Congenital aplastic anemia (CAA) indicates congenital bone marrow failure. It may be due to distinct mutations of a large variety of genes whose gene products are involved in hematopoietic stem cell differentiation and maturation. In most cases, CAA is accompanied by additional congenital anomalies that negatively affect the patients' quality of life and prognosis, but that usually facilitate the diagnosis of the underlying disease. For instance, CAA may be observed in individuals suffering from Fanconi anemia, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome.
The time of symptom onset and the severity of the disease largely depends on the degree of cytopenias. In severe cases, CAA is diagnosed at birth or shortly thereafter , in less severe cases patients may present years later. Leukemia, a long-term sequelae of CAA, has been diagnosed in adult patients unaware of their primary disease . In general, the following symptoms may be caused by anemia, leukopenia and thrombocytopenia:
Genetic disorders resulting in CAA may also provoke developmental disturbances and malformations of non-hematopoietic tissues and organs. For instance, pigmentary changes, thumb aplasia, VACTERL association and asplenia may be observed in patients suffering from Fanconi anemia-like CAA. Additional physical anomalies and cancer susceptibility have also been described in these patients   . By contrast, Diamond-Blackfan anemia is often associated with growth retardation . Retarded growth is also a symptom of Shwachman–Diamond syndrome. Furthermore, individuals affected by Shwachman–Diamond syndrome suffer from hepatic and renal disorders as well as exocrine pancreatic insufficiency. It is not uncommon that such additional malformations or organ dysfunctions are detected long before cytopenias manifest .
For more detailed descriptions of congenital anomalies often observed in patients suffering from congenital amegakaryocytic thrombocytopenia, dyskeratosis congenita, and thrombocytopenia-absent radius syndrome, the interested reader is referred to the respective articles on this website or a review published by Rivers et al. in 2009 .
An early diagnosis may facilitate treatment before life-threatening complications arise and is thus crucial for the prognosis of the patient. However, diagnosis in the neonatal period requires a high index of suspicion, which may be based on data obtained in familial anamnesis or clinical observations . Therefore, it is important to gather detailed information regarding a possibly family history of bone marrow failure and cytopenias even if the patient does not momentarily suffer from serious illness , and to perform a thorough clinical examination of the newborn.
Of course, blood cell counts should be monitored. They constitute the most important criteria for the assessment of the severity of CAA. One the one hand, blood counts may reveal cytopenias in patients suspicious of CAA due to congenital malformations as mentioned above. On the other hand, repeated blood analyses help to determine whether cytopenias are of transient or permanent nature. Indeed, most neonatal cytopenias are transient . Blood counts may also provide valuable hints as to the causes of cytopenias :
The examination of bone marrow aspirates and bone marrow biopsy samples is often indispensable to diagnose bone marrow failure in the absence of clear evidence of a particular disease that can be confirmed genetically. Unfortunately, both techniques are rather challenging in neonates. If these procedures are carried out, histopathological examination of the samples obtained will reveal marked hypocellularity. Dysplastic features, e.g., hyponucleated small megakaryocytes, multinucleated red cells, hypolobulated or hypogranular myeloid cells may be recognized and are not to be considered malignant. Otherwise, bone marrow space is largely filled up by fat and fibrotic stroma .
Finally, genetic analyses are necessary to identify or confirm the causal mutation. Targeted sequencing is possible considering the results obtained in anamnesis, clinical examinations and laboratory analyses.
Precise treatment recommendations vary depending on the underlying genetic aberration and the effect of the missing or dysfunctional protein or other molecule on hematopoiesis. In any case, curative therapy can only be provided by means of hematopoietic stem cell transplantation. Those suffering from Fanconi anemia are at high risks of life-threatening bone marrow failure and hematological malignancy and are thus often considered for hematopoietic stem cell transplantion , but this treatment is usually not applied until advanced disease stages in Shwachman–Diamond syndrome: In order to treat neutropenia, granulocyte colony-stimulating factor is usually given throughout life . Besides granulocyte colony-stimulating factor, erythropoietin may be used in CAA patients to enhance erythropoiesis. The mainstay of Diamond-Blackfan anemia treatment is the prolonged application of glucocorticoids . Furthermore, CAA patients may require red blood cell or platelet transfusions to momentarily compensate for lack of blood cells.
Additional treatment is usually required to deal with symptoms accompanying CAA, i.e., anatomical anomalies and internal organ dysfunctions. Hormone therapy or surgical interventions may be carried out to this end and patients may benefit from pancreatic enzyme supplementation and other therapeutic measures as needed.
Any congenital bone marrow failure syndrome, and particularly those associated with pancytopenia, imply an increased risk of medical problems later in life . Such problems may arise due to any cytopenia, but patients suffering from CAA also tend to have a higher risk of developing myelodysplastic syndromes, leukemia or other forms of cancer  .
CAA may be caused by distinct germline mutations that are either inherited or may arise de novo. Both autosomal recessive and autosomal dominant patterns may be noted in familial anamnesis: Both Fanconi anemia and Shwachman-Diamond syndrome are usually inherited in an autosomal recessive manner, Diamond-Blackfan anemia in an autosomal dominant fashion .
Fanconi anemia may be due to sequence anomalies affecting distinct genes involved in DNA repair  . Fanconi anemia is the prime example for CAA. By contrast, Shwachman-Diamond syndrome initially manifests as neutropenia and subsequently progresses to pancytopenia. It is caused by mutations of the SBDS gene, whose gene product is called ribosome maturation factor or Shwachman-Bodian-Diamond syndrome protein . Diamond-Blackfan anemia typically starts out as a bone marrow failure syndrome of the erythrocyte lineage, but may evolve into aplastic anemia.
Even though those diseases mentioned above are among the most common causes of CAA, aplastic anemia may also develop in patients suffering from any of the following congenital disorders :
In Germany, the overall prevalence of congenital bone marrow failure syndromes has been estimated to 10 in 1,000,000 children and adolescents . It should be noted though that this value does not only consider cases of CAA, but also of congenital bone marrow failure syndromes affecting single cell lines, e.g. distinct forms of congenital neutropenia and congenital thrombocytopenia. Thus, the prevalence of CAA in Germany must be significantly lower than 10 in 1,000,000 children and adolescents. Indeed, other sources indicate an incidence of less than 5 per 1,000,000 for Fanconi anemia, the most common cause of CAA , but report a carrier frequency of 1 in 200 to 300 . Particularly high carrier rates have been observed among Spanish gypsies, Afrikaners in South Africa and Ashkenazi Jews (all >1 in 100 persons) .
A myriad of proteins and other molecules is involved in the complex process of stem cell differentiation and maturation, and those tissues with particularly high rates of cell division are most sensitive to disruptions of cell cycle, differentiation and maturation: That is the case with hematopoietic lineages . Genetic disorders underlying CAA may affect any of those sub-processes at any stage of blood cell development. Thus, pathophysiological events leading to CAA are as heterogenous as the clinical presentation of this type of disease.
CAA may be caused by mutations passed down from parents to children and inheritance patterns are known for the most common genetic disorders provoking this type of disease. Thus, affected families may benefit from genetic counseling. No recommendations can be given to prevent CAA due to de novo mutations, though.
CAA is results from congenital bone marrow failure affecting all three cell lines, i.e., erythrocytes, leukocytes and thrombocytes. In general, congenital bone marrow failure syndromes may be due to a reduction of the absolute number of stem cells required for the generation and regeneration of blood cells, due to an insufficient proliferation capacity of those stem cells or any precursor cells, or due to maturation defects affecting any intermediate stage . The overall incidence of congenital bone marrow failure syndromes is low and this is all the more true for single entities that make up this heterogeneous group of diseases. Keeping this in mind, Fanconi anemia-like CAA and Diamond-Blackfan anemia shall be mentioned as two of the more common forms of congenital bone marrow failure with CAA  . CAA may also occur in patients suffering from Shwachman–Diamond syndrome .
Stem cells located in the bone marrow differentiate and maturate in a complex process to finally give rise to erythrocytes, leukocytes, and thrombocytes, which are also known as red and white blood cells and platelets. In patients suffering from aplastic anemia, blood cell formation or hematopoiesis, as it is called by medical staff, is strongly disturbed: Neither erythrocytes, nor leukocytes, nor thrombocytes can be (re-)generated sufficiently. Since there are so many factors affecting blood cell generation, disturbances may occur at various levels. Also, disruptive factors may be present at birth or may be acquired later in life. Among those present at birth, genetic disorders are the most common ones. If there are anomalies in the DNA sequence of a newborn that affect any genes that encode for proteins required for hematopoiesis, aplastic anemia may ensue. It is then called congenital aplastic anemia (CAA). It has to be noted though that symptoms are not necessarily present at birth but may manifest later in childhood or even adulthood.
CAA-associated symptoms result from the lack of erythrocytes, leukocytes, and thrombocytes. Low counts of red blood cells bring about anemia and cause fatigue, weakness and pallor. White blood cells are essential parts of the immune systems and individuals suffering from leukopenia, i.e., lack of leukocytes, are increasingly susceptible to infectious diseases. Finally, platelets are required for coagulation and those patients with particularly low platelet counts develop cutaneous hemorrhages and hematomas even after minor traumas.
Those genetic disorders that result in CAA often also interfere with the development of the skeleton, other organs and tissues. Thus, most CAA patients show additional congenital anomalies, such as reduced height at birth or postnatal growth retardation, absence of determined bones, hepatic, pancreatic and renal dysfunction.