Malignancies in pediatric patients with ataxia telangiectasia

Murphy, Robyn; Berdon, W. E.; Ruzal-Shapiro, Carrie; Hall, Eric J.; Kornecki, Anat; Daneman, Alan; Brunelle, Françis; Campbell, John B.

doi:10.1007/s002470050578

Cited by 38 publications

(24 citation statements)

References 8 publications

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“…8,10,11 Ten cases of gastric cancer associated with A-T have been reported in the literature; 8 of these cases were reported in the English literature. [12][13][14][15][16][17][18] Among the 10 patients with gastric carcinoma, mucinous adenocarcinoma were found in 5 patients, adenocarcinoma in 4 patients, and adenocarcinoma tubulare mucocellulare in remaining 1 patient which included many signet ring cells (Table 1). Signet ring cell carcinoma is one of the 5 types of gastric adenocarcinoma.…”

Section: Discussionmentioning

confidence: 99%

Gastric Signet Ring Carcinoma in a Patient With Ataxia-Telangiectasia

Patıroğlu

Gungor²,

Arslan³

et al. 2013

Journal of Pediatric Hematology/Oncology

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Ataxia-telangiectasia (A-T) is an autosomal recessive primary immunodeficiency disease characterized by progressive cerebellar ataxia, telangiectasia, sinopulmoner recurrent infections, and cancer susceptibility. Individuals with A-T are known to be at increased risk of certain malignancies including leukemia, lymphoma, and breast and gastric cancer. We present an 18-year-old case of A-T with Hashimoto thyroiditis who admitted with complaints of nausea, vomiting, anorexia, and weight loss. An upper endoscopic biopsy revealed gastric signet ring cell carcinoma. To the best of our knowledge, we report the first case of signet ring cell carcinoma in the patient with A-T. Our experience with occurrence of Hashimoto thyroiditis and gastric signet ring cell carcinoma in the same case of A-T underlines that the clinicians handling A-T must be vigilant about both malignancy and autoimmune disorders.

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Section: Discussionmentioning

confidence: 99%

Gastric Signet Ring Carcinoma in a Patient With Ataxia-Telangiectasia

Patıroğlu

Gungor²,

Arslan³

et al. 2013

Journal of Pediatric Hematology/Oncology

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“…[4][5][6][7] It is well established that patients with AT are at increased risk of cancer, 8 in particular, neoplasms of lymphoid origin. 9,10 Somatic mutations in the ATM gene have been identified in patients with T-cell prolymphocytic leukemia (T-PLL) 11 and B-cell chronic lymphocytic leukemia (B-CLL) with no family history of AT. [12][13][14] Mutations observed in these reports are missense mutations and most occur in the PI-3 kinase domain.…”

Section: Introductionmentioning

confidence: 99%

Missense mutation and defective function of ATM in a childhood acute leukemia patient with MLL gene rearrangement

Oguchi

2003

Blood

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The possible involvement of germline mutation of the ataxia telangiectasia mutated (ATM) gene in childhood acute leukemia with mixed lineage leukemia (MLL) gene rearrangement (MLL ؉ ) was investigated. Of the 7 patients studied, 1 showed a germline missense ATM mutation (8921C>T; Pro2974Leu), located in the phosphatidylinositol-3 (PI-3) kinase domain. In reconstitution assays, the ATM mutant 8921T could only partially rescue the radiosensitive phenotype of AT fibroblasts, and in an in vitro kinase assay, it showed a defective phosphorylation of p53-Ser15. Furthermore, the introduction of 8921T in IntroductionAtaxia telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, oculocutaneous telangiectasia, and immunodeficiency. The responsible gene, ATM (ataxia telangiectasia mutated), is located on chromosome 11q22-23 and encodes a 350-kDa nuclear protein with a carboxy-terminal domain similar to the catalytic subunit of the phosphatidylinositol-3 kinases (PI-3 kinases). 1-3 PI-3 kinase-related proteins are known to function in the maintenance of genomic stability, cell cycle control, and cellular responses to DNA damage. 4,5 AT cells exhibit hypersensitivity to ionizing radiation and are defective at multiple cell cycle checkpoints. [4][5][6][7] It is well established that patients with AT are at increased risk of cancer, 8 in particular, neoplasms of lymphoid origin. 9,10 Somatic mutations in the ATM gene have been identified in patients with T-cell prolymphocytic leukemia (T-PLL) 11 and B-cell chronic lymphocytic leukemia (B-CLL) with no family history of AT. [12][13][14] Mutations observed in these reports are missense mutations and most occur in the PI-3 kinase domain. Heterozygous germline missense mutations were also found among B-CLL patients, indicating that such genetic alterations might act as predisposing factors for the development of lymphoid tumors. 12,13 The germline missense ATM mutations have been reported in patients with breast carcinoma with early onset disease and positive family history. 15 The chromosomal translocation of the mixed lineage leukemia (MLL) gene at 11q23 is involved in a subset of childhood leukemia, most frequently in infantile leukemia. [16][17][18] The MLL gene rearrangement is also involved in treatment-related leukemias secondary to chemotherapy using topoisomerase II (topo II) inhibitors. This has led to the hypothesis that in utero exposure to chemicals, such as certain antibiotics, laxatives, podophyllin resins, flavonoids, herbal medicines, and benzene metabolites may cause infantile leukemia via an effect on topo II. 19,20 Recent epidemiologic data indicate that maternal alcohol exposure and exposure to recreational drugs, pesticides, and anti-inflammatory drugs increase the risk of infantile leukemia. [21][22][23] Thus, environmental factors appear to play an important role in the development of this disease.Previous studies have shown that AT cells are hypersensitive to topo II inhibitors. [24][25][26][27][28] It is plausible that m...

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“…In our case fever and productive cough were the initial symptoms leading to the misdiagnosis of pneumonia. The recurrent infections and subsequent interstitial progressive pulmonary changes in A-T often mask and delay the diagnosis of a mediastinal HD [6,7]. In addition, the primary location of the tumor mass in the posterior mediastinum and the elevated AFP and vanylmandelic acid raised the suspicion of a solid tumor.…”

Section: Discussionmentioning

confidence: 99%

Hodgkin's Disease with Atypical Clinical Presentation, Associated with Ataxia-Telangiectasia

Spasova

Ivanov

Grudeva-Popova

et al. 2009

Scholarly Research Exchange

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The authors report a 4-year-old male with Hodgkin's disease with atypical clinical presentation, laboratory data and imaging studies as well as an increased radiosensitivity. These were the first symptoms which raised the suspicion of ataxia-telangiectasia. The lymphoma presented as a solid tumor mass in the right upper posterior mediastinum without peripheral lymphadenopathy. The alpha-fetoprotein was significantly increased and the diagnosis of a germ-cell tumor or neuroblastoma was suspected. After partial resection of the tumor the histology indicated Hodgkin's disease-mixed cellularity. The boy received chemotherapy according to DAL HD-95 protocol without any unusual toxicity. Low-dose radiation therapy of the upper and middle mediastinum was followed by early radiation-induced esophagitis and appearance of a large pericardial effusion one year later. Ataxia and bulbar and skin telangiectasias at the radiation site appeared in the next years. He suffered recurrent pulmonary infections and succumbed to severe pneumonia with respiratory failure and pulmonary hypertension five years after the diagnosis of malignant lymphoma without evidence of recurrence of Hodgkin's disease. Case ReportThe child was a 4-year-old male of Roma origin, born after second normal pregnancy without family history of immune deficiency. He had a past history of cerebral palsy, diagnosed at the age of 20 months because of a delay in motor and intellectual development. His present complaints were productive cough and fever for one month. After admission to the regional hospital physical and Xray signs of right pulmonary infiltrate were found, and he received antibiotic treatment with Clindamycin, Amikacin, Imipenem, and Cefepime without any improvement. He was referred for further diagnostic evaluation to the Department of Pediatrics, Medical University-Plovdiv. Physical examination on admission showed mask-like, sad, and relaxed face with progeroid features, growth retardation, reduced subcutaneous fat, generalized muscle hypotonia and atrophy, bronchial breathing in the right parascapular region, tracheal stridor, and enlarged liver 3 cm below the costal margin and lack of peripheral lymphadenopathy. Mental retardation was mild (IQ: 60%) with predominantly affected expressive speech and fine motor skills. Computer tomography (CT) scan showed tumor mass in the right upper posterior mediastinum (Figure 1). It deviated the trachea and was well demarked from the pulmonary parenchyma. No destruction of the adjacent bones was evident.Laboratory data showed leukocytosis, thrombocytosis; elevated erythrocyte sedimentation rate, serum fibrinogen and C-reactive protein 221 mg/L. The diagnostic workup for the mediastinal tumor revealed significant increase of alpha-fetoprotein (AFP) 238.98 ng/mL (reference range 0-5 ng/mL), moderate elevation of vanylmandelic acid 80.9 µmol/l, anergic tuberculin test, and negative blood and sputum cultures and serology for ecchinococcus.Germ-cell tumor or neuroblastoma was suspected and the boy was referred to ...

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Malignancies in pediatric patients with ataxia telangiectasia

Abstract: The lymphomas were commonly extra nodal, and infiltrative rather than mass-like. The recognition of the tumors was often delayed due to confusion with the known infectious complications in AT patients.

Cited by 38 publications

References 8 publications

Gastric Signet Ring Carcinoma in a Patient With Ataxia-Telangiectasia

Gastric Signet Ring Carcinoma in a Patient With Ataxia-Telangiectasia

Missense mutation and defective function of ATM in a childhood acute leukemia patient with MLL gene rearrangement

Hodgkin's Disease with Atypical Clinical Presentation, Associated with Ataxia-Telangiectasia

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