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Hematological problems in the neonate
Published in Prem Puri, Newborn Surgery, 2017
Andrea M. Malone, Owen P. Smith
Congenital amegakaryocytic thrombocytopenia (CAMT) is an extremely rare autosomal recessively inherited disorder of infancy and early childhood. Of all the IBMFS, it is the one most likely to present in the neonatal period. Affected newborns show no physical abnormalities. The thrombocytopenia is non-immune and usually severe, and pancytopenia can ensue. The condition results from a mutation in the c-MPL gene that encodes the thrombopoietin (TPO) receptor. Management is largely symptomatic with platelet transfusions and antifibrinolytics for patients with bleeding. Currently, the only curative option for CAMT is hematopoietic stem cell transplantation (HSCT).14
Familial Acute Myeloid Leukemia
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The above non-syndromic forms of familial AML differ in clinical presentation from well-known heritable and genetic disorders that are typically diagnosed in pediatric patients but may also be diagnosed in adults, and all of these disorders have the common feature of increased lifetime risk for developing AML. Due to space constraints, for these disorders, the reader is referred to related chapters in this book as well as excellent reviews elsewhere [8–13], from which Table 70.1 summarizes a few clinical and genetic features. These disorders include classical inherited bone marrow failure syndromes, which are a heterogeneous group of disorders often with associated clinical features including one or more somatic abnormalities, and caused by genetic aberrations in different pathways, including DNA repair (Fanconi anemia), ribosome biogenesis (Schwachman–Diamond syndrome, Diamond–Blackfan syndrome), and telomere maintenance (dyskeratosis congenita). Two additional inherited bone marrow failure disorders, severe congenital neutropenia and congenital amegakaryocytic thrombocytopenia, present in infancy, usually without somatic abnormalities, and both may progress to myelodysplasia and AML. In addition, Down syndrome (trisomy 21) increases the risk for developing AML and is included in the World Health Organization classification of AML [14,15]. Further, constitutional mismatch repair deficiency, a rare autosomal recessive disease characterized by homozygous germline mutations in DNA mismatch repair genes, MLH1, MSH2, MSH6, PMS2, and EPCAM and clinical features reminiscent of neurofibromatosis type 1, may very rarely present in pediatric patients with AML that comprises de novo and therapy-related forms [16,17], although the typical presentation for this disease is with non-Hodgkin lymphoid (and not myeloid) high grade hematologic malignancies, and brain and colonic tumors [18,19].
Clinical and molecular characteristics of acute myeloid leukemia with MPL mutation
Published in Hematology, 2022
Yu Chen, Jundan Xie, Zhen Shen, Jie Shi, Suning Chen, Gang Wang
The MPL was first reported in 1992. Thereafter, MPL mutations in congenital amegakaryocytic thrombocytopenia (CAMT) and MPN were discussed. However, these mutations are extremely rare in patients with AML. CAMT is a rare inherited bone marrow failure syndrome presenting as isolated thrombocytopenia at birth that progresses to pancytopenia due to the exhaustion of hematopoietic progenitors [8]. It is commonly caused by deleterious homozygous or compounds heterozygous mutations in MPL, which are often found in the extracellular domain. In our cases, all seven extracellular domain mutations were heterozygous, with VAFs of < 60%. However, there was no antecedent thrombocytopenia nor a significant family history. Hence, the likelihood of a pre-existing CAMT is not possible. W515R/L/S mutations are mainly found in ET and PMF in MPN [9], and patients with ET with MPL mutations have a higher risk of secondary myelofibrosis and transformation to acute leukemia. Three patients presented with hotspot mutations (W515R/L/S). Among them, case three was secondary to MDS and case five was treatment-related AML,and the other patient with no previous hematology disease.In patients with prior MPLW515L-mutant myeloproliferative neoplasm, leukemic transformation was accompanied by MPL-mutant leukemic blasts [10]. Since there was no previous NGS results in the 2 cases,the clonal evolution could not be completely assessed.
Cytokine control of megakaryopoiesis
Published in Growth Factors, 2018
Kira Behrens, Warren S. Alexander
Consistent with the key regulatory role of Tpo-Mpl signalling in megakaryopoiesis, mutations at the THPO and MPL loci are associated with thrombocytopenia, thrombocythemia and related diseases. Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare autosomal recessive bone-marrow failure syndrome that presents with reduced numbers of Mk and severe thrombocytopenia. In the majority of cases, the underlying molecular mechanism for the disorder is biallelic (homozygous or compound heterozygous) loss-of-function mutations at the MPL locus (Ballmaier et al., 2003; Ihara et al., 1999). Because Tpo signalling is vital for the maintenance of HSC, CAMT patients nearly always progress to aplastic anaemia (Ballmaier et al., 2003; King et al., 2005; Walne et al., 2012). Interestingly, the type of MPL mutation is predictive for the disease course. While nonsense MPL mutations, causing the complete loss of the receptor, induce the severe Type-I CAMT with chronically low platelet counts and an early onset of pancytopenia, missense MPL mutations that allow residual Mpl activity are associated with Type-II CAMT, a milder form of the disease in which thrombocytopenia is transiently ameliorated and pancytopenia delayed (Figure 2 C) (Ballmaier et al., 2003; Gandhi et al., 2005; Germeshausen et al., 2006).
A family case series of inherited thrombocytopenia
Published in Baylor University Medical Center Proceedings, 2023
Artur Borkowski, Jakub Gawryś, Gracjan Iwanek, Jarosław Dybko
In the conducted study, molecular assessment targeted genes related to predisposing forms of IT. In certain forms of IT, thrombocytopenia present at birth or in early childhood can evolve to bone marrow aplasia and pancytopenia.10 Since some probands presented low platelet count in infancy, molecular and cytogenetic analysis included mutations of MPL and MECOM, causative genes of congenital amegakaryocytic thrombocytopenia (CAMT) and MECOM-associated syndrome (MECOM-AS), respectively.10 While CAMT is an autosomal recessive disease, MECOM-AS presents an autosomal dominant inheritance pattern.10 Familial platelet disorder with propensity to acute myelogenous leukemia, caused by RUNX1 mutations, and ETV6-related thrombocytopenia have an autosomal dominant inheritance pattern and clinically present as mild to moderate thrombocytopenia with normal platelet size and morphology, what was reported in several probands in this study.2GATA1 mutations are found in almost all cases of transient myeloproliferative disorder and acute megakaryoblastic leukemia in children with DS, typically involving exon 2.11,12 Nearly 30% of newborns with DS are born with a GATA1 mutation.5 Since the prevalence of ITs predisposing to other diseases ranges from 45% to 50% of known forms of ITs, a complete blood count and peripheral blood smear examination once a year should be offered.2 According to Makris, a 3-week therapeutic trial of eltrombopag after diagnosis of IT is suggested to determine response to thrombopoietin receptor agonists.13