Fanconi anemia: signs and symptoms, etiology, epidemiology, diagnosis and treatment

Fanconi anemia (FA) is a rare autosomal recessive hereditary hematologic disorder that belongs to congenital re-disorders called Fanconi anemia (Fanconi anemia), in addition to typical re-impairment manifestations, such patients are accompanied by multiple congenital malformations (brown pigmentation of the skin, skeletal deformities, sexual insufficiency, etc.

Half of the patients are diagnosed before the age of 10, while about 10% of patients are diagnosed as adults

First, the general overview

FA has several subtypes that are inherited from mutations in two genes of each of at least 18 different genes

2.

The symptoms of FA vary from person to person

At least 60% of FA patients with physical abnormalities have at least one physical abnormality at birth.

- short

People with anemia may experience tiredness, increased need for sleep, weakness, light-headedness, dizziness, irritability, headaches, pale skin, difficulty breathing, and heart symptoms

There may be excessive bruising after minor injuries, as well as spontaneous bleeding from the mucous membranes, especially bleeding

Bone marrow failure

Progressive bone marrow failure usually appears at age 10 years and is usually accompanied by low platelet levels or low white blood cells

Affected people develop low levels of all cellular elements of the bone marrow – red and white blood cells – as well as platelets, which can lead to the following

The risk of malignant tumors is increased

In about 30% of cancer-related cases, the development of malignancies precedes the diagnosis

Third, the cause

The chromosomes within a person's cells with FA are unable to repair DNA damage, so it is easy to break and rearrange (chromosome instability).

Mutations in at least 18 genes can cause FA

Between 80% and 90% of FA cases are due to mutations in one of the three genes FANCA, FANCC, and FANCG
.
These genes provide instructions
for the components that produce the FA core complex.
Mutations in any one of the many genes associated with the FA core complex can cause the complex to lose function and disrupt the entire FA pathway
.
The interruption of this pathway leads to the accumulation of DNA damage, which can lead to abnormal cell death or abnormal cell growth
.
The death of cells leads to a decrease in blood cells and physical abnormalities
associated with FA.
Uncontrolled cell growth can lead to the development of acute myeloid leukemia or other cancers
.

Most cases of FA are inherited in an autosomal recessive
manner.
A recessive genetic disorder occurs when a person inherits two abnormal genes
of the same trait from both parents.
If a person inherits a normal gene and a gene for a disease, the person will be a carrier of the disease, but usually does not develop symptoms
.
Parents of both carriers pass on the altered gene at the same time, and the risk of giving birth to an affected child is 25%
per pregnancy.
The risk of giving birth to a child of a carrier like a parent is 50%
per pregnancy.
A child's chances of getting normal genes from both parents are 25%.

The risks are the same for men and women
.

Parents of close relatives (close relatives) have a higher chance of carrying the same abnormal genes at the same time than unrelated parents, which increases the risk of recessive genetic diseases in
their children.

Mutations in the following genes also cause FA and are inherited
in an autosomal recessive way.
BRCA2, BRIP1, FANCB, FANCD2, FANCE, FANCF, FANCI, ERCC4, fancl, fancm, PALB2, RAD51C, SLX4 and UBE2T
.

The FANCB gene is located on the X chromosome and causes less than 1% of FA cases
.
This FA gene is inherited as an X-linked recessive
.

X-linked genetic disorders are diseases caused by abnormal genes on the X chromosome, mainly in men
.
A woman with a mutated gene on one X chromosome is a carrier
of the disease.
Carrier women usually do not show symptoms because women have two X chromosomes and only one carries the altered gene
.
A man has an X chromosome that he inherits from his mother, and if a man inherits an X chromosome that contains altered genes, he will develop the disease
.
Female carriers of X-linked disease have a 25% chance of having a carrier daughter like themselves, a 25% chance of having a non-carrier daughter, a 25% chance of having a son affected by the disease, and a 25% chance of having an unaffected son
per pregnancy.
If a man with X-linked disease is able to reproduce, he will pass on the altered genes to all his daughters, who will be carriers
.
Men cannot pass on the X-linked gene to their sons because men always pass on their Y chromosome instead of X chromosome to male offspring
.

Mutations in the RAD51 gene lead to autosomal dominant FA
.
Dominant genetic disease occurs when only a single copy of an abnormal gene is required to cause a disease
.
Abnormal genes can be inherited from either parent or can be the result of new mutations (genetic changes) in the affected individual
.
The risk of abnormal genes being passed from affected parents to offspring is 50%
per pregnancy.
The risks are the same for men and women
.
To date, all affected individuals with FA due to mutations in the RAD51 gene have been spontaneous (de novo) gene mutations
that occur in egg or sperm cells.
In this case, the disease is not inherited from the
parents.

Solid tumors can be the first manifestation of FA
.
Head and neck squamous cell carcinoma (HNSCCs) are the most common solid tumors in patients with FE, increasing the incidence by 500 to 700 times higher than in the general population, and the age of onset is earlier (20 to 40 years), most occur in the oral cavity (such as tongue cancer), are mostly in the advanced stage, and respond poorly
to treatment.
The incidence of cutaneous, esophageal, liver, and urogenital tumors has also increased
.
A small number of patients may see multiple tumors concurrent, or hematologic and non-hematologic tumors
.
It is also significantly intolerant
to chemotherapy or radiotherapy.

Epidemiology

The incidence of FA is estimated to be about 1 in every 136,000 babies
born.
This is more common
among Jews of Ashkenazi, Roma in Spain and black South Africans.

Incidence varies
across races and regions.
The incidence in the Asian population is 1 in 160,000, with a male-to-female incidence ratio of about 1.
2:1
.
The incidence is higher
in some people who are married to close relatives.
There is very little
coverage in my country.

V.
Differential diagnosis

Fanconi anemia needs to be differentiated from other congenital bone marrow failure syndromes, including Diamond-Blackfan anemia, congenital dyskeria, Shwachman-Diamond syndrome, Pearson syndrome, severe congenital neutropenia, congenital megakaryocytic thrombocytopenia, etc
.
These diseases have negative chromosomal break tests, and second-generation sequencing molecular techniques can be identified
.
The symptoms of the following diseases may be similar
to those of FA.
Comparison may be helpful
in differentiating the diagnosis.

Chromosome instability syndromes: autosomal recessive genetic disorders associated
with chromosomal rupture and increased genetic instability.
These chromosomal abnormalities put affected people at an above-average risk of certain cancers, especially leukemia
.
Most of the affected people have other abnormalities
.
Chromosomal instability syndromes include Bloom's syndrome, ataxia telangiectasia, Nijmegen rupture syndrome, and depigmentation
.
(For more information about these diseases, please select the specific disease name as your search criteria in the Rare Diseases database
).

Acquired aplastic anemia: A rare condition caused
by deep, almost complete bone marrow failure.
Bone marrow is a spongy substance
found in the center of the body's long bones.
The bone marrow produces special cells (hematopoietic stem cells) that grow and eventually develop into red blood cells (red blood cells), white blood cells (white blood cells), and platelets
.
In acquired aplastic anemia, hematopoietic stem cells are almost completely absent, eventually leading to low levels of red blood cells, white blood cells, and platelets (pancytopenia
).
Specific symptoms associated with acquired aplastic anemia may vary, but include fatigue, chronic infection, dizziness, weakness, headache, and episodic bleeding
.
Although some cases of acquired aplastic anemia are secondary to other diseases, researchers now believe that many cases are caused by a disorder in a patient's immune system, in which the immune system mistakenly targets the bone marrow (autoimmune
).
This is based on about half of the patients' response to immunotherapy, whether it's ATG, cyclosporine, high-dose steroids, or cyclophosphamide
.
(For more information about this disease, select "Aplastic Anemia" as your search term in the Rare Diseases database
).

Thrombocytopenia-absent radius (TAR) syndrome: a rare genetic disorder that is evident at birth (congenital
).
This disease is characterized by low platelet levels in the blood (thrombocytopenia), which leads mainly to an attack of potentially severe bleeding (bleeding)
in infancy.
Other characteristic findings include missing bones (hyperplasia) on the thumb side of the forearm (radius) and sometimes skeletal dysplasia (dysplasia) or deletion
on the "little finger" side of the forearm (ulna).
Other abnormalities may also occur, such as structural malformations of the heart (congenital heart defects), renal (renal) defects, and/or intellectual disability, which may be secondary to intracranial hemorrhage (intracranial hemorrhage)
in infancy.
TAR syndrome is an autosomal recessive inheritance
.
(For more information about this disease, select "thrombocytopenia - no radius" as your search term in the rare disease database
.
)

Congenital dykeratosis (Dyskeratosis congenita), also known as Zinsser-Cole-Engman syndrome: is a rare genetic disorder characterized by darker skin color and/or unusual deletions (pigmentation), abnormal changes in the nails (atrophy), and progressive degenerative changes in the oral mucosa (leukoplakia), rarely seen in the anus or urethra
.
Many patients have eye problems, including tears due to narrow tubes that drain tear
fluid.
Other symptoms may include a decrease in red, white blood cells, and platelets in the blood (pancytopenia), leading to bone marrow failure
.
Affected people may also have thickened skin on the palms and soles of the feet, excessive sweating of the palms and soles of the feet, thinning or absent hair, fragile bones, testicular hypoplasia, and dental abnormalities
.
The disease can be hereditary or sporadic occurrence
.
X-linked recessive inheritance is the most common mode of inheritance, but autosomal dominant inheritance (a gene passed on to a child with a mutation in one parent) is also common, and autosomal recessive inheritance is rare
.

VACTERL Association: A non-random association for birth defects that affects multiple organ systems
.
The word VACTERL is an abbreviation, and each letter represents the first letter of one of the more common findings in children: (V) = vertebral abnormalities; (A) = atresia; (C) = heart (heart) defect; (T) = tracheoesophageal fistula; (E) = Esophageal atresia; (R) = renal (kidney) abnormality; (L) = limb abnormalities (including thumb and radius
).
In addition to the above characteristics, affected children may also exhibit less common abnormalities, including growth deficits and an inability to gain weight and growth (failure to thrive)
at the expected rate.
In some cases, the acronym of the VATER Association is used
.
Mental function and intelligence are usually not affected
.
Most cases occur randomly, for no apparent cause (sporadic nature
).
However, at least 5% of patients with FA have this association
.

The following diseases may be associated
with FA as secondary complications.
They are not necessary for differential diagnosis
.

Myelodysplastic syndrome (MDS): is a rare group of blood disorders that occur
due to poor blood cell development within the bone marrow.
Three main types of blood cells, namely red blood cells, white blood cells, and platelets, are affected
.
Red blood cells deliver oxygen to the body, white blood cells help fight infection, and platelets help clot to stop blood loss
.
These abnormally developed blood cells do not develop normally and enter the bloodstream
.
As a result, blood cell levels in patients with MDS are abnormally low (low blood counts
).
General symptoms associated with MDS include fatigue, dizziness, weakness, bruising and bleeding, frequent infections, and headaches
.
In some cases, MDS may develop into life-threatening bone marrow failure or develop into acute leukemia
.
The exact cause of MDS is unknown
.
There are no identified environmental risk factors
.

Acute myeloid leukemia (AML): A rare blood cancer that begins with cells that normally develop into certain types of white blood cells
.
The transition to leukemia is accompanied by a deterioration in bone marrow function and the accumulation of undeveloped "immature" cells, first in the bone marrow and then in the blood, these cells are called platelets that inhibit any remaining bone marrow cell production
.
As a result, complications of anemia, bleeding and infection become life-threatening
.
Abnormal (leukemia) cells may eventually spread through the bloodstream to other organ systems
in the body.

6.
Diagnosis

The diagnosis of FA is based on a comprehensive clinical evaluation, a detailed medical history, characteristic findings, and a variety of specialized tests
.

Currently, the definitive test for FA is the chromosomal break test: some of a patient's blood cells
are treated in a test tube with a chemical that cross-links DNA.
Normal cells are able to correct most of the damage without being severely affected, while FA cells show significant chromosomal breaks
.
There are two chemicals commonly used for this test
.
DEB (diepoxybutane) and MMC (mitomycin C
).
These tests can be performed
prenatally on cells from the chorionic or amniotic fluid.

Blood tests can be used to determine the levels
of red and white blood cells and platelets.
X-rays can show the presence and extent of skeletal deformities and internal structural abnormalities
.

Many cases of FA are not diagnosed at all, or are not diagnosed in time
.
Any infant born with the foregoing thumb and arm abnormalities should be suspected and tested for FA
.
People with aplastic anemia at any age should have a FA test, even if there are no other defects
.
Any patient with squamous cell carcinoma of the head and neck, gastrointestinal tract, or gynaecological system in the early years should have a FA test
, regardless of whether they have a history of tobacco or alcohol use.
Many patients with FA have no other abnormalities
.
FA must be tested before a stem cell transplant is considered for aplastic anemia or for the treatment of cancer, as standard chemotherapy and radiation regimens can be toxic to patients with FA
.

All 18 genes associated with FA can be tested
for molecular genes.
Complement testing is usually performed first to determine which FA gene has been mutated
.
The corresponding gene can then be sequenced to determine the specific mutation
of that gene.
If no mutation is found, deletion/repeat analysis
of FA-related genes can be performed clinically.

Targeted mutation analysis can be used for common Ashkenazi Jewish FANCC mutations
.

Clinical testing/progress
of work To determine the extent of the disease in patients diagnosed with FA, the following assessments
are recommended as needed.

- Ultrasonography
of the kidneys and urinary tract - Formal hearing tests
- Developmental assessment (especially important for young children and school-age children
).

- Referrals to ophthalmologists, otolaryngologists, endocrinologists, hand surgeons, gynecologists (for women, if necessary), gastroenterologists, urologists, dermatologists, otolaryngologists, genetic advisors
- evaluated by hematologists, including complete blood count, fetal hemoglobin, bone marrow sampling to check cell morphology and chromosomal studies (cytogenetics), and cell biopsy
.

- HLA classification of affected people, siblings and parents in order to consider hematopoietic stem cell transplantation
.

- Complete hematotyping
- blood chemistry test (to assess the status of the liver, kidneys, thyroid, lipids, and iron
).

Diagnosis and treatment process

7.
Treatment

Treatment of FA is specific to the obvious symptoms
of each person.
Treatment may require the coordinated efforts
of a team of experts.
Pediatricians, surgeons, cardiologists, nephrologists (nephrologists), urologists, gastroenterologists, specialists who evaluate and treat hearing problems (audiologists and otolaryngologists), ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan treatment
for affected individuals.

Recommendations on treatment were reached at the consensus meeting in 2014
.

- Androgen (androgen) management
.
Androgens can improve blood counts
in about 50% of FA patients.
The earliest reactions are seen in red blood cells, and an increase in hemoglobin generally occurs in the first or second month
of treatment.
The response to the WBC count and platelet count is variable
.
Platelet reactions are generally incomplete and may not be seen
until several months of treatment.
The improvement in red blood cell count is generally the greatest
.
Resistance to treatment may develop
over time.

- Hematopoietic growth factor
.
Granulocyte colony-stimulating factor (G-CSF) can improve neutrophil counts
in some people.
It is usually only used for intermittent disease support
.

- Hematopoietic stem cell transplantation (HSCT): the only curative therapy for the hematological manifestations of FA
.
Donor stem cells can be obtained
from bone marrow, peripheral blood, or umbilical cord blood.

- Cancer treatment
.
Treatment of malignancies is challenging because chemotherapy and radiation therapy for FA increase toxicity
.
Care should be obtained from a centre with experience treating patients with FA
.

Surgery may be necessary to correct skeletal deformities, such as those affecting the thumb and forearm bones, heart defects, and gastrointestinal abnormalities such as tracheoesophageal fistula or oesophageal atresia, and atresia
.

Certain chemicals may increase the risk of chromosomal rupture in patients with FA and should be avoided
as much as possible.
These chemicals include tobacco smoke, formaldehyde, herbicides and organic solvents such as gasoline or paint thinners
.

Genetic counseling
is recommended for affected individuals and their families.

8.
Registration of rare disease information

If you would like to seek information that is constantly updated, it is recommended that you register your patient's information here, even if you are not fully diagnosed, you can register, click on:

Information Registration System for Patients with Rare Diseases

Resources:

Alter BP.
Fanconi Anemia.
NORD Guide to Rare Disorders.
Philadelphia, PA: Lippincott Williams & Wilkins; 2003:366.

Buyse ML.
Editor-in-Chief.
Birth Defects Encyclopedia.
Dover, MA: Blackwell Scientific Publications.
Center for Birth Defects Information Services, Inc.
; 1990:1359-61,1784.

Ebens CL, MacMillan ML, Wagner JE.
Hematopoietic cell transplantation in Fanconi anemia: current evidence, challenges and recommendations.
Expert Rev Hematol.
2017 Jan; 10(1):81-97.
doi: 10.
1080/17474086.
2016.
1268048.

Schneider M, Chandler K, Tischkowitz M, Meyer S.
Fanconi anaemia: genetics, molecular biology, and cancer – implications for clinical management in children and adults.
Clin Genet.
2015 Jul; 88(1):13-24.
doi: 10.
1111/cge.
12517.

Triemstra J, Pham A, Rhodes L, Waggoner DJ, Onel K.
A Review of Fanconi Anemia for the Practicing Pediatrician.
Pediatr Ann.
2015 Oct; 44(10):444-5, 448, 450 passim.
doi: 10.
3928/00904481-20151012-11.

Khincha PP, Savage SA.
Genomic characterization of the inherited bone marrow failure syndromes.
Semin Hematol.
2013 Oct; 50(4):333-47.
doi: 10.
1053/j.
seminhematol.
2013.
09.
002.

Kee Y, D’Andrea AD.
Molecular pathogenesis and clinical management of Fanconi anemia.
J Clin Invest.
2012 Nov; 122(11):3799-806.
doi: 10.
1172/JCI58321.

Tolar J, Becker PS, Clapp DW, Hanenberg H, de Heredia CD, Kiem HP, Navarro S, Qasba P, Rio P, Schmidt M, Sevilla J, Verhoeyen E, Thrasher AJ, Bueren J.
Gene therapy for Fanconi anemia: one step closer to the clinic.
Hum Gene Ther.
2012 Feb; 23(2):141-4.
doi: 10.
1089/hum.
2011.
237.

Rosenberg PS, Tamary H, Alter BP.
How High are Carrier Frequencies of Rare Recessive Syndromes? Estimates for Fanconi Anemia in the United States and Israel.
American Journal of Medical Genetics Part A.
2011; 155:1877-1883.

Alter BP, Giri N, Savage SA, Peters JA, Loud JT, Leathwood L, Carr A, Greene MH, Rosenberg PS.
Malignancies and Survival Patterns in the National Cancer Institute Inherited Bone Marrow Failure Syndromes Cohort Study.
British Journal of Haematology.
2010; 150:179-188.

Shimamura A, Alter BP.
Pathophysiology and Management of Inherited Bone Marrow Failure Syndromes.
Blood Reviews.
2010; 24:101-122.

Moldovan G-L and D’Andrea AD.
How the Fanconi Anemia Pathway Guards the Genome.
Annual Review of Genetics.
2009; 43: 223-249.

Taniguchi T, D’Andrea AD.
Molecular pathogenesis of Fanconi anemia: recent progress.
Blood.
2006; 107:4223-3.

Bagby GC, Lipton JM, Sloand EM, Schiffer CA.
Marrow failure.
Hematology Am Soc Hematol Educ Program.
2004; 318-36.

Bagby GC.
Genetic basis of Fanconi Anemia.
Curr Opin Hematol.
2003; 10:1:68-76.

D’Andrea AD, Grompe M.
The Fanconi anaemia/BRCA pathway.
Nat Rev Cancer.
2003:3:23-34.

Meetei AR, de Winter JP, Medhurst AL, et al.
, A novel ubiquitin ligase is deficient in Fanconi anemia.
Nat Genet.
2003; 35:165-70.

Tischkowitz MD, Hodgson SV.
Fanconi Anemia.
J Med Genet.
2003; 40:1-10.

Joenje H, Patel KJ.
The emerging genetic and molecular basis of Fanconi anaemia.
Nat Rev Genet.
2001; 2:446-57.

Mehta PA, Tolar J.
Fanconi Anemia.
2002 Feb 14 [Updated 2018 Mar 8].
In: Adam MP, Ardinger HH, Pagon RA, et al.
, editors.
GeneReviews® [Internet].
Seattle (WA): University of Washington, Seattle; 1993-2020.
Available from:  Accessed May 4, 2020.

Frohnmayer D, Frohnmayer L, Guinan E, Kennedy T, Larsen K, Editors.
Fanconi Anemia: Guidelines for Diagnosis and Management, Fourth Edition, 2014.
Fanconi Anemia Research Fund, Inc.
Available at:  Accessed May 4, 2020.

Moustacchi E.
Fanconi Anemia.
Orphanet.
Last Update November 2011.
  Accessed May 4, 2020.

National Institutes of Health.
What is Fanconi Anemia? Last Update November 1, 2011.
  Accessed May 4, 2020.