Fanconi anemia

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Fanconi anemia is a condition that is characterized by bone marrow failure, physical differences, organ problems, and an increased risk of certain cancers.

Approximately 90 percent of people with Fanconi anemia have impaired bone marrow function. Bone marrow primarily produces new blood cells. These include red blood cells, which carry oxygen to the body's tissues; white blood cells, which fight infections; and platelets, which are necessary for normal blood clotting. In people with Fanconi anemia, impaired bone marrow function leads to a decrease in the production of all blood cells (aplastic anemia). Affected individuals experience extreme tiredness (fatigue) due to low numbers of red blood cells (anemia), frequent infections due to low numbers of white blood cells (neutropenia), and clotting problems due to low numbers of platelets (thrombocytopenia). People with Fanconi anemia may also develop myelodysplastic syndrome, a condition in which immature blood cells fail to develop normally.

People with Fanconi anemia often have growth problems before or after birth that often result in short stature. Affected individuals can also have irregular skin coloring such as unusually light-colored skin (hypopigmentation) or café-au-lait spots, which are flat patches on the skin that are darker than the surrounding area. People with Fanconi anemia can have skeletal problems that often include malformed thumbs or forearms or an unusually small head size (microcephaly).

Problems in hormone-producing (endocrine) tissues are common in people with Fanconi anemia, including abnormally low levels of thyroid hormones (hypothyroidism), and high blood glucose levels (hyperglycemia). Individuals with Fanconi anemia can also have eye abnormalities such as small or abnormally shaped eyes or malformed or absent kidneys and other defects of the urinary tract. Less frequent problems include gastrointestinal abnormalities, heart defects, brain abnormalities, and hearing loss. People with Fanconi anemia may have abnormal genitalia or malformations of the reproductive system, which can result in difficulty having biological children (infertility).

Individuals with Fanconi anemia have an increased risk of developing a cancer of blood-forming cells called acute myeloid leukemia (AML). They are also at risk of developing tumors of the liver, gastrointestinal system, genital tract, or head and neck (known as head and neck squamous cell carcinoma). The likelihood of a person with Fanconi anemia developing one of these cancers is between 10 and 30 percent.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Variants (also called mutations) in more than 20 genes can cause Fanconi anemia. The proteins produced from these genes are involved in a process known as the Fanconi anemia (FA) pathway. The FA pathway turns on (activates) when the process of making new copies of DNA, called DNA replication, is blocked due to DNA damage. The FA pathway triggers DNA repair so DNA replication can continue.

The FA pathway prevents a certain type of DNA damage known as interstrand cross-links (ICLs). ICLs are abnormal connections between two DNA building blocks (nucleotides) on opposite strands of DNA. These cross-links stop the process of DNA replication and can be caused by a buildup of toxic substances produced in the body or by treatment with certain cancer therapy drugs (sometimes known as DNA cross-linking agents).

Eight proteins associated with Fanconi anemia group together to form part of a complex known as the FA core complex. The FA core complex activates two proteins, called FANCD2 and FANCI. The activation of these two proteins brings DNA repair proteins to the area of the ICL so the cross-link can be removed and DNA replication can continue.

Eighty to 90 percent of cases of Fanconi anemia are due to variants in one of three genes: FANCA, FANCC, and FANCG. These genes provide instructions for producing components of the FA core complex. Variants in any of the genes associated with the FA core complex prevent the complex from functioning properly and disrupt the FA pathway. As a result, DNA damage is not repaired efficiently and ICLs build up over time. The ICLs impair DNA replication, which leads to either abnormal cell death due to an inability to make new DNA molecules or uncontrolled cell growth due to a lack of DNA repair.

Cells that divide quickly, such as bone marrow cells and cells of the developing fetus, are particularly sensitive to problems with DNA replication. The death of these cells results in the decrease in blood cells and the physical differences that are seen in people with Fanconi anemia. When the buildup of errors in DNA leads to uncontrolled cell growth, affected individuals can develop acute myeloid leukemia or other cancers.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Fanconi anemia is typically inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a variant to cause the disorder. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

Very rarely, Fanconi anemia is inherited in an autosomal dominant pattern or in an X-linked pattern. An autosomal dominant pattern of inheritance means one copy of the altered gene in each cell is sufficient to cause the disorder. X-linked inheritance means the altered gene is located on the X chromosome, one of the two sex chromosomes in each cell. In males (who only have one X chromosome), a variant in the only copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosome), one altered copy of the gene typically does not cause the condition. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Fanconi anemia occurs in 1 in 100,000 to 160,000 individuals worldwide. The condition is more common among certain populations, including people of Ashkenazi Jewish descent, the Roma population of Spain, the Afrikaner population of South Africa, and the Japanese population.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormal thumb morphology · Very frequent (99-80%)

An abnormal structure of the first digit of the hand.

Abnormality of blood and blood-forming tissues · Very frequent (99-80%)

An abnormality of the hematopoietic system.

Abnormality of chromosome stability · Very frequent (99-80%)

A type of chromosomal aberration characterized by reduced resistance of chromosomes to change or deterioration.

Abnormality of skin pigmentation · Very frequent (99-80%)

An abnormality of the pigmentation of the skin.

Abnormality of the upper limb · Very frequent (99-80%)

An abnormality of the arm.

Anemia · Very frequent (99-80%)

A reduction in erythrocytes volume or hemoglobin concentration.

Aplasia/Hypoplasia of the radius · Very frequent (99-80%)

A small/hypoplastic or absent/aplastic radius.

Leukopenia · Very frequent (99-80%)

An abnormal decreased number of leukocytes in the blood.

Other findings in the same source

From: Orphanet

Additional reported features include Pyridoxine-responsive sideroblastic anemia (Very frequent (99-80%)); Short stature (Very frequent (99-80%)); Thrombocytopenia (Very frequent (99-80%)); Hypopigmented skin patches (Very frequent (99-80%)); Irregular hyperpigmentation (Very frequent (99-80%)); Abnormal cardiac septum morphology (Frequent (79-30%)); Abnormal renal morphology (Frequent (79-30%)); Abnormality of the urinary system (Frequent (79-30%)); Almond-shaped palpebral fissure (Frequent (79-30%)); Global developmental delay (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Fanconi anemia is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

Additional services that may be relevant, depending on the findings, include: Haematology.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Fanconi anemia. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.