Mazurr Patients with biallelic truncating mutations in PALB2 have a severe form of Fanconi jaladie FA-Nwith a predisposition for developing embryonal-type tumours in infancy. Fanconi anemia FA is a rare inherited disorder clinically characterized by congenital malformations, progressive bone marrow failure and cancer susceptibility. The gene encodes 3 mRNA of 2. These play an important role in oncogenesis and may be pharmacologically manipulated.
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Subtle immunological defects. Progressive bone marrow failure BMF , leading to anemia, thrombocytopenia or pancytopenia. Differential diagnosis Diagnosis is based on standard, ie on Giemsa stained metaphases, cytogenetic analysis of the level of chromosome fragility following exposure to a DNA crosslinking agent exposure.
Due to the risk of mosaicism linked to the spontaneous reversion of the mutation in the highly replicative hematopoietic precursors, cytogenetic analysis must be performed on fibroblasts and not simply on lymphocytes culture stimulated in vitro. An eventual confirmation of the diagnosis could be realized at molecular level thanks to the identification of the complementation group and, eventually, of the mutation s in the involved gene. Treatment Androgens and steroids to improve hematopoietic function.
Evolution The BMF, which is the central characteristic of the syndrome, is progressive and culminate in pancytopenia and, in a fraction of the cases, in AML. Prognosis The clinical presentation of the FA is extremely heterogenous. It is generally admitted that BMF appears at around 7 years.
Most patients die from marrow aplasia haemorrhage, sepsis , and others from malignancies; MDS and AML in FA bear a very poor prognosis median survival of about 6 mths ; survival is also poor in the case of a squamous cell carcinoma. Significant phenotypic differences were found between the various complementation groups. In FA group A, patients homozygous for null mutations had an earlier onset of anemia and a higher incidence of leukemia than those with mutations producing an altered protein.
FA group G patients had more severe cytopenia and a higher incidence of leukemia. FA group G patients patients and patients homozygous for null mutations in FANCA are high-risk groups with a poor hematologic outcome and should be considered as candidates both for frequent monitoring and early therapeutic intervention. There may also be a certain degree of clinical heterogeneity. Therefore, clinical manifestations may be variable within a given family, according to the stage of embryonic development at which the somatic reverse mutation occurred.
Cytogenetics Inborn conditions Spontaneous elevated levels of chromatid and chromosome gaps and breaks, presence of abnormal figures, in particular triradials and quadriradials. Hypersensitivity to the clastogenic effects of DNA crosslinking agents, like mitomycin C, diepoxybutane or cis-Platin. Giemsa staining - Jean Loup Huret.
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