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Platelet Biology & its Disorders
CAMT-MPL: congenital amegakaryocytic thrombocytopenia caused by MPL mutations - heterogeneity of a monogenic disorder -
a comprehensive analysis of 56 patients
Manuela Germeshausen and Matthias Ballmaier
Central Research Facility Cell Sorting, Hannover Medical School, Hannover, Germany
ABSTRACT
Congenital amegakaryocytic thrombocytopenia caused by deleteri- ous homozygous or compound heterozygous mutations in MPL (CAMT-MPL) is a rare inherited bone marrow failure syndrome presenting as an isolated thrombocytopenia at birth progressing to pan- cytopenia due to exhaustion of hematopoietic progenitors. The analysis of samples and clinical data from a large cohort of 56 patients with CAMT-MPL resulted in a detailed description of the clinical picture and reliable genotype-phenotype correlations for this rare disease. We extend- ed the spectrum of CAMT causing MPL mutations regarding number (17 novel mutations) and impact. Clinical courses showed great variability with respect to the severity of thrombocytopenia, the development of pancytopenia and the consequences from bleedings. The most severe clinical problems were (i) intracranial bleedings pre- and perinatally and the resulting long-term consequences, and (ii) the development of aplastic anemia in the later course of the disease. An important and new finding was that thrombocytopenia was not detected at birth in a quarter of the patients. The rate of non-hematological abnormalities in CAMT-MPL was higher than described so far. Most of the anomalies were related to the head region (brain anomalies, ocular and orbital anomalies) and con- sequences of intracranial bleedings. The present study demonstrates a higher variability of clinical courses than described so far and has impor- tant implications on diagnosis and therapy. The diagnosis CAMT-MPL has to be considered even for those patients who are inconspicuous in the first months of life or show somatic anomalies typical for other inherited bone marrow failure syndromes.
Introduction
Congenital amegakaryocytic thrombocytopenia (CAMT, MIM #604498) is a rare inherited bone marrow failure syndrome (IBMFS) which usually presents as severe thrombocytopenia at birth without specific characteristics and progresses to aplas- tic anemia during the first years of life.1,2 Deleterious mutations in MPL coding for the thrombopoietin receptor have first been identified as single molecular cause of CAMT,3,4 but the disease is now regarded to be genetically heterogeneous.5 Indeed, mutations in the gene for thrombopoietin (THPO) have been recently described in some of these patients.6-8 Furthermore, newborns with other IBMFS like Dyskeratosis congenita, Fanconi anemia, MECOM associated syndrome or microdeletion syndromes can present phenotypically as CAMT since pathogno- monic signs of these syndromes might be not yet apparent.9-12 In the following we use the term CAMT-MPL for the IBMFS caused by biallelic mutations in MPL.
Previous descriptions of CAMT-MPL are based on single case reports or small case series, not allowing for a comprehensive evaluation of the phenotypic spec- trum of the disease.1,2,13 Over the last 20 years we analyzed samples and clinical data from patients suspicious for inherited thrombocytopenia and could identify 56 patients with CAMT-MPL. The aims of our analysis of clinical, genetic and lab- oratory data are (i) a detailed description of the clinical picture of CAMT-MPL, (ii) the establishment of genotype-phenotype correlations allowing for the prediction
Ferrata Storti Foundation
Haematologica 2021 Volume 106(9):2439-2448
Correspondence:
MANUELA GERMESHAUSEN
germeshausen.manuela@mh-hannover.de
MATTHIAS BALLMAIER
ballmaier.matthias@mh-hannover.de
Received: May s4, 2020. Accepted: July 17, 2020. Pre-published: July 23, 2020.
https://doi.org/10.3324/haematol.2020.257972 ©2021 Ferrata Storti Foundation
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