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1.
Eur J Med Genet ; 64(10): 104293, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34352413

ABSTRACT

Bloom Syndrome (BS) is a genetic DNA repair disorder, caused by mutations in the BLM gene. The clinical phenotype includes growth retardation, immunodeficiency and a strong predisposition to different types of malignancies. Treatment of malignancies in BS patients with radiotherapy or chemotherapy is believed to be associated with increased toxicity, but clinical and laboratory data are lacking. We collected clinical data of two Dutch BS patients with solid tumors. Both were treated with radiotherapy before the diagnosis BS was made and tolerated this treatment well. In addition, we collected fibroblasts from BS patients to perform in vitro clonogenic survival assays to determine radiosensitivity. BS fibroblasts showed less radiosensitivity than the severely radiosensitive Artemis fibroblasts. Moreover, studies of double strand break kinetics by counting 53BP1 foci after irradiation showed similar patterns compared to healthy controls. In combination, the clinical cases and laboratory experiments are valuable information in the discussion whether radiotherapy is absolutely contraindicated in BS, which is the Case in other DNA repair syndromes like Ataxia Telangiectasia and Artemis.


Subject(s)
Bloom Syndrome/complications , Carcinoma/radiotherapy , Radiotherapy/adverse effects , Adult , Bloom Syndrome/genetics , Carcinoma/complications , Cells, Cultured , DNA Breaks, Double-Stranded , DNA Repair , Female , Fibroblasts/radiation effects , Humans , Male , Middle Aged , Radiation Tolerance , RecQ Helicases/genetics
2.
Eur J Pediatr ; 179(2): 251-256, 2020 Feb.
Article in English | MEDLINE | ID: mdl-31709473

ABSTRACT

Ataxia telangiectasia (A-T) is a severe neurodegenerative disorder with variable immunodeficiency. Together with the Dutch A-T community, we investigated the opinion of A-T parents on an early A-T diagnosis in the asymptomatic phase of the disease. During an annual national meeting for A-T patients and families, the topic of an early A-T diagnosis was discussed in relation to the recent introduction of neonatal screening for severe combined immunodeficiency (SCID) in the Netherlands. Based on the discussion, individual arguments were identified and processed into a questionnaire, which was sent out to 64 A-T parents (32 families). Arguments included were insecurity to diagnosis, possible medical advantages, appropriate genetic counseling and family planning, loss of "golden" year(s), and early cancer screening for parents. The response rate was 55% (n = 35 parents). Twenty-six (74%) parents felt that the advantages of an early diagnosis outweighed the disadvantages, five parents thought that the disadvantages would outweigh the advantages (14%), and four parents did not indicate a preference.Conclusion: The majority of parents of a child with A-T would have preferred an early diagnosis during the asymptomatic phase of the disease, because the uncertainty during the diagnostic process had had a major impact on their lives. In addition, the knowledge of being carriers of an ATM gene mutation influenced decisions about family planning. Parents who opposed against an early diagnosis emphasized the joy of having a seemingly healthy child until diagnosis.What is Known:• Ataxia telangiectasia (A-T) is a devastating DNA repair disorder with a huge impact on quality of life of patients and their parents.• Patients with A-T may incidentally be identified at birth as the consequence of neonatal screening for severe combined immunodeficiency (SCID).What is New:• The majority of Dutch parents of A-T patients (74%) would have preferred an early diagnosis of their child in the asymptomatic phase of the disease.• Major arguments for an early A-T diagnosis were (1) the experienced insecurity in diagnostic trajectories and its impact on families and (2) the knowledge of being ATM mutation carriers when deciding about family planning. An argument against an early diagnosis is losing the joy of having a seemingly healthy child until diagnosis.


Subject(s)
Ataxia Telangiectasia/diagnosis , Ataxia Telangiectasia/genetics , Early Diagnosis , Genetic Counseling , Neonatal Screening/methods , Surveys and Questionnaires , Adult , Ataxia Telangiectasia/epidemiology , Child, Preschool , Female , Genetic Predisposition to Disease , Humans , Incidence , Infant, Newborn , Male , Middle Aged , Netherlands/epidemiology , Parent-Child Relations , Parents/psychology , Risk Assessment
3.
Eur J Med Genet ; 61(5): 284-287, 2018 May.
Article in English | MEDLINE | ID: mdl-29288088

ABSTRACT

Ataxia Telangiectasia (AT) is named after the two key clinical features that characterize its classical phenotype, namely a progressive cerebellar gait disorder (ataxia) and vascular anomalies (telangiectasias) visible in the conjunctivae and skin. AT is an autosomal recessively inherited disorder, caused by mutations in the ATM gene that encodes the ATM protein. While the ataxia is subject of many publications, the telangiectasias are under emphasised. We here describe the observation that the absence or presence of ATM protein and the level of residual ATM kinase activity are related to the occurrence of telangiectasias and describe the clinical consequences of these vascular malformations. Finally, we hypothesize that ATM dysfunction dysregulates angiogenesis.


Subject(s)
Ataxia Telangiectasia Mutated Proteins/deficiency , Ataxia Telangiectasia/diagnosis , Adolescent , Adult , Ataxia Telangiectasia/genetics , Ataxia Telangiectasia Mutated Proteins/genetics , Ataxia Telangiectasia Mutated Proteins/metabolism , Child , Child, Preschool , Female , Humans , Male , Middle Aged , Neovascularization, Physiologic , Phenotype
4.
Eur J Paediatr Neurol ; 21(6): 807-815, 2017 Nov.
Article in English | MEDLINE | ID: mdl-28803159

ABSTRACT

Telangiectasias are prominent small vessels (venules, capillaries or arterioles) that are visible as small red-purple focal lesions in the skin and mucous membranes. They can serve as a cutaneous marker for a number of primary (mostly hereditary) disorders and they can be secondary to other (systemic) diseases. Patients with telangiectasias are seen by general health practitioners, pediatricians, (pediatric) neurologists, dermatologists, and ophthalmologists. In this article we give an overview of the different disorders in which telangiectasias are a prominent feature, focusing on neurocutaneous disorders in which they serve as a marker for establishing the right diagnosis. The pattern of distribution of the telangiectasias, their age of onset and associated features are helpful to distinguish between the different disorders.


Subject(s)
Telangiectasis/etiology , Telangiectasis/pathology , Female , Humans , Telangiectasis/diagnosis
5.
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
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