Takeshi Rikiishi

Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies.

Noonan syndrome is an autosomal dominant disease characterized by dysmorphic features, webbed neck, cardiac anomalies, short stature and cryptorchidism. It shows phenotypic overlap with Costello syndrome and cardio-facio-cutaneous (CFC) syndrome. Noonan syndrome and related disorders are caused by germline mutations in genes encoding molecules in the RAS/MAPK pathway. Recently, a gain-of-function mutation in SHOC2, p.S2G, has been identified as causative for a type of Noonan-like syndrome characterized by the presence of loose anagen hair. In order to understand the contribution of SHOC2 mutations to the clinical manifestations of Noonan syndrome and related disorders, we analyzed SHOC2 in 92 patients with Noonan syndrome and related disorders who did not exhibit PTPN11, KRAS, HRAS, BRAF, MAP2K1/2, SOS1 or RAF1 mutations. We found the previously identified p.S2G mutation in eight of our patients. We developed a rapid detection system to identify the p.S2G mutation using melting curve analysis, which will be a useful tool to screen for the apparently common mutation. All the patients with the p.S2G mutation showed short stature, sparse hair and atopic skin. Six of the mutation-positive patients showed severe mental retardation and easily pluckable hair, and one showed leukocytosis. No SHOC2 mutations were identified in leukemia cells from 82 leukemia patients. These results suggest that clinical manifestations in SHOC2 mutation-positive patients partially overlap with those in patients with typical Noonan or CFC syndrome and show that easily pluckable/loose anagen hair is distinctive in SHOC2 mutation-positive patients.

Hypercalcemia due to all-trans retinoic acid therapy for acute promyelocytic leukemia : A case report of effective treatment with bisphosphonate

of vitamin A, has been introduced to the therapy of acute promyelocytic leukemia (APL).1 Most cases of APL show t (15;17) (q22;q21) chromosomal translocation, which produces PML/retinoic acid receptor α (RARα) fusion gene. The maturation of APL cells is blocked at the promyelocyte stage of myeloid differentiation, and ATRA can induce terminal differentiation and apotosis of leukemic cells.2 A very high rate of complete remission (CR) by use of ATRA for APL has been reported, whereas several side-effects including hypercalcemia have been reported to be associated with systemic ATRA therapy.1,3 In this study, we reported an 11-year-old boy with severe hypercalcemia caused by ATRA therapy for APL. Interestingly, bisphosphonate was effective to control ATRA-induced hypercalcemia in this patient.

GNE myopathy associated with congenital thrombocytopenia: A report of two siblings

GNE myopathy is an autosomal recessive muscular disorder caused by mutations in the gene encoding the key enzyme in sialic acid biosynthesis, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE/MNK). Here, we report two siblings with myopathy with rimmed vacuoles and congenital thrombocytopenia who harbored two compound heterozygous GNE mutations, p.V603L and p.G739S. Thrombocytopenia, which is characterized by shortened platelet lifetime rather than ineffective thrombopoiesis, has been observed since infancy. We performed exome sequencing and array CGH to identify the underlying genetic etiology of thrombocytopenia. No pathogenic variants were detected among the known causative genes of recessively inherited thrombocytopenia; yet, candidate variants in two genes that followed an autosomal recessive mode of inheritance, including previously identified GNE mutations, were detected. Alternatively, it is possible that the decreased activity of GNE/MNK itself, which would lead to decreased sialic content in platelets, is associated with thrombocytopenia in these patients. Further investigations are required to clarify the association between GNE myopathy and the pathogenesis of thrombocytopenia.

Vincristine-resistant Kasabach–Merritt phenomenon successfully treated with low-dose radiotherapy

In 1940, Kasabach and Merritt reported the case of an infant with a huge angioma causing thrombocytopeniarelated purple spots. This condition became known as the Kasabach–Merrit phenomenon (KMP), characterized by a huge hemangioma associated with thrombocytopenia and microangiopathic hemolytic anemia due to consumption coagulopathy [1]. The incidence of KMP in infants with a huge hemangioma is approximately 0.3%, but it is said that the mortality rate exceeds 30% among patients. A number of therapies have been reported for the treatment of KMP, but none have been uniformly effective. We report a case of life-threatening KMP, in which hemangioma of the right thigh (tufted angioma type) was successfully treated by low-dose radiotherapy after concurrent therapy with the agents prednisolone (PSL), interferon a-2a (IFN a-2a), and vincristine (VCR) failed to control it. 2 Case report

Somatic BRAF c.1799T>A p.V600E Mosaicism syndrome characterized by a linear syringocystadenoma papilliferum, anaplastic astrocytoma, and ocular abnormalities

Genetic mosaicism for somatic mutations of oncogenes is common in genodermatoses, which can be complicated with extra‐cutaneous abnormalities. Here we describe an infant with a congenital anaplastic astrocytoma, a linear syringocystadenoma papilliferum, and ocular abnormalities. The BRAF c.1799T>A p.V600E mutation was detected in both the brain and skin tumor cells but not in the blood or normal skin cells, suggesting somatic mosaicsism for the mutation. Clinically, the brain tumor gradually became life threatening without any response to conventional chemotherapies including carboplatin, etoposide, and temozolomide. Vemurafenib, a BRAF p.V600E inhibitor, was administered daily after the detection of the BRAF mutation. This single‐agent therapy was dramatically effective against the anaplastic astrocytoma; the tumor regressed, the cerebrospinal fluid cell count and protein levels decreased to normal levels, and hydrocephalus resolved. Moreover, other lesions including a corneal cyst also responded to vemurafenib. The brain tumor continued shrinking after 6 months of treatment. We present a genodermatosis syndrome associated with BRAF c.1799T>A p.V600E mosaicism. This syndrome may represent a new entity in the mosaic RASopathies, partly overlapping with Schimmelpenning‐Feuerstein‐Mims syndrome, which is driven by mosaicism of HRAS and/or KRAS activating mutations. Screening for BRAF c.1799T>A p.V600E is especially useful for those with malignant tumors, because it is one of the most‐druggable targets.

Casitas B-cell lymphoma mutation in childhood T-cell acute lymphoblastic leukemia

Somatic CBL mutations have been reported in a variety of myeloid neoplasms but are rare in acute lymphoblastic leukemia (ALL). We analyzed 77 samples from hematologic malignancies, identifying a somatic mutation in CBL (p.C381R) in one patient with T-ALL that was associated with a uniparental disomy at the CBL locus and a germline heterozygous mutation in one patient with JMML. Two NOTCH1 mutations and homozygous deletions in LEF1 and CDKN2A were identified in T-ALL cells. The activation of the RAS pathway was enhanced, and activation of the NOTCH1 pathway was inhibited in NIH 3T3 cells that expressed p.C381R. This study appears to be the first to identify a CBL mutation in T-ALL.

Successful cord blood transplantation with reduced-intensity conditioning for childhood cerebral X-linked adrenoleukodystrophy at advanced and early stages.

Niizuma H, Uematsu M, Sakamoto O, Uchiyama T, Horino S, Onuma M, Matsuhashi T, Rikiishi T, Sasahara Y, Minegishi M, Tsuchiya S. Successful cord blood transplantation with reduced‐intensity conditioning for childhood cerebral X‐linked adrenoleukodystrophy at advanced and early stages. 
Pediatr Transplantation 2012: 16: E63–E67.

Refractory chronic immune thrombocytopenic purpura in a child with acute lymphoblastic leukemia

Immune thrombocytopenic purpura (ITP) has been associated with several hematologic malignancies such as Hodgkin and non-Hodgkin lymphomas and chronic lymphocytic leukemia, but it is rare in children with acute lymphoblastic leukemia (ALL). Here, we report a 7-year-old girl with chronic ITP during early intensive phase of chemotherapy for ALL. She underwent splenectomy because thrombocytopenia had persisted even after treatment with intravenous immunoglobulin (IVIG), steroids, vincristine, rituximab, and anti-D antibody. After splenectomy, her platelet count had recovered, and maintenance therapy could be resumed with a support of IVIG. To our knowledge, this is the first child case of chronic ITP during chemotherapy for ALL and splenectomy was effective in this patient.

Mesenchymal chondrosarcoma diagnosed on FISH for HEY1‐NCOA2 fusion gene

Mesenchymal chondrosarcoma (MC) is an extremely rare subtype of chondrosarcoma that has a small round‐cell sarcoma with focal cartilaginous differentiation, often with a pericytomatous vascular pattern. The non‐cartilaginous components are usually dominant, and such lesions might be confused with other small round‐cell tumors. Recently, a tumor‐specific HEY1‐NCOA2 fusion gene was identified in MC. Here we report the case of a 9‐year‐old boy who was diagnosed with MC by detection of HEY1‐NCOA2 fusion signals in almost 50% of tumor cells in tissue sections on fluorescence in situ hybridization (FISH). In this way, the tumor was definitively diagnosed as MC. This case suggests that the detection of the HEY1‐NCOA2 fusion gene on FISH is of diagnostic value for MC.

A case series of CAEBV of children and young adults treated with reduced‐intensity conditioning and allogeneic bone marrow transplantation: a single‐center study

Epstein–Barr virus (EBV)‐infected T or NK cells cause chronic active EBV infection (CAEBV). Allogeneic hematopoietic stem cell transplantation (HSCT) is curative treatment for CAEBV patients. However, chemotherapy prior to HSCT and optimal conditioning regimen for allogeneic HSCT are still controversial.