OVERVIEW
A rare inherited bone marrow failure disorder.
A syndrome characterized by congenital abnormalities of physical or mental development, progressive bone marrow failure, and susceptibility to tumors
Caused by a genetic abnormality that results in genomic instability of hematopoietic stem and progenitor cells.
Hematopoietic stem cell transplantation is the main treatment, supplemented by drugs and surgery.
Definition
Fanconi anemia is a rare inherited disorder with onset in childhood and is the leading cause of inherited bone marrow failure syndromes.
The majority of Fanconi anemia is inherited in an autosomal recessive manner, with a few X-linked recessive and autosomal dominant [1-5].
Incidence
The incidence of Fanconi anemia is about 1/200,000 and can occur in various ethnic groups.
The incidence in Asian populations is about 1/160,000, with a male to female ratio of about 1.2:1 [1,5].
It develops mostly in childhood.
Causes
Causes
Fanconi anemia is a genetic disorder with autosomal recessive, X-linked and autosomal dominant inheritance.
The pathogenesis of Fanconi anemia is associated with genetic mutations, and genomic instability of hematopoietic stem and progenitor cells is the main cause of the disease.
Pathogenesis
Mutations in Fanconi anemia-related genes (FANCA, FANCB, FANCC, FANCD1/BRCA2, etc.) lead to dysfunction of DNA damage repair, resulting in spontaneous chromosome breaks, misalignments, and aberrations, which affect the corresponding cellular functions, leading to clinical manifestations such as progressive bone marrow failure, congenital malformations, and a predisposition to malignant neoplasms [4].
Symptoms
Main Symptoms
The symptoms of Fanconi anemia are complex and varied, with the main symptoms being congenital abnormalities of physical or intellectual development, progressive bone marrow failure, and increased risk of tumorigenesis [1,3,5-6].
Congenital developmental abnormalities
They are characterized by a variety of physical and intellectual developmental abnormalities. Most patients have congenital anomalies at the time of diagnosis, and milk coffee spots are most common in localized skin, followed by skeletal malformations, growth retardation, central nervous system malformations, urinary tract malformations, reproductive system malformations, gastrointestinal malformations, and ocular malformations.
Milk Coffee Spot
This is characterized by light brown pigmentation of the skin.
Skeletal deformities
Skeletal deformities such as missing forearms, little fingers, multiple fingers, syndactyly, missing thumbs, deformed feet, prominent foreheads, etc. may be present.
Backward growth and development
The development of height, weight, intelligence and motor ability lags behind that of normal children of the same age.
Central nervous system malformation
Symptoms such as mental retardation, motor disorders and behavioral abnormalities may occur.
Urinary tract malformation
Abnormal urination, hematuria, abdominal pain, abdominal mass and other symptoms.
Reproductive malformation
Symptoms such as small penis, missing testicles, vaginal atresia may occur.
Gastrointestinal malformation
Gastrointestinal malformations such as anal atresia, small intestinal atresia, megacolon, etc. may occur, resulting in the patient’s inability to eat and defecate normally.
Eye malformations
Symptoms such as small eyes, opposable eyes, excessive spacing between eyes, protruding eyeballs, blindness, and tear overflow may occur.
Progressive Bone Marrow Failure
is the most severe clinical feature of Fanconi anemia.
It may be manifested by single or total blood cell reduction, such as thrombocytopenia manifested by bleeding tendency such as skin petechiae and ecchymosis; leukopenia manifested by susceptibility to infections, etc.; and erythrocytopenia manifested by anemia symptoms such as pallor, dizziness, and fatigue.
Thrombocytopenia or leukopenia usually precedes anemia.
Increased risk of tumor development
Including hematologic malignancies and non-hematologic malignant solid tumors.
There is an increased incidence of acute myeloid leukemia, which occurs at a risk 500 times that of the general population.
Squamous cell carcinoma of the head and neck is the most common solid tumor in Fanconi anemia [1].
Consultation
Department of Medicine
Hematology
Prompt medical attention is recommended in case of congenital somatic malformations and symptoms such as pallor, dizziness, weakness, subcutaneous bleeding, and bleeding gums.
Preparation for medical treatment
Consultation: Registration, Preparation of Documents, Frequently Asked Questions
Tips for seeking medical treatment
Record the symptoms, duration and past medical history.
Preparation Checklist
Symptom list
Pay particular attention to the time of onset of symptoms, special manifestations, etc.
Is there any light brown pigmentation of the skin, polydactyly, syndactyly, missing thumb, growth retardation, mental retardation, small penis, missing testicles, vaginal atresia, etc.?
Are there any anemia symptoms such as dizziness, fatigue, loss of appetite, muscle weakness, etc.?
Are there any symptoms such as skin petechiae, ecchymosis, purpura, bleeding gums, nosebleeds, etc.?
How often do these symptoms flare up?
What conditions aggravate or relieve these symptoms?
Medical History Checklist
Is there a history of Fanconi anemia among first-degree relatives such as parents, siblings, etc.?
Checklist.
Test results from the last six months to bring to the doctor’s office
Laboratory tests: routine blood work, bone marrow examination, chromosome breakage test, gene sequencing analysis.
Medication list
Medication use in the last 3 months, if available in boxes or packages, can be brought to the doctor’s office
Androgens: oxymetholone, danazol, etc.
Fludarabine.
Diagnosis
Diagnosis based on
medical history
History of consanguineous marriage, family history of anemia, history of abnormal physical and mental development, history of tumor.
Clinical manifestations
Symptoms
Congenital abnormalities of physical and mental development
Inadequate mobility, movement disorders, difficulty in urination, difficulty in eating, abdominal pain, etc. due to skeletal malformations, genitourinary malformations, gastrointestinal malformations, etc.; intelligence is lower than the average level of the same age group.
Progressive bone marrow failure
Symptoms of anemia such as dizziness, fatigue, loss of appetite, etc. Symptoms such as bleeding from skin and gums, nosebleeds, black stools, etc.
Physical signs
Skeletal deformities: cephalo-facial deformities, microcephaly, forehead projection, flat head, short neck, spinal deformities, rib deformities, oligodactyly, polydactyly, syndactyly, and other somatic deformities.
Reproductive malformations: small penis, cryptorchidism, missing testicles, vaginal atresia, etc.
Backward growth and development: lagging behind normal peers in height, weight, intelligence and athletic ability.
Eye deformities: small eyes, opposite eyes, large distance between eyes, protruding eyeballs, etc.
Anemia-related signs: pale skin on nail beds, palmar skin wrinkles, mucous membranes of lips and mouth and conjunctiva of eyelids, increased heart rate, systolic blowing murmur of moderate intensity can be heard in pulmonary valve or apical region.
Laboratory Tests
Routine blood tests
Purpose: To find out the peripheral blood cells.
Significance: It often shows macrocytic anemia, with mean corpuscular volume (MCV) >100fl, and the blood cells show triple lineage reduction or single lineage reduction.
Precautions: Note fasting before the examination.
Bone marrow examination
Purpose: To understand the condition of bone marrow.
Significance: Bone marrow failure with markedly low bone marrow proliferation and reduced or absent megakaryocytes.
Precautions: No need for fasting, patients need to rest in bed for about 20 minutes after the examination, and also pay attention to keep the puncture point clean and dry to avoid infection caused by water.
Chromosome breakage test
Purpose: It is the preferred screening method for Fanconi anemia.
Significance: A positive test is usually diagnostic of most Fanconi anemias and also provides a reliable method for prenatal diagnosis of Fanconi anemia.
Cautions: False-negative or false-positive results may occur with chromosome breakage tests due to the presence of somatic cell chimerism and other genetic disorders; if the chromosome breakage test is negative and the clinical picture is highly suspicious for Fanconi anemia, a chromosome breakage test of skin fibroblasts should be performed.
Gene sequencing analysis
Purpose: To detect the presence of Fanconi anemia-related gene mutations in patients for the diagnosis and typing of the disease.
Significance: It can rapidly detect molecular genetics mutations in Fanconi anemia and identify new mutated genes and gene carriers.
Precautions: Before the test, pay attention to fasting, avoid strenuous exercise, as well as avoid drinking alcohol and eating a greasy, high-protein diet.
Differential Diagnosis
Acquired aplastic anemia
Similarities: Acquired aplastic anemia and Fanconi anemia can both cause a reduction in the three lineages leading to anemia, bleeding and other related manifestations.
Differences:
Acquired aplastic anemia is not a congenital disorder and is often not associated with congenital somatic malformations.
Fanconi anemia is a congenital genetic disease, accompanied by congenital somatic malformations, such as cephalo-facial malformations, microcephaly, frontal projection, flat head, short neck, rib deformities, etc. It is helpful to differentiate after perfecting the chromosome breakage test, gene sequencing and other tests.
Other hereditary bone marrow failure syndromes
Similarities: Other hereditary bone marrow failure syndromes such as congenital dyskeratosis and Fanconi anemia have chromosomal or genetic abnormalities, and both are susceptible to malignant tumors.
Differences: The genetic mutations that cause these disorders are different, so perfect gene sequencing is an important method of identification.
Neoplastic myelodysplastic syndromes (MDS)
Similarity: Both can cause hematopoietic hypoplasia and peripheral blood cell reduction leading to anemia, bleeding and other related symptoms.
Differences:
Neoplastic myelodysplastic syndromes have negative chromosome breakage tests and do not have Fanconi anemia gene mutations or congenital somatic malformations.
Patients with Fanconi anemia have congenital abnormalities of physical and mental development, such as cephalo-facial malformations, microcephaly, frontal projection, flat heads, short necks, and rib deformities, and positive chromosome breakage tests.
Drug-induced or infection-related pancytopenia
Similarities: both can cause pancytopenia.
Differences:
Drug-induced or infection-associated pancytopenia has a clear trigger (e.g., chemical exposure, viral and bacterial infections, etc.), which can be reversed after removal of the trigger, and a negative chromosome breakage test.
Patients with Fanconi anemia have congenital abnormalities of physical and mental development and positive chromosome breakage tests.
Treatment
Aim of treatment: to delay bone marrow failure and prolong survival.
Treatment principle: hematopoietic stem cell transplantation as the mainstay, supplemented by drugs, surgery and other treatments.
Hematopoietic stem cell transplantation
Hematopoietic stem cell transplantation is the only curative treatment for Fanconi anemia [1].
Patients remain at risk of developing solid tumors after HSCT and require regular monitoring.
The pretreatment regimen for hematopoietic stem cell transplantation should avoid radiotherapy as much as possible.
Drug therapy
Androgens
Indications: those who are unable to undergo allogeneic hematopoietic stem cell transplantation or those who have progressed to hematologic malignancies such as myelodysplastic syndromes and acute myeloid leukemia.
Commonly used drugs: hydroxymetholone, danazol, etc.
Adverse reactions: acne, hoarseness, increased hairiness, clitoral hypertrophy, amenorrhea or menstrual disorders, spermatogenesis, semen reduction, increased oiliness of the skin or hair, swelling of the lower extremities or weight gain, hepatic impairment, nausea, vomiting, dyspepsia, diarrhea, and so on.
Contraindications: contraindicated in patients with thrombosis, patients with renal failure, patients with abnormal genital bleeding, pregnant and lactating women, prohibited from combining with insulin, warfarin.
Precautions: During the use of the drug should pay attention to a light diet, do not eat spicy stimulating greasy food.
Granulocyte colony-stimulating factor (G-CSF)
May increase neutrophil count in some patients. Be wary of G-CSF stimulating clonal growth of leukemia cells.
Fludarabine
Indications: pretreatment drug prior to allogeneic hematopoietic stem cell transplantation, but has no therapeutic effect on Fanconi anemia per se.
Adverse reactions: rash, nausea, vomiting, electrolyte disorders, and hematopenia.
Contraindications: contraindicated in pregnant women and those with severe renal impairment.
Precautions: during the use of drugs, pay attention to monitoring the blood routine, electrolytes and other indicators of change.
Supportive therapy such as blood transfusion
According to the patient’s blood cell level, choose to transfuse red blood cells, platelets and so on.
Surgery
Tumor resection
Suitable for patients with early solid tumors who can tolerate surgery.
Surgery to repair organ defects
Such as heart surgery to correct heart defects, orthopedic surgery to correct bone deformities, etc.
Chemotherapy, radiation therapy
For the treatment of solid tumors. However, patients with Fanconi anemia have poor sensitivity and tolerance to chemotherapy and radiation therapy, so it is important to pay attention to dose reduction and closely monitor the bone marrow status to avoid severe or irreversible bone marrow suppression.
Gene therapy
Gene therapy such as FANCA gene therapy and gene editing technology are still under research and may provide new treatment methods for Fanconi anemia in the future [7-9].
Prognosis
Cure
Patients with Fanconi anemia generally have a poor prognosis, with congenital abnormalities in physical and intellectual development affecting their lives and susceptibility to malignant tumors further threatening their lives. Most patients will eventually develop acute myeloid leukemia.
Daily Management
Daily management
Adopt a good daily routine, strengthen immunity, and avoid bumps and trauma.
Nutritional support is needed if eating is difficult due to digestive tract abnormalities.
Patients with Fanconi anemia have a higher risk of developing squamous cell carcinoma of the head and neck and should take care to protect their skin.
Avoid contact with carcinogenic substances.
Disease monitoring
Watch for symptoms such as subcutaneous bleeding, nosebleeds, bleeding gums, dark stools, fatigue, and infections.
For patients after hematopoietic stem cell transplantation, pay attention to the monitoring of solid tumors, such as regular tumor marker tests as well as CT, ultrasound and other imaging tests.
Follow-up examination
Follow the doctor’s instructions for regular review so that the doctor can assess the condition and adjust the treatment plan.
The specific time for follow-up examination should be determined by the doctor according to the patient’s condition.
The follow-up checkups usually include routine blood tests, bone marrow tests, etc., and the screening of tumors should be paid attention to.
Prevention
Avoid marriage between close relatives.
Couples with a family history of the disease need prenatal counseling before giving birth [10].