Congenital amegakaryocytic thrombocytopenia

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare, autosomal recessive inherited bone marrow failure syndrome. It typically manifests in infancy as isolated severe thrombocytopenia caused by a marked reduction or complete absence of bone marrow megakaryocytes, initially presenting with preservation of the granulopoietic and erythroid lineages.

Pathophysiology and Genetics

The primary defect in CAMT is directly related to pathogenic variants in the MPL gene, which encodes the stem cell receptor for thrombopoietin (THPO). THPO is a critical growth factor that promotes hematopoietic stem cell (HSC) survival and stimulates the proliferation and maturation of megakaryocytes. Due to the defective receptor, biologically active plasma THPO levels are consistently elevated in all patients with CAMT. The disorder can be subdivided based on the type of genetic mutation, which predicts the disease course:

• CAMT Type I: This severe form is caused by nonsense mutations that result in a complete loss of function of the THPO receptor. Patients present with persistently low platelet counts from early infancy and experience a rapid progression to pancytopenia and aplastic anemia. The evolution into aplastic anemia is explained by the impaired survival of HSCs, as THPO normally exerts antiapoptotic and cell-survival effects on these stem cells.
• CAMT Type II: This form is associated with missense mutations, which allow for some residual receptor function. These patients tend to have a milder disease course, a later presentation, and may show a partial, transient increase in platelet counts during their first year of life, along with a delayed onset of pancytopenia.

Additionally, a small proportion of patients presenting with a clinical picture identical to CAMT do not have MPL variants but instead possess homozygous pathogenic variants in the THPO gene.

Clinical Manifestations

The onset of symptoms typically occurs between birth and the first year of life. Newborns frequently present within the first few days or weeks with petechiae, purpura, bruising, or overt bleeding. A major life-threatening complication is intracranial hemorrhage, which affects approximately 25% of patients (occurring 13% in utero, 4% at birth, and 7% within the first four weeks of life).

While most patients have normal physical and imaging features, about 10–20% of cases are accompanied by physical anomalies. The most common are neurologic abnormalities, including prominent developmental delay and cerebral or cerebellar atrophy. Congenital heart defects (such as atrial and ventricular septal defects, patent ductus arteriosus, tetralogy of Fallot, and coarctation of the aorta) are rare but possible, as are kidney malformations, eye anomalies, abnormal hips or feet, microcephaly, and cleft or high-arched palates.

Laboratory Findings

At presentation, severe thrombocytopenia is the major laboratory finding, typically accompanied initially by normal hemoglobin levels and normal white blood cell (WBC) counts. Red blood cells may be macrocytic, and fetal hemoglobin (HbF) may be elevated. Initial bone marrow aspirates and biopsies reveal normal overall cellularity but a marked reduction or total absence of megakaryocytes.

Despite the initial single-lineage defect, most patients progress to develop full pancytopenia between 6 months and 2 years of age. As aplastic anemia develops, bone marrow cellularity decreases, leading to fatty replacement and a symmetric reduction of both erythropoietic and granulopoietic cell lines.

Diagnosis and Differential Diagnosis

A bone marrow aspirate and biopsy showing deficient megakaryocytes alongside persistent thrombocytopenia strongly suggest the diagnosis of CAMT, which is then definitively confirmed by genetic analysis. CAMT must be carefully distinguished from other causes of inherited neonatal thrombocytopenia:

• Thrombocytopenia-Absent Radius (TAR) syndrome: Unlike CAMT, TAR syndrome is characterized by the bilateral absence of the radius bones.
• Dyskeratosis Congenita (DC): DC features extremely short telomere lengths (below the first percentile for age) and characteristic mucocutaneous and immunologic findings that are absent in CAMT.
• Fanconi Anemia (FA): CAMT lymphocytes do not exhibit the increased chromosomal breakage when exposed to clastogens (like diepoxybutane) that is the hallmark of FA.

Complications and Cancer Predisposition

Patients with CAMT are predisposed to malignant transformation. The disease can evolve from aplastic anemia into myelodysplastic syndrome (MDS)—often associated with cytogenetic abnormalities like monosomy 7 or trisomy 8—and subsequently into acute myeloid leukemia (AML).

Treatment and Prognosis

Without therapeutic intervention to restore bone marrow function, the mortality rate for patients with MPL nonsense mutations approaches 100% due to severe bleeding, complications of aplastic anemia, or leukemic transformation. Patients with missense mutations experience a milder course but remain at high risk for serious complications.

• Hematopoietic Stem Cell Transplantation (HSCT): Allogeneic HSCT is the only curative option for CAMT. The majority of patients who undergo HSCT are successfully cured, particularly if the procedure is performed using an HLA-matched sibling donor.
• Supportive Transfusions: Prior to HSCT, patients should receive careful platelet transfusions. Transfusions should be guided by clinical bleeding symptoms rather than absolute platelet counts, using single-donor, leuko-reduced, irradiated, and CMV-safe blood products to minimize the risk of alloimmunization.
• Medical Therapy: Thrombomimetic agents (such as eltrombopag or romiplostim) may be considered for some patients with MPL missense mutations (CAMT type II), though their use requires caution and further study due to concerns that they may promote marrow fibrosis or increase the risk of MDS and leukemia. Conversely, patients with THPO mutations have demonstrated good and sustained responses to romiplostim, and there have been no reports of progression to acute leukemia or MDS in this specific subgroup thus far.