Clinical Guidance

The clinical spectrum of FA remains heterogenous, though some genotype-phenotype correlations have been identified. In general, null variants lead to a more severe phenotype (e.g., congenital anomalies, early-onset bone marrow failure, and MDS/AML) than hypomorphic variants. A review of genotype-phenotype associations in FA is available . BRCA2. Specific splice site variants in intron 7 (e.g., and ) offer the greatest risk of AML, with all homozygotes and compound heterozygotes developing AML by age three years . FANCA. Conflicting reports have associated and refuted association of homozygous FANCA null pathogenic variants with earlier-onset anemia and higher incidence of leukemia than individuals with pathogenic variants that permit production of an abnormal FANCA protein.

Source: GeneReviews — "Fanconi Anemia"

Diagnostic Criteria

Recommendations for Fanconi anemia (FA) diagnostic criteria were agreed upon at a 2014 consensus conference and updated in 2020 (see Fanconi Anemia Clinical Care Guidelines). These guidelines have transitioned to a web-based document with interval updates of individual chapters as needed to remain current with field advances.

Suggestive Findings

FA should be suspected in individuals with the following clinical, laboratory, and pathology findings and/or family history. Clinical findings (in ~75% of affected persons)

• Prenatal and/or postnatal short stature

• Abnormal skin pigmentation (e.g., caf au lait macules, hypopigmentation)

• Skeletal malformations (e.g., hypoplastic thumb, hypoplastic radius)

• Microcephaly

• Genitourinary tract anomalies

• Ocular manifestations

• Otic anomalies/ hearing loss

Source: GeneReviews — "Fanconi Anemia"

Differential Diagnosis

Cells derived from individuals with other chromosome breakage syndromes may also exhibit high rates of spontaneous chromosome breakage; however, cells derived from individuals with Fanconi anemia (FA) exhibit increased chromosome breakage in response to diepoxybutane (DEB) and mitomycin C (MMC). Such chromosomal fragility is seen in few disorders but may be observed in cells derived from some, but not all, individuals with Seckel syndrome or Nijmegen breakage syndrome. In individuals with overlapping phenotypes, molecular genetic testing is necessary to confirm a diagnosis. See for selected examples of chromosome breakage syndromes and other disorders to consider in the differential diagnosis of FA. Table 5. Fanconi Anemia: Differential Diagnosis

Management Guidelines

Clinical practice guidelines for management of Fanconi anemia (FA) are available (see Fanconi Anemia Clinical Care Guidelines).

Evaluations Following Initial Diagnosis

To establish the extent of disease and management requirements in an individual diagnosed with FA, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended (see Fanconi Anemia Clinical Care Guidelines).

Table 6.

Fanconi Anemia: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Growth

| • Growth assessment

• Eval by endocrinologist

| Additional studies (growth hormone levels, bone age radiographs) as recommended by endocrinologist

Musculoskeletal

| Clinical assessment for limb anomalies, hip dislocation, neck/spine anomalies, scoliosis | Referral to orthopedic surgeon as indicated

Genitourinary

| Ultrasound of kidneys urinary tract | Referral to nephrologist, gynecologist, /or urologist as indicated

Endocrine

| • Exam by endocrinologist

• Thyroid function tests

• Brain MRI for pituitary abnormalities

| Additional studies (glucose tolerance testing, lipids, pituitary gonadal function testing) as recommended by endocrinologist

Eyes | Exam by ophthalmologist |

Hearing

| Formal hearing eval | Referral to otolaryngologist as indicated

Development

| Developmental assessment (esp important for toddlers school-age children) | Referral to neuropsychologist or developmental/behavioral pediatrician as indicated

Cardiac/

Vascular

| • Echocardiogram

Source: GeneReviews — "Fanconi Anemia"

Clinical Guidance

Blood transfusions. Blood products should be cytomegalovirus (CMV) safe and irradiated. To reduce the chances of sensitization, family members must not act as blood donors. Once an individual requires transfusions, the individual should be referred for transplantation. Toxic agents to avoid include smoking, secondhand smoke, and alcohol, which have been implicated in tumorigenesis. Excessive sun exposure. Sunscreen and sun-protective clothing should be used to limit UV exposure. Unsafe sex practices increase the risk for HPV-associated malignancy. Radiographic studies for the purpose of surveillance should be minimized in the absence of clinical indications. However, baseline skeletal surveys may be considered, in order to document bony anomalies that may lead to problems with age, such as anomalies of the wrist, hip, and vertebrae.

Source: GeneReviews — "Fanconi Anemia"

Therapies Under Investigation

Gene therapy. Several early phase clinical trials of FANCA gene therapy using lentiviral vectors were conducted at sites worldwide, including Stanford University and University of Washington/ Fred Hutchinson Cancer Research Center in the United States, Hospital Universitari Vall d'Hebron Research Institute in Spain, and Shenzhen Geno-Immune Medical Institute in China. All of these trials are now terminated or no longer actively recruiting. Separately, the US National Heart, Lung, and Blood Institute completed a Phase I trial of retroviral vector transduction of autologous CD34+ stem cells in individuals with FANCC-related FA (results pending).

Source: GeneReviews — "Fanconi Anemia"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended (see Fanconi Anemia Clinical Care Guidelines). Table 9. Fanconi Anemia: Recommended Surveillance

Source: GeneReviews — "Fanconi Anemia"