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Heterogeneity in CAMT-MPL
in the first year of life in CAMT II patients.4,14,15
The data from the present study allow for additional con-
clusions of clinical relevance:
- the course of the disease is mainly determined by the
type of mutation. The same MPL mutations lead to high similarities in the hematological courses of patients, even if they are from different families or different ethnical back- ground (e.g., mild course in patients with c.391+5G>C).
- the time course of pancytopenia development for patients with same MPL mutations is more variable than the course of thrombocytopenia. This could be caused by accelerated exhaustion of hematopoietic progenitors due to frequent bleedings or infections in some patients.54
- all patients with mutations leading to a complete loss of function (CAMT I) had a similar course with constantly severe thrombocytopenia. Platelet counts at birth and in the further course never exceed 50. and all of them showed a transition to pancytopenia. A complete MPL deficiency is probable in patients showing signs of aplastic anemia in the first months of life.
- missense mutations predicted to allow a residual func- tion of the MPL receptor lead to a more variable course of CAMT. The most severe phenotypes, comparable to CAMT I (severe thrombocytopenia, early development of aplasia), were observed in patients with mutations p.Leu169His and p.Trp154Arg. Milder phenotypes (late detection of thrombocytopenia and delayed development of aplasia) were observed in patients with mutations p.Asp295Tyr and p.Pro394Ser and missense mutations affecting the intracytoplasmic domain.
- milder phenotypes with late development of aplastic anemia (respectively none during the period of record) have also been observed in patients with splice site mutations allowing for a residual normal splicing,26,41 namely c.391+5G>C and c.212+5G>A.
- patients with germ line MPL mutations and a late onset form of amegakaryocytic thrombocytopenia or aplastic anemia (e.g., patients CAMT058, CAMT101, CAMT102 with moderate thrombocytopenia detected at the age of >2 years) should be also regarded as CAMT-MPL. This includes the patients previously described as familial aplas- tic anemia.55
- there may exist a small subgroup of CAMT II patients without development of pancytopenia. For patients with new mutations predicted to have minor impact on function or with mutations previously detected in patients with a mild course (namely c.391+5G>C, c.212+5G>A, or p.Pro275Thr) it might be appropriate to wait for first signs of bone marrow failure before proceeding to HSCT, espe- cially if no appropriate family donor is available.
- type and localization of MPL mutations are not predic- tive for pre- and perinatal intracranial hemorrhages. There are no differences in the frequency and severity of these
bleedings between patient groups CAMT I and CAMT II. The existence of a deleterious MPL mutation is a major risk factor for the occurrence of intracranial bleedings.
- structural and clinical non hematologic abnormalities in CAMT-MPL are not correlated with specific mutations.
- there is a small group of patients who present clinically as CAMT, but in whom a deleterious MPL mutation can only be detected in one allele. Possible explanations for the seeming inconsistency between genotype and phenotype include somatic mosaicism, deletions or changes in regula- tory sequences that prevent the translation of a functional protein, or - rather unlikely especially in family cases - acci- dental coincidence.
- a further consideration for clinical presentation of CAMT-MPL is whether, in addition to existing MPL muta- tions, mutations or functional single nucleotide polymor- phisms in other genes or epigenetic differences are involved in the observed phenotypic heterogeneity of CAMT-MPL
Our analysis of a large cohort of CAMT-MPL patients demonstrates a higher variability of clinical courses than described so far. The diagnosis CAMT-MPL has to be con- sidered even for those patients who are inconspicuous in the first months of life or show somatic anomalies typical for other BMFS. Since almost all CAMT-MPL patients inevitably develop a fatal bone marrow failure that requires treatment with HSCT, all children with unclear forms of hypomegakaryocytic thrombocytopenia should be tested for MPL mutations. If molecular confirmation of CAMT is not possible, at least those IBMFS should be excluded for which HSCT is not an option (e.g., thrombopoietin produc- tion defect) or which need another transplantation regimen (e.g., Fanconi anemia, Diamond Blackfan anemia).
Disclosures
No conflicts of interest to disclose
Contributions
MG and MB designed and performed research, analyzed data, and wrote the manuscript.
Acknowledgments
The authors would like to thank all patients and their families who participated in this study. We are also grateful to the physi- cians who provided us with material and data from their patients. We would like to acknowledge the excellent technical assistance of Yvonne Peter and Christina Struckmann.
Funding
This work was supported in part by grants from the Federal Ministry of Education and Research (German Network on Congenital Bone Marrow Failure Syndromes) and by the transna-
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