Inherited thrombocytopenias: from genes to therapy.
OBJECTIVE
Inherited thrombocytopenias are a heterogeneous group of rare diseases characterized by a reduced number of blood platelets. Some of these diseases are exclusive to megakaryocytes and platelets, while in others the pathology extends to other cell types. Although the defective genes, coding for membrane glyoproteins, cytoskeleton components and intracellular signaling pathways, as well as transcription factors, have been identified in most cases, the pathophysiology of these disorders is often unknown. This review describes recent contributions to clinical and diagnostic aspects, biology and treatments of familial thrombocytopenias.


METHODS
The information presented here derives from literature and the experience of the authors. The most relevant studies are critically analyzed and discussed.


BACKGROUND
The clinical and laboratory features of most of the inherited thrombocytopenias have been reviewed. The different forms have been classified into 3 groups depending on platelet volume. Although this criterion is not completely satisfactory, it is one of the most useful in diagnostic algorithms. We report on recent advances in Wiskott-Aldrich and Bernard-Soulier syndromes, as well as in MYH9-related diseases, a new nosological entity that groups old distinct forms known as May-Hegglin anomaly, Sebastian, Fetchner, and Epstein syndromes. Other, less frequent forms are also discussed, including non-syndromic forms of mild thrombocytopenia that are genetically heterogeneous.


CONCLUSIONS
In the past, inherited thrombocytopenias were considered exceedingly rare and the number of well-defined forms was very small. In the last few years, the widespread diffusion of electronic cell counters has allowed these conditions to be detected more frequently and several new entities have been identified through the co-ordinated efforts of physicians, biologists and geneticists. The pathogenesis of many new and old forms is being unraveled, thus providing insights on the molecular basis of platelet production and function. This knowledge will be a valuable resource for clinicians in the diagnostic approaches to such disorders.
Balduini
Carlo L
CL
Medicina Interna, IRCCS San Matteo, Piazzale Golgi, 27100 Pavia, Italy. c.balduini@smatteo.pv.it
Iolascon
Achille
A
Savoia
Anna
A
D000015:Abnormalities, Multiple / Q000235:genetics; D000208:Acute Disease; D001606:Bernard-Soulier Syndrome / Q000235:genetics; D001792:Blood Platelets / Q000648:ultrastructure; D048429:Cell Size; D003937:Diagnosis, Differential; D015316:Genetic Therapy; D016298:Hematopoietic Cell Growth Factors / Q000172:deficiency / Q000235:genetics; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics; D008533:Megakaryocytes / Q000473:pathology; D020409:Molecular Motor Proteins; D018995:Myosin Heavy Chains / Q000172:deficiency / Q000235:genetics; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics; D010980:Platelet Membrane Glycoproteins / Q000235:genetics; D011884:Radius / Q000002:abnormalities; D033581:Stem Cell Transplantation; D013577:Syndrome; D013921:Thrombocytopenia / Q000145:classification / Q000235:genetics* / Q000628:therapy; D014457:Ulna / Q000002:abnormalities; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics; D014960:X Chromosome / Q000235:genetics
D016298:Hematopoietic Cell Growth Factors; C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D010980:Platelet Membrane Glycoproteins; D018995:Myosin Heavy Chains