Sarcomatoid Variant of Primary Cutaneous Anaplastic Large Cell Lymphoma.

Sarcomatoid variant of primary cutaneous anaplastic large cell lymphoma is rare and is a diagnostic challenge. Clinical manifestation often mimics that of an infectious disease. Predominance of spindle cells in the biopsy specimen prevents from suspecting lymphoma. Here, we report the fourth case of this entity with good prognosis. A 30-year-old woman presented with several nodules on the whole body. The biopsy revealed infiltration of spindle cells in the dermis with myxomatous background. The spindle cells were positive for CD4 and CD30 and negative for CD3, CD8, CD20, and anaplastic lymphoma kinase. Although most of the skin lesions spontaneously resolved, a new red nodule progressively expanded on the left axilla. Finally, the patient received chemotherapy, which resulted in complete remission. The patient is free of disease for 18 months.

Pds5 Regulates Sister-Chromatid Cohesion and Chromosome Bi-orientation through a Conserved Protein Interaction Module.

Sister-chromatid cohesion is established by the cohesin complex in S phase and persists until metaphase, when sister chromatids are captured by microtubules emanating from opposite poles [1]. The Aurora-B-containing chromosome passenger complex (CPC) plays a crucial role in achieving chromosome bi-orientation by correcting erroneous microtubule attachment [2]. The centromeric localization of the CPC relies largely on histone H3-T3 phosphorylation (H3-pT3), which is mediated by the mitotic histone kinase Haspin/Hrk1 [3-5]. Hrk1 localization to centromeres depends largely on the cohesin subunit Pds5 in fission yeast [5]; however, it is unknown how Pds5 regulates Hrk1 localization. Here we identify a conserved Hrk1-interacting motif (HIM) in Pds5 and a Pds5-interacting motif (PIM) in Hrk1 in fission yeast. Mutations in either motif result in the displacement of Hrk1 from centromeres. We also show that the mechanism of Pds5-dependent Hrk1 recruitment is conserved in human cells. Notably, the PIM in Haspin/Hrk1 is reminiscent of the YSR motif found in the mammalian cohesin destabilizer Wapl and stabilizer Sororin, both of which bind PDS5 [6-12]. Similarly, and through the same motifs, fission yeast Pds5 binds to Wpl1/Wapl and acetyltransferase Eso1/Eco1, in addition to Hrk1. Thus, we have identified a protein-protein interaction module in Pds5 that serves as a chromatin platform for regulating sister-chromatid cohesion and chromosome bi-orientation.

rt-PA with Antithrombotic Therapies in a Case with Capsular Warning Syndrome.

We herein report a case of capsular warning syndrome (CWS) that was successfully treated with recombinant tissue plasminogen activator (rt-PA). A 70-year-old woman had repeated stereotyped transient ischemic attacks (TIAs) of right hemiparesis and dysarthria. After hospitalization, argatroban, aspirin, and cilostazol were started but were ineffective. Thirteen hours after the first episode of TIAs, severe symptoms occurred. Magnetic resonance imaging showed acute infarctions in the internal capsule to corona radiata, so we used rt-PA. Since then, the TIAs have not occurred, and the symptoms have considerably improved. This case suggests that rt-PA might be effective and safe for use in treating CWS.

RETRACTED: The inner centromere-shugoshin network prevents chromosomal instability.

Chromosomal instability (CIN) is a major trait of cancer cells and a potent driver of tumor progression. However, the molecular mechanisms underlying CIN still remain elusive. We found that a number of CIN(+) cell lines have impairments in the integrity of the conserved inner centromere-shugoshin (ICS) network, which coordinates sister chromatid cohesion and kinetochore-microtubule attachment. These defects are caused mostly by the loss of histone H3 lysine 9 trimethylation at centromeres and sometimes by a reduction in chromatin-associated cohesin; both pathways separately sustain centromeric shugoshin stability. Artificial restoration of the ICS network suppresses chromosome segregation errors in a wide range of CIN(+) cells, including RB- and BRCA1-deficient cells. Thus, dysfunction of the ICS network might be a key mechanism underlying CIN in human tumorigenesis.

Screening of the MERTK gene for mutations in Japanese patients with autosomal recessive retinitis pigmentosa.

PURPOSE: To determine whether mutations in the MERTK gene are present in Japanese patients with autosomal recessive retinitis pigmentosa (arRP). METHODS: The coding sequence of all 19 exons and the adjacent flanking intron sequences of the MERTK gene were directly sequenced in 96 unrelated Japanese patients with arRP. RESULTS: Seventeen sequence variants were found; six missense changes, three isocoding changes, and eight intron changes were also observed. One arRP patient had a novel homozygous Leu12Pro missense mutation in the MERTK gene. CONCLUSIONS: Mutations in the MERTK gene are relatively rare in Japanese patients with arRP.

Mutations in the pre-mRNA splicing gene, PRPF31, in Japanese families with autosomal dominant retinitis pigmentosa.

PURPOSE: To describe the clinical and genetic characteristics of three Japanese families with autosomal dominant retinitis pigmentosa (ADRP) associated with mutations in the PRPF31 gene. DESIGN: Case reports and results of DNA analysis. METHODS: Mutational screening of the PRPF31 gene was performed on 96 unrelated patients with ADRP by direct sequencing. The clinical features were characterized by complete ophthalmologic examinations. RESULTS: Three mutations in the PRPF31 gene, designated as 1142delG, 1155-1159delGGACG/insAGGGATT, and IVS6 to 3 to -45del, were identified in three unrelated Japanese families with ADRP. The 1142delG and 1155-1159delGGACG/insAGGGATT mutations are novel. The phenotype of affected family members was typical of retinitis pigmentosa (RP). Additionally, we identified asymptomatic obligate carriers. CONCLUSIONS: The 1142delG and 1155-1159delGGACG/insAGGGATT mutations in the PRPF31 gene cause RP. The prevalence of mutations in the PRPF31 gene in Japanese patients with ADRP is approximately 3%. However, it is important to note that there are asymptomatic obligate carriers.

Screening for mutations in the IMPDH1 gene in Japanese patients with autosomal dominant retinitis pigmentosa.

PURPOSE: To determine the presence and frequency of mutations in the IMPDH1 gene in Japanese patients with autosomal dominant retinitis pigmentosa (ADRP), and to characterize the clinical characteristics of patients with the Lys238Arg mutation in the IMPDH1 gene. DESIGN: Case reports and results of DNA analysis. METHODS: All 14 coding exons of the IMPDH1 gene were directly sequenced in 96 unrelated patients with ADRP. The clinical features were determined by visual acuity, slit-lamp biomicroscopy, and kinetic visual field tests. RESULTS: Two novel mutations, a Leu227Pro and Lys238Arg, in the IMPDH1 gene were identified in two unrelated families with ADRP. The clinical features associated with the Lys238Arg mutation were an early-onset and severe retinal degeneration. CONCLUSIONS: The most commonly reported Asp226Asn mutation was not found in the Japanese population, instead two novel mutations were found. These findings suggest that mutations of the IMPDH1 gene cause ADRP in the Japanese population.

Screening for mutations in CYP4V2 gene in Japanese patients with Bietti's crystalline corneoretinal dystrophy.

PURPOSE: To describe the clinical and genetic characteristics of six Japanese families with Bietti's crystalline corneoretinal dystrophy (BCD). DESIGN: Case reports and results of DNA analysis. METHODS: Mutation screening was performed on six unrelated patients with BCD by direct sequencing. The clinical features were characterized by the visual acuity, slit-lamp biomicroscopy, electroretinography, fluorescein angiography, and kinetic visual field testing. RESULTS: An identical IVS6 to 8delTCATACAGGTCATCGCG/insGC mutation in the CYP4V2 gene was identified in five of the patients with BCD; the sixth patient had a novel Trp340X mutation in the CYP4V2 gene. Three patients showed crystalline-like deposits at the limbus by specular microscopy. Ophthalmic findings of all patients had a rapid progression after age 50 years. CONCLUSIONS: Our findings suggest that the IVS6 to 8delTCATACAGGTCATCGCG/insGC mutation is a common mutation in Japanese patients with BCD. Although phenotypic variability was found, the natural course was almost the same in all of our patients.

Clinical features of Japanese families with a 402delT or a 555-556delAG mutation in choroideremia gene.

PURPOSE: To characterize the clinical features of two Japanese families with choroideremia associated with a 402delT and a 555-556delAG mutation in the choroideremia gene (CHM). METHODS: Four affected members and one obligate carrier from two Japanese families with choroideremia were studied. To detect mutations of the CHM gene, the products of polymerase chain reaction were directly sequenced in both directions. The ophthalmologic examination included best-corrected visual acuity, slit-lamp examination, fundus examination, kinetic perimetry, electroretinography, and fluorescein angiography. RESULTS: A 402delT and a 555-556delAG mutation were found in two Japanese families with choroideremia. All affected members had night-blindness, progressive constriction of the visual field, chorioretinal atrophy, and mottled appearance of the retinal pigment epithelium. The obligate carrier had mild patchy areas of retinal pigment epithelial atrophy with no visual symptoms. CONCLUSION: The authors found a 402delT and a 555-556delAG mutation in the CHM gene, one of which (402delT) is a novel mutation. They conclude that these mutations cause choroideremia in Japanese families.

Novel 615delC mutation in the CRX gene in a Japanese family with cone-rod dystrophy.

PURPOSE: To characterize the clinical features of a Japanese family with cone-rod dystrophy associated with a novel 615delC mutation in the cone-rod homeobox (CRX) gene. DESIGN: Case reports and results of DNA analysis. METHODS: Mutational screening by direct sequencing was performed for the three exons in the CRX gene. The clinical features were evaluated by visual acuity measurements, electroretinography, and kinetic visual field testing. RESULTS: A 615delC mutation in the CRX gene was identified and found to cosegregate with cone-rod dystrophy. The ophthalmic findings included cone-rod dystrophy with negative-type electroretinograms (ERGs) and a rapid progression after the age of 40 years. CONCLUSION: These findings indicate that the 615delC mutation causes cone-rod dystrophy with a negative-type ERG. The genotype-phenotype correlation in the CRX gene in our patient and others reported in the literature suggest that the negative-type ERG might be a good sign for having a mutation in the CRX gene.

An instrument capable of grading visual function: results from patients with retinitis pigmentosa.

There was no device to grade visual function in patients with retinitis pigmentosa (RP). We have therefore developed an instrument capable of measuring and quantifying the visual capabilities, and here present the results from patients with RP. In total, 118 eyes of 59 patients, 26 men and 33 women, with RP were studied. Seven eyes had hand movement (HM) and eight had light perception (LP) vision, and the others had better visual acuity. The Low Vision Evaluator (LoVE) consists of a pair of goggles with white, light-emitting diodes as the stimulus, a control box, an on-off button to signal the detection of the stimulus, and a printer for permanent records. There are 15 luminance levels of stimuli (combination of 5 intensities and 3 durations). The stimuli are delivered in a random sequence with an audio signal presented 0.3 seconds prior to the light stimulus. Each eye was tested separately, and each stimulus magnitude (intensity x duration) was presented 3 times for a total of 27 stimuli per eye. With 6 catch trials (audio signal without a light stimulus), a total of 60 trials were examined in a full examination. The conventional visual acuity and kinetic visual fields were determined. 59 patients had different visual acuities that ranged from no light perception (NLP) to 1.5 vision, and visual field sizes that ranged from 0.0001 to 3.96 steradians. The visual acuity and visual field size were significantly correlated with the LoVE score (r=0.58 and 0.64, respectively; p<0.01). These results indicate that the LoVE is capable of grading the visual function of RP patients with various visual acuities and visual fields. The testing procedures are simple for the patient and examiner, and this instrument can be used to assess the effectiveness of medical and surgical therapy.

Novel 2336-2337delCT mutation in RP1 gene in a Japanese family with autosomal dominant retinitis pigmentosa.

PURPOSE: To determine the frequency and kinds of mutations in the RP1 gene, and to characterize the clinical features of a Japanese family with autosomal dominant retinitis pigmentosa (ADRP) with a novel 2336 to 2337delCT mutation in the RP1 gene. DESIGN: Case reports and results of DNA analysis. METHODS: Mutational screening by direct sequencing was performed on 96 unrelated patients with ADRP. The clinical features were determined by complete ophthalmologic examinations. RESULTS: A novel 2336 to 2337delCT mutation in the RP1 gene was identified in two patients from a Japanese family with ADRP. In addition, three families with ADRP carried a previously reported nonpathogenic Arg1933X mutation. The ophthalmic findings with a 2336 to 2337delCT mutation were similar to those of typical retinitis pigmentosa with rapid progression after age 40 years. CONCLUSIONS: The most common Arg677X mutation in the white population was not found in the Japanese population; instead a novel mutation was found.

Autosomal dominant macular degeneration associated with 208delG mutation in the FSCN2 gene.

OBJECTIVE: To assess the clinical and genetic characteristics of 2 Japanese families with autosomal dominant macular degeneration (ADMD) associated with a 208delG mutation in the retinal fascin (FSCN2) gene. DESIGN: Case reports with clinical findings and results of fluorescein angiography, electroretinography, kinetic visual field testing, and DNA analysis. SETTING: University medical center. RESULTS: The 208delG mutation in the FSCN2 gene was identified in 14 members of 4 Japanese families with autosomal dominant retinitis pigmentosa and in 5 members of 2 Japanese families with ADMD. The characteristic features associated with this mutation led to 2 different phenotypes, autosomal dominant retinitis pigmentosa and ADMD. CONCLUSIONS: The 208delG mutation in the FSCN2 gene produces not only autosomal dominant retinitis pigmentosa but also ADMD in the Japanese population. This mutation is relatively common in Japanese patients with autosomal dominant retinal degeneration and showed clinical variability. CLINICAL RELEVANCE: Autosomal dominant retinitis pigmentosa and ADMD can be caused by the same 208delG mutation. We suggest that mutations in the FSCN2 gene can lead to a spectrum of phenotypes.

Ocular findings in a Japanese family with an Arg41Trp mutation of the CRX gene.

PURPOSE: To characterize the ophthalmological features and clinical course of an autosomal dominant cone-rod dystrophy (CORD2) in a Japanese family with an Arg41Trp mutation in the CRX gene. METHODS: Mutation screening by direct sequencing was performed on 42 patients with cone-rod dystrophy. The clinical features of the patients were characterized by the visual acuity and by the findings of slit-lamp biomicroscopy, electroretinography, fluorescein angiography, and kinetic visual field testing. RESULTS: An Arg41Trp mutation in the CRX gene was identified in three members from three generations of one family with cone-rod dystrophy. Fundus examination demonstrated that the retinal dystrophy worsened with increasing age. CONCLUSIONS: A heterozygous Arg41Trp mutation in the CRX gene can produce cone-rod dystrophy in Japanese patients. Clinical examination of patients of different ages demonstrated that there was a rapid progressive worsening of the disease with increasing age.