Deep-intronic variant of fukutin is the most prevalent point mutation of Fukuyama congenital muscular dystrophy in Japan.

Fukuyama congenital muscular dystrophy (FCMD), which is caused by mutations in the fukutin gene, is the second most common form of childhood muscular dystrophy in Japan. The founder haplotype is the most prevalent in the chromosomes of Japanese FCMD patients, and corresponds to an SVA retrotransposal insertion in the 3'-untranslated region of fukutin. Although other mutations have been reported, the mutation corresponding to the second most prevalent haplotype in Japanese FCMD patients remained unknown. Recently a deep-intronic point mutation c.647+2084G>T was identified in Korean patients with congenital muscular dystrophy. Here, we performed mutational analysis of 10 patients with the second most prevalent haplotype and found that all of them were compound-heterozygous for the SVA insertion and this c.647+2084G>T mutation. The fukutin mRNA of these patients contained a pseudoexon between exon 5 and exon 6, which was consistent with the previous Korean study. As expected, the mutated fukutin protein was smaller than the normal protein, reflecting the truncation of fukutin due to a premature stop codon. Immunostaining analysis showed a decrease in the signal for the glycosylated form of α-dystroglycan. These findings indicated that this mutation is the second most prevalent loss-of-function mutation in Japanese FCMD patients.

Hematopoietic progenitor cell mobilization using low-dose cyclophosphamide and granulocyte colony-stimulating factor for multiple myeloma.

High-dose chemotherapy (HDT) supported by autologous stem cell transplantation (ASCT) has long been one of the standards of care for younger patients with multiple myeloma (MM). Cyclophosphamide (CY) plus granulocyte colony-stimulating factor (G-CSF) has been the conventional preparation for hematopoietic progenitor cell (HPC) mobilization, although the optimal dosage of CY in this setting has not yet been clearly defined. This study investigated the efficacy and safety of low-dose (LD-)CY (1.5 g/m(2)) plus G-CSF for conditioning for HPC apheresis harvest (HPC-A) in 18 MM patients, and compared it with a regimen consisting of intermediate-dose (ID)-CY (4 g/m(2)) plus G-CSF for 13 MM patients. Eleven patients in the former and six in the latter were treated with bortezomib (BTZ) during the induction therapy. Both regimens were comparably effective in terms of CD34(+) cell yields, while adverse events, such as leukopenia, thrombocytopenia, and febrile neutropenia, occurred significantly less frequently in the LD-CY cohort. All patients in LD-CY cohort started and completed their apheresis on day 7 or 8, whereas for the ID-CY cohort the day of first apheresis varied widely from day 8 to 15. These findings indicate that the LD-CY regimen is as effective as ID-CY for HPC mobilization, while the former is clearly more practicable and convenient than the ID-CY regimen for patients with MM.

Ectopic hamartomatous thymoma growing in the sternocleidomastoid muscle masquerading as sarcoma.

The distinction between ectopic hamartomatous thymoma and sarcoma is difficult, and preoperative biopsy and intraoperative histopathological examination fail to give a definitive diagnosis. It is important to recognise ectopic hamartomatous thymoma as one of the differential diagnoses of a cervical tumour.

Cheek and periorbital peculiar discoid lupus erythematosus: rare clinical presentation mimicking tinea faciei, cutaneous granulomatous disease or blepharitis.

We present clinically peculiar facial discoid lupus erythematosus (DLE) that mimicked tinea faciei. Although DLE is a chronic autoimmune dermatosis, it has a variety of rare clinical presentations, including periorbital DLE, comedonic DLE and hypertrophic DLE recently. In this case, a scaly, erythematous lesion on the eyelid and the central healed, mildly elevated, annularly distributed facial DLE mimicked tinea faciei, complicating our diagnosis.

The longitudinal analysis of large granular lymphocytosis in patients with Philadelphia chromosome-positive leukemia treated with dasatinib.

Dasatinib, a 2nd-generation tyrosine kinase inhibitor (TKI), can specifically induce large granular lymphocytes (LGL) in some patients with Philadelphia chromosome (Ph)-positive leukemia. To investigate the properties of the induced LGLs, we performed prospective and longitudinal analyses. From Feb 2011 to Jan 2013, a total of 17 patients with Ph-positive leukemia who were previously untreated or refractory to imatinib were enrolled. T cell receptor (TCR)-γ/δ gene rearrangements and phenotypic profiles of lymphocytes were examined before and during administration of dasatinib. LGL lymphocytosis was observed in half of the dasatinib-treated cases (LGL+ group), showing a relation to increased achievement of complete cytogenetic response within 6 months. The phenotypes of the increased lymphocytes were revealed to be mostly natural killer cells. In the LGL+ group, clonal TCR-γ gene rearrangements were frequently detected at diagnosis (six of nine cases) and persisted during therapy, compared with only two of eight in the LGL- group. The proportion of regulatory T cells to CD4+ T cells at diagnosis was lower in the LGL+ compared with the LGL- group (median 4.2 vs. 6.6 %), and this disparity was sustained throughout the therapeutic period. These results demonstrate that immunological condition at diagnosis may affect LGL lymphocytosis in some dasatinib-treated patients.

Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation.

We recently identified mutations of ARX in nine genotypic males with X-linked lissencephaly with abnormal genitalia (XLAG), and in several female relatives with isolated agenesis of the corpus callosum (ACC). We now report 13 novel and two recurrent mutations of ARX, and one nucleotide change of uncertain significance in 20 genotypic males from 16 families. Most had XLAG, but two had hydranencephaly and abnormal genitalia, and three males from one family had Proud syndrome or ACC with abnormal genitalia. We obtained detailed clinical information on all 29 affected males, including the nine previously reported subjects. Premature termination mutations consisting of large deletions, frameshifts, nonsense mutations, and splice site mutations in exons 1 to 4 caused XLAG or hydranencephaly with abnormal genitalia. Nonconservative missense mutations within the homeobox caused less severe XLAG, while conservative substitution in the homeodomain caused Proud syndrome. A nonconservative missense mutation near the C-terminal aristaless domain caused unusually severe XLAG with microcephaly and mild cerebellar hypoplasia. In addition, several less severe phenotypes without malformations have been reported, including mental retardation with cryptogenic infantile spasms (West syndrome), other seizure types, dystonia or autism, and nonsyndromic mental retardation. The ARX mutations associated with these phenotypes have included polyalanine expansions or duplications, missense mutations, and one deletion of exon 5. Together, the group of phenotypes associated with ARX mutations demonstrates remarkable pleiotropy, but also comprises a nearly continuous series of developmental disorders that begins with hydranencephaly, lissencephaly, and agenesis of the corpus callosum, and ends with a series of overlapping syndromes with apparently normal brain structure.

The response to second-line induction with bortezomib and dexamethasone is predictive of long-term outcomes prior to high-dose chemotherapy with autologous stem cell transplantation for multiple myeloma.

OBJECTIVE: We retrospectively investigated the efficacy and predictive factors for the treatment outcomes of bortezomib plus dexamethasone (BD) as second-line induction therapy prior to high-dose chemotherapy supported by autologous stem cell transplantation (HDT/ASCT) in multiple myeloma (MM) patients. METHODS: Sixty-six transplant eligible MM patients treated by the Kyoto Clinical Hematology Study Group between 2006 and 2011 were investigated. Conventional induction chemotherapy, including vincristine, doxorubicin and dexamethasone (VAD) and high-dose dexamethasone (HDD), was used as first-line induction therapy in all patients, seven (10.6%) of whom attained a very good partial response (VGPR). Of the 59 patients who did not attain VGPR with VAD or HDD, 33 were given BD as second-line induction therapy prior to HDT/ASCT. RESULTS: Patients not treated with BD induction showed an overall response rate (ORR, i.e., better than partial response) of 85.3% after induction therapy, while the ORR of patients treated with BD induction improved from 42.4% after conventional induction therapy to 84.8% after BD. The overall survival (OS) and progression-free survival (PFS) of patients not treated with BD induction were not significantly influenced by the response to induction therapy. Among the patients treated with BD, failure in attaining VGPR prior to ASCT was associated with a significantly shorter PFS and it also tended to show a shorter OS, while the disease stage and achievement of a complete response after HDT/ASCT had no impact on OS or PFS. CONCLUSION: The achievement of at least VGPR with second-line BD induction therapy is a prerequisite for attaining longer OS and PFS after HDT/ASCT.