CAMT is an autosomal recessive disorder that presents at birth with severe thrombocytopenia. Mean platelet counts at diagnosis are 21,000/μl, and platelets are of normal size and morphology 1
. Importantly, phenotypic findings in CAMT are usually limited to those related to thrombocytopenia, such as cutaneous and intracranial hemorrhages. An increased incidence of psychomotor retardation has been described in patients with CAMT, although some neurologic abnormalities may be sequelae of intracranial bleeding 1
. Because no specific congenital malformations are characteristic of CAMT, consideration should be given to an alternative syndrome if such malformations are present.
Bone marrow evaluation in newborns with CAMT typically demonstrates normal overall cellularity with an isolated reduction or absence of megakaryocytes 1
, although in some cases marrows studied early in the course of the disease can have misleadingly minimal findings and serial marrows may be required to clarify the diagnosis (Fox et al., submitted and 2
). Although originally a clinical diagnosis, CAMT can now be molecularly defined by mutations involving the TPO receptor c-Mpl 3, 4
. Mutations have been identified throughout c-Mpl and include nonsense, missense and splicing mutations (Fox et al., unpublished data and 2, 4–11
), although in severely affected patients mutations are frequently located in exons 2 and 3, which encode the first cytokine receptor homology domain (). Some patients with CAMT have inherited two different mutations of c-Mpl, resulting in a compound heterozygous state, whereas in families with consanguinity the inheritance of homozygous mutations is more common. Clinically certified mutation analysis of c-Mpl can now be obtained at GeneDx (Gaithersburg, MD) and Prevention Genetics (Marshfield, Wisconsin).
Figure 1 Summary of reported c-Mpl mutations in CAMT. Amino acids are represented as single letters. The signal peptide (residues 1–25) is shown in dark gray, the extracellular domain of the receptor (residues 26–491) in black and the intracellular (more ...)
Another diagnostic evaluation that is useful in establishing the diagnosis of CAMT is determination of the plasma TPO level. In CAMT, plasma levels of TPO are high, consistent with severely reduced platelet production and absence of c-Mpl 3
. The relationship between TPO and thrombopoiesis reflects the normal metabolism of TPO, which is produced at a constant rate by the liver and removed from the circulation by receptor-mediated uptake and destruction 12–14
. c-Mpl receptors expressed on megakaryocytes and platelets are responsible for the majority of TPO uptake 15
. In CAMT, impaired expression of c-Mpl means that there is little if any receptor-mediated TPO destruction and therefore circulating levels of the cytokine increase to as much as 10-fold above those seen in normal controls. By comparison, in disorders such as immune thrombocytopenia where c-Mpl is normal and thrombocytopenia is caused by platelet destruction TPO levels are normal or only modestly elevated 16, 17
. Elevated TPO levels are not specific for CAMT and can be elevated in other conditions in which there is severely impaired production of megakaryocytes and platelets (for example, in acquired aplastic anemia); however, in the appropriate clinical setting a highly elevated TPO level supports a diagnosis of CAMT and justifies further confirmation by specific gene sequencing.
CAMT is a rare cause of thrombocytopenia in the newborn period; much more frequent etiologies include prenatal factors (such as pre-eclampsia, placental insufficiency and intrauterine growth retardation), anoxic insult, infection, or maternal transfer of platelet allo- or autoantibodies. The timing of onset, severity of thrombocytopenia, clinical history and maternal platelet counts are often helpful in identifying underlying factors contributing to neonatal thrombocytopenia 18
. Neonatal alloimmune thrombocytopenia (NAIT) is an especially important cause of severe thrombocytopenia that must be differentiated from CAMT. Like CAMT, NAIT typically presents as severe thrombocytopenia in an otherwise normal newborn whose mother’s platelets are normal. NAIT is more common than CAMT (1:1000-1:2000 live births 19, 20
), compared to less than 100 reported cases of CAMT. DNA-based platelet phenotyping can establish if there is incompatibility between maternal and paternal platelet antigens that would predispose to alloimmunization, and serologic assays using patient or maternal serum may detect platelet-specific alloantibodies 21–23
. Bone marrow aspiration is not usually required to diagnose NAIT but if performed typically shows normal to increased megakaryocytes. Following birth the maternally derived platelet alloantibody diminishes and after the first month of life the expectation is that platelet counts will improve. Even with antigen incompatibility consistent with the possibility of NAIT, if thrombocytopenia does not resolve after 3 months, alternative diagnoses such as CAMT should be explored (Fox et al., submitted).