Susumu Ichiyama

Effective treatment by glycolic acid peeling for cutaneous manifestation of familial generalized acanthosis nigricans caused by FGFR3 mutation

Acanthosis nigricans (AN) can occur as a cutaneous manifestation of genetic diseases, one of which is associated with activating mutations of the fibroblast growth factor receptor 3 gene (FGFR3).

Successful multitarget therapy using prednisolone, mizoribine and tacrolimus for Henoch–Schönlein purpura nephritis in children

Figure 1. Clinical, endoscopic, histopathological and electron micrography of skin, alimentary tracts and/or kidney, and mutations in CYP3A5 and MDR1. (a) Clinical images of lower limbs. (b) Histopathological observations of a skin biopsy showing hematoxylin–eosin (H-E) staining and direct fluorescent stainings with antiimmunoglobulin (Ig)A and -C3 antibodies (scale bar, 100 lm). (c) Endoscopic and histopathological findings of Henoch– Sch€ onlein purpura (HSP)-affected alimentary tracts (scale bar, 100 lm). (d) Histopathological and electron micrography observations of a renal biopsy. Arrows in periodic acid methenamine silver (PAM) and Masson-trichrome stainings indicate fibrin deposition. Direct fluorescent stainings with anti-IgA1, -IgA2 and C3 antibodies are also shown. Arrowheads and an arrow in the electron micrograph demonstrate mesangial deposits and infiltration of a macrophage, respectively. (e) DNA sequencing showing the single nucleotide polymorphisms in CYP3A5 and MDR1, whose products are involved in the metabolism of tacrolimus. The DNA analyses were conducted after obtaining written informed consent according to the guidelines of the institutional review board of Nippon Medical School Hospital in accordance with the Declaration of Helsinki guidelines.

Eczematous reactions mimicking psoriasiform dermatitis induced by nivolumab for advanced lung cancer

1. Stockman A, Delanghe J, Geerts M-L et al. Diffuse plane normolipaemic xanthomatosis in a patient with chronic lymphatic leukaemia and monoclonal gammopathy. Dermatology 2002; 204: 351–4. 2. Spanou Z, Borradori L. Diffuse plane xanthomas, a cutaneous marker for monoclonal gammopathies and lymphoproliferative diseases. Eur. J. Haematol. 2011; 86: 91. 3. Gadzia J, Kestenbaum T. Granulomatous slack skin without evidence of a clonal T-cell proliferation. J. Am. Acad. Dermatol. 2004; 50: 4–8. 4. Marcoval J, Moreno A, Bordas X et al. Diffuse plane xanthoma: clinicopathologic study of 8 cases. J. Am. Acad. Dermatol. 1998; 39: 439–42.

Dermoscopy of pigmented papillated Bowen disease: A report of two cases

(g) (h) Figure 1. (a) A 5 mm 9 3 mm brown keratotic plaque behind the left ear of the patient (case 1). (b) Dermoscopic findings showing whitish scaly fissures and bluegray to brown ridges surrounded by irregularly shaded brown areas. White arrows indicate fissures and a white arrowhead indicates ridges (case 1). (c) Histopathology showing a hyperkeratotic lesion with papillomatosis (case 1) (hematoxylin–eosin [HE], original magnification 920). (d) Atypical keratinocytes were hyperchromatic (case 1) (HE, 9400). (e) A 5 mm 9 3 mm dark brown keratotic nodule on the left knee of the patient (case 2). (f) Dermoscopic findings showing a blue-gray to brown cobblestone appearance with dark brown or whitish fissures and a continuing brown structureless area. White arrows indicate fissures and white arrowheads indicate ridges (case 2). (g) Histopathology showing hyperkeratosis, parakeratosis and papillary upward projections of the epidermis (case 2) (HE, 920). (h) Atypical keratinocytes were seen in the entire epidermis (case 2) (HE, 9200).

Assessment of medication adherence and treatment satisfaction in Japanese patients with psoriasis of various severities

Psoriasis is a chronic, relapsing, inflammatory keratotic skin disease. To elucidate the medication adherence and treatment satisfaction, we performed a questionnaire survey using the eight‐item Morisky Medication Adherence Scale (MMAS‐8) and nine‐item Treatment Satisfaction Questionnaire for Medication (TSQM‐9) of 163 psoriatic patients who regularly visited hospitals or clinics. To assess the relationship between the MMAS‐8/TSQM‐9 outcomes and severity of psoriasis, two different clinical severity indices were used: the Psoriasis Area and the Severity Index (PASI) for disease severity and the Psoriasis Disability Index (PDI) for quality of life (QOL) impairment. The MMAS‐8 score for oral medication was significantly higher than that for topical medication. The oral and topical MMAS‐8 scores were significantly correlated with the PDI score, but not with the PASI score, indicating that QOL impairment lowered treatment motivation. All of the TSQM‐9 domain scores (effectiveness, convenience and global satisfaction) were significantly correlated with both the PASI and PDI scores, suggesting that patients whose skin and QOL conditions were under good control had high satisfaction with treatment. Patients treated with biologics had higher satisfaction than those treated with non‐biologics.

Severe myalgia associated with brodalumab treatment in a patient with psoriasis

Dear Editor, Recent clinical trials have demonstrated the efficacy and safety of biologics for moderate to severe psoriatic patients. We describe here the first case of severe myalgia associated with brodalumab, an anti-interleukin (IL)-17 receptor antibody, which was administrated to a psoriatic patient but then discontinued. A 51-year-old Japanese woman with severe psoriasis was referred to our department for systemic treatment. Brodalumab 210 mg was injected into her lower abdomen at weeks 0, 1 and 2 followed by every 2 weeks until week 8. The Psoriasis Area and Severity Index score was dramatically improved from 11.6 at week 0 to 0.8 at week 4. Before brodalumab injection, all laboratory data were within normal limits, including the creatine kinase (CK) level (56 U/L; normal range, 60–170). At week 1, the patient started to complain of myalgia, which was gradually exacerbated as time passed (Table 1). Two days after week 8, she visited us complaining of severe myalgia mainly in her upper extremities. Although the CK level was still within the normal limit (78 U/L), manual muscle testing disclosed that muscular strength on the upper extremities had become slightly weaker and her grip strength was 14.0 kg/16.0 kg (left/right) (Table 1). Thyroid function tests were normal and she was negative for acetylcholine receptor antibodies. The myalgia was gradually resolved after the discontinuation of brodalumab. At week 15 (7 weeks after the discontinuation) the myalgia was almost completely resolved, manual muscle testing showed almost normal results, and grip strength returned to the normal level, 30.0 kg/30.0 kg (left/right) (Table 1). According to the brodalumab prescribing information (www.accessdata.fda.gov/drugsatfda. . ./761032lbl.pdf), myalgia occurred in 1.7% of subjects in a brodalumab group (n = 1496), in 0.3% with a placebo (n = 879) and in 0.7% with ustekinumab (n = 613), an anti-IL-12/23 monoclonal antibody. To the best of our knowledge, there has been no report of brodalumab-associated myalgia that is severe enough to result in cessation of the drug. Hinojosa et al. reported severe myalgia associated with adalimumab, an anti-tumor necrosis factor-a antibody, in a patient with Crohn’s disease. Interestingly, their case and our case have several points in common: myalgia, especially in upper extremities, was severe enough to result in discontinuation of the drugs, the results of all laboratory tests were within normal limits, including CK, the occurrence and improvement of the symptoms showed a serial order following introduction and withdrawal of the drugs, and, based on the Naranjo algorithm, the adverse reaction was scored as “probable”. Although the precise mechanism of myalgia associated with adalimumab and brodalumab is unknown, muscle tissue is highly sensitive to many drugs because of its high metabolic activity. Additional differential diagnoses include side-effects of other drugs and infections; however, their possibilities seem

Pigmented poroma on the temporal region dermoscopically mimicking basal cell carcinoma: A report of two cases

Dear Editor, Poroma is a benign neoplasm, in which tumor cells differentiate towards poroid and cuticular cells of acrosyringium. A 79-year-old woman (case 1) presented with an 18 mm 9 14 mm, bulb-shaped, light pink semipedunculated nodule with ring-like blackish macules on her left temporal region (Fig. 1a). A 58-year-old man (case 2) exhibited a similar 12 mm 9 12 mm, semipedunculated nubby nodule on his right temporal region (Fig. 1a). Dermoscopic examination revealed thick vessels and large blue-gray ovoid nests in both cases

A Case of External Dental Fistula Related to a Fixed Cantilever Bridge

An external dental fistula is a skin manifestation caused by an underlying dental problem. We report a rare case of external dental fistula associated with a fixed cantilever denture. A 77-year-old Japanese woman presented with an enlarging reddish granulomatous lesion on her right cheek that was diagnosed as an external dental fistula. A fixed cantilever denture had initially been attached to her upper jaw with her seven bona fide teeth. However, six teeth were completely lost and the denture was attached to only one tooth, which showed apical periodontitis. Subsequently, the external dental fistula developed. We should keep in mind that a patient with a fixed cantilever denture can suffer from apical periodontitis and a subsequent external dental fistula due to a failure to maintain appropriate oral hygiene.

Multiple unilaterally localized dermatofibromas in a patient with Down syndrome.

intermittent corticosteroid therapy who indicated zonal, painful and well-demarcated purpura plaques with hemorrhagic bullae on his lower abdomen, which dramatically progressed into ulcers and necrosis within a few days. The patient had initially noted back pain, followed 2 days later by purpura on the lower abdomen. Six days after onset of the back pain, high fever, over 38°C and hemorrhagic bullae appeared (Fig. 1a,b). Laboratory analyses revealed pancytopenia and elevations of C-reactive protein level, lactate dehydrogenase level and D-dimer level. Occult blood in urine was positive. An attack of hemolytic anemia triggered by an infectious disease including necrotizing fasciitis was first considered, and transfusions and antibiotic therapy were performed. Nevertheless, skin biopsy revealed subepidermal blisters and fibrin thrombi in all dermal vessels with a little inflammation. No apparent signs of vasculitis were evident (Fig. 1c–e). The skin manifestation resembled widespread cutaneous necrosis related to antiphospholipid syndrome but lupus anticoagulant and anticardiolipin-b 2-glycoprotein I complex antibody were negative. Given these results, the diagnosis of cutaneous thrombosis associated with PNH was assumed. The necrotic ulcers, secondary to intravascular clotting, were successfully recovered in 4 months by topical therapy (Fig. 1f–h). The cause of the hypercoagulability in PNH remains unclear and several mechanisms have been postulated. Platelet activation, resulting in the dissemination of procoagulant phospholipids in the blood flow, could be one of the main causes for the elevated thrombotic risk associated with PNH. The deficiency of CD55 and CD59 in the plasma membrane of platelets due to the PIG-A gene mutation also renders these cells more sensitive to complement-mediated activation. Furthermore, loss of glycosylphosphatidylinositol-linked urokinase-type plasminogen activator receptor reduces a fibrinolytic response to thrombosis. The most common sites of thrombosis in PNH include the intra-abdominal and cerebral veins, making thrombosis a leading cause of morbidity and mortality. Cutaneous thrombosis is very rare and these cases constitute approximately 0.6% of PNH cases with thrombosis. Cutaneous thrombosis is likely to appear simultaneously on several parts of the body although our case showed localized and zonal purpura on the lower abdomen. The patient usually spent a lot of time in a seated position at the office in work clothes with a belt around the skin lesion. The pressure of a belt might have been a cause of this cutaneous thrombosis in our case. In the present case, D-dimer level was steadily reduced without anticoagulant therapies but acute thrombosis in PNH is treated similarly to venous thrombosis occurring in other settings. Eculizumab, a humanized monoclonal antibody to C5 of the complement cascade, is a new therapy for PNH and also demonstrated a reduction of the risk of clinical thrombosis.

Effects of glycolic acid peeling on the cutaneous manifestation of generalized acanthosis nigricans caused by FGFR3 mutation: A report of one sporadic and two familial cases

Dear Editor, Generalized acanthosis nigricans (gAN) is a non-inflammatory keratosis characterized by thick, dark-brown, coarse skin, that can occur with activating mutations of FGFR3. We have reported two familial gAN patients (case 1, 20-year-old woman; case 2, case 1’s 50-year-old mother) both harboring a heterozygous c.1949A>C (p.K650T) mutation in FGFR3, causing constitutive activation of the coded receptor, and proposed that glycolic acid (GA) peeling can be an effective option to treat gAN. Further studies are necessary to demonstrate the therapeutic usefulness of the treatment. We herein report a newly found sporadic case of gAN having the identical FGFR3 mutation and examine the effects of GA peeling, referencing the therapeutic course after the publication of the report for cases 1 and 2. DNA analyses were conducted after obtaining written informed consent according to the guidelines of the institutional review board of Keio University School of Medicine in accordance with the Declaration of Helsinki guidelines. In February 2015, a 14-year-old female (case 3) presented with dark-brown coarse skin all over her body, especially on her neck, axilla and trunk, which had increased since she was 4 years old (Fig. 1a). No relatives showed similar symptoms