Fanconi anemia

Content

Introduction

Introduction

Fanconi's anemia is a severe form of hereditary anemia, first described in 1927 by the Swiss pediatrician Guido Fanconi, from whom it takes its name.

It is characterized by progressive functional insufficiency of the bone marrow (spongy tissue found in the large bones of the body), by birth defects (congenital) and by a high predisposition to develop leukemia (blood cancers) and various types of tumors, in particular of the head, neck and genital system.

Fanconi anemia is a rare disease present in all ethnic groups. It can affect both sexes, but has a slight predominance in males. The number of new cases (incidence) is equal to one in every 136,000 births.

The life expectancy of people with Fanconi anemia is reduced compared to the rest of the population. The average survival is around 20-30 years, but there are cases of people who have managed to reach 50 years of age.

Symptoms

Symptoms

The disorders (symptoms) caused by Fanconi's anemia are various and may be present at birth or develop gradually. In most cases they occur in childhood. Rarely, the disease does not cause disorders (symptoms) until adulthood.

Disorders (symptoms) that help to ascertain (diagnose) the disease

  • anemia, it manifests itself with a feeling of tiredness caused by the reduced number of red blood cells circulating in the blood and, consequently, by a lack of oxygenation of the different parts of the body. It can also cause shortness of breath, dizziness, headache, cold in extremities (hands and feet), paleness and chest pain
  • functional insufficiency of the bone marrow, due to a reduced production of red blood cells, white blood cells and platelets by the stem cells of the marrow (hematopoietic cells). The poor production of red blood cells, which carry oxygen from the lungs to the tissues, causes anemia. Furthermore, in the majority of people affected by Fanconi's anemia, the red blood cells may be larger than normal (macrocytes) and, therefore, not function properly. The decrease in white blood cells, which defend the body from virus and bacteria, exposes you to a high risk of contracting long-lasting and difficult-to-fight infections. In some cases, the bone marrow produces immature white blood cells that lack normal ability to function, called blasts. Their accumulation prevents the bone marrow from producing enough normal blood cells, causing acute myeloid leukemia, an aggressive form of blood cancer in some cases. The lack of platelets, essential for blood clotting, can cause frequent bleeding, bruising, internal bleeding and the appearance of red or purple spots on the skin, due to the bleeding of small subcutaneous blood vessels (petechiae)
  • congenital malformations, they may relate to bone abnormalities (incomplete development, absence of the thumb and radius, malformation of the hip, spine, dental arch and ribs); eye and ear anomalies; skin pigmentation defects such as, for example, the presence of darker spots or areas without pigmentation, vitiligo; kidney abnormalities ("horseshoe" kidneys); heart malformations (ventricular septal defect)
  • development problems, low birth weight, poor appetite, below average height, mental retardation and learning disabilities
  • abnormalities of the gastrointestinal system, malformations of the esophagus, the channel that allows food to pass from the mouth to the stomach; duodenum, part of the small intestine where food passes during digestion; and anorectal

Disorders (symptoms) that occur with advancing age

  • incomplete development of the genitals and fertility problems, in men
  • delay of the first menstruation (menarche), irregularity of the menstrual cycle, early menopause (usually around the age of 30) e difficulty carrying the pregnancy to term, in women
Causes

Causes

Fanconi's anemia is a hereditary disease caused by mutations in the genes involved in the repair of DNA damage caused by the normal functioning of the organism (metabolic processes) and by environmental factors such as, for example, ultraviolet rays. 21 abnormal genes identified, associated with approximately 95% of Fanconi anemia cases.

The disease develops when one copy of the mutated gene is inherited from the father and one from the mother. If a person, on the other hand, inherits a mutated copy of the gene and a normal copy is defined healthy carrier. This means that brings a copy of the gene that causes the disease, compensated by the healthy copy, so that it does not get sick.

Every child conceived by two parents both healthy carriers of Fanconi's anemia has:

  • 1 in 4 chance (25%) of receiving a copy of the abnormal gene from both parents, and, therefore, to be sick
  • 2 in 4 chance (equal to 50%) of inheriting a copy of the mutated gene from one parent and a copy of the normal gene from the other parent, and, therefore, to become a healthy carrier
  • 1 in 4 chance (25%) of receiving both normal copies of the gene from parents, and, therefore, to be healthy

The single-parent child who carries Fanconi's anemia does not develop the disease, but has a 50% chance of becoming a healthy carrier and to pass on the mutated gene to his children. In other words, the child from a family with the disease (family history of Fanconi anemia) is at risk of inheriting it. The likelihood is moderate if you have a single parent's family history of the disease, high if you have both parents' family history of the disease.

A small percentage of cases (less than 1%) is due to a gene located on the X chromosome, one of the two sex chromosomes (the other is the Y chromosome). In this case the disease is linked to sex and is transmitted by mother to sons only. In males, who have only one X chromosome, the one inherited from the mother, only one copy of the mutated gene is enough to develop Fanconi anemia. In females, who have two X chromosomes, one received from the father and the other from the mother, it is necessary to inherit two copies of the abnormal gene (one from both parents) for the disease to occur. As this is highly unlikely to happen, females become healthy carriers.

Any male child conceived by a mother carrier of an X-linked mutation has:

  • 1 in 2 (50%) chance of being sick

Each daughter conceived by a mother carrying an X-linked mutation has:

  • 1 in 2 (50%) chance of inheriting the mutated gene, and, therefore, to become healthy carrier

The father will never be able to pass the disease on to his sons, who inherit only the Y chromosome from him, but he will be able to transmit the abnormal gene to the daughters, who will become healthy carriers.

There are also sporadic cases of Fanconi anemia caused by a spontaneous mutation, which occurred during conception, called mutation de novo since not inherited from the parents.

Diagnosis

Diagnosis

It is not easy to recognize Fanconi's anemia because it is a rare disease characterized by very varied disorders (symptoms) common to other diseases. Its assessment (diagnosis) is based on family history, on "observation of symptoms and on" execution of specific laboratory tests.

In most cases, Fanconi's anemia is ascertained (diagnosed) between the ages of 2 and 15. Due to the variability of the disorders it causes, moreover, cases of incorrect or late diagnosis are not rare.

To ascertain (diagnose) the disease, the contribution of several specialists is required:

  • geneticist, a doctor specializing in the study of genes and methods of transmission from parents to children
  • obstetrician, assists the woman during pregnancy. It can detect the presence of birth defects in the baby before it is born
  • pediatrician, a doctor specializing in the treatment and prevention of childhood and adolescent diseases
  • hematologist, a physician who specializes in blood diseases, can identify abnormalities characteristic of the disease

Laboratory tests

The examination of breaks, or fragility, of chromosomes (long chains of genes), is the test commonly used to ascertain (diagnose) Fanconi anemia, even before birth (prenatal diagnosis). This is a sophisticated and delicate analysis, performed only in specialized laboratories, which verifies whether, in the presence of certain chemicals, the chromosomes undergo breakage. The test is performed by taking a small amount of blood from the arm or, in special cases, by taking cells from the skin (skin biopsies) to analyze them under a microscope. If the examination of chromosomal breaks is positive, a genetic test must be performed for molecular diagnosis. This allows the identification of the genetic mutation that caused the development of the disease.

Flow cytometry it is a laboratory test that allows you to observe the influence exerted by chemicals on cells. For this test, cells taken from the skin or blood are used.

Assessment before birth (prenatal diagnosis)

Women with a family history of Fanconi anemia during pregnancy should undergo prenatal diagnosis to identify any genetic abnormalities in the fetus.

The tests used for prenatal diagnosis are:

  • amniocentesis, it can be performed from the fifteenth to the eighteenth week of pregnancy. It consists in taking a sample of fluid from the sac surrounding the fetus (amniotic sac) through a fine needle inserted into the maternal abdomen under ultrasound guidance
  • chorionic villus sampling (villocentesis), it is performed between the 10th and 12th week of pregnancy. It involves the extraction, under ultrasound control, of a fragment of the placenta tissue (the temporary organ that connects the fetus and the mother). The sampling can be done by introducing a long needle into the mother's abdomen or transcervically, using a thin tube that is passed through the vagina and the cervix to the placenta

The sample taken with amniocentesis or CVS is subsequently analyzed in the laboratory to verify the presence, in fetal cells, of mutated genes associated with Fanconi anemia.

Diagnosis at birth

Three out of four newborns affected by Fanconi's anemia have one, or more, congenital malformations at the time of birth. In the event of obvious birth defects, the doctor may recommend a genetic test.

From childhood to later ages

Some people with Fanconi's anemia do not show birth defects.In this case, the detection (diagnosis) of the disease is delayed until the moment in which the loss of function of the bone marrow occurs or a tumor develops. Typically, this occurs within the first decade of life.

Signs of bone marrow failure usually appear between the ages of 3 and 12, but about 10% of cases go undiagnosed until age 16.

Bone marrow insufficiency can be a sign of aplastic anemia, of which two forms are distinguished: one inherited, such as Fanconi's anemia, and the other acquired after birth following exposure to chemicals, radiation or medications.

The assessment (diagnosis) of aplastic anemia is based on:

  • medical and family history, accompanied by the observation of disturbances (symptoms) during the medical examination
  • blood exam completed (or blood count), to check the number, size and status of red blood cells and other blood cells (white blood cells and platelets)
  • reticulocyte count, which involves the count of new red blood cells (reticulocytes) present in the blood, to assess whether their production by the marrow occurs at a regular rate
  • bone marrow analysis, to see if it produces an adequate amount of blood cells. The examination is carried out on a sample of liquid (aspirated) and solid (taken by biopsy) bone marrow extracted, generally, from the pelvic bones

If aplastic anemia is diagnosed, your doctor may ask for further tests involving a genetic test if you suspect Fanconi anemia.

Therapy

Therapy

The treatment (therapy) of Fanconi's anemia depends on the age of the person affected and the degree of severity of bone marrow failure.

There are two types of therapy. A symptomatic (supportive therapy) which consists in the reduction of disorders (symptoms). The other, aimed at treating anemia (active therapy), consists in replacing damaged bone marrow cells with healthy cells capable of producing blood cells.

Supportive therapy

If the bone marrow is still able to produce a sufficient number of blood cells, the doctor, to check the progress of the disease over time, prescribes frequent checks of the blood count (every 3-4 months), accompanied by annual analyzes of the bone marrow. For the early diagnosis of the most common cancers (such as leukemia) of the disease, it may also require periodic checks. In the event that the number of blood cells should fall and remain low, the doctor may prescribe the " use of antibiotics (for infections) and blood transfusions to restore enough blood cells. Prolonged use of transfusions could, however, compromise the results of other treatments.

Long-term therapy includes:

  • stem cell transplant
    It is the form of treatment that offers the greatest opportunities for healing. Transplantation involves replacing damaged stem cells with healthy cells taken from the bone marrow, cord blood, or circulating blood of a compatible donor. Stem cells taken from the donor are infused into the body of the sick person (recipient) intravenously, via a drip. Once injected, the stem cells travel to the bone marrow and begin making new blood cells. If the transplant is successful, the marrow will be able to produce enough of all three types of blood cells. The most likely transplant success is in children and very young people with the following conditions:
    • absence of other serious diseases
    • availability of a compatible donor (preferably a brother or sister)
    Stem cell transplantation, even if successful, does not reduce the risk of developing certain types of blood cancers and several forms of solid tumors. Therefore, even after transplantation, close oncological surveillance is necessary, in order to be able to detect as soon as possible (early) the tumors most frequently associated with the disease.
  • androgen therapy
    Before the improvement of transplant procedures, treatment (therapy) with androgens was the first choice therapy for Fanconi anemia. Androgens, in fact, are male sex hormones capable of stimulating the production of blood cells to prolonged periods of time. The administration of these hormones increases the levels of red blood cells and platelets, but fails to produce the same results on the number of white blood cells. The positive effects of therapy tend to disappear as soon as the therapy is stopped and it is therefore necessary to undergo continuous cycles of treatment which, in the long run, are less and less effective. The treatment based on androgens can cause serious undesirable effects (side effects), especially affecting the liver, and does not prevent the development leukemia (a type of blood cancer)
  • synthetic growth factors
    Growth factors are substances produced naturally by the body, capable of stimulating the production of blood cells. The use of synthetic growth factors, produced in the laboratory, in many cases has allowed to temporarily increase the amount of red blood cells and of white blood cells. The efficacy and long-term effects of the treatment are, however, still under observation
  • gene therapy
    It involves replacing the abnormal genes with healthy copies of the same genes. The results obtained so far are promising, but the studies are still in the experimental phase
  • surgery
    Fanconi anemia can cause malformations, already present at birth (congenital), in different parts of the body: thumbs, arms, hips and legs. They can be surgically corrected to restore the functionality of the affected area. Some types of anomalies, especially those affecting the heart or gastrointestinal tract, may require immediate surgery and the use of advanced surgical techniques
Prevention

Prevention

Being a hereditary disease, there is no form of prevention of Fanconi's anemia. However, precautions can be used to limit the possible complications of the disease.

Given the high tendency to cause the appearance of tumors, it is essential to undergo oncological checks (screening).

To avoid contracting infections that could become particularly dangerous, vaccinations against chickenpox, hepatitis and pneumococcal pneumonia are recommended. The vaccine against human papilloma virus (HPV), which can cause aggressive cancers of the human papilloma virus (HPV), is also recommended. genital system and oropharynx.

If fever appears, a sign of an infection in progress, it is necessary to consult the doctor immediately so that he can prescribe adequate antibiotic therapy.

Finally, it is necessary to change the lifestyle by respecting some simple rules:

  • avoid drinking alcohol and smoking tobacco, due to their well-known carcinogenic potential
  • avoid secondhand smoke
  • work in healthy environments, avoiding exposure to carcinogenic substances such as formaldehyde, herbicides and organic solvents (such as, for example, gasoline and paint thinners)
  • use sunscreens to protect yourself from sunlight, responsible for various skin cancers
  • use condoms in sexual intercourse to defend against sexually transmitted infections
  • practice thorough oral hygiene to prevent bleeding, gingivitis and infections inside the mouth
Complications

Complications

The possible complications of Fanconi's anemia include: repeated bleeding and infections, leukemia (blood cancer), myelodysplastic syndrome (insufficient production of healthy blood cells) and various types of solid tumors.

Leukemia often occurs at a young age, in about 10% of people affected by the disease, while the risk of developing a solid tumor increases with advancing age. The most frequent solid tumors affect the mouth, tongue, throat, esophagus (channel that connects the mouth and stomach) and the anogenital region. Rarer are liver tumors, which appear to develop as a result of androgen therapy.

Tumors may be the first manifestation of the disease in people who have no obvious birth defects and show no signs of bone marrow failure. In about 30% of cancer cases associated with Fanconi's anemia, in fact, the diagnosis of the tumor precedes the discovery of the disease.

Living with

Living with

Fanconi's anemia is a fatal disease. However, current stem cell transplantation techniques, increasingly effective and safe, have improved the life expectancy of those affected. Waiting for treatments they can offer new hopes for healing, the subject of studies and researches worldwide, Fanconi's anemia continues to represent a great challenge for patients and their families.

What to expect

The discovery of the disease has immediate repercussions on the whole family unit, starting with the identification of any brothers or sisters, who are also sick.

Once the initial trauma is over, strong emotional reactions can occur, including anxiety, anger, despair and depression. In the parents of children affected by Fanconi's anemia, the sense of guilt for having passed it on to their children can be added.

The first problem parents face is finding ways to explain to their children what the disease is and what consequences it will have on their lives. The support groups for Fanconi anemia suggest informing children using words appropriate to their age and answering the questions they ask in an honest and direct way, highlighting the positive aspects of the treatments. it can be given by the psychological support of an expert, who can provide the tools to manage the emotional problems related to the subsequent stages of the child's development.

Precautions

People affected by Fanconi's anemia need care and medical assistance for their whole life. The presence of the disease involves the continuous control over time (monitoring) of the values ​​of the blood cells (haematological picture), through frequent and regular analyzes. In addition, close oncological checks will also have to be performed by those who have successfully undergone stem cell transplantation as the transplant does not eliminate the risk of developing different types of cancer.

If the sick child has difficulty eating or has problems absorbing nutrients, the doctor may prescribe feeding through a gastric tube or giving vitamin supplements and supplements to promote growth and healthy development.

In the absence of serious deficiencies in nutrients, it is sufficient to follow a balanced diet, which provides all the nutrients necessary for the body to function well. However, it is necessary to be careful about the use of supplements, vitamins and herbal products if they have not been prescribed by the doctor. because they could interfere with current therapies and cause undesirable effects Before taking them you should always consult your doctor.

Regular physical activity is recommended for everyone, but in case of anemia it is necessary to learn to know one's limits, avoiding too much fatigue and taking care to practice demanding exercises only under the supervision of a professional.

In the event of a marked deficiency of platelets, it is necessary to avoid sports and activities that involve the risk of injury, even minimal. In fact, even small wounds or minor trauma can cause excessive bleeding. In case of low levels of white blood cells, it is advisable to take all the necessary measures to protect yourself from infections, such as washing your hands often (using antibacterial lotions when you are away from home) and avoiding contact with sick people and crowded places.

Support groups

People affected by Fanconi's anemia and their families can find adequate emotional support in patient support groups that offer the opportunity to dialogue and discuss, often also through dedicated websites, with those who live a similar experience. For children and adolescents, support groups offer a unique opportunity to socialize with other peers who have to face a difficult path of illness, improving their adherence to care and treatments.

In-depth link

In-depth link

Italian Association for Research on Fanconi's Anemia (AIRFA)

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