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• W2800596286 abstract "The gold standard screening test for Fanconi anaemia (FA) is based on the underlying chromosome fragility. Addition of the DNA cross-linking agents diepoxybutane (DEB) or mitomycin C to peripheral blood lymphocytes demonstrate increased rates of chromosomal breakage in FA patients (Auerbach, 1993). Elevation of alpha fetoprotein (AFP) was previously reported as a rapid screening tool for FA (Cassinat et al, 2000), with a sensitivity and specificity of 93% and 100%, respectively, and a likelihood ratio of 26. AFP levels were determined in 138 FA patients referred to the University of Minnesota between 2005 and 2015. Demographics and transplant characteristics are shown in Table 1. Haematopoietic cell transplantation (HCT) was indicated in 112 patients (81 %). Serum AFP was measured using the ADVIA Centaur® System (Siemens Diagnostics, Minnetonka, MN, USA) by chemiluminescent immunoassay with detectable concentrations of AFP from 1·3 to 1000 μg/l and with a normal range of 0–8 μg/l for patients older than 8 months of age. For patients less than 8 months of age (n = 3), the normal range varies and was determined according established guidelines (Wu et al, 1981). AFP was elevated in 98 (71%) patients (Fig 1A). As a measure of stability over time, the average AFP level, 21·7 [95% confidence interval (CI), 14·1–28·3], did not change between the first and last measurement within subjects as assessed by general linear mixed models. The average change over each consecutive measurement was -2·5 (95% CI, −7·4 to 2·4) (P = 0·32) given one measurement >8·0 μg/l and after controlling for HCT status, gender and genotype. This is an indication that patients with an AFP > 8·0 μg/l maintained this level over time. Of those with elevated levels, the median AFP level was 16·2 μg/l (range, 8·1–147·5 μg/l). There was a correlation between AFP levels and DEB sensitivity, with a DEB break/cell of 5·4 in patients with high AFP levels compared to 3·4 in patients with normal AFP levels (P = 0·01). Similarly, the level of DEB-resistant T cells among patients with elevated AFP was 0–10% in 61%, 11–20% in 15%, 21–30% in 7%, 31–40% in 4%, 41–50% in 3% and ≥50% in 10%. DEB-resistant T cell levels among the group with normal AFP were 0–10% in 58%, 11–20% in 7%, 21–30% in 2%, 31–40% in 4%, 41–50% in 7% and ≥50% in 22%. (P = 0·25). Forty-nine patients who were successfully treated by HCT had baseline AFP levels before HCT and 1 year afterward. Compared to baseline levels, AFP levels after HCT were decreased in 21 patients (median, −24%; range, −2 to −35%) and increased in 25 patients (median, 24%; range, 2 to 100%) which perhaps could be attributed to the mild hepatic dysfunction seen after HCT. Levels were unchanged in three patients. In 15 patients with AFP levels ≤8·0 μg/l at baseline, four were >8·0 μg/l at 1 year after HCT (27%). In 34 patients with AFP levels >8·0 μg/l at baseline, only one patient was ≤8·0 μg/l at 1 year post-HCT (3%). There were no statistically significant differences in AFP levels between HCT and non-HCT groups (Appendix S1). For the three patients with high AFP levels who were ≤8 months old at the time of first AFP measurement, high AFP levels (>8·0 μg/l) persisted beyond 8 months of age in two patients and normalized in the third. 81 patients (69%) had FANCA mutations, 12 patients (10%) had FANCC mutations and seven patients (6%) had mutations in FANCD1/BRCA2 with other genotypes represented at lower frequencies. All seven patients with biallelic FANCD1/BRCA2 mutations had elevated serum AFP with significantly higher levels (median, 97·4 μg/l; range, 43·5–147 μg/l) compared to patients with other FA genotypes (median, 11·4 μg/l range, 1·5–141·7 μg/l; P < 0·01) (Fig 1B). One exception was a female patient with FANCA who had an AFP of 112 μg/l. Of the seven BRCA2 patients, one had a first AFP normal baseline measurement at 1 week of life, but later had several measurements after 1 year of age that remained elevated. In this analysis, we observed a persistence of elevated AFP levels regardless of treatment. With the exception of one patient whose levels normalized 1 year after HCT, all other patients had persistently elevated levels after HCT. Additionally, 27% of patients with normal initial AFP levels had an increase in their levels at 1 year after HCT. The sensitivity of AFP in FA patients has varied in previously published reports (Cassinat et al, 2000; Aslan et al, 2002), which could be related to differences in testing methods. Cassinat et al (2001) compared 6 different AFP testing methods in both FA and non-FA patients and while certain methods reached almost 100% sensitivity and specificity; in others, one or both were significantly less than 100%. Regardless of the assay, AFP levels were still significantly higher in FA compared to non-FA patients (Cassinat et al, 2001). However, it is clear from these results that the absence of elevated AFP does not rule out FA and all patients still require diagnostic chromosomal fragility testing. Interestingly, we observed that, with one exception, AFP levels were markedly elevated in our patients with biallelic FANCD1/BRCA2 as compared to non-FANCD1/BRCA2 FA patients. The aetiology of the elevated AFP levels in FA patients remains unclear. Elevated AFP level is also a feature of Ataxia-telangiectasia (AT) and is found in the vast majority of patients where it is used as a diagnostic tool (Stray-Pedersen et al, 2007). Waldmann and McIntire (1972) observed that AFP levels were elevated in virtually all patients with A-T and hypothesized that the primary abnormality was a defect in tissue differentiation. There is some evidence that lack of post-natal inhibition of the AFP gene leads to persistence of AFP gene function (Aslan et al, 2017). In summary, although AFP is often elevated in FA patients, it cannot be considered a reliable rapid screening tool for FA. The authors thank the patients with Fanconi anaemia and their families who have entrusted us with their care to continually strive to improve upon our work. This study was supported in part by the Kidz1stFund. All authors contributed to the design of the research. TDF performed the statistical analysis; All authors analysed and interpreted the data; RM wrote the initial draft and BS edited the final draft; All authors reviewed the data, edited the manuscript and approved the final version for submission. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article." @default.
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• W2800596286 date "2018-04-20" @default.
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• W2800596286 title "Elevations in serum alpha fetoprotein levels in patients with Fanconi anaemia" @default.
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• W2800596286 doi "https://doi.org/10.1111/bjh.15223" @default.
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