Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...

bone marrow failure syndrome characterized by severe

thrombocytopenia In hematology, thrombocytopenia is a condition characterized by abnormally low levels of platelets (also known as thrombocytes) in the blood. Low levels of platelets in turn may lead to prolonged or excessive bleeding. It is the most common coag ...

, which can progress to aplastic anemia and

leukemia Leukemia ( also spelled leukaemia; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or '' ...

. CAMT usually manifests as

in the initial month of life or in the fetal phase. Typically CAMPT presents with

petechia A petechia (; : petechiae) is a small red or purple spot ( 1 cm in diameter) and purpura (3 to 10 mm in diameter). The term is typically used in the plural (petechiae), since a single petechia is seldom noticed or significant. Causes Physical t ...

e, cerebral bleeds, recurrent rectal bleeding, or pulmonary hemorrhage. The cause of CAMT is believed to be

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

s in the MPL gene coding for thrombopoietin receptor, which is expressed in pluripotent hematopoietic stem cells and cells of the

megakaryocyte A megakaryocyte () is a large bone marrow cell with a lobation, lobated nucleus that produces blood platelets (thrombocytes), which are necessary for normal blood coagulation, clotting. In humans, megakaryocytes usually account for 1 out of 10,00 ...

lineage. CAMT is diagnosed by a

bone marrow biopsy Bone marrow examination refers to the pathologic analysis of samples of bone marrow obtained by bone marrow biopsy (often called trephine biopsy) and bone marrow aspiration. Bone marrow examination is used in the diagnosis of a number of condit ...

and is often initially suspected to be fetal and neonatal alloimmune thrombocytopenia. Two types of Congenital amegakaryocytic thrombocytopenia have been identified with type I being more severe. Treatment is mostly supportive, consisting of multiple

platelet transfusion Platelet transfusion, is the process of infusing platelet concentrate into the body via vein, to prevent or treat the bleeding in people with either a thrombocytopenia, low platelet count or poor platelet function. Often this occurs in people ...

Hematopoietic stem cell transplantation Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood, in order to replicate inside a patient and produce ...

is the only known cure for CAMT. Once pancytopenia develops, the prognosis is poor. Studies have shown 30% of CAMT patients die from bleeding complications, and another 20% die from complications related to

hematopoietic stem cell transplantation Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood, in order to replicate inside a patient and produce ...

Signs and symptoms

Congenital amegakaryocytic thrombocytopenia manifests itself at birth, typically within the first few days of birth.

Thrombocytopenia In hematology, thrombocytopenia is a condition characterized by abnormally low levels of platelets (also known as thrombocytes) in the blood. Low levels of platelets in turn may lead to prolonged or excessive bleeding. It is the most common coag ...

and a near absence of

s in the

bone marrow Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...

cause

e, purpura, and

gastrointestinal The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascular system. ...

, pulmonary or

intracranial hemorrhage Intracranial hemorrhage (ICH) refers to any form of Hemorrhage, bleeding Internal bleeding, within the Human skull, skull. It can result from trauma, vascular abnormalities, hypertension, or other medical conditions. ICH is broadly categorized ...

. Less common symptoms of CAMPT include cardiac defects such as

atrial The atrium (; : atria) is one of the two upper chambers in the heart that receives blood from the circulatory system. The blood in the atria is pumped into the heart ventricles through the atrioventricular mitral and tricuspid heart valves. ...

and ventricular septal defects, cerebral and

cerebellar hypoplasia Cerebellar hypoplasia is characterized by reduced cerebellar volume, even though cerebellar shape is (near) normal. It consists of a heterogeneous group of disorders of cerebellum, cerebellar maldevelopment presenting as early-onset Non-progress ...

, and delayed psychomotor development.

Complications

Those with type I Congenital amegakaryocytic thrombocytopenia often progress to bone marrow failure and aplastic anemia around age 1, while those with type II usually don't develop bone marrow failure or aplastic anemia till age 5. About 90% of those with type II CAMT develop pancytopenia. Rates of pancytopenia are much lower in type I. Increased risk of

myelodysplastic syndrome A myelodysplastic syndrome (MDS) is one of a group of cancers in which blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may includ ...

and

acute myeloid leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with haematopoiesis, normal blood cell production. Sympt ...

has been associated with Congenital amegakaryocytic thrombocytopenia.

Cause

Congenital amegakaryocytic thrombocytopenia is most likely caused by a mutation in the gene for the TPO receptor, '' c-mpl'', despite high levels of serum TPO. In addition, there may be abnormalities with the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

including the

cerebrum The cerebrum (: cerebra), telencephalon or endbrain is the largest part of the brain, containing the cerebral cortex (of the two cerebral hemispheres) as well as several subcortical structures, including the hippocampus, basal ganglia, and olfac ...

and

cerebellum The cerebellum (: cerebella or cerebellums; Latin for 'little brain') is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as it or eve ...

which could cause symptoms.

Diagnosis

The main diagnostic features of Congenital amegakaryocytic thrombocytopenia are elevated serum TPO levels that do not respond to TPO stimulation, absent or very few

s in

, and

that worsens with age. Congenital amegakaryocytic thrombocytopenia is confirmed by

homozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mos ...

or compound

heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mos ...

s in the c-Mpl gene. The differential diagnosis for Congenital amegakaryocytic thrombocytopenia includes thrombocytopenia-absent radius syndrome and Wiskott-Aldrich syndrome. Congenital amegakaryocytic thrombocytopenia is distinguished from thrombocytopenia-absent radius syndrome on the basis of skeletal

hypoplasia Hypoplasia (; adjective form ''hypoplastic'') is underdevelopment or incomplete development of a tissue or organ.microthrombocytopenia can rule out Wiskott-Aldrich syndrome.

Classification

Two types of Congenital amegakaryocytic thrombocytopenia have been identified. Type I-CAMT is more severe and is characterized by low platelet counts and an early progression of bone marrow aplasia associated with pancytopenia. The second type of Congenital amegakaryocytic thrombocytopenia is milder and presents with a transient increase of platelet counts during the first year of life. Those with type II-CAMT often don't develop pancytopenia and if they do it tends to develop later than in type I.

Treatment

Bone marrow transplant Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood, in order to replicate inside a patient and produce a ...

is the only thing that cures Congenital amegakaryocytic thrombocytopenia. Frequent

s are required to ensure that

platelet Platelets or thrombocytes () are a part of blood whose function (along with the coagulation#Coagulation factors, coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus, blood clot. Platelets have no ...

levels do not fall to dangerous levels, although this is not always the case. It is known for patients to continue to create very small numbers of

s over time.

Outlook

Although

has been shown to cure Congenital amegakaryocytic thrombocytopenia, the association of early bone marrow aplasia worsens prognosis. About 30% of those with CAMT die from complications of bleeding and a further 20% die from complications associated with

Epidemiology

Less than 100 cases of Congenital amegakaryocytic thrombocytopenia have been reported, although the incidence of CAMT is most likely underestimated because isolated CAMT may be misdiagnosed as neonatal alloimmune thrombocytopenia. There is a slight female in preponderance in CAMT.

References

External links

Amegakaryocytic Thrombocytopenia research study of Inherited Bone Marrow Failure Syndromes (IBMFS)
{{Receptor deficiencies Coagulopathies Cell surface receptor deficiencies Genetic diseases and disorders Autosomal recessive disorders