ORPHA: 3319; DO: 0061005;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p34.2 | Amegakaryocytic thrombocytopenia, congenital, 1 | 604498 | Autosomal recessive | 3 | MPL | 159530 |
A number sign (#) is used with this entry because of evidence that congenital amegakaryocytic thrombocytopenia-1 (CAMT1) is caused by homozygous or compound heterozygous mutation in the myeloproliferative leukemia virus oncogene (MPL; 159530) on chromosome 1p34.
Congenital amegakaryocytic thrombocytopenia-1 (CAMT1) is an autosomal recessive disorder characterized by onset of thrombocytopenia and megakaryocytopenia in infancy or early childhood. The disorder is progressive and evolves to pancytopenia and bone marrow failure. Serum thrombopoietin is elevated. There is a favorable response to bone marrow transplantation (Muraoka et al., 1997; King et al., 2005).
Genetic Heterogeneity of Congenital Amegakaryocytic Thrombocytopenia
CAMT2 (620481) is caused by mutation in the THPO gene (600044) on chromosome 3q27.
Muraoka et al. (1997) found that a patient with CAMT had a defective response to thrombopoietin (TPO; 600044) in megakaryocyte-colony formation, decreased numbers of erythroid and myelocytic progenitors in clonal cultures, a lack of MPL mRNA in bone marrow mononuclear cells, and an elevated serum level of TPO. Ihara et al. (1999) provided a follow-up of the patient reported by Muraoka et al. (1997). She was a 10-year-old girl born to nonconsanguineous Japanese parents. She appeared to be healthy at birth; however, laboratory data showed an isolated thrombocytopenia in the peripheral blood and an absence of megakaryocytes in the bone marrow. The platelet count was 2,000 in the bone marrow. Magnetic resonance imaging (MRI) of the brain showed a hypoplastic cerebellar vermis with a communication between the fourth ventricle and the cisterna magna. Despite this malformation, the child exhibited normal neurologic development and normal physical and developmental growth. The karyotype of the lymphocytes was normal. In addition to thrombocytopenia, white blood cell and red blood cell counts gradually decreased with age. At the age of 6 years, the serum TPO level was significantly higher than that in healthy controls.
Ballmaier et al. (2001) analyzed 9 patients with congenital amegakaryocytic thrombocytopenia for defects in TPO production and reactivity. High levels of TPO were found in the sera of all patients; however, platelets and hematopoietic progenitor cells of patients with the disorder showed no reactivity to TPO, as measured by testing TPO-synergism to adenosine diphosphate in platelet activation or by megakaryocyte colony assays. Flow cytometry revealed absent surface expression of the TPO receptor MPL in 3 of 3 patients analyzed. Sequence analysis of the MPL gene in 8 of the patients revealed point mutations in all.
Ballmaier et al. (2001) stated that a retrospective comparison of clinical data from 18 patients with CAMT from different German clinics resulted in a division into 2 different groups. Group I patients (approximately 60%) presented with a more severe form of CAMT with an early development from isolated thrombocytopenia into pancytopenia. Group II patients demonstrated a transient increase of platelet counts during the first year of life and a later development of pancytopenia.
King et al. (2005) studied 20 children with CAMT, including 7 previously analyzed for TPO reactivity and MPL mutations by Ballmaier et al. (2001). Six (30%) of the 20 children died. Prognostic factors for survival were severity of thrombocytopenia and pancytopenia during the course of the disease; there was no correlation between outcome and initial platelet count.
Pemberton et al. (2006) reported a British boy with CAMT confirmed by genetic analysis. He presented with thrombocytopenia in infancy, developed neutropenia at age 1 year, and progressed to full pancytopenia by age 5 years. Bone marrow biopsy was hypoplastic with markedly decreased numbers of megakaryocytes and no dysplasia. He underwent a donor hematopoietic stem cell transplant and remained well with stable engraftment at 1-year follow-up.
Hematopoietic stem cell transplantation is curative for CAMT1, caused by mutation in the MPL gene. However, patients with CAMT2 (620481), caused by mutation in the THPO gene, have decreased or normal serum THPO levels and do not respond to bone marrow transplant, which may be fatal; these patients respond well to treatment with THPO receptor (MPL) agonists (Seo et al., 2017).
The transmission pattern of CAMT1 in the family reported by Muraoka et al. (1997) was consistent with autosomal recessive inheritance.
The considerable similarities between human CAMT and murine mpl deficiency prompted Ihara et al. (1999) to analyze the MPL gene in a patient with CAMT reported by Muraoka et al. (1997). MPL was not detected in her bone mononuclear cells by RT-PCR or by Northern blot analysis. By DNA studies, Ihara et al. (1999) detected compound heterozygosity for 2 mutations of the MPL gene: a gln186-to-ter substitution in exon 4 (159530.0001), and a single nucleotide deletion in exon 10 (159530.0002).
In a 2-year-old Italian boy with congenital amegakaryocytic thrombocytopenia, Tonelli et al. (2000) identified compound heterozygous missense mutations in the MPL gene (R257C, 159530.0003; P635L, 159530.0004).
In a patient with CAMT, van den Oudenrijn et al. (2000) identified compound heterozygous missense mutations in the MPL gene (R102P, 159530.0005; W491X, 159530.0006). In another patient with CAMT, they identified a homozygous splice site mutation (159530.0007).
In a patient with CAMT, Ballmaier et al. (2001) identified compound heterozygous missense mutations in the MPL gene: the previously identified R102P mutation and P275T (159530.0005).
King et al. (2005) found that patients with the more severe CAMT type I phenotype carried nonsense MPL mutations predicted to cause a complete loss of the TPO receptor, whereas those with the milder type II phenotype carried missense mutations in the MPL gene affecting the extracellular domain of the TPO receptor. King et al. (2005) suggested that the latter mutations likely result in proteins with residual function and a milder phenotype.
King et al. (2005) proposed a new classification of CAMT based on the course and outcome of the disease, as exemplified by 20 patients: CAMT type I (11 patients) was characterized by early onset of severe pancytopenia, decreased bone marrow activity, and very low platelet counts. CAMT type II (9 patients) was somewhat milder and characterized by transient increases of platelet counts up to nearly normal values during the first year of life and an onset of bone marrow failure at age 3 or later.
Animal studies showed that a deficiency of the Mpl gene results in amegakaryocytic thrombocytopenia, decreased numbers of hematopoietic progenitors, and increased concentrations of circulating TPO with no physical or developmental abnormalities. Gurney et al. (1994) found that Mpl-null mice had an 85% decrease in the number of platelets and megakaryocytes but had normal amounts of other hematopoietic cell types. These mice also had increased concentrations of circulating TPO. These results showed that MPL specifically regulates megakaryocytopoiesis and thrombopoiesis through activation by its ligand TPO.
Ballmaier, M., Germeshausen, M., Schulze, H., Cherkaoui, K., Lang, S., Gaudig, A., Krukemeier, S., Eilers, M., Straub, G., Welte, K. c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia. Blood 97: 139-146, 2001. [PubMed: 11133753] [Full Text: https://doi.org/10.1182/blood.v97.1.139]
Gurney, A. L., Carver-Moore, K., de Sauvage, F. J., Moore, M. W. Thrombocytopenia in c-mpl-deficient mice. Science 265: 1445-1447, 1994. [PubMed: 8073287] [Full Text: https://doi.org/10.1126/science.8073287]
Ihara, K., Ishii, E., Eguchi, M., Takada, H., Suminoe, A., Good, R. A., Hara, T. Identification of mutations in the c-mpl gene in congenital amegakaryocytic thrombocytopenia. Proc. Nat. Acad. Sci. 96: 3132-3136, 1999. [PubMed: 10077649] [Full Text: https://doi.org/10.1073/pnas.96.6.3132]
King, S., Germeshausen, M., Strauss, G., Welte, K., Ballmaier, M. Congenital amegakaryocytic thrombocytopenia: a retrospective clinical analysis of 20 patients. Brit. J. Haemat. 131: 636-644, 2005. [PubMed: 16351641] [Full Text: https://doi.org/10.1111/j.1365-2141.2005.05819.x]
Muraoka, K., Ishii, E., Tsuji, K., Yamamoto, S., Yamaguchi, H., Hara, T., Koga, H., Nakahata, T., Miyazaki, S. Defective response to thrombopoietin and impaired expression of c-mpl mRNA of bone marrow cells in congenital amegakaryocytic thrombocytopenia. Brit. J. Haemat. 96: 287-292, 1997. [PubMed: 9029014] [Full Text: https://doi.org/10.1046/j.1365-2141.1997.d01-2028.x]
Pemberton, L. C., Levett, D., Skinner, R., Hall, A. G., Hanley, J. P. Novel mutations in a child with congenital amegakaryocytic thrombocytopenia. (Letter) Brit. J. Haemat. 135: 742-746, 2006. [PubMed: 17054430] [Full Text: https://doi.org/10.1111/j.1365-2141.2006.06358.x]
Seo, A., Ben-Harosh, M., Sirin, M., Stein, J., Dgany, O., Kaplelushnik, J., Hoenig, M., Pannicke, U., Lorenz, M., Schwarz, K., Stockklausner, C., Walsh, T., and 11 others. Bone marrow failure unresponsive to bone marrow transplant is caused by mutations in thrombopoietin. Blood 130: 875-880, 2017. [PubMed: 28559357] [Full Text: https://doi.org/10.1182/blood-2017-02-768036]
Tonelli, R., Scardovi, A. L., Pession, A., Strippoli, P., Bonsi, L., Vitale, L., Prete, A., Locatelli, F., Bagnara, G. P., Paolucci, G. Compound heterozygosity for two different amino-acid substitution mutations in the thrombopoietin receptor (c-mpl gene) in congenital amegakaryocytic thrombocytopenia (CAMT). Hum. Genet. 107: 225-233, 2000. [PubMed: 11071383] [Full Text: https://doi.org/10.1007/s004390000357]
van den Oudenrijn, S., Bruin, M., Folman, C. C., Peters, M., Faulkner, L. B., de Haas, M., van dem Borne, A. E. G. K. Mutations in the thrombopoietin receptor, Mpl, in children with congenital amegakaryocytic thrombocytopenia. Brit. J. Haemat. 110: 441-448, 2000. [PubMed: 10971406] [Full Text: https://doi.org/10.1046/j.1365-2141.2000.02175.x]