AluY-mediated germline deletion, duplication and somatic stem cell reversion in <i>UBE2T</i> defines a new subtype of Fanconi anemia

Fanconi anemia (FA) is a rare inherited disorder clinically characterized by congenital malformations, progressive bone marrow failure and cancer susceptibility. At the cellular level, FA is associated with hypersensitivity to DNA-crosslinking genotoxins. Eight of 17 known FA genes assemble the FA E3 ligase complex, which catalyzes monoubiquitination of FANCD2 and is essential for replicative DNA crosslink repair. Here, we identify the first FA patient with biallelic germline mutations in the ubiquitin E2 conjugase UBE2T. Both mutations were aluY-mediated: a paternal deletion and maternal duplication of exons 2-6. These loss-of-function mutations in UBE2T induced a cellular phenotype similar to biallelic defects in early FA genes with the absence of FANCD2 monoubiquitination. The maternal duplication produced a mutant mRNA that could encode a functional protein but was degraded by nonsense-mediated mRNA decay. In the patient's hematopoietic stem cells, the maternal allele with the duplication of exons 2-6 spontaneously reverted to a wild-type allele by monoallelic recombination at the duplicated aluY repeat, thereby preventing bone marrow failure. Analysis of germline DNA of 814 normal individuals and 850 breast cancer patients for deletion or duplication of UBE2T exons 2-6 identified the deletion in only two controls, suggesting aluY-mediated recombinations within the UBE2T locus are rare and not associated with an increased breast cancer risk. Finally, a loss-of-function germline mutation in UBE2T was detected in a high-risk breast cancer patient with wild-type BRCA1/2. Cumulatively, we identified UBE2T as a bona fide FA gene (FANCT) that also may be a rare cancer susceptibility gene.</p

Acute encephalopathy with parvovirus B19 infection in sickle cell disease

A 13 year old girl with haemoglobin Sβ+thalassaemia developed simultaneous aplastic crisis and encephalopa-thy associated with parvovirus B19 (PB19) infection. Brain magnetic resonance imaging findings were consistent with central nervous system (CNS) vasculitis and her symptoms resolved with steroid therapy. Thus, PB19 induced CNS hypersensitivity vasculitis must be considered in the differ-ential diagnosis of encephalopathy. Human parvovirus B19 (PB19) is a well known cause ofaplastic crisis in sickle cell disease (SCD).1 Other mani-festations such as myocarditis, arthritis, and glomerulo-nephritis have been reported with PB19 infection in patients with or without SCD.2 The proposed role of PB19 in vasculitis is based on serologi-cal evidence of acute PB19 infection and/or the documenta-tion of PB19 DNA in the blood in few patients with various vasculitic syndromes, but no aetiological relation has yet bee

Fatal intracranial hemorrhage in a newborn with factor VII deficiency

Factor VII deficiency is a rare congenital coagulopathy. Prolonged prothrombin time with normal partial thromboplastin time Indicates factor VII deficiency. For the definitive diagnosis, the specific factor VII level should be Investigated. We report a seven-day-old, male, full-term newborn who was admitted with the diagnosis of sepsis. Hematological tests revealed prolonged prothrombin time and a factor VII level of five percent After antibiotic therapy and fresh frozen plasma replacement his clinical status improved but the prothrombin time continued to be prolonged. On the 14(th) day, just before the end of antibiotic therapy, the infant died of sudden intracerebral hemorrhage. In this article, the clinical features and management of factor VII deficiency are discussed

Monosomy 7 myeloproliferative disease associated with neurofibromatosis type I: A case report

A 7-year-old girl with neurofibromatosis type I (NF1) was diagnosed to have monosomy 7 myeloproliferative disease (Mo 7-MPD). Of the benign and malignant tumors that are encountered with increased incidence in NF1, those originating from the neural crest are frequent. However, tumors that do not originate from the neural crest may also be seen and among these, myeloid leukemias are prominent. Studies on NF1 patients with Mo 7-MPD and juvenile chronic myeloid leukemia (JCML) have suggested the role of the NF1 gene in the leukemogenesis. The relationship between monosomy 7 and hematological malignancies is already known. These finding are in agreement with the multistep development theory of cancer. In addition, our case is one of the very rare NF1 cases having father to daughter inheritance with a myeloid malignancy. We believe that cytogenetic and molecular genetic studies will contribute to further understanding of leukemogenesis