Anemias in childhood and adolescence, which are the most common?

During the period of youth the most frequent forms of anemia are those due to nutritional deficiencies or cell maturation factors that can only be acquired through nutrition.

Iron deficiency anemia and megaloblastic anemia are the most common in children due to nutritional factors.

These include iron deficiency (iron deficiency anemia) and lack of vitamin nutrients such as vitamin B12 or folic acid (megaloblastic anemia). Iron deficiency anemia is the most frequent and prevalent anemia worldwide, mainly observed in pre-menopausal women due to menstruation (hemorrhage) and in growing children (hyperconsumption). In countries or geographic areas affected by extreme poverty, iron deficiency anemia is caused by a lack of iron intake due to infant malnutrition resulting from lack of staple food intake and exclusive breastfeeding. Without iron supplementation many infants exhaust their iron stores by 10-14 weeks.

What are rare anemias and how many children are usually affected?

In addition to nutritional deficiency anemias, which are very common and always acquired, there are also the so-called rare anemias, which are generally congenital in origin and whose prevalence in the European population is less than 5 cases per 10,000 births. Rare anemias usually appear during childhood or adolescence and have in common the difficulty of diagnosis due to the lack of knowledge on the part of professionals. Therefore, a rare anemia is one whose diagnosis is difficult because it is an essential part of a rare disease (RD) of unknown or complex mechanism.

Rare anemias constitute one of the most important and current chapters of hematology thanks to the fact that the European Commission (EC) has been devoting preferential attention to them since 2002 through the creation and co-financing of a European network dedicated to their study and diagnosis. This network is known as ENERCA, which stands for “European Network for Rare and Congenital Anemias” or European Network for Rare and Congenital Anemias, whose coordinator is the author of this article. Since 2016, and thanks to the creation of the European Rare Diseases Network (ERN), ENERCA has been integrated into a broader European network that includes not only anemias but also all rare hematological diseases in general, and is known by the name EuroBloodNet.

Types of rare anemias in children and adolescents

Some of the most common rare anemias are:

1. Hemoglobinopathies or defects of hemoglobin, the fundamental component of the hematíe. Hemoglobinopathies may be due to congenital defects in the synthesis of globin chains (thalassemia) or to structural abnormalities of globin chains (structural hemoglobinopathies). At birth, 55 to 90% of hemoglobin is fetal hemoglobin (HbF), composed of two gamma globin chains (alpha2gamma2) and two alpha globin chains. After birth, gamma chain production decreases and beta chain production increases until adult hemoglobin (HbA) becomes predominant. Alpha-thalassemia is caused by decreased or absent synthesis of alpha chains, and beta-thalassemia by decreased or absent beta chains. Structural alterations of hemoglobin (hemoglobinopathies) are mutations of the alpha and beta chains, the best known being mutations of the beta chain, notably hemoglobinopathy S (HbS), which causes sickle cell disease, and hemoglobinopathy C, which causes moderate anemia with abundant red blood cells in the target. Beta-globin concentration is usually low at birth, which means that beta-thalassemia and beta-chain structural hemoglobinopathies do not manifest themselves during the neonatal period but after 3-4 months.
2. Another example of rare anemias are disorders of the red blood cell membrane, almost always congenital in origin due to mutations in the genes that synthesize membrane proteins, which are another cause of chronic hemolysis that is generally diagnosed during childhood or adolescence. These disorders produce alterations in the shape of the red blood cells that facilitate diagnosis, the most frequent being hereditary spherocytosis (HS), congenital elliptocytosis (CE) and congenital stomatocytosis (CS). All these disorders are accompanied by a decrease in the ability of red blood cells to deform (deformability), as a result of which they become trapped in the spleen, where they are destroyed, and disappear prematurely from the circulation (hemolysis).
3. Finally, the less frequent or very rare anemias are those due to erythrocyte enzyme defects (erythroenzymopathies). Most of these belong to anaerobic glycolysis or oxidative metabolism of the heme and virtually all of them are transmitted in an autosomal recessive manner, except for glucose-6-phosphate dehydrogenase deficiency (G6PD), a sex-linked (X chromosome) disease affecting more than 400 million people worldwide. G6PD deficiency is suffered by males (hemizygotes) and transmitted by females (heterozygotes), but many carriers do not know they have the deficiency until they come into contact with an oxidizing agent, which may be a drug (e.g. aspirin) or a food such as fava beans (fabism). This enzymopathy is characterized by its polymorphism, i.e. having many different molecular forms or variants that show prevalence in the populations of the Mediterranean coast, Africa and the Middle East. The most common variants are G6PD A (-), typical (although not exclusive) of the black race, and “Mediterranean” G6PD B (-), typical of the populations surrounding the Mediterranean Sea. Both variants present with hemolysis crises after taking an oxidizing drug agent or beans. Apart from these crises, G6PD deficiency is practically always asymptomatic.
4. G6PD deficiency is followed in frequency by pyruvate kinase (PK) deficiency, an autosomal recessively transmitted enzyme disorder, which is relatively more frequent in northern European populations. It is a prevalent erythroenzymopathy in whites, with a frequency of approximately 1 case per 20,000 births and, unlike G6PD deficiency, it presents with hemolysis and chronic anemia of variable intensity throughout life, sometimes requiring the administration of blood (transfusions). There is no treatment, except for bone marrow transplantation (BMT), which is relatively aggressive, so that in the vast majority of cases palliative treatments such as transfusions must be resorted to. The use of an allosteric enzyme activator (Mitapivat), administered orally, is currently being tested and is showing encouraging results.

How do anemias affect children and their families?

In summary, anemia is a serious health problem during childhood and adolescence because of its adverse effects on mental health and physical development at this important stage of human life. The management of anemia in these circumstances depends very much on the intensity of the symptoms because if it is not critical, children and adolescents are not usually referred to the pediatrician’s office, so the diagnosis and treatment of anemia may be delayed until the anemia becomes severe.

It should always be kept in mind that the most frequent cause of anemia during childhood and adolescence is iron deficiency, but it is not the only one. These anemias of nutritional origin, generally of low expression, are successfully treated by the administration of iron and other nutrients, such as certain vitamins (VitB12 and folic acid). In adolescence, however, the relatively common symptoms may mask rare underlying diseases that lead to misdiagnosis and delay treatment. In this situation are the so-called rare anemias which, due to their low prevalence and lack of knowledge, often lead to inadequate health care, with significant delays in diagnosis and treatment.

Some rare anemias with a significant decrease in hemoglobin concentration can affect the quality of life of the child or adolescent, with possible loss of autonomy due to the chronic nature of anemia, which is sometimes aggravated by multisystemic or multiorgan involvement that, in the most severe cases, can lead to the death of the patient. The fact that in virtually all cases there is no readily applicable curative treatment adds anxiety to the high level of pain and suffering endured by patients and their families.

In a child or adolescent, a rare anemia with significant clinical manifestations affects not only the patient but also the immediate family, especially the parents, and the public health system, thereby creating a major socio-health problem. Hematologists and pediatricians have to be aware of this special situation and take the necessary measures when anemia cannot be diagnosed by conventional procedures, trying to do everything possible to establish the diagnosis as soon as possible. Enlisting the help of European networks, e.g. ENERCA, may be a possible solution to the clinical problem created by this situation.