A novel G473A mutation in the glucose‐6‐phosphate dehydrogenase gene

Hereditary deficiency in human glucose‐6‐phosphate dehydrogenase (G6PD) is mostly caused by single nucleotide change in the G6PD gene which leads to single amino acid substitution. In 104 cases of Chinese children with G6PD deficiency, RT‐PCR‐DGGE (denaturing gradient gel electrophoresis) combined with DNA sequencing was carried out to screen the mutations within the coding region of G6PD gene. A novel missense mutation (G473A), predicting a Cys‐to‐Tyr substitution at codon 158, was identified in a male infant patient and confirmed in his mother. This G6PD variant (158 Tyr) showed decreased enzyme activity, belonging to WHO Class II. We designated this variant as G6PD Shenzhen by the birthplace of the propositus. Pediatr Blood Cancer. 2010;55:383–385. © 2010 Wiley–Liss, Inc.     

Novel p53 splicing site mutation in Li‐Fraumeni‐like syndrome with osteosarcoma

We describe a 15‐year‐old girl with a novel germline p53 splice site mutation who developed an osteosarcoma. She received several cycles of chemotherapy with complete resection of the primary tumor without amputation, and has maintained remission for 18 months. Li‐Fraumeni‐like syndrome was suspected based on familial history. Sequence analysis revealed the presence of a novel germline p53 gene mutation resulting in a G to A transition at position +1 at the donor splice site of intron 6, creating a 6 amino acid insertion. This case provides interesting insight into the phenotype‐genotype correlation in LFL syndrome with a TP53 splicing mutation.     

Case of cytomegalovirus‐associated direct anti‐globulin test‐negative autoimmune hemolytic anemia

A 1‐year‐old boy developed autoimmune hemolytic anemia after a negative direct anti‐globulin test. The concentration of erythrocyte membrane‐associated immunoglobulin G, determined using an immunoradiometric assay, correlated with disease activity. He was positive for cytomegalovirus (CMV) both serologically and by quantitative real‐time polymerase chain reaction, indicating that his autoimmune hemolytic anemia was directly caused by CMV infection. Since anti‐CMV immunoglobulin G was not absorbed by the patient's erythrocytes, cross‐reaction between erythrocyte antigens and CMV was not likely a causative factor for hemolysis.     

Cooperating G6PD mutations associated with severe neonatal hyperbilirubinemia and cholestasis

We report a novel glucose-6-phosphate dehydrogenase (G6PD) mutation, which we propose to name G6PD Cincinnati (c.1037A > T, p.N346I), found in combination with G6PD Gastonia (c.637G > T, p.V213L) in an infant who presented with neonatal cholestasis. The G6PD Cincinnati mutation results in a non-conservative amino acid substitution at the tetramer interface disturbing its formation, as seen by native gel electrophoresis and immunoblotting. G6PD Gastonia disrupts dimerization of the enzyme and by itself causes chronic non-spherocytic hemolytic anemia. The G6PD Cincinnati mutation may have aggravated the clinical picture of G6PD Gastonia with the result of severe perinatal hemolysis causing cholestasis and associated liver injury.     

Transient liver injury and severe neonatal cholestasis in infant with glucose-6-phosphate dehydrogenase deficiency due to a new mutation

We report the case of a neonate with a new, previously undescribed, glucose-6-phosphate dehydrogenase (G6PD) gene mutation, which was revealed by severe cholestasis, hyperbilirubinemia, and transient liver dysfunction. The severity of the clinical phenotype with ongoing chronic hemolytic anemia suggests that this mutation belongs to class 1 G6PD deficiency. The hemizygous mutation «c.675G>c; p.Trp225Cys» was detected by genomic sequencing. Since severe G6PD deficiency can be revealed by cholestasis, it is important to check G6PD enzyme activity when faced with a case of liver dysfunction in the neonatal period.     

Successful treatment of refractory donor lymphocyte infusion‐induced immune‐mediated pancytopenia with rituximab

A 6‐year‐old male with chronic granulomatous disease, who was transplanted with bone marrow and exhibited increasing mixed chimerism, subsequently received two donor lymphocyte infusions (DLI). Two weeks after the second DLI, the patient developed acute graft‐versus‐host disease (GVHD) and progressive pancytopenia that was associated with autoantibody production. Conventional treatment did not improve the pancytopenia. However, administration of Rituximab (RTX) (375 mg/m²/week for four consecutive weeks) resulted in a rapid resolution of the pancytopenia. The patient achieved full donor chimerism without GVHD symptoms. RTX can be valuable for managing immune‐mediated cytopenias that arise after DLI and are refractory to conventional therapies. Pediatr Blood Cancer 2010;54:329–331. © 2009 Wiley‐Liss, Inc.     

Left ventricular non‐compaction revealed by aortic regurgitation due to Kawasaki disease in a boy with LDB3 mutation

Kawasaki disease (KD) is an acute febrile illness of childhood characterized by systemic vasculitis, especially coronary arteritis. Aortic valve regurgitation (AVR) is a relatively common complication. There have been no reports to date of heart failure and left ventricular non‐compaction (LVNC) after acute KD, although the precise etiology of this condition remains unclear. A 6‐month‐old boy with KD was admitted to hospital. Despite high‐dose i.v. gammaglobulin for dilation of the coronary artery, moderate AVR appeared, and thereafter he developed heart failure. A rough, dense LV myocardium indicated LVNC. On genetic testing a heterogenous 163G > A substitution changing a valine to isoleucine in LIM domain binding protein 3 (LDB3) was identified. Additional cardiac stress, such as that caused by AVR and/or KD might have triggered cardiac failure in the form of LVNC due to LDB3 mutation.     

A novel initiation codon mutation in the ribosomal protein S17 gene (RPS17) in a patient with Diamond‐Blackfan anemia

Diamond‐Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by pure red cell aplasia, various congenital anomalies, and cancer predisposition. We report a novel mutation in the RPS17 gene in a Korean patient with DBA. The mutation occurred in the translation initiation codon, changing Atg to Gtg (c.1A>G), thus disrupting the natural start of the RPS17 protein biosynthesis. This is the third case of DBA from a RPS17 mutation in the literature and is the second case of a RPS17 mutation in the translation initiation codon, following c.2T>G. Pediatr Blood Cancer 2010;54:629–631. © 2009 Wiley‐Liss, Inc.     

Cord blood transplantation in a young child with pyruvate kinase deficiency

Unrelated cord blood transplantation (CBT) was performed for the treatment of pyruvate kinase (PK) deficiency in a female pediatric patient at the age of 1 year 7 months, who had been in severe and frequent transfusion‐dependent hemolytic anemia, despite red blood cell (RBC) PK activity 5.52 IU/gHb. pyruvate kinase‐liver and RBC (PK‐LR) had a compound heterozygous mutation located on exon 8: c.1044G > T/c.1076G > A (K348N/R359H). Hemoglobin and RBC PK corrected to 13.5 g/dL and 9.00 IU/gHb, respectively, with gene correction at 6 months after CBT. CBT should be considered as an option for useful treatment in children with severe PK deficiency in the absence of HLA identical sibling with normal RBC PK activity.     

A Say‐Barber‐Biesecker‐Young‐Simpson variant of Ohdo syndrome with a KAT6B 10‐base pair palindromic duplication: A recurrent mutation causing a severe phenotype mixed with genitopatellar syndrome

The Say‐Barber‐Biesecker‐Young‐Simpson variant of Ohdo syndrome (SBBYSS) (MIM# 603736) and genitopatellar syndrome (GPS) (MIM#606170) are allelic diseases caused by KAT6B mutation. Genotype–phenotype correlation is assumed, but a few patients manifest overlapping features of both syndromes. Here we report the case of a boy with SBBYSS. He had a KAT6B mutation previously reported in typical SBBYSS, but he also manifested severe developmental delay, as well as genital features and laryngomalacia requiring tracheostomy that conformed to GPS.     

Tyrosinemia type 1 in Spain: Mutational analysis,treatment and long‐term outcome

Background: Tyrosinemia type 1 (HT1) is a rare but treatable disease. The aim of the present study was to review the efficacy of long‐term treatment of HT1 with nitisinone, expand knowledge about the clinical spectrum of the disease and assess a possible genotype–phenotype correlation. Methods: A retrospective multicenter study was carried out based on questionnaires on genotype, phenotype, therapy and outcome in 34 Spanish patients with HT1. Results: The main manifestations that led to the diagnosis were acute liver failure (55.8%), asymptomatic hepatomegaly (44.1%) and renal tubular dysfunction (29.4%). Laboratory analysis indicated a marked increase of α‐fetoprotein and coagulopathy. The most common mutation was IVS6‐1(G > T; 66.6% of 24/34 patients for whom mutation analysis was available) and these patients presented less nephrocalcinosis and more hepatomegaly at diagnosis; two novel mutations (c.974C>T, c.398A>T) were found. The mean duration of treatment was 6.73 years. Dietary compliance was very good in 47.1% and good in 20.6%; nitisinone treatment adherence was very good in 85.2% of cases. Mean dose of nitisinone was 0.87 mg/kg per day with average plasma levels of 45.67 µmol/L. Only one patient required liver transplantation after nitisinone and none had hepatocellular carcinoma. Conclusions: Treatment with nitisinone has improved the prognosis of HT1, and compliance is good. In Spain, screening for HT1 by plasma tyrosine and urine succinylacetone determination may be implemented with IVS6‐1(G > T) mutational analysis. A correlation between low frequency of nephrocalcinosis and IVS6‐1(G > T) mutation was observed.     

Safety of ultra‐rush titration of sublingual immunotherapy in asthmatic children with tree‐pollen allergy

Mösges R, Graute V, Christ H, Sieber H‐Jochen, Wahn U, Niggemann B. Safety of ultra‐rush titration of sublingual immunotherapy in asthmatic children with tree‐pollen allergy.
Pediatr Allergy Immunol 2010: 21: 1135–1138.
© 2010 John Wiley & Sons A/S The recommendation to use sublingual‐swallow immunotherapy (SLIT) in children and adults with allergic rhinitis has been established over the past decade. Recently, ultra‐rush titration of SLIT has become more and more common, raising concerns about its safety in children with asthma. Fifty‐four children with asthma and adolescents aged 6–14 with documented allergic disease because of tree pollen (birch and possibly alder and/or hazel) from 14 study centers in Germany participated in a randomized, double‐blind, and placebo‐controlled study. Twenty‐seven were randomized to receive SLIT with standardized birch pollen allergen extract and the other 27 to receive placebo. An ultra‐rush high‐dose SLIT titration regimen reaching the maintenance dose of 300 index of reactivity (IR) within 90 min (30–90–150–300 IR) was used. The difference in mean PFR changes during ultra‐rush titration between SLIT and placebo was not significant (p = 0.056). A 95% probability that SLIT does not decrease PFR during ultra‐rush titration was demonstrated. Neither anaphylactic shock nor else serious systemic reactions to the study drug occurred. No serious adverse event assessed by the investigator as related to study drug treatment was reported.     

Effects of 4‐phenylbutyrate therapy in a preterm infant with cholestasis and liver fibrosis

The bile salt export pump is expressed at the canalicular membrane of hepatocytes and mediates biliary excretion of bile salts. 4‐Phenylbutyrate (4 PB), a drug used to treat ornithine transcarbamylase deficiency, has been found to increase the hepatocanalicular expression of bile salt export pump. The beneficial effects of 4‐phenylbutyrate therapy have been reported for patients with progressive familial intrahepatic cholestasis, an inherited autosomal recessive liver disease. This is the first study to show the therapeutic effect of 4 PB in a preterm infant with cholestasis and liver fibrosis. The preterm infant had severe cholestasis with jaundice and failure to thrive refractory to ursodeoxycholic acid. Histology indicated giant cell hepatitis, cholestasis, and severe fibrosis. Bile salt export pump immunostaining showed lower expression than in a control. Oral 4 PB was started at a daily dose of 200 mg/kg/day. After the start of 4 PB therapy, cholestasis improved.     

Phase‐1 study of siplizumab in the treatment of pediatric patients with at least grade II newly diagnosed acute graft‐versus‐host disease

Brochstein JA, Grupp S, Yang H, Pillemer SR, Geba GP. Phase‐1 study of siplizumab in the treatment of pediatric patients with at least grade II newly diagnosed acute graft‐versus‐host disease.
Pediatr Transplantation 2010:14:233–241. © 2009 John Wiley & Sons A/S. Abstract: In a phase‐1 study, siplizumab, a humanized anti‐CD2 monoclonal antibody, was administered (0.012 or 0.04 mg/kg) to 10 pediatric patients with ≥ grade‐II newly diagnosed, non‐steroid‐refractory aGvHD after BMT or PBSCT. SAEs and other AEs including infections, and GvHD staging changes (overall, skin, liver, gut) were evaluated over 364 days. Patients reported a total of 121 AEs (19 grade‐3, 5 grade‐4 0.012 mg/kg group; 17 grade‐3, 17 grade‐4 0.04 mg/kg group) and 14 SAEs (five grade‐3, three grade‐4, 0.012 mg/kg group; three grade‐3, 0.04 mg/kg group); 15 AEs in five patients and four SAEs in three patients (fever, PTLD, adenoviral infection, and EBV lymphoma) were considered siplizumab‐related. Six deaths occurred (study days 17–267); two were considered siplizumab‐related: one from EBV‐associated PTLD (0.012 mg/kg) and one from adenoviral infection (0.04 mg/kg); the other four deaths could potentially be attributed in part to study drug Three patients (one, 0.012 mg/kg group; two, 0.04 mg/kg group) developed PTLD. By study day 12, GvHD grade decreased in 3/5 and 2/5 patients in the 0.012 and 0.04 mg/kg groups, respectively; remission (grade 0) occurred in one patient in each group. Four of five patients (0.012 mg/kg group) and one of four patients (0.04 mg/kg group) achieved grade 0 GvHD during the first 100 study days (55.6% response). While treatment with siplizumab was associated with improvement of GvHD and remission in some pediatric patients, the overall high morbidity, mortality, and occurrence of PTLD is of safety concern, not warranting further development of siplizumab for the treatment of aGvHD in children.     

Long term G‐CSF‐induced remission of ulcerative colitis‐like inflammatory bowel disease in a patient with glycogen storage disease Ib and evaluation of associated neutrophil function

We present a 23‐year‐old female with Glycogen storage disease Ib (GSD Ib) who was diagnosed with ulcerative colitis‐like inflammatory bowel disease (IBD) at 7 years of age. G‐CSF therapy reversed the IBD, was required to maintain IBD remission and was well tolerated. Neutrophil functions at time of diagnosis showed impaired chemotaxis but normal superoxide anion production and bactericidal activity. Ulcerative colitis‐like IBD may also be seen in GSD Ib and is responsive to G‐CSF therapy. Neutrophil dysfunction is variable among patients with GSD Ib. Pediatr Blood Cancer. 2010;55:1410–1413. © 2010 Wiley‐Liss, Inc.     

Treatment of hepatic veno‐occlusive disease in children with N‐acetylcysteine

In our institution, hepatic veno‐occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) has been treated with N‐acetylcysteine (NAC) since 2008—a loading dose of 150 mg/kg, followed by 12 doses of 70 mg/kg 6 hourly. Nine children were diagnosed with hepatic VOD/SOS. Hepatic VOD/SOS occurred in seven children after stem cell transplantation and two were receiving chemotherapy for Wilms tumor. Their clinical severity was classified as moderate in two and severe in seven by the European Society for Blood and Marrow Transplantation criteria. All children recovered and were discharged from 4 to 16 days after diagnosis. No side effects were observed. Intravenous NAC is an effective treatment for hepatic VOD/SOS.     

Successful treatment of mixed‐type autoimmune hemolytic anemia with rituximab in a child following liver transplantation

Haller W, Hind J, Height S, Mitry R, Dhawan A. Successful treatment of mixed‐type autoimmune hemolytic anemia with rituximab in a child following liver transplantation.
Pediatr Transplantation 2010: 14: E20–E25. © 2009 John Wiley & Sons A/S. Abstract: Development of a severe form of mixed‐type AIHA after orthotopic liver transplantation is a rare, but a life‐threatening event. We report a case of mixed‐type AIHA that developed in a child after hepatocyte and living‐related orthotopic liver transplantation for factor VII deficiency.     

Estimation of glomerular filtration rate in liver‐transplanted children:Comparison of simplified procedures using 51Cr‐EDTA and endogenous markers with Sapirstein’s method as a reference standard

Berding G, Geisler S, Melter M, Marquardt P, Lühr A, Scheller F, Knoop BO, Pfister E‐D, Pape L, Bischoff L, Knapp WH, Ehrich JHH. Estimation of glomerular filtration rate in liver‐transplanted children: Comparison of simplified procedures using ⁵¹Cr‐EDTA and endogenous markers with Sapirstein’s method as a reference standard.
Pediatr Transplantation 2010: 14:786–795. © 2010 John Wiley & Sons A/S. Abstract: This study evaluated simple procedures for GFR determination in 48 liver‐transplanted children. After injection of ⁵¹Cr‐EDTA, blood samples were obtained up to four h, and activity retention in the body was measured for 60 min with scintillation probes. As a reference, GFR was calculated according to Sapirstein. Simplified calculations were performed according to Brochner‐Mortensen, Russel, Devaux and Oberhausen. Additionally, GFR was determined using plasma creatinine and cystatin C according to Schwartz and Filler, respectively. The reference revealed mildly reduced GFR (62 ± 20 mL/min/1.73 m²). Russel’s method provided the highest degree of correlation (r² = 0.95), the smallest bias in GFR determination (−2%), and only one false exclusion plus one false diagnosis of chronic kidney disease. Oberhausen’s method with blood sampling at one h post‐injection performed slightly worse (r² = 0.67, bias: 3%). All other methods resulted in significantly different GFR estimates compared to the reference. Nevertheless, notably, the second narrowest 95% limits of agreement (−31% to 45%) was observed using cystatin C. In conclusion, this data implies to prefer Russel’s method as a simplified procedure, and if patients cannot be available long enough (four h) for measurements, Oberhausen’s method instead. If radiotracer methods are not available at all or for screening GFR, cystatin C appears to be the procedure of choice.     

Interleukin‐6 polymorphism and bronchopulmonary dysplasia risk in very low‐birthweight infants

Background: The aim of the present study was to evaluate the role of interleukin (IL)‐6‐634 polymorphism in neonatal disorders such as bronchopulmonary dysplasia (BPD) and periventricular leukomalacia (PVL) in very low‐birthweight (VLBW) infants. Methods: This prospective cohort study included 202 infants (gestational age at birth, 23–34 weeks; birthweight, 500–1499 g). Genotypic analysis (polymerase chain reaction–restriction fragment length polymorphism) was performed with DNA extracted from whole‐blood samples. Results: Genotype distribution (66.8% CC, 28.2% CG, 5.0% GG) was similar to that in the adult Japanese population. BPD occurred in 85 infants (42.1%) among 202 VLBW infants. The duration of O₂ therapy in infants with CG/GG genotypes was significantly longer than that in infants with the CC genotype (CG/GG vs CC: 40.3 ± 52.2 days vs 28.4 ± 32.6 days, P < 0.05), but the prevalence of BPD was not associated with the CG/GG genotype (CG/GG, 40.0%; CC, 46.3%, P= 0.24). Infants with CG/GG genotypes were more likely to have received postnatal corticosteroid therapy for BPD than those with the CC genotype (CG/GG vs CC: 20.9% vs 11.1%, P= 0.05). PVL occurred in six infants (3.0%). There was no significant difference in the prevalence of PVL among IL‐6‐634 polymorphisms (CG/GG, 3.0%; CC, 3.0%, P= 0.65). Conclusions: IL‐6‐634 polymorphism is associated with duration of oxygen therapy in VLBW infants. This suggests that the IL‐6‐634 polymorphism G allele is an aggravating factor of BPD. IL‐6‐634 polymorphism is not associated with PVL.