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1.
Fam Cancer ; 20(4): 349-354, 2021 10.
Article in English | MEDLINE | ID: mdl-33811277

ABSTRACT

We describe a case of a boy with neurodevelopmental delay and a diffuse large B-cell lymphoma (DLBCL) in whom we discovered a germline de novo 2p16.3 deletion including MSH6 and part of the FBXO11 gene. A causative role for MSH6 in cancer development was excluded based on tumor characteristics. The constitutional FBXO11 deletion explains the neurodevelopmental delay in the patient. The FBXO11 protein is involved in BCL-6 ubiquitination and BCL-6 is required for the germinal center reaction resulting in B cell differentiation. Somatic loss of function alterations of FBXO11 result in BCL-6 overexpression which is a known driver in DLBCL. We therefore consider that a causative relationship between the germline FBXO11 deletion and the development of DLBCL in this boy is conceivable.


Subject(s)
F-Box Proteins , Lymphoma, Large B-Cell, Diffuse , F-Box Proteins/genetics , Germinal Center/metabolism , Humans , Lymphoma, Large B-Cell, Diffuse/genetics , Male , Protein-Arginine N-Methyltransferases/metabolism
2.
Eur J Med Genet ; 59(12): 641-646, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27238889

ABSTRACT

Early onset ataxia telangiectasia (A-T) is a neurodegenerative DNA-instability disorder, which presents early in childhood. Hallmarks of A-T are progressive ataxia and a dramatic increased risk of developing malignancies (25%), especially of hematological origin. In children these malignancies mainly concern aggressive Non-Hodgkin lymphoma, acute leukemias and Hodgkin lymphoma. Of the acute leukemias, T-cell lymphoblastic leukemia (T-ALL) is by far the most common. Since patients with A-T experience increased toxicity to radio- and chemotherapeutic treatment, the optimal treatment strategy of acute leukemia remains subject of debate. Review of literature of treatment of T-ALL in patients with A-T (n = 18) showed that many patients are not diagnosed with A-T at time of presentation of T-ALL. This implicates that physicians must be aware of symptoms of A-T in young patients presenting with T-ALL. Complete remission rates are high following upfront modified as well as unmodified treatment strategies. Treatment of ALL in children with A-T is feasible and should be performed. Definitive treatment strategy must be determined by shared decision making with patient, caretakers and medical team. Future prospective studies are needed to elucidate optimal treatment strategy.


Subject(s)
Ataxia Telangiectasia/drug therapy , Ataxia Telangiectasia/epidemiology , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/epidemiology , Ataxia Telangiectasia/complications , Ataxia Telangiectasia/pathology , Child , Disease-Free Survival , Humans , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/complications , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Prospective Studies
3.
Ann Oncol ; 23(7): 1906-11, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22317768

ABSTRACT

BACKGROUND: Providing high-quality care for children with cancer could improve treatment outcomes, survival and quality of life of the children and parents. The aim of this study is to select high-quality care recommendations for all children with cancer based on literature and consensus for future development of quality indicators. MATERIALS AND METHODS: We performed an extensive search in databases for scientific literature and in websites of international health care and guideline development organizations to create an inventory of recommendations for the care for all children with cancer. The RAND modified Delphi method was used to grade and select recommendations for high-quality care. RESULTS: Our search resulted in a list of 131 recommendations on care for all children with cancer. The expert panel graded, discussed and prioritized these recommendations. Analysis of these ratings resulted ultimately in a list of 109 high-quality care recommendations for all children with cancer, including 31 prioritized recommendations. CONCLUSIONS: This study defines a set of high-quality care recommendations based on literature and consensus. These recommendations provide a basis for the development of a comprehensive set of quality indicators to evaluate care in paediatric oncology.


Subject(s)
Neoplasms/therapy , Quality of Health Care , Child , Humans , Practice Guidelines as Topic , Surveys and Questionnaires
4.
Ned Tijdschr Geneeskd ; 150(12): 677-80, 2006 Mar 25.
Article in Dutch | MEDLINE | ID: mdl-16613252

ABSTRACT

A 12-year-old girl presented with chronic abdominal pain and distension that had persisted for 6 and 3 months, respectively. The cause was a Sertoli-Leydig cell tumour originating in the left ovary. The cyst and ovary were resected. The patient recovered and was asymptomatic 2 years after the operation. Ovarian tumours are rarely seen in children. The sex cordstromal tumours constitute a heterogeneous subgroup. Two of the most frequently observed sex cord-stromal tumours are the juvenile granulosa cell tumour and the Sertoli-Leydig cell tumour. Even though these tumours may contain histologically malignant characteristics, their behaviour is usually benign. Clinical characteristics are endocrine symptoms, fatigue, chronic abdominal pain and abdominal distension. In addition, pressure from the tumour mass may result in symptoms in adjacent organ systems. Surgical excision is usually curative. Patients with advanced disease may benefit from adjuvant chemotherapy. Chronic abdominal pain is frequently observed in children and, in some rare cases, may be caused by ovarian tumours.


Subject(s)
Ovarian Neoplasms/diagnosis , Sertoli Cell Tumor/diagnosis , Abdominal Pain/etiology , Child , Female , Humans , Ovarian Neoplasms/surgery , Sertoli Cell Tumor/surgery
5.
Hum Mutat ; 15(2): 123-34, 2000.
Article in English | MEDLINE | ID: mdl-10649489

ABSTRACT

We retrospectively examined clinical and biochemical characteristics of 27 patients with isolated enzymatic complex I deficiency (established in cultured skin fibroblasts) in whom common pathogenic mtDNA point mutations and major rearrangements were absent. Clinical phenotypes present in this group are Leigh syndrome (n = 7), Leigh-like syndrome (n = 6), fatal infantile lactic acidosis (n = 3), neonatal cardiomyopathy with lactic acidosis (n = 3), macrocephaly with progressive leukodystrophy (n = 2), and a residual group of unspecified encephalomyopathy (n = 6) subdivided into progressive (n = 4) and stable (n = 2) variants. Isolated complex I deficiency is one of the most frequently observed disturbance of the OXPHOS system. Respiratory chain enzyme assays performed in cultured fibroblasts and skeletal muscle tissue in general reveal similar results, but for complete diagnostics we recommend enzyme measurements performed in at least two different tissues to minimize the possibility of overlooking the enzymatic diagnosis. Lactate levels in blood and CSF and cerebral CT/MRI studies are highly informative, although normal findings do not exclude complex I deficiency. With the discovery of mutations in nuclear encoded complex I subunits, adequate pre- and postnatal counseling becomes available. Finally, considering information currently available, isolated complex I deficiency in children seems to be caused in the majority by mutations in nuclear DNA.


Subject(s)
Metabolism, Inborn Errors/enzymology , Metabolism, Inborn Errors/genetics , Mutation/genetics , NADH, NADPH Oxidoreductases/deficiency , NADH, NADPH Oxidoreductases/genetics , Child , DNA, Mitochondrial/genetics , Electron Transport/genetics , Electron Transport Complex I , Female , Humans , Male , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/pathology , NADH, NADPH Oxidoreductases/metabolism , Phenotype
6.
Ann Neurol ; 45(6): 787-90, 1999 Jun.
Article in English | MEDLINE | ID: mdl-10360771

ABSTRACT

Leigh syndrome is the phenotypical expression of a genetically heterogeneous cluster of disorders, with pyruvate dehydrogenase complex deficiency and respiratory chain disorders as the main biochemical causes. We report the first missense mutation within the nuclear encoded complex I subunit, NDUFS7, in 2 siblings with neuropathologically proven complex I-deficient Leigh syndrome.


Subject(s)
Leigh Disease/genetics , Mutation/genetics , NAD(P)H Dehydrogenase (Quinone)/genetics , Humans , Infant , Male
7.
Hum Mol Genet ; 7(10): 1573-9, 1998.
Article in English | MEDLINE | ID: mdl-9735378

ABSTRACT

The mitochondrial electron transport chain (mtETC) consists of four multi-subunit enzyme complexes. Complex I or NADH:ubiquinone oxidoreductase, the largest mtETC multisubunit complex, consists of approximately 41 subunits. Seven of these subunits are encoded by the mitochondrial genome, the remainder by the nuclear genome. Among the mitochondriocytopathies, complex I deficiencies are encountered frequently. Although some complex I deficiencies have been associated with mitochondrial DNA mutations, the genetic defect has not been elucidated in the majority of complex I-deficient patients. It is expected that many of these patients have mutations in the nuclear-encoded subunits of this complex, so vital for cellular energy production. After a brief summary of the current knowledge of complex I from cow, bacteria and fungi, this review presents the state of the art of the knowledge of the human nuclear-encoded complex I genes which, in the last 18 months, has made enormous progress. At present, the complete gene structure of four subunits and the cDNA structure of 18 of the 34 complex I nuclear-encoded subunits are known. Mapping of these subunits shows a random distribution over the chromosomes. The chromosomal localization is known for 14 complex I genes. Recently, the first mutation, a 5 bp duplication in the 18 kDa (AQDQ) subunit, has been reported. We expect that within 1 year all human nuclear-encoded complex I subunits will be cloned. Mutational analysis of these subunits is warranted in complex I-deficient patients and will not only be important for genetic counselling but will also extend the knowledge regarding the functional properties of the individual human complex I subunits.


Subject(s)
Electron Transport/genetics , Mitochondria/metabolism , NAD(P)H Dehydrogenase (Quinone)/genetics , Animals , Cattle , Escherichia coli/genetics , Escherichia coli/metabolism , Fungi/genetics , Fungi/metabolism , Humans , Mitochondria/genetics , Mutation , NAD(P)H Dehydrogenase (Quinone)/chemistry , NAD(P)H Dehydrogenase (Quinone)/deficiency , Protein Conformation
8.
Biochem Biophys Res Commun ; 253(2): 415-22, 1998 Dec 18.
Article in English | MEDLINE | ID: mdl-9878551

ABSTRACT

NADH:ubiquinone oxidoreductase (complex I) is an extremely complicated multiprotein complex located in the inner mitochondrial membrane. Its main function is the transport of electrons from NADH to ubiquinone, which is accompanied by translocation of protons from the mitochondrial matrix to the intermembrane space. Human complex I appears to consist of 41 subunits of which 34 are encoded by nDNA. Here we report the cDNA sequences of the hitherto uncharacterized 8 nuclear encoded subunits, all located within the hydrophobic protein (HP) fraction of complex I. Now all currently known 41 proteins of human NADH:ubiquinone oxidoreductase have been characterized and reported in literature, which enables more complete mutational analysis studies of isolated complex I-deficient patients.


Subject(s)
Cell Nucleus/enzymology , Cell Nucleus/genetics , DNA, Complementary/isolation & purification , NAD(P)H Dehydrogenase (Quinone)/chemistry , NAD(P)H Dehydrogenase (Quinone)/genetics , Adult , Aged , Amino Acid Sequence , Animals , Base Sequence , Cattle , Escherichia coli/enzymology , Escherichia coli/genetics , Evolution, Molecular , Female , Humans , Male , Middle Aged , Mitochondria/enzymology , Mitochondria/genetics , Molecular Sequence Data , NAD(P)H Dehydrogenase (Quinone)/isolation & purification , Neurospora crassa/enzymology , Neurospora crassa/genetics
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