ACUTE PRE-B LYMPHOBLASTIC LEUKEMIA
AND CONGENITAL ANOMALIES IN A CHILD
WITH A DE NOVO 22q11.1q11.22 DUPLICATION
Vaisvilas M, Dirse V, Aleksiuniene B, Tamuliene I, Cimbalistiene L, Utkus A, Rascon J
*Corresponding Author: Jelena Rascon, M.D., Ph.D., Center for Pediatric Oncology and Hematology, Children’s Hospital,
Affiliate of Vilnius University Hospital Santaros Klinikos, Santariskiu St. 4, LT 08406 Vilnius, Lithuania. Tel: +3705-232-
8703. Fax: +3705-272-0368. E-mail: jelena.rascon@santa.lt
page: 87
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DISCUSSION
Recent advances in the use of microarray technologies
have enabled the identification of genomic rearrangements
and led to further delineation of the phenotypes associated
with microdeletion and microduplication syndromes. Deletions
in the 22q11.22 region usually arise de novo and are
relatively common. In comparison, 22q11.2 duplications
are considered rare, with the estimated incidence depending
on the study. Up to now more than 50 unrelated cases
of 22q11.2 duplication syndrome with a high frequency
of familial duplications have been reported [5].
Here we report a proband with a de novo mosaic
22q11.1q11.22 duplication. There have been numerous
reports of patients with 22q11.2 deletion/duplication syndrome
in the literature, but to the best of our knowledge,
22q11.2 duplication associated with acute pre-B ALL in a
child has only been reported once before [2]. Both genetic
aberrations in the same region give rise to isolated or multisystemic
malformations causing extremely diverse manifestations
ranging from no symptoms to extreme organ
malformations and neuropsychiatric syndromes. Cardiac
defects are rare in duplication of the 22q11.2 region [6].
From birth, our patient had total anomalous pulmonary
venous drainage, atrial septal defect and patent ductus
arteriosus. Moreover, a correlation between duplications
and deletions and a spectrum of neuropsychiatric disorders
ranging from cognitive impairment and speech difficulties
to a spectrum of psychiatric disorders such as autism
or schizophrenia has been established in various studies
[7]. Along with dysmorphic facial features, our patient
displayed normal growth and development. The 6.6 Mb duplication encompasses more than 80
genes. The TBX1 gene is a member of the T-box family
of transcription factors that are responsible for the formation
of tissues and organs during embryonic development.
The TBX1 gene is expressed in the second heart field and
is important for normal heart development [8]. It has been
suggested that over- and/or underexpression of TBX1 may
affect the same developmental pathways and contribute to
DG/VCFS and 22q11.2 duplication syndrome [9]. We speculated
that overexpression of the TBX1 gene might have
been responsible for the patient’s congenital heart defects and
mild facial dysmorphia. Given the extremely variable clinical
presentation in 22q11.2 duplication syndrome, similarities
and the overlapping effects with microdeletions should be
kept in mind, but always distinguished from one another.
Chang et al. [2] reported a case of a small, 0.6 Mb
duplication at the 22q11.21 region associated with pre-B
ALL and cystinuria. The authors hypothesized that overexpression
of the genes in the duplicated region responsible
for the cell cycle and duplication might have contributed
to the formation of the leukemic clone in the bone marrow.
Our patient has a notably larger duplication size that
encompasses a 6.6 Mb genomic region. Both cases share
a particular part of the duplication region that contains five
genes potentially relevant to the regulation of cell cycle
division: CDC45, CLTCL1, DGCR2, GP1BB and SEPT5.
In several cases of acute leukemia the SEPT5 gene was
identified as a fusion partner with MLL gene. SEPT5 belongs
to the human septins, a highly conserved family of
guanosine triphosphate (GTP)-binding proteins. The MLLSEPTIN
chimeric proteins retain the functional domains
of MLL (AT hook domain and methyltransferase domain)
and the GTP-binding domain of the septin, suggesting
an important role for the development of leukemia [10].
With regard to the SEPT5 gene, in one case with bleeding
disorders, deletion of both the SEPT5 and GP1BB genes
was detected [11]. It was also suggested that CDC45 gene
disruption could delay DNA replication and have dominant
negative impact on this DNA damage response in MLLfusion
acute leukemias [12]. CLTCL1, known as clathrin
gene, demonstrates the presence of CLTC-ALK fusions
in diffuse large B cell lymphoma (DLBCL) and extend
the list of diseases associated with this genetic abnormality
to include classical T-cell or null anaplastic large-cell
lymphoma (ALCL), ALK+ DLBCL, and inflammatory
myo-fibroblastic tumors [13]. Finally, gene expression
data noticed that the DGCR2 gene was down-regulated
in more than five different tumors [14]. We hypothesized
that defects in any of these genes could disrupt the balance
between cell growth and differentiation and play a role in
the initiation of leukemia with a hyperdiploidic karyotype
clone. Given the large variability of the size of these aberrations,
it is possible that single gene mutations might lead
to these neoplastic changes in the body rather than a larger
number of amplified oncogenes, but evidence is lacking.
The risk of vincristine induced neurotoxicity is dependent
on the individual activity of cytochromal enzymes,
CYP3A5 in particular in patients treated for leukemia.
Vincristine is metabolized more rapidly by the enzyme
mentioned above. We did not perform analysis on the enzyme
mentioned above, hence the true nature of enhanced
toxicity is unclear for this patient. The CYP3A5 enzymes
are found not only in the liver, but in the gall bladder,
and the intestines as well. Since the patient had a bowel
resection, it remains unclear if the toxicity is genetic, or
iatro-genically induced [15].
In summary, 22q11.2 duplication syndrome is an
extremely variable disorder, that can cause multiorgan
system malformations or mental retardation or even present
with no signs or symptoms at all. Distinguishing this
syndrome from other rearrangements in the same region
is very important, because of the potential association
with neoplastic disease. This is the second case report of
22q11.2 duplication in association with pre-B ALL. Although
only two cases have been reported so far, it seems
that these patients deserve special consideration while on
chemotherapy, since therapy-associated toxicity might be
more prominent than usual.
Declaration of Interest. The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
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