Michiya Yamaguchi

The Majority of Generalized Pustular Psoriasis without Psoriasis Vulgaris Is Caused by Deficiency of Interleukin-36 Receptor Antagonist

Generalized pustular psoriasis (GPP) is a rare inflammatory skin disease that can be life-threatening. Recently, it has been reported that familial GPP is caused by homozygous or compound heterozygous mutations of IL36RN. However, the majority of GPP cases are sporadic and it is controversial whether IL36RN mutations are a causative/predisposing factor for sporadic GPP. We searched for IL36RN mutations in two groups of GPP patients in the Japanese population in this study: GPP without psoriasis vulgaris (PV), and GPP with PV. Eleven cases of GPP without PV (GPP alone) and 20 cases of GPP accompanied by PV (GPP with PV) were analyzed. Surprisingly, 9 out of 11 cases of GPP alone had homozygous or compound heterozygous mutations in IL36RN. In contrast, only 2 of 20 cases of GPP with PV had compound heterozygous mutations in IL36RN. The two cases of GPP with PV who had compound heterozygous mutations in IL36RN are siblings, and both cases had PV-susceptible HLA-A*0206. We determined that GPP alone is a distinct subtype of GPP and is etiologically distinguished from GPP with PV, and that the majority of GPP alone is caused by deficiency of the interleukin-36 receptor antagonist due to IL36RN mutations.

A case of cutaneous odontogenic sinus.

Despite the fact that cutaneous sinus tracts of odontogenic origin are well documented, the condition is still commonly misdiagnosed, because chronic periapical periodontitis may be asymptomatic and is rarely open to the skin. A 75‐year‐old Japanese woman presented to our clinic with the chief complaint of a left cheek skin lesion with mild pain. Physical examination revealed a subcutaneous nodule covered with erythematous skin on her left buccal region. Cultures from the subcutaneous nodule grew Bacteroides species and Peptostreptococcus micros but did not yield acid‐fast bacilli, fungi, or Actinomyces. Stains of smeared pus showed a considerable number of Gram‐negative rods. The histopathological examination revealed a focal abscess formation in the lower dermis and subcutaneous tissue. Dental evaluation, including an orthopantogram, showed a radiolucent alveolar area at the left lower first molar apex, suggesting a periapical abscess. Antibiotic therapy for three weeks associated with surgical root canal therapy eliminated the subcutaneous nodule. A high degree of suspicion is required to correctly diagnose a lower facial lesion as being of odontogenic origin, and prompt dental evaluation should be considered.

IgG4‐related disease manifesting the gastric wall thickening

IgG4‐related disease (IgG4‐RD) is a recently designated disease entity and its full picture has not yet been elucidated. Here, we report an unusual case of a patient with gastric wall thickening secondary to IgG4‐RD. A 68‐year‐old male visited our hospital with itchy skin lesions and an episode of organizing pneumonia. On the suspicion of malignancy‐associated skin lesions, computed tomography (CT) was performed. The CT revealed prominent thickening of the gastric wall. Due to the possibility of malignancy, the patient underwent distal gastrectomy. Histopathological examination showed fibrosis of the submucosa and prominent thickening of the muscularis propria. Most of infiltrating cells were IgG4‐positive plasma cells. Post‐operative blood test revealed significantly high serum levels of total IgG and IgG4. Based on these histological features, the patient was given a definitive diagnosis of IgG4‐RD. Further accumulation of cases like the present case that develop IgG4‐RD with rare manifestations would lead to the elucidation of pathogenesis.

Tender, red nodules and arthralgia in a young woman with mastitis

A 27-year-old Japanese woman presented with sudden onset of erythematous nodules on her arms and legs, associated with arthralgia, and swelling of elbows, knees and ankles bilaterally. The nodules and arthralgia had developed 3 days previously, while she was undergoing treatment for a painful lump in her left breast. This lump had developed about 1 month previously, and the patient had been diagnosed with mastitis and treated with oral antibiotics and drainage. The patient had a 2-year history of diabetes mellitus, but had maintained good glycaemic control with the use of an oral antihyperglycaemic agent. She did not use oral contraceptives, and she had never been pregnant. On physical examination, an indurated mass, 80 9 60 mm in size, was found in the upper inner quadrant of the left breast (Fig. 1a). There were also tender, bright red nodules and plaques, 20–40 mm in size, on the arms and the anterior legs (Fig. 1b,c). The patient’s temperature was 38.6 °C. Bacterial, fungal and mycobacterium cultures of the exudate were all negative. Chest radiography was normal. Laboratory investigations identified raised C-reactive protein level of 5.79 mg/dL (normal < 0.2 mg/dL) and an increased white cell count of 18.12 9 10/L (normal 4–10 9 10/L) with a high percentage of neutrophils (82.5%; normal range 40–60%). Serum angiotensin-converting enzyme level was normal, and tests for serum antinuclear antibody and rheumatoid factor were negative. Histopathological findings

A rare case of the cutaneous form of adult T-cell leukaemia/lymphoma: assessment of remission by PCR for clonal T-cell receptor γ gene rearrangements in an electron beam-irradiated cutaneous lesion

Adult T‐cell leukaemia/lymphoma is a lymphoproliferative disorder aetiologically associated with human T‐cell lymphotropic virus type I infection. A cutaneous lesion often develops in the disease, and in rare cases, is even the only manifestation. Here we report a rare case of ‘cutaneous’ adult T‐cell leukaemia/lymphoma with neither atypical cells in the peripheral blood nor lymph node involvement. All nodular lesions were completely eliminated after local electron beam irradiation (20 Gy/nodule in total). To evaluate whether or not there were residual lymphoma cells in the skin, we performed PCR to detect clonal T cell receptor γ gene rearrangements. The sample from the nodule before irradiation showed evidence of a rearranged band, which was not detected at the same site after treatment nor in any peripheral blood. The findings suggest that this procedure is useful for the evaluation of therapeutic effects and the early detection of lymphoma recurrence.

A case of pseudochromhidrosis due to dihydroxyacetone.

Dear Editor, The term pseudochromhidrosis is applied when initially colorless sweat becomes colored on the surface of skin when exposed unprotected to exogenous dyes, paints or chromogenic microorganisms such as Corynebacterium or Piedraia.1 Herein, we describe a patient simulating eccrine chromhidrosis turned out to be pseudochromhidrosis (PCH) after detailed history taking. Brownish pigmentation diffusely presented on the palms. He worked at a chemical factory and often used dihydroxyacetone (DHA). The combination of DHA and amino acids in the skin causes skin tanning. Therefore, we diagnosed the brownish pigmentation of the palms as PCH due to DHA in this case. A 42-year-old man complaining of diffuse brownish pigmentation on the palms was seen in our hospital. The brownish pigmentation had appeared 3 months previously. His past and family histories were not contributory. Cutaneous examination revealed diffuse brownish pigmentation on the palms (Fig. 1). He told us that he had sometimes noticed brownish pigmentation on his face and neck. Otherwise his physical condition was excellent. Routine laboratory tests and endocrinological tests including pituitary and adrenal glands were normal. A biopsy specimen obtained from the left palm revealed no increase of melanin granules in the basal layer of the skin. Initially, we suspected that the pigmentation was caused by some oil or grease, because he had begun to notice the brownish pigmentation since he had started to work at the chemical factory. However, he told us that he had never used oil or grease. Our detailed investigation of the patient informed us that he used DHA at the factory. He was engaged in transferring liquid DHA from a tank into that of a tank truck at the factory. Although he was told to obey the rule to wear gloves, he never did. He told us that another colleague who always wore gloves at work did not have the same condition. The pigmentation was continuously present for several hours after work and was easily removed with water and soap. The pigmentation was also easily wiped off with ethyl alcohol. Although we did not directly note brownish sweating, we diagnosed PCH due to DHA mainly based on the detailed history of the life and work

Two Japanese families with hypohidrotic ectodermal dysplasia: Phenotypic differences between affected individuals

of HVCD. She was referred to our hospital for treatment. At our initial examination, a firm, painless nodule of 5 cm in diameter was palpable. Her lymph nodes were not palpable. Laboratory studies revealed no abnormal findings. A well-circumscribed tumor was excised with a minimal margin. Macroscopic examination revealed an oval mass of 4 cm on the major axis, and the half-split face was yellowish. The histopathological features of the resected mass were similar to those seen in the biopsy sample. Neither monoclonal IGH gene rearrangement nor TRG gene rearrangement was detected. The patient’s condition was finally diagnosed as HV of UCD. There has been no recurrence in the 7 months since the resection operation. Extranodular CD lesions, particularly subcutaneous ones, are very rare. Only 13 subcutaneous cases of CD have been reported, including ours. Of these 13 cases, 12 were UCD and one was multicentric CD. As for the histopathological types, one of the UCD cases showed mixed histopathological features of HV and the plasma cell type, although the other cases are all classified as HV. The subcutaneous CD patients’ ages ranged 3– 69 years, with the present case being the youngest. As the present case had a very early onset CD lesion at an uncommon site, it was 6 years before she was diagnosed with UCD. We should add UCD as a differential diagnosis for subcutaneous tumors on the trunk of children.

Identification of a novel splice site mutation in the LIPH gene in a Japanese family with autosomal recessive woolly hair

Dear Editor, Among all hereditary hair disorders, a non-syndromic form of autosomal recessive woolly hair (ARWH; Online Mendelian Inheritance in Man #604379) resulting from mutations in the lipase H (LIPH) gene is known to be highly prevalent in the Japanese population. The LIPH gene is abundantly expressed in hair follicles and encodes an enzyme that produces 2-acyllysophosphatidic acid. Therefore, a lipid mediator is believed to play crucial roles in the hair follicle development. Although most Japanese patients with ARWH are caused by two founder mutations in the LIPH gene, p.C246S and p.H248N, other LIPH mutations can occasionally be found. We recently identified a Japanese family with two affected girls showing typical clinical features as non-syndromic woolly hair (Fig. 1a,b). Neither of their parents was affected. After obtaining written informed consent, we collected blood samples from the patients to extract genomic DNA. We were unable to obtain samples from either parent. We searched for mutations in the LIPH gene of the patients using primer pairs described previously. We initially identified a heterozygous mutation c.736T>A (p.C246S) in exon 6 of the LIPH gene in both patients (Fig. 1c). In addition, they carried heterozygous sequences in intron 7 of LIPH (Fig. 1d). Polymerase chain reaction (PCR) for this region amplified two distinct products from the patients’ DNA (Fig. 1e), while only a single fragment was amplified from 100 healthy control individuals (Fig. 1e; data not shown). We cloned the PCR products from the patients into a vector and sequenced each product separately, which showed that the shorter product not only had a nucleotide substitution T>A at position c.982+2, but also a 15-bp nucleotide deletion at position c.982+7_+21, and thus, the mutation was designated as c.982+2T>A; +7_+21del (Fig. 1f). To our knowledge, it has not previously been reported. As the next step, we PCR-amplified the sequences containing exons 6–8 of LIPH from the patients’ DNA and subcloned the products into the pCXN2.1 vector. Direct sequencing analysis revealed that each mutation was on a different allele. Then, we transfected the vectors into HEK293T cells, extracted total RNA after 24 h and performed reverse transcription PCR following the methods reported previously. This in vitro transcription assays demonstrated a shorter LIPH cDNA from the p.246C (c.982+2T>A; +7_+21del) allele, as compared with the p.246S allele (Fig. 1g). Sequencing of the shorter product revealed that it lacked the entire sequences of exon 7; that is, skipping of exon 7 was induced during the splicing event from the p.246C allele (Fig. 1h). In this study, we analyzed a Japanese family with ARWH and identified a novel splice site mutation c.982+2T>A; +7_+21del in the LIPH gene (Fig. 1d–f), which caused skipping of exon 7 in cultured cells (Fig. 1g,h). As exon 7 consists of 96-bp nucleotide sequences, the protein product from this aberrant transcript was predicted to have an amino acid substitution at codon 296 and an in-frame amino acid deletion from codons 297–328, thus designated p.G296V; p.Y297_M328del (Fig. 1h). Functional consequences resulting from the mutant protein need to be analyzed in the future.

Case of generalized pustular psoriasis that might have progressed from terbinafine-induced acute generalized exanthematous pustulosis

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Sporadic case of Darier disease caused by a novel splice-site mutation in the ATP2A2 gene

Darier disease (DD) (MIM 124200) is an autosomal dominant genodermatosis characterized by warty papules and plaques mainly in seborrhoeic areas, as well as neuropsychiatric abnormalities in some cases. Histologically, prominent acantholysis and hyperkeratosis with dyskeratotic cells are observed. DD is caused by mutations in the ATP2A2 gene, encoding the sarcoplasmic/endoplasmic reticulum Ca-ATPase-2 (SERCA2), which plays crucial roles in cell–cell adhesion in the epidermis. Although over 200 ATP2A2 mutations have been reported to date, splice-site mutations are relatively rare.