involved vitiligo preceding psoriasis. Although their concurrence may be coincidental, T-cellmediated autoimmunity may play a role in their onset. Recognition of tyrosinase and gp100 melanocyte antigens by CD4 T lymphoctes and recognition of MART-1 melanocyte antigen by cytotoxic T lymphocytes have been reported in VKH patients. A recent study has shown that T-helper (Th)17 cellrelated cytokines affect melanocyte function in addition to CD8 cell-mediated melanocyte destruction in vitiligo. Th17 cells and regulatory T cells (Treg) are known to play important roles in the pathogenesis of psoriasis. In VKH lesions, increased Th17 response and decreased frequency and function of Treg have been reported. It has been suggested that the vitiliginous lesions in VKH triggered psoriasis through these T-cell-mediated mechanisms. In conclusion, we reported an atypical instance of VKH, with vitiligo preceding the psoriasis. Further accumulation of cases may help elucidate the relationship between these two diseases.

Family with Legius syndrome (neurofibromatosis type 1-like syndrome).

Legius syndrome (Online Mendelian Inheritance in Man no. 611431) or neurofibromatosis type 1 (NF1)‐like syndrome was first reported by Legius et al. in 2007. We herein report the first instance of Legius syndrome occurring in two female siblings in Japan. Both individuals presented cafe‐au‐lait macules and freckling. Mutation analysis revealed a mutation of c.349C>T resulting in p.Arg117* in the SPRED1 gene as the cause of the Legius syndrome. The National Institutes of Health criteria for NF1 are insufficient to rule out the condition. For this reason, and because the clinical course of each condition is quite different, we stress the need to differentiate Legius syndrome from NF1 clearly.

Adult case of Langerhans cell histiocytosis.

Dear Editor, Langerhans cell histiocytosis (LCH) is characterized by a monoclonal proliferation of Langerhans cells. We present herein a case of LCH which had been misdiagnosed over a long period as seborrheic dermatitis (SD). A 40-year-old Japanese woman presented with a 6-month history of erythema on her forehead. Her condition had previously been diagnosed as SD by the attending dermatologist and treated with steroid ointment without results. She also had a 10-year history of central diabetes insipidus, and had been treated with vasopressin. When she visited us in October 2012, she presented infiltrative erythema with scales, papules, erosions and scars on the forehead and scalp (Fig. 1a,b). Erythema and papules were also noted on the chest and the back (Fig. 1c). T1-weighted magnetic resonance imaging of the brain showed a decrease in the high signal intensity usually found in the posterior pituitary, leading to the suspicion of diabetes insipidus. The biopsy specimens of the forehead skin demonstrated a proliferation of large, anaplastic cells in the dermis. These cells, also sporadically seen in the epidermis, where they formed broad lima bean or hoof-like configurations (Fig. 1d,e), were found to be positive for CD1a and S-100 staining but negative for CD68, CD30 and CD20 (Fig. 1f). Electron microscopy demonstrated abundant Birbeck granules, with a tennis racket-like configuration in the cytoplasm (Fig. 1g). The Birbeck granules were seen in 80% of the observed atypical cells. The patient was diagnosed with LCH based on the findings mentioned above. Her history of central diabetes insipidus was considered one of the hallmarks of multisystem LCH. Treatment with JLSG-02 protocol special C consisting of vinblastine, prednisolone, methotrexate and 6-mercaptopurine was then commenced. Nine courses in total were planned, of which six were completed. The eruptions on the chest improved after treatment but the lesion on the forehead remained. Until the current reclassification of the disease by The Writing Group of the Histiocyte Society, LCH was referred to as histiocytosis X, with three clinical subtypes, namely, Letter–Siwe disease, Hand–Sch€ uller–Christian disease and eosinophilic granuloma. Under the current definition, depending on the organs involved, LCH is categorized either as a singlesystem disease or as a multisystem disease. The multisystem disease category is further subdivided into lowand high-risk patient groups according to clinical course and response to treatment. It is worth noting that two other adult patients with SD-like eruptions have been reported in the published work during the past 10 years in Japan, raising the possibility that these, too, were cases of LCH. Hence, whenever intractable SD occurs in adults, such as in our patient, LCH should be considered in the differential diagnosis. The 5-year survival rate for adult LCH patients was 100% for the single-system type and 91.7% for the multisystem type. For this reason, some patients with the single-system disease were observed without drug intervention. In the present instance, we commenced the JLSG-02 protocol