Congenital amegakaryocytic thrombocytopenia: clinical and biological consequences of five novel mutations.
OBJECTIVE
Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare, autosomal recessive disorder induced by mutations of the gene coding for thrombopoietin (TPO) receptor (c-MPL). Patients initially present with isolated thrombocytopenia that subsequently progresses into pancytopenia. Although the mechanisms leading to aplasia are unknown, the age of onset has been reported to depend on the severity of the c-MPL functional defect. To improve our knowledge in this field, we studied clinical and biological features of five new patients.


METHODS
We diagnosed five CAMT patients, identified c-MPL mutations, including five novel alterations and investigated relationships between mutations and their clinical-biological consequences.


RESULTS
In all cases, platelet c-MPL and bone marrow colonies were reduced, while serum TPO levels were elevated. We also documented that the percentage of bone marrow cells expressing tumor necrosis factor-a and interferon-g was increased during pancytopenia as compared to in controls, suggesting that, as in other bone marrow failure diseases, these inhibitory cytokines contributed to the pancytopenia. Contrary to previously published data, we found no evidence of correlations between different types of mutations and the clinical course.


CONCLUSIONS
These results suggest that therapies, such as hematopoietic stem cell transplantation, which are potentially curative although associated with a risk of treatment-related mortality, should not be postponed even in those CAMT patients whose c-MPL mutations might predict residual activity of the TPO receptor.
Savoia
Anna
A
Medical Genetics, Department of Reproductive and Developmental Science, IRCCS Burlo Garofolo Children's Hospital, University of Trieste, Italy.
Dufour
Carlo
C
Locatelli
Franco
F
Noris
Patrizia
P
Ambaglio
Chiara
C
Rosti
Vittorio
V
Zecca
Marco
M
Ferrari
Simona
S
di Bari
Filomena
F
Corcione
Anna
A
Di Stazio
Mariateresa
M
Seri
Marco
M
Balduini
Carlo L
CL
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001792:Blood Platelets / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008533:Megakaryocytes / Q000473:pathology*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D053628:Receptors, Thrombopoietin / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D013921:Thrombocytopenia / Q000151:congenital* / Q000235:genetics* / Q000473:pathology; D013926:Thrombopoietin / Q000235:genetics
D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; D013926:Thrombopoietin