Yoshihiro Matsudate

Primary cutaneous mucormycosis caused by Mucor irregularis in an immunocompetent patient

Dear Editor, Mucormycosis, which mainly affects immunocompromised patients, is a rare, life-threatening infection caused by the order Mucorales. Among the six clinical types of mucormycosis, cutaneous mucormycosis is the rarest and is further categorized into two types: (i) the gangrenous type, which only occurs in immunocompromised patients and progresses rapidly, and (ii) the superficial type, which develops in immunocompetent individuals, manifests as erythematous plaques, and progresses slowly. We present a case of superficial cutaneous mucormycosis caused by Mucor irregularis (M. irregularis) involving an immunocompetent patient. A 16-year-oldJapanese boy who was otherwise healthy presented with a 1-year history of a gradually enlarging plaque on his leg. A physical examination demonstrated an erythematous plaque exhibiting slight desquamation on his lower right leg, which he had scraped in a bicycle accident 2 years before (Fig. 1a). A histopathological examination detected a suppurative granuloma containing neutrophils, lymphocytes, and multinucleated giant cells in the dermis (Fig. 1b). Broad, ribbon-like, hyaline, aseptate hyphae were also observed (Fig. 1c). However, fungal hyphae and microvascular thrombosis were not detected in his blood vessels. Skin tissue specimens and skin scales cultured on Sabouraud dextrose agar at 25°C yielded wool-like, light yellow colonies, but no colony growth occurred at 38°C (Fig. 1d). Microscopic examinations of slide cultures detected sporangiophores, which had formed a terminal, globose sporangium. No apophyses were observed (Fig. 1e). These findings were consistent with Mucor fungi, and the isolate was identified as Mucor irregularis based on sequencing of the D1/D2 domain of the large subunit rRNA gene (GenBank accession no. IFM 57177). Before obtaining a diagnosis, we tried itraconazole (100 mg/ day), fluconazole (200 mg/day), and voriconazole (300 mg/day), independently, as empirical therapies, but none of them was effective. However, when we administered high-dose itraconazole (400 mg/day), the patient’s plaque gradually regressed. Itraconazole was administered for a total of 9 weeks (Fig. 1f). No recurrence has been observed for 5 years. M. irregularis was originally known as Rhizomucor variabilis, but it was renamed M. irregularis based on its DNA sequence. Cases of mucormycosis due to M. irregularis are rare, and only 14 cases have been reported in the English-language literature. However, it is worth noting that mucormycosis due to M. irregularis presents with unique clinical features. In contrast to classical mucormycosis, most M. irregularis infections affect immunocompetent patients and do not exhibit angioinvasion, especially in the early stages. Moreover, the majority of M. irregularis infections manifest as the superficial cutaneous type, progress chronically, and persist for several years on exposed sites. It is unknown why M. irregularis infections display these unique features. However, the lower thermotolerance of M. irregularis could be responsible for its lack of angioinvasion. Amphotericin B is the first-line treatment for M. irregularis infections (as well as for other types of mucormycosis), and

Paraneoplastic pemphigus associated with non-Hodgkin's lymphoma

Auteur(s) : Takeshi ISHIGAMI1, Yoshiaki KUBO1 ykubo@clin.med.tokushima-u.ac.jp, Yoshihiro MATSUDATE1, Shinichi ANSAI1, Seiji ARASE1, Bungo OHYAMA2, Takashi HASHIMOTO2 1 Department of Dermatology, University of Tokushima Institute of Health Biosciences, 3-18-15 Kuramoto-cho, 770-8503 Tokushima-city, Japan 2 Department of Dermatology, Kurume University School of Medicine, Fukuoka, Japan Paraneoplastic pemphigus (PNP) is an autoimmune blistering disease described first by Anhalt et al. in 1990 [1]. [...]

Coexistence of X-linked ichthyosis and Nagashima-type palmoplantar keratosis: A case report

Dear Editor, X-linked ichthyosis (XLI) is an X-linked recessive disorder characterized by desquamation of large brown scales on the limbs and trunk, while the palms and soles are spared. XLI is caused by a deficiency in steroid sulfatase (STS) activity due to STS gene mutations. Nagashima-type palmoplantar keratosis (NPPK) is an autosomal recessive disorder characterized by hyperkeratosis and erythema on the palms and soles extending to the dorsum of the hands and feet, inner wrists and Achilles tendon area. NPPK is also characterized by a whitish spongy change in affected areas upon exposure to water. Recently, homozygous or compound heterozygous loss-of-function mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, have been identified as causative genes of NPPK. Here, we report the first case of both XLI and NPPK, which seems to be a coincidence. A 9-year-old boy presented with scaly skin on the extremities and trunk (Fig. 1a,b). He also had mental retardation, epilepsy, hyperactivity and scoliosis. His older brother, grandfather and grandfather’s brother also had scaly skin (Fig. 1c). Histopathological examination showed hyperkeratosis and a normal granular layer in the epidermis. Fluorescence in situ hybridization analysis using an LSI STS Spectrum Red/ DXZ1 Spectrum Green (Abbott Molecular, Des Plaines, IL, USA) probe showed no red fluorescent spot, suggesting deletion of the STS gene. An approximately 1.7-Mb deletion containing six RefSeq genes, including full-length STS, was detected by chromosomal microarray analysis (Fig. 1d). Based on these findings, we diagnosed him as having XLI. Subsequently, we noticed well-demarcated diffuse palmoplantar hyperkeratosis and mild erythema that extended to the dorsum of the hands and feet, inner wrists and Achilles tendon area (Fig. 1e,f). Mild hyperkeratotic lesions on the knees were also observed (Fig. 1a). The affected skin showed a whitish spongy change within 10 min of exposure to water (Fig. 1g,h). His parents were non-consanguineous and no relatives were affected by palmoplantar keratosis (Fig. 1c). Direct sequencing of SERPINB7, as previously reported, revealed a heterozygous nonsense mutation (c.796C>T: p.Arg266Ter), but no pathogenic mutations were detected in another allele except for single nucleotide polymorphisms in introns or 30-untranslated regions (rs2689399, rs1625353, rs2658459, rs1720858 and rs374963251). Gross deletion of SERPINB7 was not detected by chromosomal microarray analysis. His mother had the same heterozygous c.796C>T mutation but palmoplantar hyperkeratosis was not seen. Palmoplantar hyperkeratosis is an unusual clinical feature for XLI. Thus, we made a diagnosis of NPPK based on typical clinical features. Obvious mutations of SERPINB7 in both alleles have not been detected in all NPPK cases. Because his mother with the same heterozygous mutation shows no abnormal features in her palmoplantar regions, a novel SERPINB7 mutation in another allele may be present outside the analyzed regions such as deep introns or regulatory regions in the present case. Further examinations using additional techniques are needed to detect such mutations. The eruptions of NPPK can be overlooked if they are accompanied by other dermatoses as in our case and atopic dermatitis. Dermatologists should pay attention to characteristic lesions of NPPK in such cases.

Chemotherapy-induced inflammation of seborrheic keratoses due to pemetrexed treatment

reveal other skin or mucosal lesions. The mother reported that a few days before the visit she noticed for the first time the appearance of a blister. Clinical examination along with reflectance confocal microscopy (RCM) (Vivascope 3000 ; Caliber I.D., Rochester, NY, USA) and optical coherence tomography (OCT) (VivoSight ; Michelson Diagnostics, Maidstone, UK) performed on the tense bulla of the left leg suggested a diagnosis of bullous pemphigoid (BP) (Fig. 1c,d,g). Instead, RCM and OCT executed on the healthy skin surface adjacent to the erythematous plaque showed normal layered architecture of the skin (Fig. 1e,f,h). Then, we executed indirect immunofluorescence and two biopsies, one for histopathological examination and one for direct immunofluorescence. Histopathological examination confirmed our diagnostic suspicion (Fig. 1i). Direct immunofluorescence showed immunoglobulin (Ig)G and C3 deposit to the dermoepidermal junction (DEJ) (Fig. 1l). Indirect immunofluorescence revealed antibodies directed to the DEJ with a titer of 1:40 (Fig. 1m). Moreover, we performed enzymelinked immunoassay (ELISA) test: anti-BP180 IgG 106.89 U/mL and anti-BP230 IgG 1.20 U/mL. Based on all these findings, a diagnosis of BP was made. The patient subsequently underwent only topical corticosteroid therapy with clobetasol propionate 0.05% cream that was tapered over 4 months: every day in the first month, every other day in the second month, twice a week in the third month and once a week in the fourth month. After the end of the therapy, we observed the presence of milia and post-inflammatory pigmentation (Fig. 1n). In 2 years of follow up, there was no evidence of relapse or any additional lesion on other sites. In the published work, to the best of our knowledge, the association between BP and TSC is not reported. We did not find a correlation between BP and TSC, and we think that the occurrence of both diseases in a single individual is only accidental and extremely rare. Written informed consent was obtained from the patient’s legal guardian(s) (including the patient’s mother) for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Targeted exome sequencing and chromosomal microarray for the molecular diagnosis of nevoid basal cell carcinoma syndrome

BACKGROUND Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder mainly caused by heterozygous mutations of PTCH1. In addition to characteristic clinical features, detection of a mutation in causative genes is reliable for the diagnosis of NBCCS; however, no mutations have been identified in some patients using conventional methods. OBJECTIVE To improve the method for the molecular diagnosis of NBCCS. METHODS We performed targeted exome sequencing (TES) analysis using a multi-gene panel, including PTCH1, PTCH2, SUFU, and other sonic hedgehog signaling pathway-related genes, based on next-generation sequencing (NGS) technology in 8 cases in whom possible causative mutations were not detected by previously performed conventional analysis and 2 recent cases of NBCCS. Subsequent analysis of gross deletion within or around PTCH1 detected by TES was performed using chromosomal microarray (CMA). RESULTS Through TES analysis, specific single nucleotide variants or small indels of PTCH1 causing inferred amino acid changes were identified in 2 novel cases and 2 undiagnosed cases, whereas gross deletions within or around PTCH1, which are validated by CMA, were found in 3 undiagnosed cases. However, no mutations were detected even by TES in 3 cases. Among 3 cases with gross deletions of PTCH1, deletions containing the entire PTCH1 and additional neighboring genes were detected in 2 cases, one of which exhibited atypical clinical features, such as severe mental retardation, likely associated with genes located within the 4.3Mb deleted region, especially. CONCLUSION TES-based simultaneous evaluation of sequences and copy number status in all targeted coding exons by NGS is likely to be more useful for the molecular diagnosis of NBCCS than conventional methods. CMA is recommended as a subsequent analysis for validation and detailed mapping of deleted regions, which may explain the atypical clinical features of NBCCS cases.

Grover's disease in a patient with pemphigus vulgaris

Grover’s disease (GD) manifests as papules, papulovesicles or small nodules, which are self-limiting, usually lasting up to several months. The histopathologic hallmark of GD is primary acantholysis frequently combined with dyskeratosis. GD has been associated with a variety of systemic and cutaneous diseases. However, association with other primary acantholytic disorders has been rarely documented. Herein, we describe the first case of GD in association with pemphigus vulgaris (PV).

Two cases of eosinophilic pustular folliculitis associated with pregnancy

lated to play an important role in the pathogenesis of PG. A marked persistent leukocytosis (White blood cells, >50 000/lL) with bandemia, when the cause is other than leukemia, defines a leukemoid reaction. The major causes of leukemoid reactions include severe infections, intoxications and malignancies. A previous report showed that severe PG with extensive ulceration may have leukocytosis. That study evaluated 111 PG cases and only two cases presented with a leukemoid reaction. In our case, we speculate that an exacerbation of PG resulted in a leukemoid reaction while an exacerbation of PG by the hyperactivation of neutrophils due to a leukemoid reaction might have been possible, and that the delay of a treatment for the PG induced both a leukemoid reaction and a severe PG. A leukemoid reaction tends to be a sign of poor prognosis in various diseases. In the evaluation of the prognostic impact for PG patients, a statistical rigorous analysis is difficult due to the limited number of cases. Observations of individual cases (including our case) may suggest that a neutrophilic leukemoid reaction is an important sign that a patient is in a progressive course.

Case of nevoid basal cell carcinoma syndrome with multiple cutaneous keratocysts.

chemotherapy. Only 44 cases of primary cutaneous RMS have been reported in the published work, and they account for less than 1% of RMS. Primary cutaneous RMS presented bimodal age distribution like RMS, but without definite male predominance. To make a diagnosis of primary cutaneous RMS, the tumor should arise in the dermis or subcutaneous tissue with no evidence of deep soft tissue or metastatic origin. Of the 44 reported cases, the most common site is head and neck region (23 cases), and the most common histological subtype is alveolar (22 cases), followed by embryonal (10 cases) and pleomorphic (5 cases). Alveolar RMS is histologically characterized by the presence of small, round, neoplastic cells and alveolar-like spaces separated by connective tissue trabeculae. Muscle-specific actin and desmin have been reported as the most sensitive marker, whereas myoglobin, myogenin and MyoD1 are considered to have greater specificity. The differential diagnoses include general categories of tumors with small, round, blue cells. In our case, CD56 positivity made the differential diagnosis with Merkel cell carcinoma and malignant peripheral nerve sheath tumor difficult. However, CD56 expression has been demonstrated in RMS, and desmin and MyoD1 positivity with CK20 negativity facilitated the differential diagnosis. In cases of tumoral lesion following trauma, skeletal muscle regeneration (SMR) should also be included in the differential diagnosis. SMR is a pleomorphic proliferation with inflammatory and phagocytic reactions following trauma, and it may histologically simulate RMS. However, RMS lacks the peripheral maturation pattern observed in SMR. Our case is interesting in that the initial presentation of primary cutaneous RMS clinically resembled an atrophic scar.