FaCD Online Syndrome Fact Sheet

Last updated: 23 Oct 2013

Name: Acute Lymphoblastic Leukemia, Familial Clustering of

Synonym: Familial ALL, incl. Familial T-ALL, Familial B-ALL

Mode of Inheritance: AD?/ multifact?

Genes

CYP1A1, mapped to 15q22-q24
GSTM1, mapped to 1p13.3
HLA-DQB1, mapped to 6p21.3
PAX5, mapped to 9p13.2

Tumor features

leukemia, acute lymphoblastic (ALL)

Comment

Familial clustering of ALL has been observed[1-3]. Becker et al.[4] reported an 4-generation Irish family with childhood onset acute T-cell leukemia / lymphoblastic T-cell lymphoma in 9 relatives, which to the authors suggested autosomal dominant inheritance with reduced penetrance.

Dearden et al.[5] studied HLA-DQB1 alleles in children with ALL because of the suggestion that ALL may be caused by HLA regulated susceptibility to an unidentified neonatal infection. They observed a significant excess of the DQB1*05 allele (relative risk (RR) 2.5) and in particular of certain amino acid motifs (not restricted to that allele). Polymorphisms in the GSTM1 and CYP1A1 genes, encoding xenobiotic-metabolizing enzymes have been found to be associated with an increased relative risk of childhood ALL[6]. A germline heterozygous truncating mutation in the gene for Fanconi anemia type C has been detected in 2 sibs with T-ALL; 1 of the sibs subsequently developed AML[7].

Shah et al[9]reported a PAX5 gene mutation, c.547G>A (p.Gly183Ser) in two unrelated famlies with autosomal dominant B-ALL.

In general, there appears to be no increase in ALL risk to siblings of patients. Risk may even be decreased and it has been speculated that immunization of mothers to leukemia-specific antigens may occur which can enhance elimination of preleukemic cells in utero[8].

References

[1] Kende G, Toren A, Mandel M, Neumann Y, Kenet G, Brok-Simoni F, Ramot B, Ben-Bassat I, Rechavi G. Familial leukemia: Description of two kindreds and a review of the genetic aspects of the disease. Acta Haematol 1994; 92:208-211.
[2] Cramblett HG, Friedman JL, Najjar S. Leukemia in an infant born of a mother with leukemia. N Engl J Med 1958; 259(15):727-729.
[3] Chaganti RSK, Miller DR, Meyers PA, German J. Cytogenetic evidence of the intrauterine origin of acute leukemia in monozygotic twins. N Engl J Med 1979; 300(18):1032-1033.
[4] Becker K, Breatnach F, Green AJ. Autosomal dominant acute T-cell leukemia/lymphoblastic T-cell lymphoma in an Irish family. J Med Genet 37[suppl.1], S35. 2000.
[5] Dearden SP, Taylor GM, Gokhale DA, Robinson MD, Thompson W, Ollier W, Binchy A, Birch JM, Stevens RF, Carr T, Bardsley WG. Molecular analysis of HLA-DQB1 alleles in childhood common acute lymphoblastic leukaemia. Br J Cancer 1996; 73:603-609.
[6] Krajinovic M, Labuda D, Richer C, Karimi S, Sinnett D. Susceptibility to childhood acute lymphoblastic leukemia: Influence of CYP1A1, CYP2D6, GSTM1, and GSTT1 genetic polymorphisms. Blood 93[5], 1496-1501. 1999.
[7] Rischewski JR, Clausen H, Leber V, Niemeyer C, Ritter J, Schindler D, Schneppenheim R. A heterozygous frameshift mutation in the Fanconi anemia C gene in familial T-ALL and secondary malignancy. Klin Padiatr 2000; 212(4):174-176.
[8] Schmiegelow K, Hjalgrim H. Is the risk of acute lymphoblastic leukemia reduced in siblings to children with the disease? A novel hypothesis explored by international collaboration. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 2006; 20(7):1206-8.
[9] Shah S et al. A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia. Nature genetics 2013; 45:1226-31.