Fanconi anemia (FA) is an autosomal recessive chromosomal instability disorder which is characterized by congenital abnormalities, defective hemopoiesis and a high risk of developing AML and certain solid Tumours. The birth incidence of FA is around 3 per million. Affected individuals can have mild growth retardation (63 %), and median height of FA individuals lies around the 5th centile. Other clinical features include areas of skin hyper- and hypopigmentation (64 %), skeletal defects (75 %) including radial limb defects (absent thumb with or without radial aplasia), abnormalities of ribs and hips, scoliosis, and cardiac (13 %) and renal (34 %) malformations. Other associated anomalies include microphthalmia (38 %) and developmental delay (16 %). The phenotypic abnormalities are variable and there is marked variability between affected individuals in the same sibship. Importantly, up to one-third of FA cases do not have any obvious congenital abnormalities and are only diagnosed when another sibling is affected or when they develop a hematological problem. However, most FA cases do have some subtle clinical features, such as dermatological manifestations.
The pancytopenia usually develops between the ages of 5 and 9 years (median age 7 years), and symptoms due to this develop progressively. The cumulative incidence of any hematological abnormality in FA is up to 90 %, and the cumulative incidence of leukemia is around 10 % by age of 25 years. The crude risk (irrespective of age) for MDS is around 5 % and for leukemia is 5–10 % (Alter et al. 2003). FA patients that survive into early adulthood are around 50 times more likely to develop solid Tumours compared to the general population, and in one study 29 % developed a solid Tumours by the age of 48 years (Rosenberg et al. 2003). In particular, there is a high risk of hepatic Tumours (which may be related to androgen use) but also squamous cell carcinomas of the esophagus, oropharynx, and vulva (Alter 2003; Rosenberg et al. 2003).
The hallmark feature of FA cells is chromosomal hypersensitivity to DNA cross-linking agents such as mitomycin C (MMC) or diepoxybutane (DEB), and the resulting increase in chromosome breakage provides the basis for a diagnostic test (Auerbach 1993). The characteristic chromosomal findings are excess tri- and quadriradial and complex interchanges. The basic defect appears to be a deficiency of the repair of DNA strand cross-links. The relationship between the DNA repair defects and chromosomal aberrations found in this condition and the susceptibility to cancer is not fully understood; an increased mutation rate or incidence of Tumours-promoting translocations may be a factor.
There is some evidence that heterozygotes for FA have an increased risk of certain cancers, especially leukemia and gastric and colonic cancers, with a relative risk of 3 reported, but this did not reach statistical significance (Swift et al. 1980; reviewed in Tischkowitz and Hodgson 2003). A separate study of 125 relatives of FA patients failed to reproduce these observations (Potter et al. 1983), and a more recent study of 36 UK families also found no excess of cancers in relatives of FA cases (OR 0.97, P = 0.62) (Tischkowitz et al. 2008). Chromosome breakage testing in FA heterozygotes is complicated by overlap with the normal range (Pearson et al. 2001). Prenatal diagnosis has been achieved by demonstrating increased spontaneous and induced chromosome breakage in fetal cells (cultured amniocytes or chorionic villus cells) (Auerbach et al. 1985).
Sixteen FA genes have been identified since 1992 (see Fig. 1). FANCA mutations account for almost two-thirds of cases, FANCC and G for 25 %, and FANCE and FANCF for a further 8 %. There are only a handful of FA cases that have not yet been genetically diagnosed. Diagnosis by direct mutation detection is available. Molecular studies have established that a common pathway exists, both between the FA proteins and other proteins involved in DNA damage repair, such as NBS1, ATM, BRCA1, and BRCA2 (reviewed in Venkitaraman 2004).
Fig. 1 Tempo of discovery of 16 FA genes (Figure courtesy of Marc Tischkowitz MD, PhD)
FANCD1 has been shown to be BRCA2 (Howlett et al. 2002). FA cases due to biallelic BRCA2 mutations are rare but seem to be associated with an increased risk of medulloblastoma or Wilms Tumours that may precede development of aplastic anemia (Hirsch et al. 2004; Offit et al. 2003) or an earlier onset of leukemia (Wagner et al. 2004). A family history of breast or ovarian cancer might provide clues in these cases. At present it is not known whether such cases should have intensive screening for solid Tumours or whether they would benefit from more aggressive treatment with earlier stem cell transplants. The finding that FA can be caused by biallelic BRCA2 mutations should be taken into account when counseling BRCA2 mutation carriers, although interestingly no homozygosity for some frequent mutations, such as 6174delT, has been identified.
Perhaps not surprisingly, PALB2 (partner and localizer of BRCA2) has also been found to be a FA gene (FANCN, arrow on figure), and like BRCA2/FANCD1, children with biallelic PALB2/FANCN mutations tend to have more serious cancer-related phenotypes, with early-onset Wilms Tumours, acute myeloid leukemia, and medulloblastomas predominant (Reid et al. 2007; Xia et al. 2007; Tischkowitz and Xia 2010). The BRCA1 partner, BRIP1 (also known as BACH1), is also a FA gene – FANCJ (Levran et al. 2005; Levitus et al. 2005). Notably, children with FA type J tend to develop solid Tumours, rather than the leukemia seen with FANCD1/BRCA2 and FANCN/PALB2.
Continuing the DNA damage repair/cancer/FA theme, a handful of children with FA or FA-like disorders have been found to carry biallelic mutations in XRCC2 (Shamseldin et al. 2012) or RAD51C (Vaz et al. 2010). In contrast to the genes mentioned above, cancer has yet been noted in these children. Interestingly, while some data have suggested that monoallelic XRCC2 mutations seem to moderately increase the risk for breast cancer (Park et al. 2012), monoallelic RAD51C mutations predispose to ovarian cancer only (Meindl et al. 2010; Loveday et al. 2011).
Until recently it was thought that biallelic BRCA1 mutations were embryonic lethal, but such a case has now been described in an individual who had short stature, microcephaly, developmental delay and was diagnosed with ovarian carcinoma at age 28 (Domchek et al. 2013). She was found to have one allele with a BRCA1 c.2457delC (p.Asp821Ilefs*25) truncating mutation, and a hypomorphic c.5207T > C missense mutation (p.Val1736Ala) on the other allele. This possibly unique combination of clinical features resemble FA but are likely distinct from it. Unfortunately, DEB testing was not carried out and cannot be done as the patient has died.
At diagnosis patients should have a full hematological assessment that should include examination of the bone marrow; HLA typing in anticipation of possible bone marrow transplantation should be performed. Other investigations at presentation should include audiometry, ultrasound of the renal tract, an endocrine assessment, especially if there is evidence of growth failure, and an ophthalmology assessment. Referral to hand surgeons and plastic surgeons may be indicated to consider correction of radial ray defects with a view to improving function and appearance. It is important that siblings are also tested as they may not have any congenital abnormalities.
If there is no hemopoietic defect at time of diagnosis, hematological monitoring may only be required once per year, but as the patient becomes older and develops hematological complications, hematologists play an increasingly central role. Many patients who develop bone marrow failure initially respond to treatment with androgens and hemopoietic growth factors. Eventually most patients become refractory to these therapies, and the definitive treatment currently available for bone marrow failure is hemopoietic stem cell transplantation.