Congenital hypoplastic anemia
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Congenital hypoplastic anemia is a congenital disorder that occasionally also includes leukopenia and thrombocytopenia and is characterized by deficiencies of red cell precursors. Types of congenital hypoplastic anemia include Diamond–Blackfan anemia,
Fanconi anemia Fanconi anaemia (FA) is a rare genetic disease resulting in impaired response to DNA damage. Although it is a very rare disorder, study of this and other bone marrow failure syndromes has improved scientific understanding of the mechanisms of nor ...
,
Shwachman–Diamond syndrome Shwachman–Diamond syndrome (SDS), or Shwachman–Bodian–Diamond syndrome, is a rare congenital disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, skeletal abnormalities and short stature. After cystic fib ...
, Majeed syndrome, Congenital dyserythropoietic anemia type III, and Cartilage–hair hypoplasia.


Types

* Diamond–Blackfan anemia is a is an uncommon congenital hypoplastic anemia that often manifests in the first few months of life. Josephs initially noted Diamond-Blackfan anemia in 1936, and Diamond and Blackfan provided a more thorough description of the condition in 1938. The 1976 publication of the Diamond-Blackfan anemia diagnostic criteria states that the condition must manifest before the patient turns one year old and must include near-normal or slightly decreased neutrophil counts, reticulocytopenia, variable platelet counts,
macrocytosis Macrocytosis is the enlargement of red blood cells with near-constant hemoglobin concentration, and is defined by a mean corpuscular volume (MCV) of greater than 100 femtolitres (the precise criterion varies between laboratories). The enlarged er ...
, and normal marrow cellularity with a deficiency of red cell precursors. Diamond-Blackfan anemia in infants manifests as anemia-related symptoms such as
pallor Pallor is a pale color of the skin that can be caused by illness, emotional shock or stress, stimulant use, or anemia, and is the result of a reduced amount of oxyhaemoglobin and may also be visible as pallor of the conjunctivae of the eyes o ...
, failure to thrive, and difficulty sucking when nursing or using a bottle. Fifty percent of Diamond-Blackfan anemia patients are reported to have congenital malformations in addition to anemia. The incidence of Diamond-Blackfan anemia is 7 cases per million live births. About 40–45% of Diamond-Blackfan anemia cases are familial and have
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
inheritance; the remaining cases are either sporadic or familial and appear to have distinct inheritance patterns.
RPS19 40S ribosomal protein S19 is a protein that in humans is encoded by the ''RPS19'' gene. Function Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are c ...
currently has the most prevalent mutation. There are 113 distinct
RPS19 40S ribosomal protein S19 is a protein that in humans is encoded by the ''RPS19'' gene. Function Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are c ...
mutations linked to Diamond-Blackfan anemia. Red cell transfusions and
corticosteroid Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involv ...
s are the cornerstones of Diamond-Blackfan anemia treatment since 1951. *
Fanconi anemia Fanconi anaemia (FA) is a rare genetic disease resulting in impaired response to DNA damage. Although it is a very rare disorder, study of this and other bone marrow failure syndromes has improved scientific understanding of the mechanisms of nor ...
(FA) is a genetically and phenotypically diverse recessive disorder that is characterized by a variety of congenital malformations,
pancytopenia Pancytopenia is a medical condition in which there is significant reduction in the number of almost all blood cells (red blood cells, white blood cells, platelets, monocytes, lymphocytes, etc.). If only two parameters from the complete blood cou ...
that progresses over time, and a susceptibility to solid tumors as well as hematologic malignancies. Each patient has a unique set of congenital anomalies that can impact any major organ system or skeletal morphogenesis. Although FA can occur in patients without congenital defects and be diagnosed in adulthood, classic clinical features like growth retardation, small head size, café-au-lait spots, radial ray defects, and renal structural abnormalities can be powerful diagnostic clues. Although
macrocytosis Macrocytosis is the enlargement of red blood cells with near-constant hemoglobin concentration, and is defined by a mean corpuscular volume (MCV) of greater than 100 femtolitres (the precise criterion varies between laboratories). The enlarged er ...
and fetal hemoglobin (HbF) increases are frequently observed, their absence does not rule out illness. The MMC or DEB chromosomal breakage test is the accepted method for diagnosing FA. There are currently fifteen known FANC genes, with FANCA,
FANCC Fanconi anemia group C protein is a protein that in humans is encoded by the ''FANCC'' gene. Structure Function The protein encoded by this gene delays the onset of apoptosis and promotes homologous recombination repair of damaged DNA. M ...
, FANCG, and
FANCD2 Fanconi anemia group D2 protein is a protein that in humans is encoded by the ''FANCD2'' gene. The Fanconi anemia complementation group ( FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2 (this gene), FANCE, FANCF, FA ...
being the most common. For certain FA patients, androgen therapy works well in treating bone marrow failure. Hematopoietic abnormalities in FA patients have been successfully treated with synthetic androgens like danazol and oxymetholon. When bone marrow fails in FA, hematopoietic stem cell transplantation is still the first line of treatment of choice. *
Shwachman–Diamond syndrome Shwachman–Diamond syndrome (SDS), or Shwachman–Bodian–Diamond syndrome, is a rare congenital disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, skeletal abnormalities and short stature. After cystic fib ...
(SDS) is a leukemia predisposition and
exocrine pancreatic insufficiency Exocrine pancreatic insufficiency (EPI) is the inability to properly digest food due to a lack of digestive enzymes made by the pancreas. EPI is found in humans afflicted with cystic fibrosis and Shwachman–Diamond syndrome, and is common in ...
-related
autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
marrow failure syndrome. Roughly 90% of patients who fit the clinical criteria for SDS diagnosis have
SBDS Ribosome maturation protein SBDS is a protein that in humans is encoded by the ''SBDS'' gene. An alternative transcript has been described, but its biological nature has not been determined. This gene has a closely linked pseudogene that is distal ...
gene mutations.
SBDS Ribosome maturation protein SBDS is a protein that in humans is encoded by the ''SBDS'' gene. An alternative transcript has been described, but its biological nature has not been determined. This gene has a closely linked pseudogene that is distal ...
corresponds to chromosome 7's 7q11 centromeric region.
Steatorrhea Steatorrhea (or steatorrhoea) is the presence of excess fat in feces. Stools may be bulky and difficult to flush, have a pale and oily appearance, and can be especially foul-smelling. An oily anal leakage or some level of fecal incontinence may oc ...
and failure to thrive are the typical early presentations of SDS patients. Reduced levels of fat-soluble vitamins ( A, D, E, and K) may occur. Young patients with SDS frequently have hepatomegaly with elevated liver transaminases, usually two to three times higher than the normal range. In 88% to 100% of patients with SDS,
neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...
—generally defined as a neutrophil count of less than 1,500 109/L—is the most prevalent sign of
bone marrow failure Bone marrow failure occurs in individuals who produce an insufficient amount of red blood cells, white blood cells or platelets. Red blood cells transport oxygen to be distributed throughout the body's tissue. White blood cells fight off infectio ...
. About two thirds of patients have intermittent neutropenia, while the remaining third have chronic
neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...
. Neutrophil counts can be anywhere from normal to very low. In vitro, there is a reduction in neutrophil numbers as well as neutrophil
chemotaxis Chemotaxis (from '' chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemica ...
. There might be more
cytopenia Cytopenia is a reduction in the number of mature blood cells. It is common in cancer patients being treated with radiation and/or chemotherapy. Types Anemia – a reduction of the red blood cells in the body. Leukopenia – a deficiency of whit ...
s present as well. 42% to 66% of patients have been reported to have anemia. Usually, the reticulocyte count is not raised. RBCs can be either macrocytic or
normocytic Normocytic anemia is a type of anemia and is a common issue that occurs for men and women typically over 85 years old. Its prevalence increases with age, reaching 44 percent in men older than 85 years. The most common type of normocytic anemia is a ...
. A common characteristic of many inherited marrow failure syndromes is elevated hemoglobin F levels, which are frequently present. Typically defined as less than 150 109/L, thrombocytopenia affects 24% to 60% of patients. Endocrine abnormalities in SDS include
hypothyroidism Hypothyroidism (also called ''underactive thyroid'', ''low thyroid'' or ''hypothyreosis'') is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as po ...
, hypogonadotropic hypogonadism, growth hormone deficiency, and
insulin-dependent diabetes Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for ...
. Cardiomyopathies have also been reported in some cases. The main characteristics of SDS are pancreatic exocrine and bone marrow dysfunction, which are the basis for the majority of clinical phenotype-based diagnoses. Currently, the sole treatment for the hematological complications in SDS is hematopoietic stem cell transplantation. * Majeed syndrome is a multi-system inflammatory disease that manifests as
congenital dyserythropoietic anemia Congenital dyserythropoietic anemia (CDA) is a rare blood disorder, similar to the thalassemias. CDA is one of many types of anemia, characterized by ineffective erythropoiesis, and resulting from a decrease in the number of red blood cells (RBCs) ...
, chronic multifocal osteomyelitis, and neutrophilic dermatosis. The
phosphatidic acid phosphatase The enzyme phosphatidate phosphatase (PAP, EC 3.1.3.4) is a key regulatory enzyme in lipid metabolism, catalyzing the conversion of phosphatidate to diacylglycerol: :a 1,2-diacylglycerol 3-phosphate + H2O \rightleftharpoons a 1,2-diacyl-''sn''-gl ...
gene, LPIN2, is mutated in the disease, which is an autosomal recessive disorder. * Congenital dyserythropoietic anemia type III (CDAII) is an
autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
disease characterized by hemolysis,
erythroblast A nucleated red blood cell (NRBC), also known by several other names, is a red blood cell that contains a cell nucleus. Almost all vertebrate organisms have hemoglobin-containing cells in their blood, and with the exception of mammals, all of the ...
morphological abnormalities, hypoglycosylation of certain RBC membrane proteins, and ineffective erythropoiesis. * Cartilage–hair hypoplasia is a metaphyseal chondrodysplasia that is autosomally recessive and characterized by short stature, hypoplastic hair, impaired immunity, and aberrant erythrogenesis.


See also

*
Congenital dyserythropoietic anemia Congenital dyserythropoietic anemia (CDA) is a rare blood disorder, similar to the thalassemias. CDA is one of many types of anemia, characterized by ineffective erythropoiesis, and resulting from a decrease in the number of red blood cells (RBCs) ...
* Birth defect


References


Further reading

* * *


External links

* Diamond–Blackfan anemia
MedlinePlusCleveland ClinicNational Organization for Rare DisordersWebMD
an
Orphanet
* Fanconi anemia
MedlinePlusCleveland ClinicNational Organization for Rare DisordersWebMD
an
Orphanet
* Shwachman–Diamond syndrome
MedlinePlusCleveland ClinicNational Organization for Rare DisordersBoston Children’s Hospital
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Orphanet
* Majeed syndrome
MedlinePlusOMIMGenetic and Rare Diseases Information CenterOrphanet
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DermNet
* Congenital dyserythropoietic anemia type III
OMIM 1OMIM 2Orphanet
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Genetic and Rare Diseases Information Center
* Cartilage–hair hypoplasia
MedlinePlusGenetic and Rare Diseases Information CenterOrphanetJohns Hopkins Medicine
an

{{Set index article Aplastic anemias