title: A new congenital dysmegakaryopoietic thrombocytopenia (Paris-Trousseau) associated with giant platelet alpha-granules and chromosome 11 deletion at 11q23.
abstract: This study characterizes a new congenital thrombocytopenia with mild hemorrhagic tendency occurring in a woman and her child with the following features. We found a deletion of the distal part of one chromosome 11 [del(11)q23.3-->qter] that was detected by cytogenetic analysis and confirmed by chromosome painting in the two patients and also an increased number of bone marrow megakaryocytes (MKs), including numerous micromegakaryocytes (mMKs) associated with a normal platelet life span. A normal number of MK colonies in culture was observed with one third of them containing a few large MKs; however, these were always associated with mMKs identified by immunologic staining. A massive cell lysis was observed at the end of the maturation. Fifteen percent of the platelets in the peripheral blood showed giant alpha-granules resulting from the fusion of alpha-granules. These giant granules, which appeared in red on giemsa stain, had a mean diameter of 1.5 microns and showed all markers (detected at electron microscopy by immunogold method) of matrix and alpha-granule membrane, ie, von Willebrand factor, fibrinogen, CD41, CD62P (P-selectin); however, they differed from lysosomes because acid phosphatases were not present. These giant alpha-granules were unable to release their contents after stimulation by thrombin, in contrast to platelets with normal morphology. Abnormalities in bone marrow MK maturation that were detected at the electron microscopic level and that led to lysis of numerous MKs were responsible for thrombocytopenia and were similar in both patients. MK abnormalities are probably the consequence of the chromosome aberration. ETS 1 and FLI, two proto-oncogenes that appear to be essential with GATA1 for the normal expression of MK-specific genes, map to 11q23-q24 and are, thus, deleted in this thrombocytopenia. In conclusion, the association of all these abnormalities constitutes a new familial platelet disorder and may present a valuable model for exploring the role of some genes involved in the regulation of thrombopoiesis.
authors.affiliation: INSERM U.91, Hôpital Henri Mondor, Créteil, France.
authors.forename: J
authors.initials: J
authors.lastname: Breton-Gorius
authors.forename: R
authors.initials: R
authors.lastname: Favier
authors.forename: J
authors.initials: J
authors.lastname: Guichard
authors.forename: D
authors.initials: D
authors.lastname: Cherif
authors.forename: R
authors.initials: R
authors.lastname: Berger
authors.forename: N
authors.initials: N
authors.lastname: Debili
authors.forename: W
authors.initials: W
authors.lastname: Vainchenker
authors.forename: L
authors.initials: L
authors.lastname: Douay
mesh_terms: D000328:Adult; D001792:Blood Platelets / Q000473:pathology*; D001853:Bone Marrow / Q000473:pathology; D016923:Cell Death; D002478:Cells, Cultured; D002869:Chromosome Aberrations / Q000235:genetics; D002872:Chromosome Deletion; D025063:Chromosome Disorders; D002880:Chromosomes, Human, Pair 11 / Q000648:ultrastructure*; D003594:Cytoplasmic Granules / Q000648:ultrastructure*; D005145:Face / Q000002:abnormalities; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D015539:Platelet Activation; D013921:Thrombocytopenia / Q000151:congenital* / Q000235:genetics / Q000473:pathology