Congenital amegakaryocytic thrombocytopenia: The diagnostic importance of combining pathology with molecular genetics

Abstract

Congenital Amegakaryocytic Thrombocytopenia (CAMT) is a rare bone marrow failure syndrome that presents with isolated thrombocytopenia within the first year of life. Classic diagnostic bone marrow findings reveal absent or significantly decreased megakaryocytes with otherwise normal marrow cellularity. We present a newborn with thrombocytopenia whose initial bone marrow aspirate showed an appropriate number of megakaryocytes. CAMT was subsequently diagnosed after molecular testing demonstrated a mutation in the thrombopoietin receptor. The presence of a normal number of megakaryocytes on an initial bone marrow aspirate should not exclude CAMT from the differential diagnosis of thrombocytopenia within the first year of life.

Congenital amegakaryocytic thrombocytopenia with severe neurological findings

“…NAIT is more common than CAMT (1 : 1000-1 : 2000 live births [7,8] compared with less than 100 reported cases of CAMT). In a child suspected to have NAIT, if thrombocytopenia does not resolve after 3 months, alternative diagnoses such as CAMT should be explored [9]. NAIT was not considered because of the ongoing thrombocytopenia after 6 months in our patient.…”

The thrombopoietin receptor P106L mutation functionally separates receptor signaling activity from thrombopoietin homeostasis

“…9 The c-Mpl P106L show constitutive activity that can be further stimulated by THPO The P106L mutation affects an extracellular domain of the c-Mpl receptor, which is a hotspot for both gain-of-function and loss-offunction mutations. 9,[25][26][27][28] Thus, this domain appears to be of critical physiological importance, which led us to perform detailed functional studies of the P106L gain-of-function and of mutations that have been reported to cause loss of receptor function but are located in close proximity. [25][26][27][28] To this end, we designed c-Mpl constructs coding for the WT receptor, the loss-of-function mutations R102P and F104S, and the P106L gain-of-function mutation, and we stably expressed these genes in cytokine-dependent Ba/F3 cells.…”

“…[25][26][27][28] THPO binding to CRM1 has been shown to initiate signal transduction. 29,30 Deletion of this critical domain activates c-Mpl, suggesting an inhibitory function that can be relieved by ligand binding.…”

“…[22][23][24] Interestingly, c-Mpl mutations that result in loss of receptor function and have been located in the immediate vicinity of the activating c-Mpl P106L mutation in thrombocytopenia (R102P, F104S), which indicates that amino acids 102 to 106 within the first cytokine receptor homology module are critical for activity. [25][26][27][28] THPO binding to CRM1 has been shown to initiate signal transduction. 29,30 Deletion of this critical domain activates c-Mpl, suggesting an inhibitory function that can be relieved by ligand binding.…”

Congenital Amegakaryocytic Thrombocytopenia and Thrombocytopenia with Absent Radii

“…Bone marrow evaluation in newborns with CAMT typically demonstrates normal overall cellularity with an isolated reduction or absence of megakaryocytes 1, although in some cases marrows studied early in the course of the disease can have misleadingly minimal findings and serial marrows may be required to clarify the diagnosis (Fox et al, submitted and 2). Although originally a clinical diagnosis, CAMT can now be molecularly defined by mutations involving the TPO receptor c-Mpl 3, 4.…”