What are the other Names for this Condition? (Also known as/Synonyms)

• CAMT (Congenital Amegakaryocytic Thrombocytopenia)

What is Congenital Amegakaryocytic Thrombocytopenia? (Definition/Background Information)

• Congenital Amegakaryocytic Thrombocytopenia (CAMT) is a rare inherited bone marrow failure syndrome characterized by an isolated and severe decrease in the number of platelets and megakaryocytes during the first years of life that develops into bone marrow failure with pancytopenia later in childhood
• CAMT manifests since birth, often in the first day or at least within the first month of life, with petechiae, purpura, and gastrointestinal, pulmonary or intracranial hemorrhage due to isolated thrombocytopenia and a near absence of megakaryocytes in the bone marrow
• Two types of CAMT have been identified:
  • Type I-CAMT is the severe form of the disease and is characterized by persistently low platelet counts and early progression (usually by the age of 2 years) to bone marrow aplasia associated with pancytopenia
  • Type II-CAMT is a milder form which presents with transient increase of platelet counts over 50x109/L during the first year of life and late (by the age of 3-6 years) or no development of pancytopenia
• Cardiac defects (atrial and ventricular septal defects, abnormalities of the central nervous system (cerebral and cerebellar hypoplasia), and retardation of psychomotor development have occasionally been reported

(Source: Congenital Amegakaryocytic Thrombocytopenia; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Who gets Congenital Amegakaryocytic Thrombocytopenia? (Age and Sex Distribution)

• The exact prevalence of Congenital Amegakaryocytic Thrombocytopenia is unknown and less than 100 cases have been reported in the literature
• In addition, the incidence may be underestimated due to difficult and inconsistent diagnosis of the disease

(Source: Congenital Amegakaryocytic Thrombocytopenia; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

What are the Risk Factors for Congenital Amegakaryocytic Thrombocytopenia? (Predisposing Factors)

• A positive family history may be an important risk factor, since Congenital Amegakaryocytic Thrombocytopenia is an inherited condition

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Congenital Amegakaryocytic Thrombocytopenia? (Etiology)

Congenital Amegakaryocytic Thrombocytopenia is due to mutations in the MPL gene (1p34) coding for Thrombopoietin (TPO) receptor (c-MPL), expressed in pluripotent hematopoietic stem cells and cells of the megakaryocyte lineage. The inheritance pattern is autosomal recessive.

• The binding of TPO to c-MPL stimulates platelet and megakaryocyte production. Different types of mutations have been associated with different phenotypes. Nonsense mutations predicted to result in a complete loss of function of the TPO receptor lead to type I-CAMT, whereas missense mutations predicted to lead to a residual function of the receptor are associated with type II-CAMT
• Cases with no defects in the MPL gene are referred to as type III-CAMT
• Recently, a 21q22 deletion resulting in RUNX1 haploinsufficiency has been reported in a case of CAMT associated with various anomalies (growth retardation, hearing deficits, hernias, poor feeding)

(Source: Congenital Amegakaryocytic Thrombocytopenia; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Congenital Amegakaryocytic Thrombocytopenia?

Based on the frequency of symptoms observed, the following information may be noted:

Very frequently present symptoms in 80-99% of Congenital Amegakaryocytic Thrombocytopenia cases:

• Abnormal hemoglobin
• Thrombocytopenia

Frequently present symptoms in 30-79% of the cases:

• Abnormal form of the vertebral bodies
• Anemia
• Coarse facial features 
• Melanocytic nevus 
• Scoliosis 
• Short neck

Occasionally present symptoms in 5-29% of the cases:

• Abnormality of the cardiac septa 
• Decreased skull ossification

Other signs and symptoms of Congenital Amegakaryocytic Thrombocytopenia include:

• Amegakaryocytic thrombocytopenia
• Cerebellar vermis hypoplasia
• Megakaryocytopenia
• Pancytopenia

(Source: Congenital Amegakaryocytic Thrombocytopenia; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is Congenital Amegakaryocytic Thrombocytopenia Diagnosed?

• Diagnosis is based on clinical signs, on the evidence by blood tests of thrombocytopenia (platelet count below 50x109/L) with a normal mean platelet volume and of highly elevated serum levels of TPO, and on the observation in a bone marrow aspirate of absent or very few megakaryocytes. Genetic testing can confirm the diagnosis
• The initial presentation of Congenital Amegakaryocytic Thrombocytopenia with isolated thrombocytopenia can be misdiagnosed as idiopathic thrombocytopenic purpura (ITP), while the late pancytopenic phase is indistinguishable from aplastic anemia. Fanconi anemia, thrombocytopenia-absent radius (TAR), syndrome and Wiscott-Aldrich syndrome (WAS) should be also ruled out.
• Prenatal diagnosis is possible for families in which the disease-causing mutation has been identified

(Source: Congenital Amegakaryocytic Thrombocytopenia; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Congenital Amegakaryocytic Thrombocytopenia? 

The complications of Congenital Amegakaryocytic Thrombocytopenia may include:

• Bone marrow failure
• Heart abnormalities

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Congenital Amegakaryocytic Thrombocytopenia Treated?

• The management of Congenital Amegakaryocytic Thrombocytopenia is supportive, mainly consisting of multiple platelet transfusions
• At present, hematopoietic stem cell transplantation (HSCT) is the only curative therapy.

(Source: Congenital Amegakaryocytic Thrombocytopenia; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

How can Congenital Amegakaryocytic Thrombocytopenia be Prevented?

Currently, Congenital Amegakaryocytic Thrombocytopenia may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of Congenital Amegakaryocytic Thrombocytopenia? (Outcomes/Resolutions)

• Prognosis is poor and with supportive therapy, progression to full marrow failure (tri-linear marrow aplasia) occurs during the first years of life
• 30% of patients with Congenital Amegakaryocytic Thrombocytopenia die due to bleeding complications before the HSCT and 20% due to the HSCT

(Source: Congenital Amegakaryocytic Thrombocytopenia; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Additional and Relevant Useful Information for Congenital Amegakaryocytic Thrombocytopenia:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/