Anales de Pediatría (English Edition) Anales de Pediatría (English Edition)
An Pediatr (Barc) 2017;87:170-1 - Vol. 87 Num.3 DOI: 10.1016/j.anpede.2017.03.007
Scientific Letter
Two siblings with acute lymphoblastic leukaemia: Chance or genetics?
Dos hermanos con leucemia linfoblástica aguda: ¿casualidad o herencia?
Elena Carceller, David Ruano, Luis Madero López, Álvaro Lassaletta,
Hospital Infantil Universitario Niño Jesús, Madrid, Spain
Dear Editor:

Acute lymphoblastic leukaemia (ALL) is the most frequent childhood cancer and accounts for 80% of cases of acute leukaemia.1 Its underlying mechanisms are largely unknown. There is growing evidence of the role of genetic factors in its aetiology. This statement is based on the following: (1) there is a strong association between ALL and some chromosomal translocations; (2) the incidence of acute leukaemia is greater in relatives of patients with acute leukaemia, and (3) there is a higher incidence of leukaemia in individuals with certain genetic syndromes (Down syndrome, Klinefelter syndrome, neurofibromatosis, Shwachman syndrome, etc.).1 In recent years, genetic mutations associated with an increased risk of ALL have been reported, in spite of which its heritability remains uncertain. We present a case of ALL in a sibling of a patient that had received a diagnosis of ALL 4 years earlier.

The patient was a boy aged 18 months brought to the emergency department with fever of up to 39°C lasting 2 days and associated with cold symptoms and breathing difficulties. There had been no complications during pregnancy, delivery or the neonatal period. The boy had received vaccinations conforming to the official schedule. There were no other medical or surgical diseases. The complete blood count revealed pancytopenia. A bone marrow sample was obtained 48h after admission whose analysis revealed infiltration with 60% of blast cells and markers compatible with common ALL (B-cell precursor). The relevant family history included an older brother aged 6 years with B-cell precursor ALL diagnosed 4 years earlier that had completed treatment 2 years after the diagnosis. The father had insulin-dependent diabetes mellitus since age 25 years, the mother was healthy, and a paternal aunt had died of cancer at age 40 years.

The 2 siblings were treated according to the PETHEMA BR protocol and responded well to chemotherapy. Both are in full remission at present, 6 and 10 years after diagnosis, respectively.

Most cases of ALL in children are sporadic, and ALL is not considered an inherited disease. Direct evidence of a genetic heritable predisposition to ALL due to certain genetic syndromes, such as Bloom syndrome, neurofibromatosis, ataxia-telangiectasia and trisomy 21 is only found in a small percentage of ALL cases (<5%). The genetic basis of the heritable susceptibility to ALL outside these syndromes has not been elucidated. However, there have been advances on this matter in recent years: genomic studies have found that somatic variants of ARD5B, IKZF1 and CDKN2A are associated with an increased risk of ALL (odds ratio, 1.3–1.9).2,3 Other rare germline mutations in PAX5, ETV6 and especially p53 may also predispose to leukaemia.4 Despite all these findings, there is no sufficient evidence to prove a familial risk of ALL in children, which may be due, in part, to the low incidence of the disease. A Scandinavian study that included 3.994 patients with ALL identified 36 cases of ALL in siblings: 10 cases in singleton siblings and 26 in twins. The study showed that compared to the general population, twins of children with ALL had an increased risk of developing leukaemia (standardised incidence ratio [SIR], 163; 95% CI, 70–320), while the increase in risk in singleton siblings was small (SIR, 3; 95% CI, 2–6).5 It is believed that the high risk found in twins results from sharing the prenatal blood circulation.6 The increased risk in singleton siblings is not associated with the aforementioned genomic findings, so the authors suggested that other germline mutations or polymorphisms yet unknown may underlie this familial effect. To date, this is the first study in the literature that attributes an increased risk of developing ALL in siblings of patients with the disease.

In the case of our patient, in whom none of the findings suggested the presence of a genetic syndrome associated with an increased predisposition for ALL, and based on the data currently available in the literature, we did not have sufficient evidence to establish whether this familial aggregation was hereditary in nature. On the other hand, since the incidence of ALL is low in the general population and the mild increase in the relative risk of siblings of patients with ALL does not result in a high probability of developing leukaemia, we do not recommend routine screening of siblings of patients with leukaemia.

It is important that research on the genetic basis of ALL continues, not only to establish its heritability, but also to learn its potential impact on prognosis and treatment.

References
1
A. Lassaletta
Leucemias. Leucemia linfoblástica aguda
Pediatr Integral, 20 (2016), pp. 380-389
2
L.R. Treviño,W. Yang,D. French,S.P. Hunger,W.L. Carroll,M. Devidas
Germline genomic variants associated with childhood acute lymphoblastic leukemia
Nat Genet, 41 (2009), pp. 1001-1005 http://dx.doi.org/10.1038/ng.432
3
E. Papaemmanuil,F.J. Hosking,J. Vijayakrishnan,A. Price,B. Olver,E. Sheridan
Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia
Nat Genet, 41 (2009), pp. 1006-1010 http://dx.doi.org/10.1038/ng.430
4
J. Zhang,M.F. Walsh,G. Wu,M.N. Edmonson,T.A. Gruber,J. Easton
Germline mutations in predisposition genes in pediatric cancer
N Engl J Med, 373 (2015), pp. 2336-2346 http://dx.doi.org/10.1056/NEJMoa1508054
5
E. Kharazmi,M.I. da Silva Filho,E. Pukkala,K. Sundquist,H. Thomsen,K. Hemminki
Familial risks for childhood acute lymphocytic leukaemia in Sweden and Finland: far exceeding the effects of known germline variants
Br J Haematol, 159 (2012), pp. 585-588 http://dx.doi.org/10.1111/bjh.12069
6
M. Greaves
Infection, immune responses and the aetiology of childhood leukaemia
Nat Rev Cancer, 6 (2006), pp. 193-203 http://dx.doi.org/10.1038/nrc1816

Please cite this article as: Carceller E, Ruano D, Madero López L, Lassaletta Á. Dos hermanos con leucemia linfoblástica aguda: ¿casualidad o herencia? An Pediatr (Barc). 2017;87:170–171.

Corresponding author. (Álvaro Lassaletta lassaalvaro@yahoo.com)
Copyright © 2017. Asociación Española de Pediatría
An Pediatr (Barc) 2017;87:170-1 - Vol. 87 Num.3 DOI: 10.1016/j.anpede.2017.03.007
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