DISEASES

Fanconi's Anemia

Definition, characteristics and diagnosis

Fanconi´s  Anemia (FA) was first described by a Swiss pediatrician, Guido Fanconi. In 1927, he Published his clinical observations on siblings who had inherited various abnormal physical conditions and who also experienced bone marrow failure. These children suffered severe life-threatening aplastic anemia. Their blood system could not successfully eliminate infection. As a result of anemia, they were also chronically fatigued. Because their platelet counts were low, they suffered spontaneous bleeding.

Research has established the following:

-          FA is one of several deadly inherited anemias.

-          Both parents must be carriers of a recessive FA gene for their child to be born with this disorder. If both parents carry the recessive gene, the chances are one in four that any of their children will inherit the disease (25%).

-          FA patients may have a variety of noticeable birth defects, ranging from minor to serious. These defects may affect every major system of the body. Other FA patients are free from any visible disorder – other than ultimate bone marrow failure.

-          FA patients experience a high incidence of leukemia (18-20%) and have a much higher incidence of cancer than the general population.

-          The chromosomes in the cells of FA patients, when studied in the lab, break and rearrange, a tool used as a diagnostic test for the disease.

In  many patients, the first sign of FA is the appearance of aplastic anemia, a condition in which the bone marrow does not produce enough red cells, white cells or platelets to protect the body and allow the patient to thrive. In a small number of cases, the presence of FA was first detected when the patient developed a myelodysplastic syndrome.

Is Fanconi Anemia the same as Fanconi Syndrome?

No. Fanconi Syndrome is a rare and serious disorder of kidney function, occurring mainly in childhood. In this syndrome, several important nutrients and chemicals are lost in the urine. This leads to failure to thrive, stunted growth and bone disorders such as rickets.

FA patients may be born with abnormal kidneys and may experience growth problems, but the treatment of Fanconi Anemia is very different from that for Fanconi Syndrome. The two disorders should not be confused with each other.

How is FA related to other types of aplastic anemia?

Scientists divide aplastic anemia into two categories: “acquired” and “inherited” (genetic) aplastic anemia. The causes of “acquired” aplastic anemia may be exposure to excessive radiation, toxic chemicals, pesticides, drugs, infections or agents in the environment that damage the bone marrow. In many cases of acquired aplastic anemia, the specific cause is never discovered. These cases are known as “idiopathic aplastic anemia”.

Fanconi Anemia is an “inherited” anemia. It is one of several rare genetic conditions that lead to aplastic anemia. It is unknown why FA patients develop bone marrow failure, but it is thought that the interaction between toxic environmental factors and an FA patient’s genetic vulnerability to marrow failure may contribute to aplastic anemia.

How is FA diagnosed?

Scientists believe that FA is underdiagnosed. The reason is obvious: FA makes its first appearance in different ways. Some babies are diagnosed at birth. Other children may grow into adulthood before discovering that they are affected by FA. Some FA patients undoubtedly are never correctly diagnosed. Efforts are underway to educate doctors in various medical specialties about the kinds of symptoms and signs that may indicate FA.

The most common test for FA is to take a small sample of blood from the patient and combine the blood’s lymphocytes (a type of white cell) with chemical agents such as diepoxybutane (DEB) o mitomycin C (MMC). In the laboratory, the chromosomes within FA cells break and rearrange under the influence of these destructive agents; the chromosomes in normal cells are most stable. Tests should also be performed on the siblings of an FA patient. Even normal-appearing brothers and sisters may also have the condition. If your family is considering a bone marrow transplant from a family member, it is crucial to test for chromosome breakage in potential donors as well as testing for matching HLA types.

Existence of birth defects

Birth defects are found in the majority of FA patients. There seems to be no predictability about the types of anomalies, even within families where more than one child is an FA patient. Since the clinical variety of these features is so great, doctors often refer to the “heterogeneous” nature of Fanconi Anemia. Among the more common birth defects problems or features are the following:

Ø       Short stature.- This feature is common and very striking. It has been concluded that over 50 % of FA patients are below the third percentile in height.

Ø       Anomalies of the thumb and arm.- FA is often suspected when a child is born with missing, misshapen or extra thumbs, or an incompletely developed or missing arm bone, the radius. These conditions in the scientific literature are described as “absent, hypoplastic, supernumerary or bifid thumbs” and “hypoplastic or absent radii”.

Ø       Additional skeletal abnormalities.- About one-fifth of FA patients suffer from a wide range of skeletal defects, such as congenital hip abnormalities, spinal malformations, scoliosis and rib abnormalities.

Ø       Kidney (renal) problems.- Some FA patients are born with a missing kidney, rotated or misshapen kidneys or fused (joined) kidneys. Approximately one-fourth of FA patients have these problems, which the literature refers to as “structural renal malformations”.

Ø       Skin discoloration.- Many FA patients develop café-au-lait spots, which are patches (larger than freckles) of darker discoloration on the skin. Or the entire body or large portions of it may have a suntanned appearance, a condition called “hyperpigmentation”.

Ø       Small head or eyes.- FA patiens may have a small head or eyes, characteristics that the literature calls “microcephaly” and “microphthalmia”.

Ø       Mental retardation.- Some FA children are retarded, although this is by no means as common as some of the early literature on FA suggested. However, learning disabilities without retardation may be common.

Ø       Low birth weight and “failure to thrive”.- Some cases of FA are detected after parents seek medical advice because their child is born with a low birth weight or does not grow and develop as expected.

Ø       Abnormalities of the gastrointestinal tract.- Some FA patients are born requiring immediate surgery to correct serious problems of the stomach, esophagus or intestinal tract. Experts report that a very large number of FA patients with no observable internal defects often experience problems with their digestive systems, including poor appetite.

Ø       Heart defects.- Some patients are born with heart defects, usually in the tissue separating chambers of the heart.

Ø       Sexual anomalies.- Female FA patients often have a delay in the start of menstrual periods, irregular periods and a decrease in fertility. Menopause occurs early, often in the 30’s. Male FA patients often have undeveloped male organs (hypogonadism) and may have decreased sperm production and fertility.

Ø       Solid tumor malignancies.- Patients over the age of 20 are at high risk of developing cancers of the head, neck and esophagus. Women are at risk of developing cancers of the reproductive tract

Which is the function of the bone marrow?

The central portion of bones is filled with a spongy red tissue called “bone marrow”. The marrow is the site of our body’s blood production. Marrow daily produces millions of blood cells that sustain our lives. The bone marrow harbors oand nourishes stem cells, which divide and evolve into mature red cells, white cells and platelets. This process of formation and development of blood cells is called hematopoiesis.

Each type of blood cell performs an essential role. Red cells (erythrocytes) carry oxygen from the lungs to all areas of the body. White cells (leukocytes) help fight infection and disease by attacking and destroying germs. Platelets (thrombocytes) help heal wounds and control bleeding by forming blood clots in areas of injury. They also prevent spontaneous internal bleeding.

When normal blood cell production declines because the marrow no longer functions properly in the FA patient, a number of serious conditions can appear, separately or together. These are:

Anemia: when the body lacks adequate oxygen-carrying red cells, the patient experiences weakness, fatigue, shortness of breath and visibly pale appearance. The red cell deficiency is known as anemia.

Infection: when the body lacks adequate numbers of infection-fighting white blood cells, the patient can be extremely vulnerable to common germs. Fever may be the first sign of a serious infection. The medical term for a low white blood count is leucopenia. FA patients are often deficient in a particular class of white blood cells called neutrophils. This condition is called neutropenia.

Bleeding: Hemorrage-fighting platelets help us stop bleeding from wounds. Abnormally low platelet counts lead to easy bruising and sometimes to internal bleeding that can be fatal. A low platelet count is sometimes discovered by the appearance of petechiae. These are small red spots that result from spontaneous bleeding in tiny blood vessels under the skin. The medical term for abnormally low platelet count is thrombocytopenia. When low counts exist in all three major lineages of blood cells, the condition is described as pancytopenia. Another way to describe this condition is aplastic anemia.

When does Aplastic Anemia occur in FA?

No one can predict the age when marrow failure begins in FA patients. The median age of onset is around 7 years. Most children first experience signs of marrow failure between the ages of 3 and 12. At least 10% of cases were diagnosed after age 16, and one individual was 48 at the time of diagnosis. A few FA patients diagnosed and identified by chromosome breakage tests have had no blood or physical problems into their 30’s. Thus, FA is not exclusively a childhood disease.

What is the prognosis for an FA patient?

No one is certain how long any given individual with FA will survive. This illness is unpredictable. According to cases reported to the International Fanconi Anemia Registry, the average life expectancy is approximately 22 years. But life expectancy for any one individual can be quite different from any “average”.

New research discoveries have led to life-extending treatments and improved bone marrow transplant outcomes. It is important to mention that, as FA patients live longer, more will develop solid tumor malignancies. 

What treatments exist for FA?

There are several types of treatment: a) bone marrow or peripheral stem cells transplants (from a related or a non-related donor); b) umbilical cord stem cells transplant; c) androgen therapy; d) synthetic growth factors therapy; and e) gene therapy.

For the first two types (a and b), the best compatibility must be checked, through a genetic system calledHLA (Human Leukocyte Antigens). Identical twins will be HLA identical. If this is not the case, the next step is to look for an HLA compatible donor among the siblings. The possibility of having an HLA identical sibling is only 25 %. Serious complications can arise in marrow transplantation for FA patients. The likelihood of these complications increases when a bone marrow donor is not a perfect HLA sibling match for the patient. Graft versus host disease (GVHD) occurs when certain lymphocytes (T cells) from the donor recognize the patient’s cells as foreign and attack them. This attack may result in mild, temporary symptoms, such as skin rash, or in severe, long-term symptoms including multiple organ failure and possibly death. Many transplant centers now remove T cells from the donor marrow before transplantation (a procedure called “T cell depletion”); this greatly reduces the risk of GVHD.

For case c), androgen therapy, between 50 and 75% of FA patients respond to a group of drugs known as androgens. Androgens, such as oxymetholone (AnadrolR) are artificial male hormones that often stimulate production of one or more types of blood cells for extended periods of time. Androgens are most effective in improving the red blood cell count. Often they increase platelet production as well. Androgens prolong the lives of many FA patient, but are not a “cure”. Most patients eventually fail to respond to androgens, although some patients experience improved blood counts for many years. Androgens may have serious side effects, which often diminish or disappear if the dose can be lowered significantly. They can cause liver disease and can have masculinizing effects.

 Hematopoietic growth factors (d) stimulate production of blood cells. There are the cytokines GM-CSF and G-CSF, as well as erythropoietin and interleukin. Gene therapy (e) is based upon the possibility of modifying defective genes (which cause the disease), in a way that they are able to produce proteins necessary for the patient’s body and blood system. Four of the FA genes (complementation groups A, C, F and G) have now been isolated. Numerous laboratories are studying the normal FA genes, the normal protein products and how the proteins or the healthy genes might be introduced into the cells of FA patients. Mutations in the A gene account for about  65% of FA cases.

Fuente: Fanconi Anemia: A Handbook for Families and their physicians. Lynn and Dave Frohnmayer. Third Edition. March, 2000. Fanconi Anemia Research Fund. Eugene, Oregon USA