Fanconi Anemia

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Genes: FANCA (HGNC:3582) BRCA2 (HGNC:1101) FANCG (HGNC:3588) BRIP1 (HGNC:20473) FANCC (HGNC:3584) PALB2 (HGNC:26144)
• Mode(s) of Inheritance: Autosomal Recessive
• Literature Search: 10/28/2019
• Curation Status: Released (1.2.0)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
FANCA	Fanconi anemia complementation group A (0009215)	227650	Moderate Actionability
BRCA2	Fanconi anemia complementation group D1 (0011584)	605724	Moderate Actionability
FANCG	Fanconi anemia complementation group G (0013565)	614082	Moderate Actionability
BRIP1	Fanconi anemia complementation group J (0012187)	609054	Moderate Actionability
FANCC	Fanconi anemia complementation group C (0009213)	613899	Moderate Actionability
PALB2	Fanconi anemia complementation group N (0012565)	610832	Moderate Actionability

Actionability Assertion Rationale

• All experts agreed with the assertion computed according to the rubric

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Morbidity due to bone marrow failure / Evaluation by hematologist with blood counts and bone marrow aspirate to monitor bone marrow failure to initiate further treatment	2	3C	2D	2	9CD
Morbidity due to FA-related solid tumors / Evaluation by provider with experience in FA to detect solid tumors and initiate treatment	2	2C	2C	3	9CC

Severity of Outcome

Prevalence of the Genetic Condition

Fanconi anemia (FA) is a very rare disorder. Carrier frequencies give an expected prevalence at birth of 1/160,000. Until now, more than 2,000 cases have been reported in the literature. It is also the most common genetic cause of aplastic anemia and one of the most common genetic causes of hematologic malignancy.

Clinical Features (Signs / symptoms)

FA is characterized by physical features, bone marrow failure, and cancer susceptibility. Physical features include growth deficiency, abnormal skin pigmentation, skeletal malformations of upper and lower limbs, microcephaly, ophthalmic anomalies, genitourinary tract anomalies, endocrine disorders, hearing loss, congenital heart defects, gastrointestinal anomalies, gastrointestinal symptoms, central nervous system issues, and gynecologic issues. Developmental delay and/or intellectual disability may be present. Endocrine disorders include growth hormone deficiency, hypothyroidism, and diabetes. Gastrointestinal symptoms include poor food intake, nausea, abdominal pain, and diarrhea. Gynecologic issues include structural abnormalities, delayed puberty, decreased fertility, excessive bleeding, and early menopause. Bone marrow failure manifests as anemia, thrombocytopenia, and leukopenia. Pancytopenia generally worsens over time. Cancer susceptibility includes an increased risk for acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), and solid tumors. The most common solid tumors are head and neck squamous cell carcinoma (HNSCC) and lower genital tract squamous cell carcinoma (SCC) in women with FA, including cervical, vaginal, vulvular, and anal cancers.

Natural History (Important subgroups & survival / recovery)

In 2/3 of patients, the first signs of FA are congenital malformations. When congenital malformations are not prominent, diagnosis may be delayed until the onset of bone marrow failure. The age of onset of bone marrow failure is highly variable; an analysis of 754 cases indicated an average age of 7.6 years. Most individuals with AML are diagnosed between ages 15 and 35 years. Solid tumors may be the first manifestation of FA in individuals with no birth defects or bone marrow failure. HNSCCs typically occur at an earlier age (20-40 years), at an advanced stage, and respond more poorly to therapy than in the general population. After cure of the primary HNSCC, patients with FA are more likely to develop a second primary cancer (>60%) than the general population (about 30%). On average, women with FA tend to develop cervical and vulvar cancer at ages 25 and 27 years, respectively, compared ages 47 and 72 years, respectively, in the general population. Overall, it is estimated that one-third of patients with FA will develop a solid tumor by the age of 48 years, most likely in the second and third decades of life. Women with FA may be able to have children, but they often experience reduced fertility and a shortened reproductive lifespan due to delayed menarche and/or early menopause. Very few patients with FA become pregnant after age 30 years; most reach their maximum childbearing potential by their mid-20s. Estimates of pregnancy rates range from 15% among women taking androgens to 29% for women not taking androgens. Severe, usually transient, bone marrow failure can develop in non-transplanted female patients with FA during pregnancy. Males are often infertile, in part due to reduced sperm count. The ratio of males to females with FA is 1.2:1.

The clinical spectrum of FA is heterogeneous and manifestations can vary by genotype. BRCA2 is associated with an increased frequency for all outcomes compared to other genotypes as well as early-onset AML and solid tumors, with a cumulative risk of 95% for any cancer by age 6 years. PALB2 is associated with an increased risk of congenital anomalies, AML, and solid tumors compared to other genotypes. Specific solid tumors, mainly medulloblastoma and Wilms tumor, are associated with BRCA2 and PALB2 as well as earlier age of onset of leukemia. FA-causing variants in BRCA2, PALB2, and BRIP1 are associated with an increased risk of breast cancer. FANCA and FANCC are associated with lower rates of anomalies; however, certain FANCA and FANCC variants are associated with earlier bone marrow failure. Ethnicity also plays an important role in the clinical manifestations.

Quality of life varies greatly for patients with FA and may need assistance with education, vocation, workplace, community, relationship, and health care issues. Patients may experience anxiety, depression, and social withdrawal. Due to a variety of factors, including increased recognition of disease diversity, increased scientific understanding of FA, improved transplant results, better supportive care options, and early detection, approximately 80% of patients with FA will survive beyond age 18. The median survival of all patients with FA is now greater than 30 years; however, patients with variants in BRCA2 have much lower median survival.

Likelihood of Outcome

Mode of Inheritance

Autosomal Recessive

The forms of FA included in this report are inherited in an autosomal recessive manner; however, autosomal dominant and X-linked recessive forms exist.

Prevalence of Genetic Variants

1-2 in 500

Carrier frequency has been estimated as 1:181 in North Americans and 1:93 in Israel. Specific populations have founder variants with increased carrier frequencies (<1:100), including Ashkenazi Jews (FANCC, BRCA2), northern Europeans (FANCC), Afrikaners (FANCA), sub-Saharan Blacks (FANCG), Spanish Gypsies (FANCA), and others.

Tier 3

Unknown

Within FA, approximately 60-70% of cases are attributed to FANCA, 14% to FANCC, 3% to BRCA2, 9-10% to FANCG, 2-3% to BRIP1, and <1% to PALB2.

Tier 4

Penetrance (Includes any high-risk racial or ethnic subgroups)

>= 40 %

Physical abnormalities are present in approximately 75% of affected individuals, with estimates of specific manifestations of:

• Abnormal skin pigmentation: 40%

• Sweet’s syndrome (SS), also called acute neutrophilic dermatosis: 12%

• Skeletal malformations of upper limbs: 35-50%

• Skeletal malformations of lower limbs: 5%

• Microcephaly: 20%

• Ophthalmic: 20%

• Renal anomalies: 20%

• Genitourinary anomalies (male): 25%

• Genitourinary anomalies (female): 2%

• Congenital heart defects: 6%

• Gastrointestinal anomalies: 5-7%

• Central nervous system issues: 3%

• Developmental delay and/or intellectual disability: 10%.

Tier 4

>= 40 %

Approximately 3 out of every 4 patients develop evidence of marrow failure ranging from mild to severe within the first decade of life. The cumulative incidence of bone marrow failure by age 40 years has been reported as 90%, with median time to onset of 7 years.

Tier 3

>= 40 %

The risk of developing any hematologic abnormality is 90% by age 40 years.

Tier 3

>= 40 %

About 3 of every 20 patients with FA have ear malformations. Reported prevalence of hearing loss in patients with FA ranges from 11% up to 50%.

Tier 3

>= 40 %

About 8 of 10 children and adults with FA have at least one endocrine abnormality, which could be primary to FA or secondary to treatment. Osteopenia or osteoporosis has been reported in up to 92% of adults with FA and almost 1/3 of adults have a low bone mineral density score (<2 SD).

Tier 3

>= 40 %

Diabetes mellitus occurs more commonly in patients with FA than in the general population. Patients with FA also have a relatively high incidence of high blood sugars. One study detected diabetes in approximately 8-10% of patients with FA, an additional 27-68% had impaired glucose tolerance, and 72% of patients had elevated insulin levels 1-2 hours after eating.

Tier 3

>= 40 %

Published literature includes lipid test results from 29 patients with FA. About half (55%) had unhealthy levels of cholesterol and triglycerides; 21% had elevated levels of LDL, 31% had low levels of HDL, and 10% had elevated triglycerides. An abnormal lipid profile was observed in nearly half (40%) of patients with hyperglycemia or insulin resistance. Of the patients with FA and diabetes, 75% were overweight or obese. Adults with FA and diabetes tended to be overweight or obese, compared with those without these metabolic abnormalities. About 1 in 5 (21%) adults with FA were diagnosed with metabolic syndrome. Half of the 24 children tested had at least one metabolic abnormality, including 4 children with insulin resistance, 1 with diabetes, and 7 with dyslipidemia. In a more recent report of 40 pediatric and adult patients, 17% had total cholesterol >200 mg/dl.

Tier 3

>= 40 %

More than half (60%) of children and adults with FA have short stature (average height SD of -2.2 for children and -2.0 for adults), which can be due to endocrine abnormalities, genetic variants, parental height, birth size, poor nutrition, transplant status, medications, or total body irradiation in preparation for HCST.

Tier 3

>= 40 %

In one registry study of 54 patients, more than half (54%) of patients younger than 20 years failed to produce growth hormone (GH) in response to clonidine, a GH stimulator. Similarly, most patients (72%) failed to raise GH levels in response to another GH stimulator, arginine. Using a more stringent criterion for diagnosing GH deficiency (GHD) (specifically, peak GH levels < 5 mcg/L), but without priming the patients in advance, 12% of 32 children tested had GHD. GHD was more common in patients who had undergone HSCT (25%) than in patients who did not have HSCT (8%).

Tier 3

>= 40 %

Hypothyroidism is present in 37% to 60% of adults with FA older than 18 years.

Tier 4

>= 40 %

Hypogenitalism with small testes and penis size affects 50-64% of men with FA.

Tier 3

5-39 %

Hypogonadism has been seen in 30% of women with FA.

Tier 3

>= 40 %

Premature ovarian failure affects most (77%) females with FA.

Tier 3

>= 40 %

An analysis of 4 cohorts of patients with FA revealed that the cumulative incidence of AML is between 15% and 33% by age 40, and the incidence of MDS reached about 40% by age 50. There is no difference in the cumulative incidence of hematologic malignancy between the FA complementation groups A, C, and G.

Tier 3

5-39 %

Approximately 1 in 7 (or about 14%) of patients with FA who survive to the age of 40 will be diagnosed with HNSCC during their lifetimes.

Tier 3

5-39 %

Approximately 1 out of every 10 patients with FA in case reports, case series, and cohort studies had a solid tumor. However, this statistic does not account for age. Combined data from the four cohort studies indicate that approximately 1 of 4 patients with FA develop a solid tumor by the age of 45. The theoretical risk in patients with normal bone marrow increases to nearly 3 out every 4 patients, since these patients will live long enough to develop a cancer. Another estimate is that one-third of patients with FA will develop a solid tumor by the age of 48.

Tier 3

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

The relative risk for AML is increased approximately 500-fold.

Tier 3

Unknown

The incidence of HNSCCs is 500- to 700-fold higher than in the general population.

Tier 3

Unknown

Young women with FA have a several thousand-fold higher risk for vulvar cancer and at least a 100-fold higher risk for cervical cancer compared with young women in the general population.

Tier 3

Expressivity

Clinical features of FA can vary, with some cases having neither physical abnormalities nor bone marrow failure. Bone marrow failure can also vary in age at onset and severity, with many patients progressing to aplastic anemia while others maintain mildly abnormal blood counts for years or even decades. Siblings who have identical FA pathogenic variants often have radically different clinical signs and symptoms.

Tier 4

Intervention Effectiveness

Patient Management

At diagnosis, patients should undergo a complete laboratory work up and physical examination that includes the following components:

• Family history: consanguinity, family members with anemia, physical abnormalities, and cancer

• Medical history: blood counts, congenital malformations, surgery, and medications

• Hematologic assessment: complete blood count and differential and bone marrow aspiration, biopsy, and cytogenetic evaluation

• Hepatic assessment: liver enzymes and total bilirubin

• Renal assessment: serum electrolytes and creatinine and ultrasound to rule out renal dysplasia, hydronephrosis, and anomalies of the bladder and related areas

• Gastrointestinal assessment: history of symptoms and physical exam

• Urologic exam: external structural abnormalities, genitourinary reflux, urinary tract infections, and genitourinary malformations

• Endocrine evaluation: thyroid function, growth hormone parameters, puberty, gonadal function, serum glucose and/or glucose tolerance, insulin, lipid assessment, and bone mineral density

• Ear and hearing exam: assess for hearing loss and/or structural abnormalities

• Exam for head and neck cancer: performed by an otolaryngologist

• Gynecological exam: performed by a gynecologist with external exam for female patients aged 13 and older and comprehensive exam for female patients 18 and older.

Tier 2

The following evaluations are also recommended at diagnosis:

• Echocardiogram

• Developmental assessment (particularly important for toddlers and school-age children).

Tier 4

Well-orchestrated multidisciplinary care across several specialties (e.g., hematology, gastroenterology, gynecology, endocrinology) is typically required for adequate monitoring and treatment. Patient care should be coordinated by a hematologist with expertise in FA in conjunction with the patient’s local physician. Physicians must continuously coordinate and monitor prescribed and over-the-counter medications as well as complementary and alternative therapies taken by a patient to prevent hazardous pharmaceutical cross-reactions.

Tier 2

Early high-resolution human leukocyte antigen (HLA)-typing of the patient and immediate family members is recommended to assess availability of potential bone marrow donors, should a transplant be necessary. A transplant physician can then decide whether there is a suitable family donor and/or make reasonable estimates of the time required to find a donor in donor registries based on HLA-typing. To ensure prompt and effective medical care, a donor search (if no sibling donor) should be initiated at least 4 months before the need for transplant and long before the development of MDS or AML.

Tier 2

Androgen therapy should be considered when hemoglobin drops below 8g/dL or platelet count falls below 30,000/mm3. Because there is no evidence that androgens can forestall bone marrow failure, treatment should begin before the marrow becomes completely devoid of hematopoietic stem cells for androgens to stimulate. The major outcome of androgen therapy is increased/stabilized hemoglobin levels, although it may also improve/stabilize the platelet count. Neutrophil counts may also improve. More than half of patients with FA treated with androgens will respond at least transiently. Although a subset of patients who initially respond become refractory over time, 10-20% might never need a transplant, unless MDS/AML develops. Thus, androgen treatment may delay a transplant for months and even years in responsive patients. However, risk of delaying transplant include: 1) androgens do not prevent progression to AML, which, once developed, may significantly increase the risks associated with transplant and 2) patients will be older when transplantation may be necessary, or may have acquired viral infections, which will be problematic at transplant.

Tier 2

Hematopoietic stem cell transplantation (HSCT) is currently the only cure for bone marrow failure, although it does not cure non-hematopoietic complications of FA. Transplants from HLA-identical sibling donors are generally associated with excellent outcomes. Currently, survival rates exceed 85% for children younger than 10 years, 65% for children and adults combined, and 50% in adults. Alternative donor (i.e., HLA-mismatched related or unrelated) transplants are more complex due to increased immunological risks. Over time, however, survival rates are increasingly similar between donor sources. Given the best transplant outcomes occur in younger patients who have not yet developed medical complications from bone marrow failure, patients and families who opt to pursue transplantation are generally encouraged to proceed early in the disease course.

Tier 2

Patients should receive the human papillomavirus (HPV) vaccination series, beginning at age 9 up to age 26 for both boys and girls to prevent HPV infection and possibly prevent SCC associated with HPV. However, it remains unclear whether vaccination at such a young age protects against SCCs that may develop during young childhood.

Tier 2

Given the increased risk of HNSCC, patients should maintain good oral hygiene and have regular dental exams at least every 6 months by a dentist who is well versed in FA cancer risks. The exam should include a thorough screening for possible oral cancer. If radiographs are necessary, the dentist should make a conscious effort to reduce radiation risk.

Tier 2

FA specialists should be consulted when tumors are diagnosed, as treatment may require different modalities than used in the general population. For example, given the significant negative effects of the use of chemotherapy and radiation, surgery is the preferred primary therapeutic modality in patients with FA and HNSCC. Previous reports of the treatment of solid tumors in patients with FA are generally limited to single case reports. There are no prospective studies to date.

Tier 2

In a retrospective report of 35 patients with FA diagnosed with HNSCC at a mean age of 32 years, 30 underwent surgical resection and 16 received radiation therapy (13 post-operatively). Radiation was used in the high stage cancers (11 of the 15 patients with stage 4 cancer had radiation while 3 of the 8 patients with stage 1 cancer had radiation). Surgical resection was well tolerated. Toxicities associated with radiation therapy included high-grade mucositis (9/16), hematologic abnormalities (8/16), and dysphagia (8/16). Thus, careful screening of the head and neck in patients with FA is essential to discover lesions at an early stage. Overall, the 5-year overall survival rate was poor at 39%, which did not differ by treatment.

Tier 5

No standard therapy has been established for patients with FA who have MDS or AML. Treatment options include chemotherapy, HSCT, and Phase I/II trials. Chemotherapy should be undertaken by centers experienced with FA. Because chemotherapy may cause severe, prolonged, or even irreversible myelosuppression in patients with FA, back-up plans for potential stem cell rescue should be considered. Published reports of chemotherapy regimens for AML in patients with FA are sparse and limited by the lack of longitudinal follow up. It remains unclear whether chemotherapy prior to transplant improves or worsens outcomes.

Tier 2

Given the increased risk of diabetes, dyslipidemia, and obesity, patients with FA are at risk for metabolic syndrome. A healthy diet that avoids excessive intake of concentrated sweets, a regular exercise regimen. The diet should also provide adequate caloric, protein, calcium, and vitamin D intake.

Tier 2

While pregnancy for women with FA who have not been transplanted is not life-threatening, it may impact onset or severity of bone marrow failure, requiring intensified surveillance. The pregnancy should be considered high risk and should be co-managed by a maternal/ fetal medicine specialist and a hematologist.

Tier 2

Surveillance

Gastrointestinal symptoms should be monitored during routine clinic visits.

Tier 2

Endocrine assessments for thyroid function, glucose and insulin homeostasis, reduced fertility, and osteoporosis should be assessed annually.

Tier 2

Onset of puberty should be evaluated at least at the annual physical exam to evaluate stage and progression. After usual age of start of puberty clinical evidence for hypogonadism should be assessed annually. After age 12, pubertal hormone concentrations should be obtained at least every 2 years to assess pubertal progression.

Tier 2

Women with FA should undergo regular gynecologic assessments to monitor of menses, manage fertility, and assess for menopause.

Tier 2

Bone mineral density should be monitored annually by assessing dietary calcium and vitamin D intake and measuring 25OH-vitamin D level.

Tier 2

Fasting lipid profile should be considered on an annual basis in patients >10 years of age. Screening should also include blood pressure measurement.

Tier 2

Patients with normal hearing should have hearing monitored approximately every 2-3 years. Hearing tests should be performed more frequently in children, because they are unable or unlikely to self-report concerns about difficulties hearing or communicating.

Tier 2

Patients with FA are at extremely high risk of developing HNSCC. Proper prevention, surveillance, and treatment of HNSCC are essential. Beginning at age 9-10, the patient should obtain a thorough examination every 6 months from an otolaryngologist, oral surgeon, or other doctor who is experienced in head and neck cancer detection and is familiar with FA.

Tier 2

Given the high risk of SCC of the lower genital tract, women with FA should begin receiving gynecologic care at a younger age than is typically recommended in the general population. Women with FA should begin annual examinations by a gynecologist for visual inspection of the external genitalia beginning at age 13. Annual comprehensive gynecological exams with cervical cytology testing can begin when women become sexually active or by age 18, whichever comes earlier. Exams should also include a discussion of STDs and contraception.

Tier 2

BRCA2 is a breast cancer susceptibility gene; thus, patients with FA may be at increased risk of breast cancer, although few such cases have been reported. Screening guidelines for BRCA2 can be extrapolated to patients with FA, regardless of FA gene variant, because variants in BRCA2 and genes underlying FA disrupt the same DNA repair pathway. Women with an elevated risk of breast cancer should begin regular breast cancer surveillance, including a clinical breast exam and education about breast self-examination, by early 20s. Mammography may be considered beginning at age 25. It is unclear whether the mammography screening recommendations apply to patients with FA, as these patients have elevated sensitivity to radiation exposure. The long-term risks of radiation exposure must be weighed against the benefits of early detection. In the future, magnetic resonance imaging (MRI) may be preferred over mammography in post-menopausal patients with FA to minimize radiation exposure; however, this concept has not been studied in this population.

Tier 2

Cancers of the gastrointestinal system are potential complications of FA. Only one case of colon cancer in a person with FA has been documented. Thus, early colon cancer screening for patients with FA is not recommended. Screening for esophageal carcinoma can be done using an endoscope. Some experts recommend yearly ultrasound imaging of the liver to screen for liver tumors, even for the youngest patients.

Tier 2

All patients should be monitored by a hematologist with experience in FA, regardless of bone marrow involvement. Patients with normal blood counts with normal to mild bone marrow failure should be monitored for blood counts and bone marrow evaluation (including morphology and cytogenetics for chromosomal abnormalities associated with MDS and AML) until therapeutic intervention is warranted. Peripheral blood counts should be reviewed every 1 to 4 months and a bone marrow aspirate and biopsy every 2-12 months. Evaluation of the bone marrow starting at age 2 allows for comparison of a marrow from previous specimens to assess progression. Patients with more severe bone marrow involvement and/or clonal cytogenetic abnormalities could be considered for more frequent blood counts and bone marrow evaluations.

Tier 2

The risk of developing skin cancer appears to be increased for adult patients with FA, making early education on sun protection and skin cancer prevention essential. Patients aged 18 year and older should undergo annual skin exams. Patients should maintain adequate vitamin D levels.

Tier 2

Circumstances to Avoid

Because patients with FA have increased sensitivity to radiation, the primary physician involved in managing the patient should work with the patient’s family and all patient care providers to reduce exposure to diagnostic radiation as much as possible. Imaging techniques that don’t involve radiation exposure, such as ultrasound or MRI, may be substituted.

Tier 2

The genetic instability of FA means that environmental carcinogens likely pose special risks to people with FA. Thus, lifestyle choices, such as tobacco (as well as exposure to second-hand smoke) and alcohol, may have serious adverse consequences, even beyond those encountered in the general population. For the increased risk of HNSCC, the limited exposure to alcohol includes mouthwashes that contain alcohol.

Tier 2

All patients with FA should limit sun exposure and wear sunscreen to reduce the risk of skin cancer.

Tier 2

Transfusion may adversely affect transplant outcomes and should be avoided if possible. If transfusions are essential, blood products should be cytomegalovirus (CMV)-safe and irradiated. Family members should not be used as blood donors for the patient. Timely consideration of transplant is recommended if regular transfusions are required.

Tier 2

Nature of Intervention

Nature of Intervention

Monitoring for FA is multi-disciplinary, involving several medical and surgical specialties for adequate monitoring and treatment, and is lifelong. The advantages of androgens include the absence of short-term, and low long-term, risks of therapy-related mortality. However, side effects of androgen administration include virilization and liver toxicity such as elevated liver enzymes, cholestasis, peliosis hepatis, and hepatic tumors. Other side effects include hyperactivity and behavioral changes, hypertension, and impaired growth, bone maturation and insulin secretion/action. HSCT involves several factors: pre-transplant conditioning to destroy the diseased FA marrow and suppress the immune system to reduce reject of donor marrow, graft versus host disease (GVHD) immunosuppression, infectious disease prophylaxis, and a long hospital stay (minimum of 100 days). Total body irradiation used in preparation for HCST directly impacts spinal growth potential and longitudinal growth, and may affect thyroid and gonadal function. HCST is associated with transplant-related morbidity and mortality and unknown long-term side effects. Patients undergoing HSCT have an increased risk of GVHD, which is associated diarrhea, poor absorption of nutrients, narrowing of intestinal tract, cholestasis, and risk of SCCs. Additional complications include graft failure, organ toxicity, endocrinopathies, osteoporosis, and avascular necrosis. Most importantly, as it is currently not possible to predict for the vast majority of patients who will progress to severe marrow failure and who will not, transplantation prior to the development of significant marrow failure may unnecessarily subject a subset of patients to both early and late transplant-related morbidity and mortality.

Context: Adult Pediatric

Chance to Escape Clinical Detection

The FA phenotype is quite variable and leads to misdiagnosis and failure of diagnosis.

Context: Adult Pediatric

Tier 4

In adults as compared to children, FA is less commonly diagnosed due to primary bone marrow failure. Instead, the diagnosis of FA more commonly occurs as a consequence of presentation with cancer or with severe toxicity after chemotherapy treatment for a malignancy. In one study, approximately 25% of reported patients with FA were not aware that they had FA until they developed cancer and/or significant complications from a standard cancer treatment. This indicates that older patients with FA may be significantly underdiagnosed.

Context: Adult Pediatric

Tier 3

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			FANCA			227650	0009215	0019391
BRCA2			605724	0011584	0019391
FANCG			614082	0013565	0019391
BRIP1			609054	0012187	0019391
FANCC			613899	0009213	0019391
PALB2			610832	0012565	0019391

References List

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