Kiriko Tokuda

Hemophagocytic lymphohistiocytosis secondary to Mycoplasma pneumoniae infection

In 1979 the term ‘virus-associated hemophagocytic syndrome’ was introduced by Risdall et al . 1 to describe a disease characterized by a reactive histiocytic proliferation with marked hemophagocytosis associated with viral infections. Today, it has been well recognized that hemophagocytic lymphohistiocytosis (HLH) can occur in patients with non-viral infections, immunological disorders such as collagen disease, and malignancies. 2,3 We report two patients with HLH secondary to Mycoplasma pneumoniae infection.

CLTC-ALK fusion as a primary event in congenital blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a subtype of acute myeloid leukemia, affecting mainly the elderly. It is thought to be derived from plasmacytoid dendritic cell precursors, which frequently present as cutaneous lesions. We have made a detailed analysis of an infant with BPDCN, who manifested with hemophagocytic lymphohistiocytosis. The peripheral blood leukocytes revealed the t(2;17;8)(p23;q23;p23) translocation and a CLTC‐ALK fusion gene, which have never been reported in BPDCN or in any myeloid malignancies thus far. Neonatal blood spots on the patients Guthrie card were analyzed for the presence of the CLTC‐ALK fusion gene, identifying the in utero origin of the leukemic cell. Although the leukemic cells were positive for CD4, CD56, CD123, and CD303, indicating a plasmacytoid dendritic cell phenotype, detailed analysis of the lineage distribution of CLTC‐ALK revealed that part of monocytes, neutrophils, and T cells possessed the fusion gene and were involved in the leukemic clone. These results indicated that leukemic cells with CLTC‐ALK originated in a multipotent hematopoietic progenitor in utero. This is the first report of the CLTC‐ALK fusion gene being associated with a myeloid malignancy, which may give us an important clue to the origin of this rare neoplasm.

High aromatase activity and overexpression of epidermal growth factor receptor in fibrolamellar hepatocellular carcinoma in a child.

An 11-year-old boy was admitted with a liver tumor and underwent right trisegmentectomy for a diagnosis of fibrolamellar hepatocellular carcinoma. He had suffered from bilateral gynecomastia for a year, which improved after complete resection of the tumor. The tumor cells had significant aromatase activity (8.03 pmol/g/h) and contained high levels of estradiol (82.1 pg/mL), which contributed to gynecomastia. Furthermore, overexpression of epidermal growth factor receptor was determined in the tumor cells, which suggests that antitumor strategies using epidermal growth factor receptor antagonists may be effective.

A complete deficiency of coagulation factor XIII A-subunit due to a novel compound heterozygote of Ser 413 Leu missense and an nt 389 (ins G) frameshift mutation

Coagulation factor XIII consists of two A‐ and two B‐subunits, and either gene mutation can cause a complete deficiency. In a newborn patient with persistent bleeding from the umbilical cord stump, the plasma A‐subunit protein was not detectable. Direct PCR sequencing revealed an nt 389 (ins G) frameshift mutation in exon 4 resulting in a new stop codon and a Ser 413 Leu missense mutation in exon 10 in either allele. His mother and father were heterozygous for the nt 389 (ins G) and the Ser 413 Leu, respectively, with about 50% reduction of the plasma A‐subunit proteins. In all family members examined only those with either mutation showed the reduced subunit A protein levels. Thus, this complete deficiency of factor XIII was due to a novel compound heterozygous mutation in the A‐subunit gene.

Outcome of non-T-cell-depleted HLA-haploidentical hematopoietic stem cell transplantation from family donors in children and adolescents.

Non-T-cell-depleted HLA-haploidentical hematopoietic stem cell transplantation (SCT) from family members has been reported, but its effectiveness and safety are not fully known. In this study, we examined the outcomes of 83 children and adolescents with nonmalignant (n = 11) or malignant (n = 72) disorders who underwent SCT mismatched at 2 or 3 HLA loci, either from the mother (n = 56), a noninherited maternal antigen (NIMA)-mismatched sibling (n = 14), or the father/a noninherited paternal antigen (NIPA)-mismatched sibling (n = 13). Engraftment was satisfactory. Severe (grade III-IV) acute graft-versus-host disease (GVHD) was noted only in malignant disease, with an incidence of 21 of 64 evaluable patients. GVHD prophylaxis with a combination of tacrolimus and methotrexate was significantly associated with a lower risk of severe acute GVHD, compared with other types of prophylaxis(P = .04). Nine of 11 patients with nonmalignant disease and 29 of 72 patients with malignant disease were alive at a median follow-up of 26 months (range, 4-57 months). Outcomes were not significantly different among the 3 donor groups (mother versus NIMA-mismatched sibling versus father/NIPA-mismatched sibling) for the malignancy disorders. Our results indicate that non-T-cell-depleted HLA-haploidentical SCT may be feasible, with appropriate GVHD prophylaxis, for young recipients who lack immediate access to a conventional stem cell source.

Acquired hypothyroidism in a very young infant with Omenn’s syndrome

A very young male infant with Omenns syndrome had acquired hypothyroidism that was most likely caused by autoimmune thyroiditis. The hypothyroidism appeared at 3 months of age. These 2 rare conditions have not previously been reported occurring together. This case suggests that autoimmune thyroiditis may be another abnormal finding in Omenns syndrome.

Prenatally detected cystic adrenal neuroblastoma

Routine US for term pregnancy identifi ed a male fetus with an intra-abdominal cystic lesion. The 2846 g boy was born by normal vaginal delivery at 40 weeks, with an Apgar score of 9. He was referred to Ehime University Hospital because postnatal US indicated a right adrenal cystic mass. Findings on physical examination were normal. Urinary vanillylamandelic acid (VMA), urinary homovanillic acid (HVA), and serum neuronspecifi c enolase (NSE) were within normal ranges. Computed tomography (CT) 2 weeks later showed a 4 cm multicystic lesion located suprarenally on the right side, with a small solid component ( Fig. 1 ). There were no fi ndings suggestive of metastasis to lymph node or liver. At 27 days old the patient underwent laparotomy because neuroblastoma could not be excluded. The mass was present in the right adrenal gland, displaying a smooth surface and no infi ltration of the surrounding tissue. Tumor excision including the right adrenal gland was performed. The multilocular tumor measured 3.5 × 2.5 × 2.5 cm and contained hemorrhagic material. Histological examination showed the cyst to be lined with a thick fi brous wall, which contained a proliferation of small round tumor and adrenal gland cells ( Fig. 2 ). The tumor cells were diagnosed as poorly differentiated neuroblastoma, of rosette-fi brillary type. Histological appearance was favorable with low mitosis – karyorrhexis index according to the Shimada classifi cation. 7 The patient had favorable biological markers, including no amplifi cation of N-myc, and expression of Ha-ras (2+) and Trk A (3+). Bone scintigraphy after operation showed no metastasis and so the tumor was staged as I. Postoperative course was uneventful and the patient is doing well at 3 years of age. Discussion

Lineage-dependent skewing of loss of heterozygosity (LOH) of KRAS gene in a case of juvenile myelomonocytic leukemia.

Juvenile myelomonocytic leukemia (JMML) is a clonal disease arising from abnormal hematopoietic stem cells, although the involvement of lymphoid lineage differs among reported cases. Here, we present a case of JMML with a KRAS G13D mutation. The mutation was detected in various hematopoietic lineages, including T and B lymphocytes and also in lineage− CD34+CD38− hematopoietic stem cells, showing a different percentage of affected cells in each lineage. Single cell‐based analysis of hematopoietic cells revealed the loss of wild‐type KRAS in a significant proportion of G13D‐harboring cells. The percentage of loss of heterozygosity (LOH)/non‐LOH cells showed lineage‐dependent skewing in hematopoietic cells. The loss of the wild‐type KRAS allele may be a common secondary genetic change in KRAS‐related JMML and may affect the differentiation behavior of early JMML progenitors.