Fanconi's anaemia and pregnancy

Alter, Blanche P.; Frissora, Christine L.; Halpérin, Daniel; Freedman, Melvin H.; Chitkara, Usha; Álvarez, Elena; Lynch, Lauren; Adler-Brecher, Barbara; Auerbach, Arleen D.

doi:10.1111/j.1365-2141.1991.tb08593.x

Cited by 80 publications

(59 citation statements)

References 50 publications

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“…Male Fanconi patients have greatly reduced fertility and sperm count and an increased frequency of sperm with abnormal morphology. Female patients are also infertile, with an increased prevalence of primary ovarian failure and premature menopause [3,7,[14][15][16]. Despite this, in a very few instances both FA males and females can give rise to progeny.…”

Section: Developmental Abnormalitiesmentioning

confidence: 99%

The Fanconi anaemia pathway orchestrates incisions at sites of crosslinked DNA

Crossan

Patel

2011

The Journal of Pathology

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Fanconi anaemia (FA) is a rare, autosomal recessive, genetically complex, DNA repair deficiency syndrome in man. Patients with FA exhibit a heterogeneous spectrum of clinical features. The most significant and consistent phenotypic characteristics are stem cell loss, causing progressive bone marrow failure and sterility, diverse developmental abnormalities and a profound predisposition to neoplasia. To date, 15 genes have been indentified, biallelic disruption of any one of which results in this clinically defined syndrome. It is now apparent that all 15 gene products act in a common process to maintain genome stability. At the molecular level, a fundamental defect in DNA repair underlies this complex phenotype. Cells derived from FA patients spontaneously accumulate broken chromosomes and exhibit a marked sensitivity to DNA-damaging chemotherapeutic agents. Despite complementation analysis defining many components of the FA DNA repair pathway, no direct link to DNA metabolism was established until recently. First, it is now evident that the FA pathway is required to make incisions at the site of damaged DNA. Second, a specific component of the FA pathway has been identified that regulates nucleases previously implicated in DNA interstrand crosslink repair. Taken together, these data provide genetic and biochemical evidence that the FA pathway is a bona fide DNA repair pathway that directly mediates DNA repair transactions, thereby elucidating the specific molecular defect in human Fanconi anaemia.

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Section: Developmental Abnormalitiesmentioning

confidence: 99%

The Fanconi anaemia pathway orchestrates incisions at sites of crosslinked DNA

Crossan

Patel

2011

The Journal of Pathology

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“…1,2 As base-line, in non-transplanted FA patients who reach adult age, the rate of successful pregnancy has been estimated at 15%. 3 Hematopoietic stem cell transplantation (HSCT), using an adapted attenuated conditioning regimen, represents the only curative therapy capable of restoring normal hematopoiesis in patients with FA. In FA, the conditioning has been reduced because of the toxic effect of alkylating agents.…”

Section: Introductionmentioning

confidence: 99%

“…Vanderson Rocha, 1 Gérard Socié, 6 Jakob Passweg, 7 Kumiko Goi, 8 Jean Sanders, 9 John Snowden, 10 Hiromasa Yabe, 11 Ricardo Pasquini, 2 and Eliane Gluckman 1 on behalf of the Aplastic Anaemia Working Party, EBMT 1 Eurocord Office, Hôpital Saint Louis, Paris, France; 2 Hospital de Clínicas, Curitiba, Brazil; 3 Hôpital Sainte-Justine, Montreal, QC, Canada; 4 Instituto Português de Oncologia, Lisbon, Portugal; 5 Istituto Giannina Gaslini and SAAWP, Genova, Italy; 6 Hôpital Saint Louis, Paris, France and SAAWP;…”

mentioning

confidence: 99%

Fertility recovery and pregnancy after allogeneic hematopoietic stem cell transplantation in Fanconi anemia patients

Nabhan¹,

Bitencourt²,

Duval³

et al. 2010

Haematologica

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Reduced fertility is one clinical manifestation among other well known Fanconi anemia features. Most recipients of allogeneic hematopoietic stem cell transplantation suffer from secondary infertility owing to gonadal damage from myeloablative conditioning. In order to evaluate the rate of pregnancy in Fanconi anemia transplanted patients, we performed a retrospective analysis of female patients transplanted in 15 centers from 1976 to 2008. Among 578 transplanted Fanconi anemia patients, we identified 285 transplanted females of whom 101 patients were aged 16 years or over. Ten became pregnant (4 twice). Before hematopoietic stem cell transplantation all had confirmed Fanconi anemia diagnosis. Median age at transplantation was 12 years (range 5-17 years). Conditioning regimen consisted of cyclophosphamide with or without irradiation. During follow up, 5 of 10 patients presented signs of ovarian failure. Among those, 2 patients spontaneously recovered regular menses, and 3 received hormonal replacement therapy. Pregnancy occurred from four to 17 years after hematopoietic stem cell transplantation. Three patients had preterm deliveries, one patient had a hysterectomy for bleeding. All 14 newborns had normal growth and development without congenital diseases. In conclusion, recovery of normal ovarian function and a viable pregnancy is a realistic but relatively rare possibility even in Fanconi anemia patients following hematopoietic stem cell transplantation. Mechanisms of fertility recovery are discussed

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“…[4] The condition is rare, with a worldwide incidence of about 1/300 000 [5] and a minimum carrier frequency of 1/300. [6] FA is a highly heterogeneous condition, both clinically and genetically, arising from mutations in 1 of at least 15 genes.…”

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confidence: 99%

Fanconi anaemia in black South African patients heterozygous for the FANCG c.637-643delTACCGCC founder mutation

et al. 2013

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Background. Fanconi anaemia (FA) is an autosomal recessive, genetically heterogeneous disorder, characterised by interstrand crosslinkinduced chromosome breaks, congenital abnormalities and predisposition to malignancies. It has a prevalence of about 1/40 000 in black South Africans (SAs). A founder mutation in the FANCG gene occurs in the homozygous state in 77.5% of southern African blacks. Objective. To locate additional pathogenic mutations in the FANCG gene of black FA patients who were heterozygous for the founder mutation. Methods. Further mutation analysis of the FANCG gene was undertaken in 7 patients clinically suspected of having FA. The parents of two of the patients were tested for the presence of the founder mutation to determine true heterozygosity in the patients. To clarify whether or not previously unreported variants were pathogenic, 58 random black SA individuals were screened. Results. Three novel single base pair deletions, resulting in frameshift mutations (c.247delA, c.179delT and c.899delT) were identified in 3/7 patients. A fourth patient was found to have a single base substitution resulting in a splice site mutation (c.1636+1G>A). The remaining three patients were not found to harbour any pathogenic mutations. Two non-pathogenic variants were also identified among the seven patients. Conclusion. The results of this small sample suggest that a second common mutation in the FANCG gene is unlikely in this population. However, FANCG sequencing should be performed on patients heterozygous for the common founder mutation to attempt to confirm their diagnosis.

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Fanconi's anaemia and pregnancy

Cited by 80 publications

References 50 publications

The Fanconi anaemia pathway orchestrates incisions at sites of crosslinked DNA

The Fanconi anaemia pathway orchestrates incisions at sites of crosslinked DNA

Fertility recovery and pregnancy after allogeneic hematopoietic stem cell transplantation in Fanconi anemia patients

Fanconi anaemia in black South African patients heterozygous for the FANCG c.637-643delTACCGCC founder mutation

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