Abstract
Fanconi’s anemia (FA) is an inherited DNA repair disorder with very high risks of aplastic anemia (AA), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and squamous cell carcinomas (SCC). Patients with FA often have physical anomalies, and may develop endocrinopathies; these phenotypic features may be associated with adverse outcomes. While most of these abnormalities have been previously-reported, only prospective follow-up of a meticulously-characterized cohort can accurately quantify the prevalence and natural history of each, and determine whether specific abnormalities are strongly predictive of adverse outcomes; such information will be invaluable for evidence-based management of FA patients. To begin our formal investigation of these associations, we reviewed the medical records of 42 study participants with FA, and began prospective evaluation of a subset of 20 patients who underwent multidisciplinary evaluation at the NIH Clinical Center (FA Clinical Center Cohort - CC). The remaining 22 patients were in the FA Field Cohort (FC). We studied 17 males and 25 females. The CC and FC subjects were similar except that the former were older at the time of study (median 21.5 vs 14.3 yrs in the FC, p=0.01) and had later onset of aplastic anemia (11.8 vs 7.2 yrs, p=0.03). 36/42 (86%) had at least one FA-related congenital anomaly. 11 patients were FANCA, 9 FANCC, and 1 each FANCD1/BRCA2, FANCF, and FANCJ. 34/42 (81%) had aplastic anemia; 10 had mild to moderate and 24 had severe AA. 13/33 (38 %) had clonal cytogenetic bone marrow abnormalities, some for >3 years. 8/42 (19%) developed MDS, one of whom evolved to AML. 12 (29%) underwent BMT, 9 of whom are alive (median 4 yrs, range 9 mo-21 yrs). 3 patients were hematopoietic somatic mosaics, in whom the diagnosis of FA was confirmed by detection of chromosome breakage in skin fibroblasts; all 3 had mutations in FANCA. 23/36 (64%) had hearing loss, 4 of whom had surgery for middle ear bony abnormalities. 28/32 had microcornea, 20 microophthalmia, 21 myopia, and 4 had ptosis. 32/36 (89%) had multiple café-au-lait spots and hyper/hypopigmented areas, and 2 had Sweet’s syndrome with MDS. 9/19 (47%) had leukoplakia; 1 biopsy was positive for SCC. 29/42 (69%) had one or more endocrinopathy, including short stature, hypothyroidism, growth hormone deficiency, glucose intolerance, diabetes, dyslipidemia and metabolic syndrome. 5 patients had mid-line structural anomalies of the brain, and 1 each had a lipoma and a brain tumor. 2 patients had nonalcoholic steatohepatitis, 1 had transfusional hemosiderosis and 1 had a liver adenoma. 7/8 adult females had infertility and premature ovarian failure; 5 males had hypogenitalia. 7/7 females and 2/4 males older than 18 yrs had osteopenia or osteoporosis. 9 patients had 12 prevalent cancers at a median age of 29 yrs (range 5–44), including 5 head and neck, 4 vulvar, and 1 each nasopharyngeal, skin and brain tumor. One of the head and neck SCC occurred 13 years after BMT. Prospective screening at the NIH identified recurrent head and neck SCC in 3 patients. We conclude that FA patients need to be examined frequently in comprehensive subspecialty clinics to identify and treat significant co-morbidities, including hematologic, endocrine, and neoplastic disorders. Analysis of genotype/phenotype/cancer correlations in FA will require thorough evaluations of the type outlined here, involving larger numbers of patients; accrual to, and follow-up of, our FA cohort continues.
Fanconi’s Anemia—Rare Aplastic Anemia at Ten Year-Old Boy in Mogadishu-Somalia: Case Report