Inherited Aplastic Anemia Syndromes

Akiko Shimamura

Blanche P. Alter

The inherited bone marrow failure syndromes may primarily affect a single or multiple hematopoietic lineages. Four inherited bone marrow failure syndromes associated with aplastic anemia will be discussed in this chapter: Fanconi anemia (FA), dyskeratosis congenita (DC), Shwachman-Diamond syndrome (SDS), and congenital amegakaryocytic thrombocytopenia (CAMT). The congenital bone marrow failure disorders affecting primarily one cell line are discussed elsewhere in this text (Diamond Blackfan anemia, Chapter 39; Congenital Neutropenias, Chapter 57). While the inherited marrow failure disorders are rare, early diagnosis is important for optimal medical management, cancer surveillance, and family planning. Some of the disorders are associated with sensitivity to chemotherapy and radiation, and thus diagnosis of those underlying disorders prior to initiation of treatment of aplastic anemia or associated malignancies is crucial.

A careful medical and family history together with a thorough physical examination may provide important clues to distinguish acquired from inherited bone marrow failure.¹ A family history suggestive of cancer predisposition, such as malignancies at an unusually young age, may be obtained. A history of excessive toxicity following treatment with genotoxic agents may be present. A family history of congenital anomalies or stigmata characteristic of the inherited bone marrow failure syndromes may provide additional clues. Other potential etiologies for cytopenias should be ruled out. Once the diagnosis of an inherited bone marrow failure syndrome is made, it is important to test all family members at risk for the disease regardless of clinical symptoms since manifestations may vary widely among family members.

These disorders are increasingly being recognized in adults, who often manifest milder clinical phenotypes and whose first manifestation of an underlying inherited bone marrow failure syndrome may be aplastic anemia or malignancy.² With the advent of genetic and laboratory diagnostic testing, the diseases are also increasingly recognized in patients who lack the characteristic physical stigmata conventionally associated with the disease. Genetic test results must be interpreted critically and within the clinical context of the patient. Methodologic limitations of genetic testing and the distinction between functional mutations versus rare polymorphisms are important considerations.

FANCONI ANEMIA

FA is an inherited chromosomal instability syndrome with a variable clinical presentation that includes congenital anomalies, progressive pancytopenia, and cancer susceptibility. Guido Fanconi first reported a familial syndrome of pancytopenia and congenital physical abnormalities in 1927.³, ⁴ The diagnostic hallmark of FA is increased chromosomal breakage in response to DNA damaging agents such as mitomycin C (MMC) or diepoxybutane (DEB). Remarkable advances in the last few years have elucidated the molecular pathways disrupted in FA cells. Potential clinical implications of recent molecular studies will be discussed.

Clinical Features

FA should be considered in patients with congenital anomalies, aplastic anemia, or a family history of bone marrow failure or cancer susceptibility. The International Fanconi Anemia Registry (IFAR) analysis of 370 patients found that nearly 40% of patients had no reported physical findings.⁵ Aplastic anemia or malignancy may be the presenting sign of the underlying diagnosis of FA in the absence of physical anomalies or prior family history. The manifestations of FA can vary between affected members of the same family, suggesting that additional genetic, epigenetic, or environmental factors likely influence the disease course.

A wide range of congenital anomalies has been reported in FA patients (reviewed in Refs. 1, 6) (Table 37.1). Skin pigmentary changes, short stature, and radial bone and thumb abnormalities are the most common manifestations associated with FA, although these may be seen in some of the other inherited bone marrow failure syndromes as well. Abnormalities of the skeletal, ocular, renal, genital, aural, gastrointestinal (GI), cardiac, and central nervous systems have also been reported with high frequency.

The hematologic complications of FA typically present within the first decade of life. Early manifestations include moderate single or bilineage cytopenia with red cell macrocytosis. Elevated levels of fetal hemoglobin (Hb F) help to distinguish inherited from acquired aplastic anemia. Marrow failure may range in severity from mild asymptomatic cytopenias to severe aplastic anemia. This is in contrast to other chromosomal instability syndromes, such as ataxia telangiectasia, or Bloom syndrome, which are not typically associated with bone marrow failure.

Patients with FA are at increased risk of developing myelodysplasia (MDS) or acute myeloid leukemia (AML).⁷, ⁸ In a cohort study of 145 patients with FA, the cumulative incidence of AML reached 10% by age 24 years and plateaued thereafter.⁸ Patients with FA are also at increased risk of developing solid tumors, particularly squamous cell carcinomas of the head and neck, skin, GI tract, and genital tract.⁹ The cumulative incidence of solid tumors was low in younger patients but progressively increased with age starting at around 20 years of age, and reached 29% by age 48 years.⁸ FA patients, particularly those who have received
androgen treatment, are also at increased risk of liver tumors. Treatment of malignancies is limited by the low tolerance of FA patients to chemotherapy and radiation. Myeloid malignancies in FA patients have been successfully treated with hematopoietic stem cell transplantation (HSCT), though patient numbers are small and follow-up is limited. The role of pretransplant chemotherapy is unclear.¹⁰ For solid tumors, surgical resection is the mainstay of therapy. Regular and frequent surveillance for cancers is particularly important in this population and is discussed further in the section “Supportive Care.” Patients with the FANCD1/BRCA2 subtype manifest an especially high rate of early onset AML and specific solid tumors (brain and Wilms) compared with other FA subtypes.¹¹, ¹², ¹³

TABLE 37.1 PHYSICAL FINDINGS ASSOCIATED WITH FA

Skeletal
	Short stature
	Radial ray anomalies (thumbs, hands, radii)
	Hip and spine anomalies
Skin
	Hyperpigmentation (Café au lait spots)
	Hypopigmentation
Genitourinary
	Renal structural anomalies
	Hypogonadism
Craniofacial
	Microcephaly ophthalmic anomalies (microphthalmia, epicanthal folds)
	Otic anomalies (external and middle ear anomalies, deafness)
Genitourinary
	Hypogonadism
	Renal anomalies
Gastrointestinal malformations
	Esophageal atresia or tracheoesophageal fistula
	Imperforate anus
Cardiac malformations

Growth hormone deficiency has been observed in rare FA patients,¹⁴ and treatment with growth hormone improved growth in a subset of these patients¹⁵; its use is controversial because of a hypothetical risk of cancer or leukemia.¹⁶ Additional endocrine disorders associated with FA include hypothyroidism with or without thyroid hormone binding globulin deficiency, abnormal glucose tolerance, and diabetes mellitus.¹⁴, ¹⁷ Although FA is associated with short stature, endocrine evaluation is important to rule out treatable endocrine causes that might further contribute to poor growth.

There are currently 15 known FA subtypes (A, B, C, D1 [BRCA2] , D2, E, F, G, I, J [BRIP1, BACH1], L, M, N [PALB2], O [RAD51C], and P [SLX4]). With the exception of subtype B, which is X-linked recessive, all the other FA subtypes follow an autosomal recessive pattern of inheritance.¹⁸, ¹⁹ FA is found with similar frequencies in both genders and has no known ethnic restriction. The heterozygote carrier frequency has been recently reestimated at 1 in 181 in the United States and is higher in regions with founder effects such as Israel.²⁰ The mean age at diagnosis is generally reported to be between 7 and 9 years of age, with 75% of cases diagnosed between the ages of 4 and 14; however, FA has been diagnosed in neonates as well as in adults in their fifties.

Differential Diagnosis

Other inherited and acquired causes of bone marrow failure should be considered (see Chapter 41). FA may be considered in patients with characteristic congenital anomalies and may be the underlying diagnosis in patients with VACTERL-H (vertebral anomalies, anal atresia, cardiovascular malformations, tracheoesophageal fistula, renal and limb anomalies, plus hydrocephalus, MIM 276950).²¹ Cells derived from patients with other chromosomal breakage syndromes or syndromes with similar constitutional findings, such as Bloom syndrome or ataxia telangiectasia, may also exhibit high rates of spontaneous chromosomal breakage; however, they do not generally show increased chromosomal breakage in response to DNA crosslinkers such as MMC or DEB. Other chromosomal breakage syndromes are not typically associated with marrow failure. The exception is Nijmegen breakage syndrome, which may be associated with some increased chromosomal breakage with MMC and may be confused with FA.²² FA may also be considered in patients with a family history suggestive of cancer predisposition, patients presenting with cancers at an unusually young age, or patients who experience severe toxicity with chemotherapy or radiation.

FIGURE 37.1. Chromosomal breakage in FA. Peripheral blood lymphocytes from a FA patient were cultured without (left panel) or with (right panel) mitomycin C (MMC). The black arrows indicate chromosomal breaks. The red arrows indicate radial chromosomal fusions characteristic of FA. (Courtesy of Lisa Moreau, Dana Farber Cancer Institute, Boston, MA.)

Laboratory

Cell morphology on peripheral blood smear is typically unremarkable except for red cell macrocytosis and mild anisocytosis, though these are variably present. Thrombocytopenia or leukopenia typically precede anemia. Pancytopenia may be progressive over time. Erythrocyte macrocytosis and increased Hb F levels may be present even in the absence of cytopenias.

Bone marrow biopsy findings vary from normal cellularity to frank aplasia. Morphologic examination of the bone marrow aspirate may show dysplastic features, with nuclear-cytoplasmic maturation disynchrony. Dyserythropoiesis with multinucleate forms or nuclear fragmentation may be seen. Bone marrow aspirates should be sent for cytogenetic analysis, as FA patients are at high risk for malignant transformation. The appearance of cytogenetic clones of unclear clinical significance in the absence of morphologic evidence of MDS must be considered carefully, since cases of persistent or transient clonal abnormalities without apparent progression to leukemia have been reported.²³ At a minimum, patients with persistent unexplained changes in blood counts or new cytogenetic marrow abnormalities should be monitored closely with serial blood counts and a follow-up bone marrow examination to assess for possible malignant evolution. Amplification or gains of chromosome 3q26q29 were shown to correlate with increased risk of MDS and AML in one study.²⁴

The diagnosis of FA is based on the demonstration of increased chromosomal breakage in the presence of DNA cross-linking agents, such as MMC or DEB.²⁵, ²⁶ (Fig. 37.1) DEB is preferred in some centers since it is associated with less variability in chromosomal breakage among normal controls. The chromosomal breakage test is usually performed on metaphase spreads of peripheral blood lymphocytes cultured with MMC or DEB. A total of 50 metaphase cells are analyzed for chromosomal
breakage, including the formation of radial figures—a hallmark of this disease. Results are compared to a normal control and a positive control that have been run in parallel. Results are generally reported as aberrations per cell and the number of cells with breaks or radial forms. Increased spontaneous chromosomal breakage may be observed in some FA patients¹²; nonetheless, the rate of breakage is markedly enhanced by exposure to MMC or DEB regardless of patient phenotype or severity of disease. Chromosomal breakage in response to MMC/DEB can also be assessed in fetal cells obtained for prenatal diagnosis by amniocentesis or chorionic villus sampling.²⁷, ²⁸ If the disease-causing mutation is known for a given family, these assays can be used for prenatal diagnosis or preimplantation genetic diagnosis.²⁹ FA patient cells also exhibit cell cycle abnormalities with G2 phase prolongation and arrest by flow cytometry.³⁰, ³¹ Studies comparing results of DEB chromosomal breakage with cell cycle analyses of patients referred for FA testing showed close correlation between the results of these two tests.³² Constitutive elevation of serum alpha-fetoprotein (AFP) has been reported in FA patients,³³ although variations in AFP levels determined by different methodologies and the lack of specificity has limited the diagnostic utility of this test so far.³⁴ FA heterozygous carriers cannot be reliably detected by testing for chromosomal breakage. Genetic mutation testing is available for the FA genes.³⁵

Clonal somatic reversion to wild-type has been observed in a subset of cells from some FA patients. Increased chromosomal breakage may be limited to a subpopulation of lymphocytes in such patients. The reversion to normal cellular phenotype has been attributed to recombination or gene conversion events leading to selective growth advantage of the reverted cells³⁶, ³⁷; somatic reversion has been reported in early hematopoietic lineages.³⁸ Patients with a high degree of wild-type mosaicism may be difficult to diagnose. In cases with a high degree of suspicion for FA and normal blood breakage analysis, the MMC/DEB test should be performed on skin fibroblasts, since somatic mosaicism has not been observed in fibroblasts.

Pathophysiology

Models of the FA biochemical pathway have emerged from molecular studies of the cloned FA gene products. The reader is referred to recent excellent reviews of this rapidly evolving field.³⁹, ⁴⁰, ⁴¹ At least 15 different FA complementation groups (A, B, C, D1 [BRCA2], D2, E, F, G, I, J [BRIP1, BACH1], L, M, N [PALB2], O [RAD51C], and P [SLX4]) have been identified, and the corresponding genes have also been identified⁴² (Table 37.2). The gene for Fanconi subtype D1 is the previously identified tumor suppressor gene, BRCA2.⁴³ Biallelic mutations in BRCA2 are associated with an increased risk of early onset leukemia¹¹ and solid tumors, particularly Wilms and midline brain tumors.¹², ¹³ The FANCJ/BACH1/BRIP1 gene encodes a DNA helicase, which is an enzyme that unwinds DNA. The FANCM (Hef) gene shares regions of homology with both helicases and endonucleases, though these functions have yet to be directly demonstrated. FANCM may function in DNA translocation. The FANCL/PHF9/POG gene shares homology with other E3 ubiquitin ligases. The most common FA subtype is FA-A (60%), followed by FA-C (14%) and FA-G (10%)⁴⁴; the other FA subtypes are rare. The types of mutations associated with FA are highly variable.

TABLE 37.2 FA GENES

Subtype	Gene	FA patients (Estimated) %	Inheritance Pattern	Chromosome Location	Ubiquitinated FANCD2
A	FANCA	60	Autosomal recessive	16q24.3	Absent
B	FANCB	2	X-linked recessive	Xp22.31	Absent
C	FANCC	14	Autosomal recessive	9q22.3	Absent
D1	FANCD1/BRCA2	3	Autosomal recessive	13q12-13	Present
D2	FANCD2	3	Autosomal recessive	3p25.3	NA
E	FANCE	3	Autosomal recessive	6p21-22	Absent
F	FANCF	2	Autosomal recessive	11p15	Absent
G	FANCG	10	Autosomal recessive	9p13	Absent
I	FANCI	1	Autosomal recessive	15q25-q26	Absent
J	FANCJ/BACH1/BRIP1	2	Autosomal recessive	17q22-q24	Present
L	FANCL/PHF9/POG	<1	Autosomal recessive	2p16.1	Absent
M	FANCM/Hef	<1	Autosomal recessive	14q21.3	Absent
N	FANCN/PALB2	<1	Autosomal recessive	16p12	Present
O	FANCO/RAD51C	<1	Autosomal recessive	17q22	Present
P	FANCP/SLX4	<1	Autosomal recessive	16p13 .3	Present

The FA genes function coordinately in a common molecular pathway to regulate DNA repair. Loss of function of any FA gene results in sensitivity to DNA interstrand crosslinks, which block the progression of DNA replication. The FA proteins FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM associate into a nuclear complex (“FA complex”) together with proteins FAAP24 and FAAP100 and the E2 ubiquitin conjugating enzyme UBE2T. A model (Fig. 37.2) has emerged whereby stimuli such as S phase entry, or DNA damage by agents such as MMC, or ionizing radiation leads to activation of the FA complex, which functions as an E3 ubiquitin ligase to covalently attach a ubiquitin protein (monoubiquitinate) to the FANCI and FANCD2 proteins. The monoubiquitinated FANCD2/FANCI dimer translocates to nuclear foci with BRCA1, a known cancer susceptibility gene product implicated in DNA repair, as well as FANCD1/BRCA2, FANCN/PALB2, RAD51, ATR, NBS1, and FANCJ/BACH1/BRIP1. Monoubiquitination of FANCD2 and FANCI is required for MMC resistance and is dependent on the functional integrity of the upstream Fanconi proteins. FANCD2 monoubiquitination remains intact in bone marrow failure syndromes other than FA.⁴⁵ FANCD2 monoubiquitination can be assessed on a Western blot and serves as a useful biochemical diagnostic screen for FA.¹³ FANCM, in complex with FAAP24 and MHF, binds to stalled replication forks at sites of unresolved interstrand crosslinks. FANCM recruits the FA complex, which in turn monoubiquitinates the FANCD2/FANCI dimer. Ubiquitinated FANCD2/FANCI associates
with the nuclease FAN1 which can cleave and release the crosslink to allow DNA replication to proceed by translesion synthesis. RAD51 functions in homologous recombination. FANCJ/BRIP1 is a DNA helicase that is important for homologous recombination repair. FANCP/SLX4 interacts with and stimulates the DNA repair endonucleases XPF-ERCC1, MUS81-EME1, and SLX1, and may be important for resolution of homologous recombination intermediates. Elucidation of the Fanconi biochemical pathway in turn led to the identification of interactions between the Fanconi proteins and other known tumor suppressor pathways. These findings provide biochemical support for a role of the Fanconi pathway in tumorigenesis. For example, FANCD2 was subsequently shown to be phosphorylated by ATM kinase at a serine residue at amino acid position 222.⁴⁶ This phosphorylation is required for the cell cycle S phase checkpoint in response to radiation.⁴⁶ ATM function is disrupted in the chromosomal instability syndrome ataxia telangiectasia. Thus, FANCD2 links two DNA repair pathways, the Fanconi pathway and the ataxia telangiectasia pathway. Dysfunction of the Fanconi pathway or the ATM pathway is associated with increased cancer susceptibility. The Fanconi biochemical pathway was further implicated in DNA repair by the identification of the gene for FANCD1 as the tumor suppressor gene, BRCA2.⁴³ The FA pathway also interacts with other DNA damage checkpoint proteins including ATR, CHK1, and γ-H2AX.

FIGURE 37.2. Schematic diagram of the Fanconi anemia (FA) pathway. FA proteins (A, B, C, D1, D2, E, F, G, I, J, L, M, N) are depicted with shaded circles. Additional DNA repair proteins interacting with the FA pathway are denoted in non-shaded circles. Following activation of the FA core complex by DNA damage or the cell cycle, the D2 and I proteins are monoubiquitinated. Monoubiquitinated D2/I are translocated to chromatin where they colocalize with additional DNA repair proteins to participate in interstrand DNA crosslink repair. Ub, ubiquitin; P, phosphorylation.

Given the compelling biochemical data linking the Fanconi pathway to other known DNA repair pathways functioning in tumor suppression, the question of whether asymptomatic FA heterozygotes carry an increased risk of developing malignancies is a subject of active investigation. Heterozygous BRCA2 mutations are associated with increased risks of breast and ovarian cancer.⁴⁷ The reason why breast and ovarian cancer is uncommon in the FA patient population is not known, but may be related to decreased estrogen levels in these patients. Currently, not all FANCD1/BRCA2 mutations reported in FA patients have been associated with increased cancer risk in heterozygous carriers in the general population, and it is currently unclear whether all the FANCD1/BRCA2 mutations leading to FA (when both alleles are mutated) will also confer cancer predisposition in family members in whom only one BRCA2 allele may be mutant.¹³ Counseling of family members of patients with the FA-D1 subtype must currently be tempered with caution. Cancers have been reported in some heterozygous carriers of different FA genes (FANCD1/BRCA2 FANDJ/BRIP and FANCN/PALB2) with loss of heterozygosity of the FA gene in the tumor consistent with a tumor suppressor gene model (reviewed in Ref. 48).

In addition to a nuclear role in DNA repair, numerous studies suggest additional potential functions for the FA proteins. FA cells are sensitive to many different extracellular apoptotic signals, such as interferon-γ, TNF-α, and double-stranded RNA.⁴⁹, ⁵⁰, ⁵¹, ⁵² Furthermore, Fanconi proteins such as FANCC may have additional roles in other signaling pathways.⁵³

Studies also suggest a role for the FA proteins in mediating oxidative stress.⁵⁴, ⁵⁵ DEB, a clastogen to which Fanconi cells are especially susceptible, can cause oxidative DNA damage. FA cells may exhibit increased susceptibility to oxidative damage, and reactive oxygen species can damage DNA and lead to DNA crosslinks and double-stranded breaks.

The molecular etiology of marrow failure in FA remains an area of active investigation. A recent study reports p53 hyperactivation in hematopoietic stem/progenitor cells deficient in FA gene expression resulting in cell cycle arrest.⁵⁶ This finding is further supported by the demonstration that knockdown of p53 expression in a zebrafish model of FA rescues the developmental abnormalities.⁵⁷ Since p53 knockdown rescues the hematopoietic abnormalities in other marrow failure syndromes, p53 may represent a final common pathway for cellular stress or DNA damage in marrow failure syndromes. Abrogation of DNA damage checkpoints has been associated with a milder marrow failure phenotype; however, these FA patients remained at risk for malignant transformation to leukemia.⁵⁸ A potential role for environmental toxins in the severity of the FA phenotype has been demonstrated in murine models where disruption of the FA pathway results in increased sensitivity to reactive aldehydes associated with an increased risk of developmental anomalies and a propensity to develop leukemias.⁵⁹

Supportive Care

Cancer surveillance and education play an important role in the management of FA patients. Physicians should counsel patients regarding established behavioral and environmental risk factors associated with increased cancer risk. Since FA patients have a defect in DNA repair, imaging studies should minimize exposure to ionizing radiation. For example, when clinically feasible, it is reasonable to use MRI scans or ultrasound rather than CT scans for FA patients.

Because of the increased risk of MDS and leukemia in patients with bone marrow failure syndromes, frequent complete blood counts and annual bone marrow aspirates and biopsies with cytogenetic analysis are recommended, particularly since hematopoietic stem cell transplant outcomes are superior for patients transplanted prior to emergence of leukemia. FA patients are at risk for clonal cytogenetic abnormalities (reviewed in Ref. 60). Assessment of the clinical significance of a cytogenetic clonal abnormality requires consideration of the specific clone, the number of chromosomal abnormalities, the presence of significant marrow dysplasia (some baseline mild dysplasia is common in FA), and whether there are concomitant progressive peripheral cytopenias.²³, ⁶¹ Chromosomal abnormalities common in AML, such as t(8:21), inv(16), or trisomy 8, have not been reported in FA.²³, ⁶² Amplifications of 3q are common in FA but rarely seen in AML. FA AML also had a higher frequency of 1q amplification, loss of part or all of chromosome 7, and gain of 13q and del 20q.⁶², ⁶³

For patients on androgen therapy, regular physical examinations for liver size, liver ultrasound for masses or abnormalities every 6 to 12 months, and frequent liver enzyme tests are recommended. Annual examination by an otolaryngologist for leukoplakia or other signs of squamous cell carcinoma of the
oral cavity and oropharynx is important for patients with FA, DC, and those FA patients previously treated with bone marrow transplantation. Annual endoscopy can be considered in older FA and DC patients. Regular dental exams are important both for maintenance of oral hygiene and for detecting leukoplakia. Patients should be evaluated immediately for symptoms of pain in the mouth or throat, difficulty swallowing, changes in voice, anorexia, or weight loss. Suspicious lesions should be biopsied immediately, since early surgical excision is the mainstay of cancer therapy in FA patients. Annual gynecologic examinations, including Pap smears and HPV (human papilloma virus) exams, are recommended at puberty or after the age of 16. Counseling regarding sexual activity should be provided. Barrier methods of contraception may be particularly pertinent for the FA patients who are already at risk of cervical and vulvar malignancies. Regular breast exams are also recommended, although it is not clear what role mammography should play in cancer screening of these patients. HPV, which may be associated with an increased risk of squamous cell carcinoma of the head and neck, exhibits increased proliferation and epithelial cell expansion secondary to elevated levels of the viral E7 protein when the FA pathway has been disrupted.⁶⁴ Vaccination against HPV should be offered to all FA patients, males and females, in accordance with current guidelines.

Regular endocrinology evaluations are important, particularly in the pediatric population if the patient exhibits poor growth or delayed puberty. Hypothyroidism and diabetes are not infrequent in FA patients. A recent study reported one or more endocrine abnormalities in more than 70% of patients with FA.¹⁷, ⁶⁵ GI symptoms may present in FA patients, necessitating prompt referral to a gastroenterologist.

Treatment

HSCT is the only curative therapy for the hematologic manifestations of FA. Patients with FA are exquisitely sensitive to the toxicity of the usual chemotherapy and radiation regimens used in preparation for BMT,⁶⁶ particularly organ toxicity and graft-versus-host disease (GVHD). In addition, these regimens confer an increased risk of subsequent malignancies, primarily squamous cell carcinomas of the head and neck.⁶⁷, ⁶⁸ Reduced dose conditioning regimens are used for FA patients (reviewed in Ref. 69). An appropriate conditioning regimen combined with use of a matched sibling donor has resulted in survivorship of up to 80%.⁷⁰, ⁷¹, ⁷² Post-HSCT malignancies, especially squamous cell carcinomas of the head and neck, remain a long-term risk. Acute and chronic GVHD and radiation are risk factors for post-transplant squamous cell carcinomas.⁶⁷, ⁶⁸, ⁷³, ⁷⁴ Regimens with the goal of reducing transplant-related toxicity and long-term cancer risk are under investigation.⁷⁵, ⁷⁶, ⁷⁷ Clinical trials replacing radiation with fludarabine, a potent immunosuppressive agent with less cytotoxicity, have reported successful engraftment using either HLA-matched family member donors or alternative donors.⁷⁸, ⁷⁹, ⁸⁰, ⁸¹, ⁸², ⁸³, ⁸⁴ Some families opt to pursue preimplantation genetic diagnosis to provide a donor for patients who lack an unaffected HLA-identical sibling donor.⁸⁵ Treatment of AML in FA patients is challenging,¹⁰ and HSCT is generally the treatment of choice for eligible candidates.

Medical therapies are available for patients who either lack a suitable HSCT donor or for whom the risk of HSCT is high. Androgens may improve the blood counts in approximately 50% of patients with FA. Experience is greatest with oxymetholone, but widespread use is limited by its associated virilizing side effects, which are particularly problematic for female patients or very young patients. In a recent study, improvement in anemia and thrombocytopenia were noted in 7 of 8 patients with FA treated with danazol with minimal side effects.⁸⁶ Suggested treatment guidelines have been proposed by a consensus committee of the FA Research Foundation, although these guidelines must be individualized for each patient and undergo continuous modification as new data emerge. The suggestion of the committee is to consider an allogeneic stem cell transplant or androgen therapy if the hemoglobin falls below 8g/dl, if anemia is symptomatic, if the platelet count falls below 30,000/mm³, or if the neutrophil count falls below 500/mm³ ⁸⁷ The earliest and most frequent response to androgens is seen in red cells, with reticulocytosis and increase in hemoglobin generally occurring within the first 1 to 2 months of treatment. Responses in the white cell count and platelet count are variable and may not be seen until after 6 to 12 months of therapy. Resistance to therapy may develop over time (generally years). A common starting androgen regimen consists of oxymetholone 2 to 5 mg/kg/day given orally. Androgen doses may be slowly tapered to the minimal effective dose with careful monitoring of the blood counts. Side effects of androgen administration include liver toxicity, such as elevated liver enzymes, cholestasis, peliosis hepatis, and increased propensity to develop hepatic tumors (benign adenomas and malignant hepatomas). Other side effects of androgens include acne, oily skin, enlarged penis/clitoris, hoarseness/voice deepening, hair growth or hair loss, behavioral changes, hot flashes, breast enlargement or tenderness, amenorrhea, fluid retention, and secondary hypertension.

Hematopoietic growth factors such as G-CSF or GM-CSF have been shown to improve the neutrophil count in the majority of treated patients.⁸⁸, ⁸⁹ In a few patients, platelet or red cell counts also improved following treatment with G-CSF.⁸⁹ Growth factor treatment is generally not recommended for patients with MDS and is generally avoided for those with a clonal cytogenetic abnormality of the bone marrow, although there are no available data that directly address whether G-CSF increases leukemia risk. It is reasonable to perform a bone marrow aspirate and biopsy as well as cytogenetic studies prior to the initiation of growth factor therapy and monitor regularly throughout therapy.

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