Fanconi anemia overview

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2]

Overview

Fanconi anemia (FA) is a genetic disease that affects children and adults from all ethnic backgrounds.[1] The disease is named after the Swiss pediatrician who originally described this disorder, Guido Fanconi. FA is characterized by short stature, skeletal anomalies, increased incidence of solid tumors and leukemias, bone marrow failure (aplastic anemia), and cellular sensitivity to DNA damaging agents such as mitomycin C.

Historical perspective

The discovery of Fanconi anemia is largely the work of the Swiss pediatrician Guido Fanconi who observed various findings of the disease to be different than pernicious anemia. Over the coming decades, multiple advances in diagnostics have been made by various groups. Bone marrow transplant was optimized for Fanconi anemia in the 1980s. Most recently, in the 2010s, various new genomic alterations have been associated with Fanconi anemia.

Classification

Pathophysiology

Due to the similarities in the phenotypes of the different FA complementation groups, it was reasonable to assume that all affected genes interacted in a common pathway. Up until the late 90s, nothing was known about the proteins encoded by FA genes.[2][3][4]

  • However, more recently, studies have shown that eight of these proteins, FANCA, -B, -C, -E, -F, -G, -L and –M assemble to form a core protein complex in the nucleus.
  • This complex has also been suggested to exist in cytoplasm and its translocation into the nucleus is dependent on the nuclear localization signals on FANCA and FANCE.
  • Assembly is thought to be activated by DNA damage due to cross-linking agents or reactive oxygen species (ROS). Indeed, FANCA and FANCG have been observed to multimerize when a cell is faced with oxidative stress-induced damage.

Classification

There are at least 13 genes of which mutations are known to cause FA.

Common Genes

  • FANCA, FANCB, FANCC, FANCD1 (BRCA2).
  • FANCD2, FANCE, FANCF FANCG

Differentiating Fanconi's Anemia From Other Diseases

Fanconi Anemia must be differentiated from Aplastic Anemia, Paraoxysomal Nocturnal Hemoglobinuria, and Chromosomal breakage syndrome and Hereditary Bone marrow failure syndrome (Dyskeratosis congenita and other short telomere syndromes).

  • Fanconi Anemia must be differentiated from other diseases that cause Pancytopenia, Congenital anomalies, and associated with malignancy such as Aplastic Anemia, Rare chromosomal breakage syndrome and inherited bone marrow failure.[5]
  • As Fanconi Anemia resembles with variety of other diseases that causes pancytopenia.
  • Must be differentiated on basis on congenital anomalies and chromosomal breakage test.[6]

Epidemiology and Demographics

FA is rare overall, but it is one of the most common inherited bone marrow failure syndromes.

  • The incidence of FA is approximately 1 in 100,000 to 250,000 births.
  • Approximately 10 to 20 children are born with FA each year in the United States.[7]
  • The probability of FA in the US population, FA, was estimated to be 1 in 129,600 births
  • Most children are diagnosed between six and nine years of age, concurrent with the onset of bone marrow failure . Rarely, marrow failure from FA can present in infants and small children

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

History and Symptoms

Physical Examination

  • Congenital malformations are the most common presenting features of FA.
  • Patients with FA usually present with hypo/hyperpigmentation, café-au-lait spots, short staure and thumb or other radial abnormalities.
  • Vital Signs Usually normal sometime patients present with fever due to superimposed infection.
  • Skin abnormalities in Fanconi anemia can include generalized hyperpigmentation on the trunk, neck, and intertriginous areas, the aforementioned café au lait spots, and hypopigmented areas. Delicate features can also be characteristic of patients.

Laboratory Findings

Electrocardiogram

X-ray

CT

MRI

Ultrasound

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

References

  1. Krausz C, Riera-Escamilla A, Chianese C, Moreno-Mendoza D, Ars E, Rajmil O; et al. (2018). "From exome analysis in idiopathic azoospermia to the identification of a high-risk subgroup for occult Fanconi anemia". Genet Med. doi:10.1038/s41436-018-0037-1. PMID 29904161.
  2. Krausz C, Riera-Escamilla A, Chianese C, Moreno-Mendoza D, Ars E, Rajmil O; et al. (2018). "From exome analysis in idiopathic azoospermia to the identification of a high-risk subgroup for occult Fanconi anemia". Genet Med. doi:10.1038/s41436-018-0037-1. PMID 29904161.
  3. Kulanuwat S, Jungtrakoon P, Tangjittipokin W, Yenchitsomanus PT, Plengvidhya N (2018). "Fanconi anemia complementation group C protection against oxidative stress‑induced β‑cell apoptosis". Mol Med Rep. doi:10.3892/mmr.2018.9163. PMID 29901137.
  4. Guan J, Fransson S, Siaw JTT, Treis D, Van den Eynden J, Chand D; et al. (2018). "Clinical response of the novel activating ALK-I1171T mutation in neuroblastoma to the ALK inhibitor ceritinib". Cold Spring Harb Mol Case Stud. doi:10.1101/mcs.a002550. PMID 29907598.
  5. Hartung HD, Olson TS, Bessler M (2013). "Acquired aplastic anemia in children". Pediatr Clin North Am. 60 (6): 1311–36. doi:10.1016/j.pcl.2013.08.011. PMC 3894991. PMID 24237973.
  6. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM; et al. (2016). "The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia". Blood. 127 (20): 2391–405. doi:10.1182/blood-2016-03-643544. PMID 27069254.
  7. Rochowski A, Rosenberg PS, Alonzo TA, Gerbing RB, Lange BJ, Alter BP (2012). "Estimation of the prevalence of Fanconi anemia among patients with de novo acute myelogenous leukemia who have poor recovery from chemotherapy". Leuk Res. 36 (1): 29–31. doi:10.1016/j.leukres.2011.09.009. PMC 4008327. PMID 21974856.