Anemia Fanconi is a rare hereditary genetic (monogenic) disease that occurs with a frequency of 1 case per 350,000 newborns. The disease occurs due to a hereditary defect in the genes encoding the structure of certain protein molecules responsible for DNA repair processes in case of damage. Unfortunately, the defective proteins cannot fully perform their function, which leads to chromosomal instability (increased vulnerability and fragility of DNA) and manifests itself in a variety of serious health problems, the main of which is a severe form of anemia.
As a result of such changes, 20% of patients with Anemia Fanconi eventually develop various forms of malignant diseases (most often – acute myeloid leukemia, myelodysplastic syndrome), and in 90% there is a complete inhibition of bone marrow function with the development of aplastic anemia and pancytopenia (the bone marrow ceases to form all blood cells - leukocytes, erythrocytes, and platelets). Also, 60-75% of patients have various congenital malformations.
The average life expectancy of patients with Anemia Fanconi is 30 years, but a large number of children do not live to the age of 10. Symptomatic treatment with androgens and hematopoietic growth factors helps to temporarily maintain bone marrow function, but for a permanent result, such patients require allogeneic bone marrow transplantation from a donor.
Our pediatric hematologists work in close cooperation with Israeli partner clinics, so at any time they can receive recommendations and advice from their Israeli colleagues, and if necessary, even organize an online consultation for their patient.
It is clear that only specialists with relevant experience should treat such difficult patients. Since the disease is an orphan disease (very rare), it is not easy to accumulate such experience. But pediatric hematologists at world- renowned Israeli medical centers have such experience and can correctly and effectively help children with Anemia Fanconi. One of the leading specialists in this hematological problem treatment is Professor Amos Toren, who heads the Pediatric Hemato-Oncology and BMT department at the Haim Sheba Israel Medical Center. It is this person who supervises the Pediatric Hematology project in Maimonides Multidisciplinary Medical Center.
Causes and prevalence of Anemia Fanconi
Anemia Fanconi is an autosomal recessive genetic disease. It means that it develops only if both parents are carriers of the defective gene and pass it on to the child during conception. In this case the probability of sick child birth is 25%. If only one parent passes on the defective gene, the disease does not develop, but the child in this case will be a carrier of the mutation and can pass it on to his offspring. Nowadays, there are 13 known genes whose mutations lead to the development of Anemia Fanconi.
They are: FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM and FANCN.
The FANCB gene is considered an exception because it is located on the X- chromosome, and for the development of the disease, it is enough to transfer it from one of the parents, namely from the mother, and in this case the disease will develop only in boys. Only up to 2% of cases with such disease are linked to the X-chromosome and at the same time the disease develops in 50% of male children.
As already mentioned, this is a very rare disease. There are currently approximately 1,000 people worldwide with Anemia Fanconi. Families with at least one case of Anemia Fanconi are recommended to plan all pregnancies with medical genetic counseling and genetic testing for carriers of relevant mutations.
Symptoms and complications
The main manifestation of the disease is hematological disorders, but, unfortunately, they can appear not immediately after the birth of a child, but over time. Therefore, relying on them in terms of early diagnosis is wrong. Approximately 60-75% of children with Anemia Fanconi will have some or other external manifestations that make it possible to suspect the problem immediately after birth and conduct targeted genetic diagnostics to confirm the diagnosis.
Characteristic symptoms and accompanying malformations in children with Anemia Fanconi are:
- chromosomal instability;
- forearm aplasia or hypoplasia (underdevelopment or complete absence of forearm bones);
- multiple hypopigmented or hyperpigmented skin areas (white and brown spots);
- persistent decrease in the number of leukocytes in blood;
- sideroblastic anemia (anemia with large erythrocytes in blood);
- persistent thrombocytopenia (decrease platelets in blood platelets);
- microcephaly (reduced head, skull dimensions);
- scoliosis;
- different levels of severity of mental retardation;
- femur bone development anomalies;
- carotid arteries, aorta development anomalies;
- fingers and toes aplasia or hypoplasia (underdevelopment or their absence).
If the disease is not diagnosed in the first years of life, severe complications develops in child over time, which become the cause of premature death in Anemia Fanconi. Among them are:
- complete bone marrow aplasia with the development of aplastic anemia;
- acute myeloid leukemia;
- myelodysplastic syndrome.
The only chance to prolong life for such patients - is modern treatment using all the possibilities of progressive medicine.The leading Israeli medical centers for Pediatric Hematology can provide such help to all our patients.
The main condition for successful treatment - is timely diagnosisbecause it is much easier to prevent complications and not lead to them than to fight such problems as acute myeloid leukemia, etc. in patients with Anemia Fanconia. Their arsenal of treatment methods is much smaller, since in this disease there is a pronounced chromosomal instability, therefore, it is not possible to use a large number of effective chemotherapy drugs, immunobiological agents, radiation therapy due to the increased risk of all oncological processes development.
Modern diagnostics possibilities
The disease can be suspected in a child with a characteristic appearance (short stature, a set of certain malformations of the skeleton, internal organs) and certain hematological changes.
All children with suspected Anemia Fanconi must undergo:
- general and biochemical blood analysis;
- meticulous physical examination;
- detailed family anamnesis (detection of similar cases in relatives);
- bone marrow puncture and myelogram study.
If any procedure is painful and invasive, it is provided under general anesthesiaso as not to cause the child fear, pain or other psychological discomfort. All our doctors know how to establish a trusting relationship with a child and close contact. It is very important for obtaining a positive result in the treatment and diagnostic process. And if necessary, a professional psychologist can be involved in communication with children.
Based on the obtained data of the previous stage, the doctor can more confidently suspect such a rare disease as Anemia Fanconi. However, to confirm it, modern high-tech tests are needed:
- Chromosome fragility test.
- Genome sequencing – detection of specific mutations in certain genes.
- MLPA method – specific deletions and amplifications of mutant genes detection.
These genetic studies make it possible to confirm the disease in a child with a corresponding clinical picture.
Importantly! Various modifications of genome sequencing can be used at the stage of prenatal and preimplantation diagnostics. This is necessary to prevent the birth of a sick child in a family where the parents are carriers of the mutation. If in the process of medical and genetic counseling of the couple it turns out that both are mutant gene carriers, then in order to give birth to a healthy child, they are recommended an artificial insemination program with genetic pre-implantation diagnosis of embryos. That is, all embryos will be tested, and only healthy ones (those without mutations) will be selected. They will be used for embryo transfer and the onset of a healthy pregnancy. Thus, thanks to modern technologies, such couples have almost a 100% guarantee of having a child without Anemia Fanconi.
Also, genetic preimplantation diagnostics can be used to select healthy embryos from couples who already have a sick child, but there is no suitable bone marrow donor for this child (best in this case is not a foreign donor, but siblings who do not have the corresponding mutation ). It happens when a family goes to such a step to save an older sick child. That is, a smaller child is born with the help of an artificial insemination program with preimplantation diagnosis of embryos. After the birth, a healthy baby becomes an ideal bone marrow donor for his or her older sister or brother, helping to save his or her life.
New treatment methods of children with Anemia Fanconi
All treatment methods of Anemia Fanconi can be divided into symptomatic and radical. In the case of symptomatic therapy, the patient does not get rid of the main problem and the corresponding risks, he manages to maintain bone marrow function for some time with the help of certain drugs. Androgens and hematopoietic growth factors (substances that affect the bone marrow and make it produce blood cells) are most often used. Approximately 50% of patients respond positively to such treatment and manage to extend their lives by an average of 9 years, compared to 2.5 years for those who did not respond to symptomatic therapy.
The only radical and effective treatment method for patients with Anemia Fanconi is allogeneic (from a native or foreign suitable donor) transplantation of hematopoietic stem cells (bone marrow transplantation).
A feature of bone marrow transplantation in children with Anemia Fanconi is preparation for the procedure. Because of their increased chromosomal fragility and extremely high risk of various malignancies, they cannot eceive aggressive chemotherapy chemotherapy is often used or radiation therapy to suppress their own bone marrow before the transplant procedure. Also, the ideal donor for them is their own brothers or sisters. It is very rare to find someone else's donor whose bone marrow is suitable.
Therefore, the management of such patients should be handled only by specialists with practical experience, as standard schemes and treatment protocols can be dangerous here. Therefore, the health and life of such children should be trusted only in the hands of professionals who practice an individual approach to each individual patient. All our specialists are aware of these nuances of managing patients with Anemia Fanconi, so such gross errors in treatment are absolutely excluded.
An important feature for our patients is the opportunity to participate in clinical trials of Anemia Fanconi experimental treatment methods. Often this is the only chance for life in children whose disease progresses and there is no suitable donor for a bone marrow transplant. For example, such an experimental treatment as the Crispr/Cas9 technology for the p.67delG mutation correcting of the FANCC gene has already shown the first positive results. Soon we expect drugs that will be effective in treatment of this severe rare genetic disease, and our patients will be among the first to know about this possibility.