Dyskeratosis congenita with corneal limbal insufficiency

We describe a newly diagnosed Turkish adolescent female with Dyskeratosis congenita along with the novel ocular finding of corneal limbal insufficiency. Corneal limbal insufficiency was suggested to be a premature aging sign resulting from a deficiency in corneal stem cell activity, a biological process caused by underlying telomeric defect in this disease. Pediatr Blood Cancer 2009;53:95–97. © 2009 Wiley‐Liss, Inc.     

Dyskeratosis Congenita: Unusual Presenting Features Within a Kindred

We report on a family in which one member is affected by dyskeratosis congenita (DC), who had two cousins who died at 44 months and 36 months, respectively, with aplastic anemia and neurological abnormalities. The patient affected by DC presented with bone marrow hypoplasia at age 4; DC was diagnosed at age 6.

In DC the marrow abnormalities rarely appear before the skin manifestations. The observation of this kindred poses the question whether an extremely early onset with a rapidly fatal course before the appearance of skin abnormalities is possible. We believe this report to be important for the differential diagnosis of DC and other forms of congenital aplastic anemia.     

Dyskeratosis congenita: The first NIH clinical research workshop

Dyskeratosis congenita (DC) is a heterogeneous inherited bone marrow failure syndrome, characterized by abnormally short telomeres and mutations in telomere biology genes. The spectrum of telomere biology disorders is growing and the clinical management of these patients is complex. A DC‐specific workshop was held at the NIH on September 19, 2008; participants included physicians, patients with DC, their family members, and representatives from other support groups. Data from the UK's DC Registry and the NCI's DC cohort were described. Updates on the function of the known DC genes were presented. Clinical aspects discussed included androgen therapy, stem cell transplant, cancer risk, and cancer screening. Families with DC met for the first time and formed a family support group ( http://www.dcoutreach.com/ ). Ongoing, open collaboration between the clinical, scientific, and family communities is required for continued improvement in our understanding of DC and the clinical consequences of telomeric defects. Pediatr Blood Cancer 2009;53:520–523. © 2009 Wiley‐Liss, Inc.     

Dyskeratosis congenita: advances in the understanding of the telomerase defect and the role of stem cell transplantation

DC is a multisystem bone marrow failure syndrome exhibiting marked clinical and genetic heterogeneity. X-linked, autosomal dominant and autosomal recessive subtypes are recognized. The gene mutated in X-linked DC (DKC1) encodes a highly conserved nucleolar protein called dyskerin. Dyskerin associates with the H/ACA motif class of small nucleolar RNAs in small nucleolar ribonucleoprotein particles that are important in guiding the conversion of uracil to pseudouracil during the maturation of ribosomal RNA. Dyskerin also associates with the TERC, which is important in the maintenance of telomeres. Mutations in TERC have been identified in patients with autosomal dominant DC and in a subset of patients with aplastic anemia and myelodysplasia. Recently, heterozygous mutations in TERT have been found in some patients with autosomal dominant DC and aplastic anemia. Additionally, patients with the severe multisystem disorder, Hoyeraal-Hreidarsson syndrome, have been found to have DKC1 mutations. Collectively, these observations have demonstrated that classical DC, Hoyeraal-Hreidarsson syndrome and a subset of aplastic anemia are due to a primary defect in telomerase. The critical role of telomeres and telomerase in humans is seen in the multisystem abnormalities found in these patients, including the increased incidence of malignancy. As bone marrow failure is the principal cause of death, conventional allografts have been attempted with limited success due to the high rate of pulmonary and endothelial complications. However, outcomes have improved with the use of non-myeloablative protocols, although the follow up is too short to evaluate long term toxicity and the natural course of the disease and it may be that correction of the telomerase defect is essential for the treatment of these patients.     

Disappearance of neutrophil fluctuations in a child with cyclic neutropenia by combination therapy of granulocyte colony-stimulating factor and high-dose immunoglobulin

We report on a patient with cyclic neutropenia who was treated by granulocyte colony-stimulating factor (G-CSF) and high-dose immunoglobulin. The serial examination revealed cyclic fluctuations in the numbers of neutrophils, monocytes, platelets in peripheral blood, and in the serum G-CSF concentration. Bone marrow examination confirmed a cyclic fluctuation of both progenitor cells (CFU-GM) and CD10-positive B cells. The therapy of G-CSF followed by high-dose immunoglobulin achieved a disappearance of neutrophil oscillations. It suggested that the combination therapy of G-CSF with high-dose immunoglobulin might be effective for cyclic neutropenia.     

Randomized comparison of antibiotics with and without granulocyte colony-stimulating factor in children with chemotherapy-induced febrile neutropenia: a report from the Children's Oncology Group

PURPOSE: To determine if granulocyte colony-stimulating factor (G-CSF) with empirical antibiotics accelerates febrile neutropenia resolution compared with antibiotics without it. PATIENTS AND METHODS: Eligible children were treated without prophylactic G-CSF and presented with fever (temperature >38.3 degrees C) and neutropenia afterward. Patients with acute myelogenous leukemia and myelodysplastic syndrome were excluded. Assignments were randomized between G-CSF (5 microg/kg/day) or none beginning within 24 hr of antibiotics. Subcutaneous administration was recommended, but intravenous G-CSF was allowed. Patients remained on study until absolute neutrophil count (ANC) >500/microl and > or =48 hr without fever. RESULTS: One of 67 patients enrolled was ineligible, 59 had acute lymphoblastic leukemia (ALL). Thirty-four were assigned to antibiotics, 32 to G-CSF plus antibiotics. Adding G-CSF significantly reduced neutropenia and febrile neutropenia recovery times. Median days to febrile neutropenia resolution was nine earlier with G-CSF (4 vs. 13 days) (P < 0.0001). However, there was no difference in the resolution of fever between arms. Hospitalization median was shorter by 1 day with G-CSF (4 vs. 5 days) (P = 0.04). There was no difference in the duration of IV and oral antibiotic treatment, addition of antifungal therapy, and shock incidence. A trend for decreased incidence of late fever with G-CSF was noted (6.3 vs. 23.5%) (P = 0.08). CONCLUSIONS: Adding G-CSF to empiric antibiotic coverage accelerates chemotherapy-induced febrile neutropenia resolution by 9 days in pediatric patients, mainly with ALL, which results in a small but significant difference in the median length of hospitalization.     

Pegfilgrastim in children with severe congenital neutropenia

Two pediatric patients affected by severe congenital neutropenia (SCN) were treated with 100 mcg/L/dose every 9–12 days within a pilot study (Observatory of the Italian Ministry of Health, Eudract Code 2005‐003096‐20) on the use of pegfilgrastim in patients with chronic neutropenia. Both children increased their absolute neutrophil count, reduced their infectious load, and improved their quality of life. Serum concentrations of G‐CSF observed in pegfilgrastim mirrored those seen in filgrastim. These data suggest that pegfilgrastim may be beneficial in SCN patients with an exposure of hematopoietic cells to G‐CSF similar to that on filgrastim. Pediatr Blood Cancer 2010;54:465–467. © 2009 Wiley‐Liss, Inc.     

Complex glycerol kinase deficiency: An X-linked disorder associated with adrenal hypoplasia congenita

Complex glycerol kinase deficiency (GKD) results from the contiguous deletion on Xp21 of all or part of the gene for glycerol kinase together with that for adrenal hypoplasia congenita (AHC) and/or Duchenne muscular dystrophy (DMD). The authors present the case of a newborn whose initial issues were refractory hypoglycaemia along with hyponatremia and hyperkalemia. He also had low serum cortisol levels and raised urinary excretion of glycerol and required steroid supplementation. His creatinine phosphokinase (CPK) levels were normal. Molecular studies revealed a contiguous Xp21 deletion. Therapy in such cases must be prompt and includes correction of hypoglycaemia and dyselectrolytemia, a low fat diet and steroid replacement.     

Clinical and electrophysiological reports in a case of early onset myotonia congenita (Thomsen''s disease) successfully treated with mexiletine

A sporadic event of myotonia congenita in a infant admitted to the Paediatric Clinic for frequent crises of apnoea, cyanosis, vomiting and difficult feeding is reported. EMG analysis was consistent with the dominant variety of myotonia congenita. Mexiletine therapy showed excellent results in reducing myotonic activity. It is worthwhile stressing that early symptoms may go unnoticed or may be misinterpreted and that information on the genetic form of the disease can be obtained also from the EMG analysis through a repetitive stimulation test.     

Fever and neutropenia in children with cancer: diagnostic parameters at presentation

We evaluated 91 episodes of fever in 46 profoundly neutropenic children with cancer, in a search for any symptom, sign or laboratory test that would serve to identify patients with septicemia and differentiate them from those in no immediate need of prompt antimicrobial therapy. Seventeen episodes (19%) were bacteremias, 59 (64%) were suspected septic infections, 9 (10%) were focal bacterial infections and 6 (7%) proved not to be bacterial infections. We were unable to detect any parameter, either on admission or after two days of antimicrobial therapy (except for blood culture findings), that would be helpful in differentiating bacteremia from an episode not of bacterial origin. We focused on serum levels of C reactive protein and found them unreliable on an individual level. Prompt institution of antimicrobial therapy at the occurrence of fever results in low mortality, but does not allow assignment of cases to different categories.     

Strong evidence for autosomal dominant inheritance of severe congenital neutropenia associated with ELA2 mutations

OBJECTIVE: To investigate cases of severe congenital neutropenia (SCN) to ascertain SCN inheritance after determining that the same sperm donor was used by 4 different families to impregnate mothers. STUDY DESIGN: Because the donor sperm was not available, alternative methods were used to determine whether the sperm donor transmitted SCN. DNA isolated from leukocytes was used to sequence the ELA2 gene in the affected children and their mothers. ELA2 was amplified by polymerase chain reaction (PCR), and the product was sequenced. PCR was also performed with genomic DNA from the mothers and affected children using a set of 22 microsatellite PCR primers on chromosomes 14 and 19 to establish linkage to the paternal allele. RESULTS: None of the mothers had a mutation in ELA2, but all 5 affected children had the same mutation affecting the fourth exon at site S97L. Linkage mapping analysis confirmed that all affected children had the same paternal allele on chromosome 19, which contains ELA2. CONCLUSIONS: Our findings indicate that the father provided consistent haplotypes leading to the expression of SCN in all affected children, supporting an autosomal dominant inheritance in which ELA2 mutations occur.     

Deep brain stimulation in childhood: an effective treatment for early onset idiopathic generalised dystonia

Background

Early onset idiopathic generalised dystonia is a progressive and profoundly disabling condition. Medical treatment may ameliorate symptoms. However, many children have profound, intractable disability including the loss of ambulation and speech, and difficulties with feeding. Following the failure of medical management, deep brain stimulation (DBS) of the globus pallidus internus (GPi) has emerged as an alternative treatment for the disorder.

Methods

We describe four children who presented with dystonia.

Results

Following the failure of a range of medical therapies, DBS systems were implanted in the GPi in an attempt to ameliorate the children''s disabilities. All children found dystonic movements to be less disabling following surgery. Compared with preoperative Burke, Fahn and Marsden Dystonia Rating Scale scores, postoperative scores at 6 months were improved.

Conclusions

DBS is effective in improving symptoms and function in children with idiopathic dystonia refractory to medical treatment. Whilst surgery is complex and can be associated with intraoperative and postoperative complications, this intervention should be considered following the failure of medical therapy.     

中性粒细胞缺乏合并脓毒症时前B细胞克隆增强因子水平的研究

目的研究前B细胞克隆增强因子(PBEF)在中性粒细胞缺乏状态合并脓毒症时的水平变化及临床应用价值。方法选取28例急性淋巴细胞白血病(ALL)化疗后处于中性粒细胞缺乏状态的患儿为研究对象,其中无感染14例,脓毒症14例。收集所有患儿的临床资料及血清标本,用酶联免疫吸附法(ELISA)检测PBEF浓度,比较两组PBEF水平,分析PBEF与临床常用感染指标CRP、PCT的相关性,探讨中性粒细胞缺乏时PBEF在脓毒症的临床应用价值。结果脓毒症组PBEF浓度为(5.526±1.548)ng/mL,无感染组PBEF浓度为(5.184±1.295)ng/mL,两组PBEF水平比较无明显差异(p=0.536)。脓毒症组PBEF与其他常见炎性指标CRP、PCT无显著相关(尸值分别为0.159和0.311)。结论中性粒细胞缺乏状态合并脓毒症时PBEF水平无明显改变,可能与外周血中合成和分泌PBEF的细胞减少相关,PBEF是否可作为感染指标应用于临床有待进一步探讨。     

婴幼儿期起病的儿童哮喘与母亲孕期相关因素分析

目的 探讨婴幼儿期起病的儿童哮喘与母亲孕期相关因素的关系, 为今后儿童哮喘的防治工作及发病机制的深入研究提供依据。方法 采用回顾性临床流行病学调查方法, 选取3 岁前起病的哮喘患儿100 例, 并随机选取无过敏性疾患的儿童100 例作为对照, 通过对患儿母亲问卷调查的形式, 询问儿童一般情况、病史资料、个人及家族过敏史资料、围生期资料、母亲孕期饮食、疾病、环境暴露等情况。主要调查指标经初步分析后进行筛选和赋值, 运用单因素和多因素logistic 回归分析方法对资料进行分析。结果 单因素及多因素logistic 回归分析均显示胎儿性别、孕前特应性疾病史、孕期呼吸道感染史及孕期鱼虾蟹类、水果类、肉类、辛辣食品摄入量7 个因素与婴幼儿期起病的儿童哮喘有显著相关性, 其OR 值依次为2.868、5.051、4.640、3.746、2.971、3.075、2.225(P<0.05)。结论 婴幼儿期起病的儿童哮喘与母亲怀孕期间多种因素相关, 预防孕期呼吸道感染, 孕期合理饮食可减少婴幼儿期起病的儿童哮喘的发病风险。     

Using fluorescence-activated cell sorting followed by fluorescence in situ hybridization to study lineage relationships: the 8;21 translocation is present in neutrophils but not monocytes in a patient with severe congenital neutropenia and a granulocyte colony-stimulating factor-responsive clonal abnormality

Severe congenital neutropenia (Kostmann syndrome) is a disorder that presents in the neonatal period, but predisposes to leukemia later in life. This report describes a 4-y-old female with a history of severe congenital neutropenia, who developed a clonal abnormality associated with the translocation (7;21;8) (q32;q22;q22) (AML-1/ETO). She had circulating peripheral blasts and bone marrow blast counts as high as 64% when she received recombinant granulocyte colony-stimulating factor (rG-CSF). Her marrow blasts decreased to 4-20% when rG-CSF was discontinued. Fluorescence in situ hybridization analysis was performed on bone marrow cell populations sorted by flow cytometry to determine which cell populations had the AML-1/ETO translocation. The translocation was found in mature neutrophils and blasts, but not in monocytes, lymphocytes or stem cells.
Conclusion : These findings suggest that the translocation occurred in a neutrophil progenitor, past the point in ontogeny where monocytes and neutrophils separate. The techniques described may be useful in understanding lineage relationships and leukemogenesis in other clonal abnormalities associated with myelodysplasia and leukemia.