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Congenital Aplastic Anemia

Aplastic Anemia Constitutional

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.


Presentation

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 [1], 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 [2]. 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 [2] [3] [4]. By contrast, Diamond-Blackfan anemia is often associated with growth retardation [4]. 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 [2].

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 [2].

Easy Bruising
  • These are common symptoms for each: Low red blood cell count: Tiredness Shortness of breath Dizziness Pale skin Headaches Chest pain Irregular heartbeat Low white blood cell count: Infections Fever Low platelet count: Easy bruising and bleeding Nosebleeds[webmd.com]
  • Symptoms Aplastic anemia symptoms may include: Fatigue Shortness of breath with exertion Rapid or irregular heart rate Pale skin Frequent or prolonged infections Unexplained or easy bruising Nosebleeds and bleeding gums Prolonged bleeding from cuts Skin[mayoclinic.org]
  • Aplastic anemia may present with the following signs and symptoms: Fatigue Dyspnea on exertion Easy bruising and bleeding (for example, epistaxis, gum bleeding, heavy menses, subconjunctival hemorrhages, melena, etcetera.)[cancertherapyadvisor.com]
Anemia
  • Fanconi anemia may be due to sequence anomalies affecting distinct genes involved in DNA repair. Fanconi anemia is the prime example for CAA.[symptoma.com]
  • A seven-year-old girl with Fanconi's anemia-like congenital aplastic anemia and concurrent asplenia without the congenital heart defects or the abdominal heterotaxia is reported.[ncbi.nlm.nih.gov]
  • Comparison of several hematological and clinical parameters in Fanconi anemia (FA) (DEB ) and non-Fanconi anemia (non-FA)(DEB ) patients disclosed no statistically significant differences.[ncbi.nlm.nih.gov]
  • 2015 ICD-9-CM Diagnosis Code 284.0 Constitutional aplastic anemia There are 2 ICD-9-CM codes below 284.0 that define this diagnosis in greater detail. Do not use this code on a reimbursement claim.[icd9data.com]
  • (pure) red blood cell aplasia D61.09 Other constitutional aplastic anemia D61.1 Drug-induced aplastic anemia D61.2 Aplastic anemia due to other external agents D61.3 Idiopathic aplastic anemia D61.8 Other specified aplastic anemias and other bone marrow[icd10data.com]
Fatigue
  • Low counts of red blood cells bring about anemia and cause fatigue, weakness and pallor.[symptoma.com]
  • May present with sequelae of neutropenia (infections), anaemia (fatigue, pallor, dyspnoea, tachycardia), or thrombocytopenia (bleeding, bruising). Laboratory findings may include leukopenia, neutropenia, anaemia, and thrombocytopenia.[bestpractice.bmj.com]
  • Aplastic anemia leaves you feeling fatigued and with a higher risk of infections and uncontrolled bleeding. A rare and serious condition, aplastic anemia can develop at any age.[mayoclinic.org]
  • Too few red blood cells lead to a decrease in hemoglobin and symptoms of fatigue. A reduced number of neutrophils (a major type of white blood cell important for defense against bacterial and fungal infections) increases susceptibility to infection.[childrenshospital.org]
  • Symptoms of chronic aplastic anemia include weakness and fatigue in the early stages, followed by shortness of breath, headache, fever, and pounding heart.[britannica.com]
Pallor
  • Low counts of red blood cells bring about anemia and cause fatigue, weakness and pallor.[symptoma.com]
  • May present with sequelae of neutropenia (infections), anaemia (fatigue, pallor, dyspnoea, tachycardia), or thrombocytopenia (bleeding, bruising). Laboratory findings may include leukopenia, neutropenia, anaemia, and thrombocytopenia.[bestpractice.bmj.com]
  • There is usually a waxy pallor, and hemorrhages occur in the mucous membranes, skin, and other organs.[britannica.com]
  • The symptoms are related to the low levels of blood cells: Low numbers of red blood cells cause anemia, with symptoms such as a headache, dizziness, fatigue, and paleness (pallor) Low numbers of platelets (necessary for blood clotting) cause unusual bleeding[verywell.com]
  • In children parent complains of growth abnormalities Signs Pallor Tachycardia Petechia and ecchymosis In children: – growth retardation Associated renal, cardiac, skin problems and any abnormal fingers may be indicating inherited bone marrow failures.[epomedicine.com]
Abdominal Pain
  • The severe adverse events included abdominal pain due to gastroparesis, skin rash on cephalosporin, febrile neutropenia, and gingival bleeding. Seven of 11 patients with a response remained on treatment for 16 months.[hematology.org]
  • The patient did not have any fever, abdominal pain, jaundice, or rash. There was no history of abdominal distension, weight loss, or prior bleed. Also, the patient had never smoked or consumed alcohol. He did not have any other chronic illness.[jscisociety.com]
Skin Discoloration
  • Clinical Information Familial or idiopathic form, usually fatal; fanconi's anemia presents before age 10, marked by microcephaly, skin discolorations, and sexual and mental retardation ICD-9-CM codes are used in medical billing and coding to describe[icd9data.com]
Headache
  • Symptoms of chronic aplastic anemia include weakness and fatigue in the early stages, followed by shortness of breath, headache, fever, and pounding heart.[britannica.com]
  • A brain tumor may cause headaches and seizures as well as many other nervous system problems. Breast cancer occurs when abnormal cells grow out of control in the breast.[northwell.edu]
  • The symptoms are related to the low levels of blood cells: Low numbers of red blood cells cause anemia, with symptoms such as a headache, dizziness, fatigue, and paleness (pallor) Low numbers of platelets (necessary for blood clotting) cause unusual bleeding[verywell.com]
  • These are common symptoms for each: Low red blood cell count: Tiredness Shortness of breath Dizziness Pale skin Headaches Chest pain Irregular heartbeat Low white blood cell count: Infections Fever Low platelet count: Easy bruising and bleeding Nosebleeds[webmd.com]
  • […] anemia symptoms may include: Fatigue Shortness of breath with exertion Rapid or irregular heart rate Pale skin Frequent or prolonged infections Unexplained or easy bruising Nosebleeds and bleeding gums Prolonged bleeding from cuts Skin rash Dizziness Headache[mayoclinic.org]

Workup

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 [2]. 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 [5], 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 [2]:

  • For instance, reticulocyte counts may allow for the differentiation of anemia due to decreased production from anemia provoked by peripheral destruction. In neonates, corrected reticulocyte counts <2% indicate aplastic anemia [2]. Also, an increased mean corpuscular volume in the absence of reticulocytosis suggest bone marrow failure [2].
  • Platelet size is a less reliable parameter with regards to the recognition of bone marrow aplasia. In most cases though, thrombocytes of CAA patients are of normal or reduced size. The determination of the immature platelet fraction may be more useful to this end.

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 [6].

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.

Hypercellular Bone Marrow
  • Occasionally, it is used for a condition in which there is peripheral pancytopenia but a normally cellular or even hypercellular bone marrow. Such a state may be associated with a good prognosis even without therapy.[nejm.org]
  • bone marrow but about 15% of cases have a hypocellular bone marrow.[cancertherapyadvisor.com]

Treatment

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 [7], 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 [8]. 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 [9]. 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.

Prognosis

Any congenital bone marrow failure syndrome, and particularly those associated with pancytopenia, imply an increased risk of medical problems later in life [2]. 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 [2] [10].

Etiology

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 [6].

Fanconi anemia may be due to sequence anomalies affecting distinct genes involved in DNA repair [7] [11]. 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 [1]. 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 [2]:

  • Congenital amegakaryocytic thrombocytopenia. While thrombocytopenia is the main finding in affected individuals, many of them develop aplastic anemia [12]. The disease may be inherited in an autosomal recessive or X-linked manner, and many cases are due to mutations of the C-MPL gene. This gene encodes for the thrombopoietin receptor.
  • Dyskeratosis congenita. This disease is characterized by nail dystrophy, leukoplakia, and pigmentary changes and affected individuals don't usually develop aplastic anemia until their second decade of life [13]. Case reports of aplastic anemia preceding skin changes have been published, though [5]. Mutations of distinct genes have been associated with dyskeratosis congenita.
  • Thrombocytopenia-absent radius syndrome. With regards to blood cell counts, thrombocytopenia is the main finding in patients affected by this disease. Thrombocytopenia-absent radius syndrome results from deletions on chromsome 1, presumably affecting gene RBM8A, encoding for RNA-binding motif protein 8A [14].

Epidemiology

In Germany, the overall prevalence of congenital bone marrow failure syndromes has been estimated to 10 in 1,000,000 children and adolescents [4]. 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 [10], but report a carrier frequency of 1 in 200 to 300 [6]. Particularly high carrier rates have been observed among Spanish gypsies, Afrikaners in South Africa and Ashkenazi Jews (all >1 in 100 persons) [6].

Sex distribution
Age distribution

Pathophysiology

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 [6]. 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.

Prevention

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.

Summary

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 [4]. 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 [3] [4]. CAA may also occur in patients suffering from Shwachman–Diamond syndrome [1].

Patient Information

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.

References

Article

  1. Kuijpers TW, Nannenberg E, Alders M, Bredius R, Hennekam RC. Congenital aplastic anemia caused by mutations in the SBDS gene: a rare presentation of Shwachman-Diamond syndrome. Pediatrics. 2004; 114(3):e387-391.
  2. Rivers A, Slayton WB. Congenital cytopenias and bone marrow failure syndromes. Semin Perinatol. 2009; 33(1):20-28.
  3. Erduran E, Okten A, Kaya G, Yildiran A. Asplenia in a patient with Fanconi's anemia-like congenital aplastic anemia. Turk J Pediatr. 2000; 42(2):155-157.
  4. Zeidler C, Welte K. [Congenital bone marrow failure syndromes. The last 20 years by the example of congenital neutropenia]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2007; 50(12):1564-1568.
  5. Forni GL, Melevendi C, Jappelli S, Rasore-Quartino A. Dyskeratosis congenita: unusual presenting features within a kindred. Pediatr Hematol Oncol. 1993; 10(2):145-149.
  6. Moore CA, Krishnan K. Bone Marrow Failure. StatPearls. Treasure Island (FL): StatPearls Publishing LLC; 2017.
  7. Morimoto K, Moore TB, Schiller G, Sakamoto KM. Transplantation for congenital bone marrow failure syndromes. Bone Marrow Res. 2011; 2011:849387.
  8. Burroughs L, Woolfrey A, Shimamura A. Shwachman-Diamond syndrome: a review of the clinical presentation, molecular pathogenesis, diagnosis, and treatment. Hematol Oncol Clin North Am. 2009; 23(2):233-248.
  9. Howell JC, Joshi SA, Hornung L, Khoury J, Harris RE, Rose SR. Growth hormone improves short stature in children with Diamond-Blackfan anemia. Pediatr Blood Cancer. 2015; 62(3):402-408.
  10. Altay C, Alikasifoglu M, Kara A, Tuncbilek E, Ozbek N, Schroeder-Kurth TM. Analysis of 65 Turkish patients with congenital aplastic anemia (Fanconi anemia and non-Fanconi anemia): Hacettepe experience. Clin Genet. 1997; 51(5):296-302.
  11. Cheung RS, Taniguchi T. Recent insights into the molecular basis of Fanconi anemia: genes, modifiers, and drivers. Int J Hematol. 2017.
  12. Lang Z, Dinndorf P, Ladisch S, Bayever E, Reaman G. Chromosomal transformation in donor cells following allogeneic bone marrow transplantation. Bone Marrow Transplant. 2004; 33(12):1253-1256.
  13. Sinha S, Trivedi V, Krishna A, Rao N. Dyskeratosis congenita- management and review of complications: a case report. Oman Med J. 2013; 28(4):281-284.
  14. Nicchia E, Giordano P, Greco C, De Rocco D, Savoia A. Molecular diagnosis of thrombocytopenia-absent radius syndrome using next-generation sequencing. Int J Lab Hematol. 2016; 38(4):412-418.

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Last updated: 2019-07-11 20:27