T-LYMPHOBLASTIC LEUKEMIA/LYMPHOMA
IN MACEDONIAN PATIENTS WITH
NIJMEGEN BREAKAGE SYNDROME
Kocheva SA, Martinova K, Antevska-Trajkova Z, Coneska-Jovanova B, Eftimov A,
Dimovski AJ
*Corresponding Author: Svetlana A. Kocheva, M.D., Ph.D., Department of Hematology and Oncology,
University Children’s Hospital, Mother Teresa 17, 1000 Skopje, Macedonia. Tel:+38-971-378-184. E-mail:
svetlana.kocheva@t.mk
page: 91
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CLINICAL REPORT
Case 1. The first patient (proband 1) was a
7-year-old boy of Macedonian origin. He was referred
to the Hematology Department, University
Pediatric Clinic, Skopje, Republic of Macedonia,
with lymphadenopathy in the neck region. He was
the first-born child after a normal pregnancy of
38 weeks duration, with a birth weight of 2500 g
(data concerning length and head circumference
at birth were not available). The neonatal period
passed without complications. The development of
language skills was normal. There was no history
of developmental regression. His admission to the
hospital occurred after a few-days history of cough,
fever and enlarged lymph nodes. The physical examination
revealed bilateral lymphadenopathy,
hepatomegaly, microcephaly, and syndactyly of the
toes. A lymph node fine needle biopsy confirmed
the diagnosis of malignant T-cell acute lymphoblastic
lymphoma [Non Hodgkin lymphoma (T-NHL)].
The patient was treated according to the International
Berlin-Frankfurt-Münster (BFM 1990) protocol
consisting of induction, consolidation, reinduction
and maintenance. During treatment, no significant
side effects of chemotherapy were observed. He
achieved a complete remission that lasted for 21
months. Subsequently, he developed a medullar relapse
with hyper-leukocytosis and died due to lethal
central nervous system (CNS) complications.
Case 2. The second patient (proband 2) was a
9.5-year-old boy, the second-born child in the same
family. He was also born after a normal pregnancy.
His psychomotor development was normal, but the
physical examination showed microcephaly, micrognatia
and syndactyly of the toes. He was admitted
to the Hematology Department at the age
of 9.5 with fever, disseminated lymphadenopaty,
hepatosplenomegaly and leucocytosis of 27,000 ×
109/L. The evaluation of the peripheral blood smear
showed the presence of 32.0% blast cells. The diagnosis
of T-cell acute lymphoblastic leukemia
(T-ALL) was established based on a standard immunohystological
panel analysis. It was quite clear
that the malignant disease in both children in this
family was partly due to the clinical presentation of
NBS. The patient was treated with the International
Collaborative Treatment Protocol for Children and
Adolescents with Acute Lymphoblastic Leukemia
2009 (AIOP-BFM ALL 2009) protocol. A remission
was not achieved in this patient and he passed
away after a very brief and severe episode of gramnegative
sepsis and systemic inflammatory response
syndrome (SIRS) during bone marrow aplasia after
an intensive chemotherapy block in the induction
phase for bone marrow transplantation.
Family History. The probands 1 and 2 were
children born to non consanguineous parents. The
mother was of Croatian ancestry, while the father
was of Macedonian origin. The family history was
negative for hereditary or malignant disorders.
Molecular Diagnosis and Genetic Counseling.
Genetic analysis to determine the mutation in
the NBS1 gene was made after the manifestation of
acute leukemia in the second patient. Mutation detection
using genomic DNA was performed by polymerase
chain reaction (PCR) with specific primers
for the human NBS1 gene, followed by an automated
DNA sequence analysis. The molecular analysis of
the family members showed homozygosity for the
657 del5 mutation in the NBS1 gene in both patients.
The parents were heterozygotes for the 657del5 mutation.
They had no knowledge of a consanguineous
relationship. Families with a 25.0% risk of having an
affected child may be offered prenatal diagnosis if
both disease-causing mutations in the NBN gene are
established. The molecular analysis is the method
of choice. Fetal DNA for analysis can be obtained
either by chorionic villus sampling (CVS) or by
amniocentesis. Siblings of a patient’s parents are at
50.0% risk of being carriers. Heterozygous carriers of an NBN mutation do not present with any symptoms.
However, in some population studies, a strong
association with an increased cancer risk was noted
for carriers of the founder mutation [12].
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