Fanconi Anemia, Complementation Group D1

A number sign (#) is used with this entry because Fanconi anemia complementation group D1 can be caused by homozygous or compound heterozygous mutation in the BRCA2 gene (600185) on chromosome 13q13.

Description

Fanconi anemia (FA) 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).

For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see 227650.

Biochemical Features

Timmers et al. (2001) presented evidence that FA complementation group D is heterogeneous, consisting of 2 distinct loci, FANCD1 and FANCD2 (227646). They identified mutations in the FANCD2 gene in cell lines (PD20, VU008, and PD733) from 3 unrelated families with FANCD. Retroviral transduction of the cloned FANCD2 cDNA into FANCD2 cells resulted in functional complementation of mitomycin C sensitivity. The authors found, however, that the gene mutated in the FANCD cell lines HSC62 and VU423 was distinct from FANCD2 and does not map to chromosome 3; they designated this locus FANCD1.

Clinical Features

Based on patient outcome data as reported to the International Fanconi Anemia Registry, the cumulative incidence of bone marrow failure by age 40 years is 90%, with median time to onset of 7 years. In contrast, the cumulative incidence of hematologic malignancy, defined as the onset of acute leukemia or myelodysplastic syndrome (MDS), by age 40 years is 33%, with no significant difference between the FA complementation groups A (607139), C (227645), and G (614082) (Kutler et al., 2003).

Wagner et al. (2004) reported the genetic, hematologic, and clinical findings in 7 children from 5 kindreds with mutation in the BRCA2 gene segregating with Fanconi anemia. They described the presence of unique characteristics in these families and suggested the use of different monitoring and treatment practices for this specific patient cohort. They identified 6 children in these kindreds with the cooccurrence of BRCA2 mutations, Fanconi anemia, and early-onset acute leukemia. Leukemia occurred at a median of 2.2 years of age in the BRCA2 patients, in contrast to a median onset of 13.4 years in all other Fanconi anemia patients in the International Registry. Breast cancer was noted in 4 of the 5 kindreds. Of the 6 children with leukemia, 4 were treated with bone marrow transplantation and 2 were alive at 3 and 9 months after treatment. Wagner et al. (2004) suggested that BRCA2 testing should be considered in all patients with Fanconi anemia in whom the complementation group cannot be defined or in whom leukemia is diagnosed at or before 5 years of age.

Alter et al. (2007) described a female infant with FANCD1 in whom hydrocephalus, fused kidneys, and growth retardation had been identified in utero. At birth, she had intrauterine growth retardation, corneal opacities (diagnosed as Peters anomaly; see 604229), an anteriorly placed anus, small kidneys, and long thumbs with increased laxity; this constellation led to a later diagnosis of VACTERL-H (276950). Other physical findings included microcephaly, facial dysmorphia, microphthalmia, esotropia, growth failure, cafe-au-lait spots, and malposition of the kidneys. The surgical procedures during the first year included a ventricoperitoneal shunt, anoplasty, and repair of a tethered spinal cord due to a lipoma of the filum terminale. The karyotype was 46,XX, with 'structural chromosome changes that may reflect chromosome instability.' The chromosome breakage test for Fanconi anemia done at the age of 20 months showed chromosome breakage with both diepoxybutane and mitomycin C. At age 3.1 years, she was diagnosed with medulloblastoma.

In an analysis of the clinical and molecular features associated with BRCA2 mutations in FANCD1 patients using data from 27 patients (26 previously reported), Alter et al. (2007) noted 5 of 27 (19%) with VATER association (192350), suggesting that there may be a higher proportion of VATER association among patients with FANCD1 than among those with Fanconi anemia overall. They noted that a VATER phenotype had been reported in Fanconi anemia of complementation groups A, C, E (600901), F (603467), and G. Leukemia was reported in 13 patients, and solid tumours in 15; 6 patients had 2 or more malignancies. The small group of patients with biallelic mutations in BRCA2 was distinctive in the severity of the phenotype with early onset and high rates of leukemia and specific solid tumours. The authors postulated that these may comprise an extreme variant of Fanconi anaemia.

Weinberg-Shukron et al. (2018) reported 2 sisters with Fanconi anemia, aged 20 and 15 years, from a nonconsanguineous family of Ethiopian ancestry, who presented with short stature, primary amenorrhea, and absence of spontaneous pubertal development. Both sisters had a normal female karyotype and hypergonadotrophic hypogonadism, and had no detectable uterus or ovaries on initial imaging studies, findings consistent with complete XX ovarian dysgenesis. Thyroid, adrenal, and ovarian antibodies and serum antimullerian hormone were undetectable. Cortisol levels and findings from adrenal imaging were normal. After 18 months of receiving oral estradiol, in doses that were increased gradually, followed by ongoing treatment with a combined estrogen-progesterone oral contraceptive, both sisters had grown to mean familial height and had secondary sexual characteristics, adult-sized uteri, and regular menstrual periods. Physical examination revealed microcephaly and a few small cafe-au-lait spots in both sisters. The sisters had normal intelligence. The older sister was in a long-term (more than 14 years) remission from acute myelocytic leukemia which had been diagnosed when she was 5 years of age. An older brother of the sisters had died from acute promyelocytic leukemia at 13 years of age. Three other siblings (2 female and 1 male) were healthy and had normal puberty. Lymphocytes from the 2 affected sisters showed many chromosomal breaks after exposure to mitomycin C. BRCA2 mRNA was lower in the affected sisters than in their unaffected relatives and unrelated controls.

Molecular Genetics

Howlett et al. (2002) found biallelic inactivation of BRCA2 in Fanconi anemia D1 cell lines (600185.0018-600185.0023). Their results linked Fanconi anemia genes with BRCA1 (113705) and BRCA2 in a common pathway. Germline mutations of genes in this pathway may result in cancer risks similar to those observed in families with BRCA1 and BRCA2 mutations.

Hirsch et al. (2004) described the clinical, cytogenetic, and molecular findings in 2 Fanconi anemia complementation group D1 kindreds initially identified through a young child with a solid tumor (medulloblastoma and Wilms tumor). Each kindred subsequently had a second affected child; 1 developed Wilms tumor followed by a medulloblastoma, and the other developed T-lineage acute lymphoblastic leukemia. Cytogenetic studies demonstrated an unusually high spontaneous chromosome aberration, contrasted with other FA subtypes. Molecular analysis revealed biallelic mutations in the BRCA2 gene (600185.0027-600185.0030). The patients did not exhibit bone marrow failure. Hirsch et al. (2004) suggested that the D1 subtype represents a severe end of the cytogenetic spectrum within FA, consistent with a critical downstream role of BRCA2 in the FA pathway. Furthermore, this FA subgroup may be preferentially associated with an increased predisposition to solid tumors in early childhood.

In 2 brothers who developed Wilms tumor (see 194070) and brain tumors, Reid et al. (2005) identified 2 truncating BRCA2 mutations: an 886delGT (600185.0027) and S1882X (600185.0031). One boy developed a glioblastoma (see 613029); the other had recurrent medulloblastoma (see 155255) as well as pre-B-cell acute lymphoblastic leukemia. Neither child had the typical clinical features of Fanconi anemia. No first- or second-degree relative had cancer when the family presented; however, after the boys died their mother developed breast cancer at age 45 as did a paternal aunt at age 48.

The FANCD1 patient identified by Alter et al. (2007) with VACTERL-H association carried compound heterozygous mutations in the BRCA2 gene, the 6174delT mutation (600185.0009) and Q3066X (600185.0032).

In 2 sisters with Fanconi anemia who presented primarily with XX ovarian dysgenesis, Weinberg-Shukron et al. (2018) detected compound heterozygosity for a nonsense mutation (V2527X) and a frameshift mutation (c.9693delA) in the BRCA2 gene.