IDIM   12530
INSTITUTO DE INVESTIGACIONES MEDICAS
Unidad Ejecutora - UE
artículos
Título:
ANKRD26-related thrombocytopenia and myeloid malignancies.
Autor/es:
NORIS P; FAVIER R; ALESSI MC; GEDDIS A; KUNISHIMA S; HELLER PG; GIORDANO P; NIEDERHOFFER K; BUSSEL J; PODDA G; VIANELLI N; KERSSERBOOM R; PECCI A; GNAN C; MARCONI C; AUVRIGNON A; COHEN W; YU G; IUCHI A; MILLER IMAHIYEROBO A; BOEHLEN F; GHALLOUSSI D; DE ROCCO D; MAGINI P; CIVASCHI E; BIINO G; SERI M; SAVOIA A; BALDUINI C
Revista:
BLOOD, THE JOURNAL OF THE AMERICAN SOCIETY OF HEMATOLOGY - ONLINE
Editorial:
American Society of Hematology
Referencias:
Año: 2013 vol. 122 p. 1987 - 1989
ISSN:
1528-0020
Resumen:
Background: It has been recently shown that mutations in the 5?UTR
of ANKRD26 result in an autosomal dominant form
of thrombocytopenia with normal size
platelets that has been named ANKRD26-Related Thrombocytopenia (ANKRD26-
RT) ( Am J Hum Genet 2011;88:115-20).
Gene overexpression seems to be the consequence of mutations. It has been
suggested that ANKRD26-RT is one
of the less rare forms of inherited thrombocytopenias in that it was identified
in 21 of
210 families with genetically transmitted
low platelet counts (Blood 2011;117:6673-80). Analysis of 78 patients revealed
that thrombocytopenia and bleeding
tendency were usually mild or moderate, and bone marrow examination suggested
that thrombocytopenia was derived from
dysmegakaryopoiesis. Unexplained high values of hemoglobin and leukocytes
were observed in some cases. The most
important clinical remark of ANKRD26-RT was the association with acute
leukemia, which affected 6% of patients.
Aims: The purpose of this study was to confirm the clinical and laboratory
characteristics of ANKRD26-RT that have been
identified in the first case series of
patients. In particular, we wanted to confirm that the disease increases the
risk of
hematological malignancies. Moreover, we
wanted to ascertain whether the 5 'UTR of ANKRD26 is mutated in de
novo
acute leukemias.
Methods: We searched for mutations in the 5?UTR of ANKRD26 in patients
with inherited thrombocytopenias who had
remained without a definite diagnosis at
the end of the diagnostic procedure. The search for mutations in the 5?UTR of
ANKRD26 was also performed in 254 subjects with
acute leukemia.
Results: We identified 11 heterozygous single nucleotide substitutions and 1
small deletion in the 5?UTR of ANKRD26 in
65 patients from 21 pedigrees with
inherited thrombocytopenia. Four of these mutations (c.-116C>G,
c.-126T>C, c.-
127delAT, c.-128G>C) had not been
detected previously. Bleeding tendency was mild (most patients with grade 1 or
2 of
the WHO bleeding scale), platelet count
was moderately reduced (mean value/SD: 51/29 x109/L) and mean platelet
volume was usually normal (mean value/SD:
9/2 fL). Hemoglobin and leukocyte levels higher than normal were observed
in 5 and 13 cases, respectively.
Considering also 27 affected family members who died before our study, the
extended
series of 92 patients includes 6 subjects
with AL, 3 with myelodysplastic syndrome (MDS) and 2 with chronic
myelogenous leukemia (CML).
Mutation screening in patients with de
novo acute leukemias identified mutations in the 5?UTR of ANKRD26 in
one
subject. However, medical history
revealed that he was thrombocytopenic before developing leukemia and that other
family members were known to be affected
by ANKRD26-RT.
Summary / Conclusion: Our study brings the number of families with ANKRD26-RD
described in the literature to 42 and
makes this form of inherited
thrombocytopenia one of the most frequently reported. Analysis of this new case
series
confirmed that the typical picture of ANKRD26-RT
is that of an autosomal dominant disorder characterized by moderate
thrombocytopenia with normal sized
platelets and mild bleeding diathesis. It also confirmed that mutations in 5?UTR
of
ANKRD26 predispose to hematological malignancies,
in that 11 of 92 affected subjects developed AL, MDS or CML.
However, our study excluded that these mutations are
frequently involved in de novo AL.