Genotype-phenotype and outcome associations in patients with Fanconi anemia: the National Cancer Institute cohort

Abstract

Fanconi anemia (FA) is caused by pathogenic variants in the FA/BRCA DNA repair pathway genes, and is characterized by congenital abnormalities, bone marrow failure (BMF) and increased cancer risk. We conducted a genotype-phenotype and outcomes study of 203 patients with FA in our cohort. We compared across the genes, FA/BRCA DNA repair pathways (upstream, ID complex and downstream), and type of pathogenic variants (hypomorphic or null). We explored differences between the patients evaluated in our clinic (clinic cohort) and those who provided data remotely (field cohort). Patients with variants in upstream complex pathway had less severe phenotype [lacked VACTERL-H (Vertebral, Anal, Cardiac, Trachea-esophageal fistula, Esophageal/duodenal atresia, Renal, Limb, Hydrocephalus) association and/or PHENOS (Pigmentation, small-Head, small-Eyes, Neurologic, Otologic, Short stature) features]. ID complex was associated with VACTERL-H. The clinic cohort had more PHENOS features than the field cohort. PHENOS was associated with increased risk of BMF, and VACTERL-H with hypothyroidism. The cumulative incidence of severe BMF was 70%, solid tumors (ST) 20% and leukemia 6.5% as the first event. Head and neck and gynecological cancers were the most common ST, with further increased risk after hematopoietic cell transplantation. Among patients with FANCA, variants in exons 27-30 were associated with higher frequency of ST. Overall median survival was 37 years; patients with leukemia or FANCD1/BRCA2 variants had poorest survival. Patients with variants in the upstream complex had better survival than ID or downstream complex (p=0.001 and 0.016, respectively). FA is phenotypically and genotypically heterogeneous; detailed characterization provides new insights towards understanding this complex syndrome and guiding clinical management.

Fanconi anemia and dyskeratosis congenita/telomere biology disorders: Two inherited bone marrow failure syndromes with genomic instability

“…The spectrum of these type of anomalies includes hemivertebrae, hypoplastic vertebrae, vertebral fusion (Klippel-Feil syndrome), spina bifida, coccygeal aplasia, scoliosis, kyphosis, and atlantoaxial instability ( 37 , 133 , 260 ). A recent prospective study published that vertebrae anomalies are found in almost 50% of patients after intentional evaluation ( 245 ), which is in sharp contrast with the 4% described in the literature ( 37 , 133 ). Some reports have depicted less frequent anomalies, such as rib hypoplasia, Sprengel deformity, and hip dysplasia ( 149 , 225 , 261 – 264 ).…”

“…The most common alterations are pigmentary changes such as café-au-lait macules, generalized hyperpigmentation, and hypopigmented macules ( 37 , 133 ). Cross-sectional studies that intentionally looked for skin changes in patients with FA have found at least one pigmentary anomaly in 82–97% of evaluated patients ( 243 – 245 ). The most frequent finding was café-au-lait macules, with a mean of 7.5 per patient; they were distributed across the whole body ( 243 ).…”

Fanconi anaemia: A syndrome with distinct subgroups

“…We combined data obtained from families seen at the NIH [Clinical Center (CC) cohort] with information from those for whom we had data who had not been seen at the NIH [the Field Cohort (FC)]. Further details about the cohort and analytic methods are provided in recent publications 8,12–14 …”

“…Further details about the cohort and analytic methods are provided in recent publications. 8,[12][13][14] We classified patients by the age at which FA was diagnosed as FA-PED (below age 18), and FA-ADULT (at or above age 18 years), with the additional complexity that each age group includes patients recognized as the index cases in the family, as well as others who were secondary cases within a family (Table 1). We included STs as an additional discriminant since that was the first sign in two FA-ADULT cases and was the eventual outcome for many of the FA-PED cases (Table 2).…”

“…The primary data were obtained from information from patients with FA enrolled in the National Cancer Institute (NCI) programme for families with IBMFS at the National Institutes of Health (NIH). 13,14 The study (clini caltr ials.gov identifier 00027274) was approved by the NCI Institutional Review Board; participants and/or their proxies signed consent and medical release forms. Information was provided by the patients and/or family members.…”