VACTERL-H Association and Fanconi Anemia

Abstract

Patients with Fanconi anemia (FA) often have birth defects that suggest the diagnosis of VATER association. A review of 2,245 cases of FA reported in the literature from 1927 to 2012 identified 108 cases with at least 3 of the defining features of VATER association; only 29 had been so noted by the authors. The FA VATER signature was the significantly higher frequency of renal and limb (radial and/or thumb) anomalies (93% of cases had both) compared with less than 30% of VATER patients; the presence of one or both of these birth defects should lead to testing for FA. The relative frequencies of the genotypes of the patients with FA VATER were strikingly different from those expected from the general FA population; only 19% were FANCA, while 21% were FANCB, 14% FANCD1/BRCA2, and 12% FANCD2. Consistent with their genotypes, those with the FA VATER phenotype had a worse prognosis than FA patients with milder phenotypes, with shorter median survival and earlier onset of malignancies. The early identification of FA patients among infants with VATER association should lead to earlier more proactive management, such as cancer surveillance and genetic counseling.

Keywords: Birth defects; Fanconi anemia; VACTERL-H; VATER.

Fig. 1

Individual features of FA VATER. All patients had at least 3 of the VACTERL-H features. RL (renal and limb; radial ray)anomalies were the most frequent individual features, reported in 104 of the 108 patients with FA VATER.

Fig. 2

Pairs of features of FA VATER. RL anomalies occurred together in 101 patients; the next most frequent pairs were cardiac and R or L anomalies (61 and 60 patients), followed by vertebral and L or R (24 and 25 patients).

Fig. 3

Unique combinations of FA VATER features. The most frequent triplets were CRL in 36, and VRL and ARL in 12 and 9 patients, respectively. The most common combination of 4 features was VCRL in 5 patients. The identification of VACTERL-H in FA essentially included any combination in which R and L were found.

Fig. 4

Genotypes of FA and FA VATER patients. A All FA patients, adapted from published frequencies of FA genotypes (http://www.rockefeller.edu/fanconi/). Group A comprises more than 65% of all patients. B Frequencies of FA genotypes reported in 42 of the 108 FA VATER patients. The most frequent groups were B, A, D1 and D2, followed by J, C, and I. C Frequencies of FA VATER genotypes according to their location in the FA/BRCA DNA repair pathway: the core complex (A, B, C, G; n = 21) was the largest group, followed by downstream genes (D1, J, N, O; n = 13), and then the D1/I group (n = 8). FA VATER features appear to be distributed throughout the FA/BRCA DNA repair pathway.

Fig. 5

Percent of all FA cases with genotype reported in the literature in which criteria were met for VATER association. The VATER features were more frequent than expected in FANCB, D1, D2, I, J, N, and O, compared with an expected uniform distribution across genotypes.

Fig. 6

Single features of VACTERL-H and FA pathway groups. The patterns of the single anomalies are very similar, and suggest that the pattern of the FA VATER association is not unique to a specific FA pathway location.

Fig. 7

Comparison of single features in 108 FA VATER with 286 VATER patients [Botto et al., 1997]. The features in higher percent in FA VATER than in VATER were R and L, followed by C and H, while those in higher percent in VATER without FA were V, A and T. * Higher in FA VATER. ** Higher in VATER.

Fig. 8

Unique combinations of VATER features in the literature [Botto et al., 1997]. The most frequent were VAR in 26%, ATR in 19% and VATR in 7%. Both the VATER shown here and the FA VATER in figure 3 include combinations that are unique to each: CRL in FA VATER, and VAR and ATR in VATER.

Fig. 9

Overall survival of FA VATER patients (A) and all FA cases reported in the literature from 1927 to 2012 (B). The FA VATER group had a median survival of 14 years, compared with 25 years in the literature cases. Survival is by Kaplan-Meier method.

Fig. 10

Cumulative incidence of cancer calculated as 1 minus Kaplan-Meier curve with censoring at stem cell transplant or death. A FA VATER has a bolus of early-onset cases ages 10 or younger, while in all FA (B) the accumulation is sigmoid, low in the early years, and approximating a linear incidence starting at around age 20. In FA VATER, the cumulative incidence of cancer was 15% by age 10, while it was 9% by that age in the entire FA group.