Mizuka Miki

Neurodevelopmental abnormalities associated with severe congenital neutropenia due to the R86X mutation in the HAX1 gene

Objective: Severe congenital neutropenia (SCN), also known as Kostmann syndrome (SCN3, OMIM 610738), includes a variety of haematological disorders caused by different genetic abnormalities. Mutations in ELA2 are most often the cause in autosomal dominant or sporadic forms. Recently, mutations in HAX1 have been identified as the cause of some autosomal recessive forms of SCN, including those present in the original pedigree first reported by Kostmann. We sought to determine the relationship between HAX1 gene mutations and the clinical characteristics of Japanese cases of SCN. Methods: The genes implicated in SCN (ELA2, HAX1, Gfi-1, WAS, and P14) were analysed in 18 Japanese patients with SCN. The clinical features of these patients were obtained from medical records. Immunoblotting of HAX1 was performed on cell extracts from peripheral blood leucocytes from patients and/or their parents. Results: We found five patients with HAX1 deficiency and 11 patients with mutations in the ELA2 gene. In HAX1 deficiency, a homozygous single base pair substitution (256C>T), which causes the nonsense change R86X, was identified in three affected individuals. Two sibling patients showed a compound heterozygous mutation consisting of a single base pair substitution (256C>T) and a 59 bp deletion at nucleotides 376–434. There was no detectable phenotype in any heterozygous carrier. All patients with HAX1 deficiency had experienced developmental delay. Three patients carrying R86X also suffered from epileptic seizures. In contrast, no SCN patient with heterozygous mutations in the ELA2 gene suffered from any neurodevelopmental abnormality. Conclusions: These findings suggest that the R86X mutation in the HAX1 gene is an abnormality in Japanese SCN patients with HAX1 deficiency and may lead to neurodevelopmental abnormalities and severe myelopoietic defects.

Heterozygosity for the Y701C STAT1 mutation in a multiplex kindred with multifocal osteomyelitis

Heterozygosity for dominant-negative STAT1 mutations underlies autosomal dominant Mendelian susceptibility to mycobacterial diseases. Mutations conferring Mendelian susceptibility to mycobacterial diseases have been identified in the regions of the STAT1 gene encoding the tail segment, DNA-binding domain and SH2 domain. We describe here a new heterozygous mutation, Y701C, in a Japanese two-generation multiplex kindred with autosomal dominant Mendelian susceptibility to mycobacterial diseases. This mutation affects precisely the canonical STAT1 tyrosine phosphorylation site. The Y701C STAT1 protein is produced normally, but its phosphorylation is abolished, resulting in a loss-of-function for STAT1-dependent cellular responses to interferon-γ or interferon-α. In the patients’ cells, the allele is dominant-negative for γ-activated factor-mediated responses to interferon-γ, but not for interferon-stimulated gene factor-3-mediated responses to interferon-α/β, accounting for the clinical phenotype of Mendelian susceptibility to mycobacterial diseases without severe viral diseases. Interestingly, both patients displayed multifocal osteomyelitis, which is often seen in patients with Mendelian susceptibility to mycobacterial diseases with autosomal dominant partial IFN-γR1 deficiency. Multifocal osteomyelitis should thus prompt investigations of both STAT1 and IFN-γR1. This experiment of nature also confirms the essential role of tyrosine 701 in human STAT1 activity in natura.

Identification of the integrin β3 L718P mutation in a pedigree with autosomal dominant thrombocytopenia with anisocytosis

αIIbβ3 integrin mutations that result in the complete loss of expression of this molecule on the platelet surface cause Glanzmann thrombasthenia. This is usually autosomal recessive, while other mutations are known to cause dominantly inherited macrothrombocytopenia (although such cases are rare). Here, we report a 4‐generation pedigree including 10 individuals affected by dominantly inherited thrombocytopenia with anisocytosis. Six individuals, whose detailed clinical and laboratory data were available, carried a non‐synonymous ITGB3 gene alteration resulting in mutated integrin β3 (ITGB3)‐L718P. This mutation causes partial activation of the αIIbβ3 complex, which promotes the generation of abnormal pro‐platelet‐like protrusions through downregulating RhoA (RHOA) activity in transfected Chinese Hamster Ovary cells. These findings suggest a model whereby the integrin β3‐L718P mutation contributes to thrombocytopenia through gain‐of‐function mechanisms.

Deficiency of regulatory T cells in children with autoimmune neutropenia.

CD4+ 25+ regulatory T cells (Tregs) play a role in controlling the development and progression of autoimmunity. The transcription factors Foxp3 and NFATC2 (NFAT1) play key roles in regulating the development and function of Tregs. The present study examined the involvement of Tregs in the pathophysiology of autoimmune neutropenia in children. Tregs were analysed by flow cytometry, based on the expressions of CD4, CD25, and intracellular Foxp3. The expressions of FOXP3 and NFATC2 mRNA in the CD4+ 25+ cells were determined by quantitative real‐time polymerase chain reaction. The percentage of CD4+ 25high Tregs in patients with autoimmune neutropenia was significantly lower than that in age‐matched healthy subjects. The intracellular expression of Foxp3 of CD4+ 25+ cells in patients similarly decreased in comparison to that in healthy subjects. The expression of FOXP3 and NFATC2 mRNA of CD4+ 25+ cells in patients also significantly decreased in comparison to that in healthy subjects. These results suggest that the deficiency of Tregs might thus play an important role in the immunopathophysiology of autoimmune neutropenia in children.

Hematopoietic stem cell transplantation for patients with acute lymphoblastic leukemia and Down syndrome

Hematopoietic stem cell transplantation (HSCT) is one curable option for high‐risk acute lymphoblastic leukemia (ALL); however, transplant‐related toxicities might be severe in patients with Down syndrome and ALL (DS‐ALL).

Successful bone marrow transplantation in chronic granulomatous disease

WC. Urinary tract infections due to Candida albicans. Rev. Infect. Dis. 1982; 4: 1107–18. 3 Wimalendra M, Reece A, Nicholl RM. Renal fungal ball. Arch. Dis. Child. Fetal Neonatal Ed. 2004; 89: F376. 4 Blanc PL, Berne D, Annweiler M, Marc JM, Béal A, Bedock B. [Candidal bezoar of the urinary tract during Candida albicans septicemia]. Nephrologie 1993; 14: 19–22. 5 Jantausch B, Kher K Urinary tract infections. In: Kher K, Schnaper HW, Makker SP (eds). Clinical Pediatric Nephrology, 2nd edn. Informa UK, Abingdon, Oxon, 2007; 553–74. 6 Krishnamurthy R, Aparajitha C, Abraham G, Shroff S, Sekar U, Kuruvilla S. Renal aspergillosis giving rise to obstructive uropathy and recurrent anuric renal failure. Geriatr. Nephrol. Urol. 1998; 8: 137–9. 7 Baetz-Greenwalt B, Debaz B, Kumar ML. Bladder fungus ball: A reversible cause of neonatal obstructive uropathy. Pediatrics 1988; 81: 826–9. 8 Sánchez Sanchís M, Pastor Lence J, San Juan de Laorden C, Llopis Guixot B, Tarin Planes M, Carrascosa Lloret V. [Candidiasis of the upper urinary tract. Report of a case]. Arch. Esp. Urol. 1996; 49: 66–8. 9 Alkalay AL, Srugo I, Blifeld C, Komaiko MS, Pomerance JJ. Noninvasive medical management of fungus ball uropathy in a premature infant. Am. J. Perinatol. 1991; 8: 330–2. 10 Hershman-Sarafov M, Tubi O, Srugo I, Bader D. [Fungus-ball in a preterm infant successfully treated with fluconazole]. Harefuah 1998; 134: 28–30. 11 Burguet A, Menget A, Fromentin C, Aubert D, Costaz R, Lemouel A. [Anuria in an infant caused by an intrapyelic mycelial bezoar in a solitary kidney]. Arch. Fr. Pediatr. 1988; 45: 341–2. 12 Alvarez Kindelán J, Alameda Aragonéses V, Regueiro López JC et al. [Management of obstructive renal candidiasis. Report of a clinical case]. Actas Urol. Esp. 1997; 21: 290–92. 13 Levin DL, Zimmerman AL, Ferder LF, Shapiro WB, Wax SH, Porush JG. Acute renal failure secondary to ureteral fungus ball obstruction in a patient with reversible deficient cell-mediated immunity. Clin. Nephrol. 1975; 4: 202–10. 14 Navarro Sebastián J, Hidalgo Togores L, Cárcamo Valor P et al. [Renal candidiasis: Percutaneous endoscopic treatment of the pyeloureteral fungus-ball]. Arch. Esp. Urol. 1990; 43: 543–9. 15 Martínez Bengoechea J, Allepuz Losa C, Gil Sanz MJ, Minguez Pemán J, Rioja Sanz LA. [Systemic candidiasis and ureteral fungus ball. Ketoconazole and irrigating solutions in the management of urinary candidiasis]. Actas Urol. Esp. 1990; 14: 314–18. 16 Prat O, Schurr D, Pomeranz A, Farkas A, Drukker A. Renal candidiasis in infancy: A case with fungus ball obstruction. Int. J. Pediatr. Nephrol. 1984; 5: 223–6. 17 Lo Cascio M, Podestà E, Fatta G, De Angelis M, Toma P. [A rare cause of urologic emergency in childhood: Obstruction of the urinary tract caused by Candida]. Pediatr. Med. Chir. 1987; 9: 239–42. 18 Burgués Gasión JP, Alapont Alacreu JM, Oliver Amorós F, Benedicto Redón A, Boronat Tormo F, Jiménez Cruz JF. [Pyeloureteral fungus ball in patients with urinary lithiasis. Treatment with ureterorenoscopy]. Actas Urol. Esp. 2003; 27: 60–64. 19 Montalvo JA, Montaner A, Torino JR, Ribó JM, Morales L. [Obstructive candidiasis: A process with surgical solution]. Cir. Pediatr. 1994; 7: 204–6. 20 Fisher J, Mayhall G, Duma R, Shadomy S, Shadomy J, Watlington C. Fungus balls of the urinary tract. South. Med. J. 1979; 72: 1281–4. 21 Abramowitz J, Fowler JE, Talluri K et al. Percutaneous identification and removal of fungus ball from renal pelvis. J. Urol. 1986; 135: 1232–3. 22 Menéndez López V, Elia López M, Llorens Martínez FJ, Galán Llopis JA, de Nova Sánchez E, García López F. [Treatment of pelvis fungus ball with ureteral catheterization, fluconazole, and urine alkalinization]. Actas Urol. Esp. 1999; 23: 167–70. 23 Benjamin DK Jr, Fisher RG, McKinney RE Jr, Benjamin DK. Candidal mycetoma in the neonatal kidney. Pediatrics 1999; 104: 1126–9. 24 Biyikli NK, Tugtepe H, Akpinar I, Alpay H, Ozek E. The longest use of liposomal amphotericin B and 5-fluorocytosine in neonatal renal candidiasis. Pediatr. Nephrol. 2004; 19: 801–4.

Population pharmacokinetics and pharmacodynamics of biapenem in paediatric patients

Objective:  To develop a population pharmacokinetic model for biapenem in paediatric patients and to use the parameter estimates to assess pharmacodynamic exposure of common bacterial populations.

Comparison of second transplantation and donor lymphocyte infusion for donor mixed chimerism after allogeneic stem cell transplantation for nonmalignant diseases

Donor mixed chimerism (MC) is an increasing problem after hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases.

Effective Treatment of a Childhood Blastic Plasmacytoid Dendritic Cell Neoplasm with a Cutaneous Tumor Alone by Stem Cell Transplantation with Reduced Intensity Conditioning

Pediatric blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy that has an extremely poor prognosis despite the use of intensive chemotherapy. Recently, treatment of BPDCN with bone marrow transplantation (BMT) using myeloablative conditioning has been reported to increase survival in adults. We report a 9-year-old girl with cutaneous BPDCN who was successfully treated with combination chemotherapy followed by BMT using reduced intensity conditioning (RIC), without any adverse complications. The success of this treatment regimen suggests that BMT with RIC may be a feasible option for treating children with cutaneous BPDCN.

MSH2 deletion with CREBBP and KRAS mutations in pediatric high-hyperdiploid acute lymphoblastic leukemia

PBSI usually occur in patients with an underlying chronic condition, such as immunocompromisation and the presence of medical devices. The present patient, however, had no apparent pre-disposing conditions, such as malignancy, gastrointestinal or genitourinary disease, recent surgical procedures, or central venous catheters. We cannot determine the cause for PBSI in the present case. One reason why PBSI is rare in children compared with adults is the lower number of blood culture sets performed in children. Increasing the number of blood culture sets may identify PBSI in children. In conclusion, the present case has shown that PBSI involving two bacterial strains (S. pneumoniae and H. influenzae) simultaneously is possible in a previously healthy child. This case demonstrates that PBSI should be considered even in previously healthy children.