Fanconi anemia

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Description from OMIM

Fanconi anemia is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (summary by Deakyne and Mazin, 2011). Soulier et al. (2005) noted that the FANCA, -C, -E, -F, -G, and -L proteins are part of a nuclear multiprotein core complex which triggers activating monoubiquitination of the FANCD2 protein during S phase of the growth cycle and after exposure to DNA crosslinking agents. The FA/BRCA pathway is involved in the repair of DNA damage. Some cases of Fanconi anemia have presented with a VACTERL (192350) or VACTERL-H (276950, 314390) phenotype. In a group of 27 patients with Fanconi anemia group D1 (605724) due to biallelic mutations in the BRCA2 gene (600185), Alter et al. (2007) found that 5 patients had 3 or more VATER association anomalies and 1 was diagnosed with VACTERL-H. A VATER phenotype has also been reported in Fanconi anemia of complementation groups A, C (227645), E (600901), F (603467), and G (602956); VACTERL-H has also been described in patients with FANCB (300515) mutations (McCauley et al., 2011). Savage et al. (2015) added patients with FANCI (609053) to this list and stated that patients with FANCD2 (227646) and FANCL (614083) had also been reported to have features of VACTERL association. Genetic Heterogeneity of Fanconi Anemia Other Fanconi anemia complementation groups include FANCB (300514), caused by mutation in the FANCB (300515) on chromosome Xp22; FANCC (227645), caused by mutation in the FANCC (613899) on chromosome 9q22; FANCD1 (605724), caused by mutation in the BRCA2 (600185) on chromosome 13q12; FANCD2 (227646), caused by mutation in the FANCD2 gene (613984) on chromosome 3p25; FANCE (600901), caused by mutation in the FANCE gene (613976) on chromosome 6p21; FANCF (603467), caused by mutation in the FANCF gene (613897) on chromosome 11p15; FANCG (614082), caused by mutation in the XRCC9 gene (FANCG; 602956) on chromosome 9p13; FANCI (609053), caused by mutation in the FANCI gene (611360) on chromosome 15q26; FANCJ (609054), caused by mutation in the BRIP1 gene (605882) on chromosome 17q22; FANCL (614083), caused by mutation in the PHF9 gene (FANCL; 608111) on chromosome 2p16; FANCN (610832), caused by mutation in the PALB2 gene (610355) on chromosome 16p12; FANCO (613390), caused by mutation in the RAD51C (602774) on chromosome 17q22; FANCP (613951), caused by mutation in the SLX4 gene (613278) on chromosome 16p13; FANCQ (615272), caused by mutation in the ERCC4 gene (133520) on chromosome 16p13; FANCR (617244), caused by mutation in the RAD51 gene (179617) on chromosome 15q15; FANCS (617883), caused by mutation in the BRCA1 gene (113705) on chromosome 17q21; FANCT (616435), caused by mutation in the UBE2T gene (610538) on chromosome 1q31; FANCU (617247), caused by mutation in the XRCC2 gene (600375) on chromosome 7q36; FANCV (617243), caused by mutation in the MAD2L2 gene (604094) on chromosome 1p36; and FANCW (617784), caused by mutation in the RFWD3 gene (614151) on chromosome 16q23. The previously designated FANCH complementation group (Joenje et al., 1997) was found by Joenje et al. (2000) to be the same as FANCA. A patient originally reported to have Fanconi anemia of complementation group M (FANCM) due to mutation in the FAAP250 gene (609644) by Meetei et al. (2005) was subsequently found by Singh et al. (2009) to have FANCA.

Prevalence of clinical parameters (%)

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List of symptoms

Symptom/sign Organ system Percent affected Pubmed id Added on(yyyy-mm-dd) Edit/add reference
Pancytopenia circulatory 100 % 20132664 2011-10-19
Anemia circulatory 100 % 20132664 2012-05-04
Hypersensitivity to DNA cross-linking multi 100 % 17426088 2015-09-21
Osteopenia skeletal 92 % 17426088 2015-09-21
Short stature skeletal 82 % 20132664 2011-10-02
Skin pigmentation changes integumentary 82 % 17426088 2011-10-12
Hyperinsulinemia endocrine 72 % 11335753 2011-10-12
Short stature skeletal 61 % 2917181 2011-10-02
Skin pigmentation changes integumentary 58 % 2917181 2011-10-02
Hearing loss nervous 56 % 17426088 2011-10-12
Microphthalmia nervous 56 % 17426088 2011-10-12
Hypogonadism reproductive 53 % 17426088 2011-10-12
Short stature multi 51 % 17426088 2011-10-12
Thumb abnormalities skeletal 51 % 17426088 2015-09-21
Microcephaly nervous 47 % 17426088 2011-10-12
Skin pigmentation changes integumentary 45 % 20132664 2011-10-02
Microcephaly nervous 44 % 2917181 2011-10-02
Pancytopenia circulatory 39 % 2917181 2011-10-02
Anemia circulatory 39 % 2917181 2012-05-04
Microphthalmia nervous 38 % 2917181 2011-10-02
Myelodysplastic syndrome circulatory 38 % 17426088 2011-10-12
Osteoporosis skeletal 38 % 17426088 2015-09-21
Developmental delay nervous 33 % 17426088 2011-10-12
Developmental delay nervous 30 % 20132664 2011-10-02
Cancer lymphatic 27 % 20132664 2011-10-02
Hypothyroidism endocrine 25 % 11335753 2011-10-12
Hearing loss nervous 22 % 2917181 2011-10-02
Cancer lymphatic 4 % 2917181 2011-10-02

List of references:

Clinical, genetic and cytogenetic study of Fanconi anemia in an Indian population.
Seema Korgaonkar, Kanjaksha Ghosh, Babu Rao Vundinti,

Fanconi anemia (FA) is a rare autosomal recessive genetic disease, associated with congenital anomalies and a predisposition to cancers. FA patients exhibit spontaneous chromosome breakage and FA cells are sensitive to DNA interstrand crosslink agents and expresses high frequency of chromosome breakage. Recently 13 genes have been shown to be involved with the FA phenotype. We have carried out a detailed study in clinically diagnosed FA patients in an Indian population. Thirty three patients were clinically diagnosed with FA and had aplastic anemia and bleeding abnormalities. The genetic analysis revealed a significantly (P<0.0001) high frequency (36.4%) of parental consanguinity in FA patients compared to controls (3.33%). Chromosomal analysis revealed spontaneous chromosome breakage in 63.64% FA patients. The mitomycin C and diepoxybutane induced cultures showed a significantly (P<0.001) high frequency of chromosome breakage and radial formation compared to controls. Among 33 patients, nine (27.27%) patients developed malignancies and chromosomal abnormalities were detected in five (55.5%) patients bone marrow cells including monosomy 5 and 7, trisomy 10, der(1q) and inv(7). Cytogenetic investigation is important in aplastic anemia to rule out FA. The clinical presentation and the associated high frequency of consanguinity in FA, and the molecular analysis are complementary in the study of an Indian population.

Hematology (Amsterdam, Netherlands) - Feb 2010

Endocrine abnormalities in patients with Fanconi anemia.
Neelam Giri, Dalia L Batista, Blanche P Alter, Constantine A Stratakis,

Fanconi anemia (FA) is an inherited disorder with chromosomal instability, bone marrow failure, developmental defects, and a predisposition to cancer. Systematic and comprehensive endocrine function data in FA are limited.

The Journal of clinical endocrinology and metabolism - Jul 2007

Evaluation of growth and hormonal status in patients referred to the International Fanconi Anemia Registry.
M P Wajnrajch, J M Gertner, Z Huma, J Popovic, K Lin, P C Verlander, S D Batish, P F Giampietro, J G Davis, M I New, A D Auerbach,

1) To determine the extent of short stature in patients with Fanconi anemia (FA); 2) to determine the extent and nature of endocrinopathy in FA; 3) to assess the impact on height of any endocrinopathies in these patients; and 4) to study the correlation, if any, between height, endocrinopathy, and FA complementation group.

Pediatrics - Apr 2001

International Fanconi Anemia Registry: relation of clinical symptoms to diepoxybutane sensitivity.
A D Auerbach, A Rogatko, T M Schroeder-Kurth,

Fanconi anemia (FA) is characterized clinically by a progressive pancytopenia, diverse congenital abnormalities and increased predisposition to malignancy. Although a variable phenotype makes accurate diagnosis on the basis of clinical manifestations difficult in some patients, study of cellular sensitivity to the clastogenic effect of DNA cross-linking agents such as diepoxybutane (DEB) has been used to facilitate the diagnosis. Data from DEB-induced chromosomal breakage studies of 328 peripheral blood specimens from patients considered at risk for FA were analyzed using a stepwise multivariate logistic regression, in order to determine which method of representing the data best discriminated between DEB-sensitive (DEB+) and DEB-insensitive (DEB-) cases. Similar methods were applied to the data from the International Fanconi Anemia Registry (IFAR) to determine whether DEB+ and DEB- cases may be considered as distinct clinical entities, and if so, which variables provide the best discrimination between the two groups. We conclude that hypersensitivity to the clastogenic effect of DEB is a useful discriminator for FA. A simplified scoring method for classifying patients on the basis of eight clinical manifestations that are the best predictors for FA is presented. Our data indicate that the clinical diversity in FA is more widespread than previously recognized.

Blood - Feb 1989