Algorithm for diagnosis of familial thrombocytopenia. Platelet size, best determined by review of the peripheral smear, is a readily available measurement and forms the basis of the initial assessment. Small platelets are characteristic of mutations in WASp (Wiskott Aldrich Syndrome protein), located on the X chromosome. Large platelet disorders include BSS (Bernard Soulier syndrome), an autosomal recessive disorder with low to absent expression of platelet GPIb/IX complex; MYH9-related disorder, an autosomal dominant disorder with granulocyte inclusions and renal or hearing impairment; von Willebrand disease IIB, and mutation of GPIb, in which activating mutations in vW factor or platelet GPIb result in loss of high molecular weight vW factor multimers and enhanced platelet aggregation in response to low dose ristocetin; congenital thrombotic thrombocytopenic purpura (TTP) a recessive disorder with ultra-large vW factor multimers because of deficiency of ADAMTS13; GATA1 and ABCG5 or ABCG8 mutations, in which red cells are typically abnormal; and Gray platelet syndrome in which α granules are deficient. Normal-sized platelets are characteristic of congenital amegakaryocytic thrombocytopenia (CAMT), a recessive disorder that is associated with extremely high plasma thrombopoietin levels because of the absence of receptor mediated uptake; thrombocytopenia with absent radii (TAR) and amegakaryocytic thrombocytopenia with radioulnarsynostosis (ATRUS), which have characteristic skeletal malformations; Runx1 mutations, which result in autosomal dominant thrombocytopenia with predisposition to myeloid leukemias; Paris Trousseau syndrome, characterized by congenital heart defects and deletions of chromosome 11q23; autosomal dominant cytochrome C mutation; and the recently described mutations in the 5′UTR of ANKRD26 discussed here.