Congenital amegakaryocytic thrombocytopenia and thrombocytopenia with absent radii

Abstract

Thrombocytopenia is a relatively common clinical problem in hospitalized neonates, and it is critical to distinguish infants who have rare congenital thrombocytopenias from those who have acquired disorders. Two well-described inherited thrombocytopenia syndromes that present in the newborn period are congenital amegakaryocytic thrombocytopenia (CAMT) and thrombocytopenia with absent radii (TAR). Although both are characterized by severe (< 50,000/microL) thrombocytopenia at birth, the molecular mechanisms underlying these disorders and their clinical presentations and courses are distinct. CAMT is an autosomal recessive disorder caused by mutations in the thrombopoietin (TPO) receptor c-Mpl. TAR is a syndrome of variable inheritance and unclear genetic etiology consisting of thrombocytopenia in association with bilateral absent radii and frequently additional congenital abnormalities. This article summarizes the current understanding of the pathophysiology and clinical course of CAMT and TAR.

Figure 1

Summary of reported c-Mpl mutations in CAMT. Amino acids are represented as single letters. The signal peptide (residues 1–25) is shown in dark gray, the extracellular domain of the receptor (residues 26–491) in black and the intracellular domain of the receptor (residues 492–635) in light gray. The WSXW motifs and Box 1 are noted with open boxes. Identified mutations are highlighted and the resulting changes are listed below. Changes resulting in stop codons (X) and frameshifts (fs) are highlighted with black whereas substitutions are highlighted in gray. Arrows indicate the positions of splicing mutations.