FaCD Online Syndrome Fact Sheet

Last updated: 14 Mar 2012

Name: Myelodysplasia and Acute Myeloid Leukemia (AML), Familial

Synonym: incl.: Familial Myelodysplastic syndrome (late-onset), Familial AML, Familial Monocytic Leukemia, Familial Monosomy 7 and AML

Mode of Inheritance: AD/ AR?/ multifact ?

Genes

FAML^#, mapped to 16q21-2q3.2
GATA2, mapped to 3q21.3
GSTT1, mapped to 22q11.2

Tumor features

leukemia, acute myeloblastic (AML, M2)
leukemia, acute myeloid (AML, incl. ANLL)
leukemia, chronic myelomonocytic (CMML)
myelodysplastic syndrome (MDS)

Non-tumor features

bone marrow monosomy 7 karyotype

Non-tumor features (possible)

ins(16)(p11.2) (constitutional)
t(7;16)(p10;q10) (constitutional)

Comment

Myelodysplastic syndrome, often associated with monosomy of chromosome 7 in bone marrow and often progressing into acute myeloid leukemia, has been reported to occur in familial clusters[1-7,26-28,30; for review see refs 24 and 30]. Familial late-onset MDS without AML[8] and Familial AML without MDS[9-13] have also been reported. Although late age of onset is the rule in familial MDS, Kumar et al[14] reported familial MDS with an age of onset before 55 years. In general, a familial history of hematopoietic malignancies in first or second-degree relatives appears to be associated with an increased risk of acute myeloid leukemia[25].

This database entry includes the report of Kjellstrom et al.[15] on two families with the AML type monocytic leukemia(McKusick no 151380). Hasle et al[16] studied the occurrence of cancer in relatives of children with MDS. They found no evidence of an increased overall risk of cancer, and leukemia/MDS in particular, in relatives. They concluded that the proportion of familial MDS may be considerably lower than the percentage of up to 1/3 of children with MDS that had been quoted before.

The genetics of this probably heterogenous group of familial clusters are unclear. Suggested mechanisms include GSTT1 null genotype[17], a constitutional insertion of unknown origin in chromosome 16 (ins(16)(p11.2)[18], constitutional translocation between 7 and 16[19] and linkage to the 16q21-q23.2 region[20]. Horwitz et al[21] studied 9 families with AML and observed a decrease in age at diagnosis with each successive generation, referred to this phenomenon as anticipation. The authors suggested that a dynamic mutation, as e.g. in Fragile X syndrome might be responsible for this phenomenon. Baozhang et al[22] suggested that a germline c-ERBB gene rearrangement predisposes to AML development, based on their findings in a large AML family. Additional GATA2 germline mutations have been reported in a small number of MDS & MDS-AML families[29,31].

See Familial AML associated with CEBPA mutations for the condition associated with germline mutations in that gene and RUNX1 associated platelet & myeloid disorder.

Links

MDS Foundation 23 9 2011

References

[1] Kamiyama R, Shibata T, Mori W. Two autopsy cases of atypical myeloploliferative disorder with group C monosomy occurring in siblings. Acta Pathol Jpn 1973; 23(4):815-835.
[2] Carroll WL, Morgan r, Glader BE. Childhood bone marrow monosoly 7 syndrome: a familial disorder? J Pediat 1985; 107(4):578-580.
[3] Paul B, Reid MM, Davison EV, Abela M, Hamilton PJ. Familial myelodysplasia: progressive disease associated with emergence of monosomy 7. Br J Hematol 1987; 65:321-323.
[4] Gilchrist DM, Friedman JM, Rogers PCJ, Creighton SP. Myelodysplasia and leukemia syndrome with monosomy 7: a genetic perspective. Am J Med Genet 1990; 35:437-441.
[5] Olopade OI, Roulston D, Baker T, Narvid S, Le Beau MM, Freireich EJ, Larson RA, Golomb HM. Familial myeloid leukemia associated with loss of the long arm of chromosome 5. Leukemia 1996; 10(4):669-674.
[6] Horwitz M, Sabath DE, Smithson WA, Radich J. A family inheriting different subtypes of acute myelogenous leukemia. Am J Hematol 52[4], 295-304. 1996.
[7] Kwong YL, Ng MH, Ma SK. Familial acute myeloid leukemia with monosomy 7: late onset and involvement of a multipotential progenitor cell. Cancer Genet Cytogenet 2000; 116(2):170-173.
[8] Marsden K, Challis D, Kimber R. Familial myelodysplastic syndrome with onset late in life. Am J Hematol 1995; 49:153-156.
[9] De Lord C, Powles R, Mehta J, Wilson K, Treleaven J, Meller S, Catovsky D. Familial acute myeloid leukaemia: four male members of a single family over three consecutive generations exhibiting anticipation. Br J Hematol 100[3], 557-560. 1998.
[10] He LZ, Lu LH, Chen ZZ. Genetic mechanism of leukemia predisposition in a family with 7 cases of acute myeloid leukemia. Cancer Genet Cytogenet 1994; 76:65-69.
[11] Heath CW, Moloney WC. Five cases of acute leukemia in three generations. N Engl J Med 1965; 272(17):882-887.
[12] Fischer P, Karpas A, Nacheva E, Haas O, Winterleitner H, Krepler P. Characteristics of a cell line established from a child with familial acute myeloid leukaemia. Br J Hematol 1980; 46:23-31.
[13] Snyder AL, Li FP, Henderson ES, Todaro GJ. Possible inherited leukaemogenic factors in familial acute myelogenous leukaemia. Lancet 1970;586-589.
[14] Kumar T, Mandla SG, Greer WL. Familial myelodysplastic syndrome with early age of onset. Am J Hematol 2000; 64(1):53-58.
[15] Kjellstrom T, Barkenius G, Malmquist J, Rausing A. Familial monocytic leukaemia: a report of two families. Scand J Haematol 1979; 23:272-276.
[16] Hasle H, Olsen JH. Cancer in relatives of children with myelodysplastic syndrome, acute and chronic myeloid leukaemia. Br J Hematol 97[1], 127-131. 1997.
[17] Chen HW, Sandler DP, Taylor JA, Shore DL, Liu E, Bloomfield CD, Bell DA. Increased risk for myelodysplastic syndromes in individuals with glutathione transferase theta 1 (GSTT1) gene defect. Lancet 1996; 347:295-297.
[18] Clark RE, Geddes D, Whittaker K, Jacobs A. Meylodysplastic syndrome in a kindred with ins(16)(p11.2). Clin Genet 1988; 33:418-423.
[19] Passmore SJ, Hann IM, Stiller CA, Ramani P, Swansburry GJ, Gibbons B, Reeves BR, Chessells JM. Pediatric myelodysplasia: a study of 68 children and a new prognostic scoring system. Blood 1995; 85(7):1742-1750.
[20] Horwitz M, Benson KF, Li FQ, Wolff J, Leppert MF, Hobson L, Mangelsdorf M, Yu S, Hewett D, Richards RI, Raskind WH. Genetic heterogeneity in familial acute myelogenous leukemia: evidence for a second locus at chromosome 16q21-23.2. Am J Hum Genet 1997; 61:873-881.
[21] Horwitz M, Goode EL, Jarvik GP. Anticipation in familial leukemia [see comments]. Am J Hum Genet 1996; 59(5):990-998.
[22] Feng B, Lei J, Lin Z, Hao J, Chen W. Genetic studies on a family with acute myelogenous leukemia. Cancer Genet Cytogenet 1999; 112:134-137.
[23] Minelli A, Maserati E, Giudici G, Tosi S, Olivieri C, Bonvini L, De Filippi P, Biondi A, Lo Curto F, Pasquali F, Danesino C. Familial partial monosomy 7 and myelodysplasia: different parental origin of the monosomy 7 suggests action of a mutator gene. Cancer genetics and cytogenetics 2001; 124(2):147-51.
[24] Owen C, Barnett M, Fitzgibbon J. Familial myelodysplasia and acute myeloid leukaemia--a review. British journal of haematology 2008; 140(2):123-32.
[25] Ripert M, Menegaux F, Perel Y, Méchinaud F, Plouvier E, Gandemer V, Lutz P, Vannier JP, Lamagnére JP, Margueritte G, Boutard P, Robert A, Armari-Alla C, Munzer M, Millot F, de Lumley L, Berthou C, Rialland X, Pautard B, Clavel J. Familial history of cancer and childhood acute leukemia: a French population-based case-control study. European journal of cancer prevention 2007; 16(5):466-70.
[26] Abdul-Wahab J, Naznin M, Suhaimi A, Amir-Hamzah AR. Favourable response to splenectomy in familial myelodysplastic syndrome. Singapore medical journal 2007; 48(7):e206-8.
[27] Wróbel T, Mazur G, Pyszel A, Biedron M, Kuliczkowski K. [Familial incidence of myelodysplastic syndromes]. Wiadomosci lekarskie 2006; 59(3-4):285-8.
[28] Maserati E, Minelli A, Menna G, Cecchini MP, Bernardo ME, Rossi G, De Filippi P, Lo Curto F, Danesino C, Locatelli F, Pasquali F. Familial myelodysplastic syndromes, monosomy 7/trisomy 8, and mutator effects. Cancer genetics and cytogenetics 2004; 148(2):155-8.
[29] Hahn CN, Chong CE, Carmichael CL, Wilkins EJ, Brautigan PJ, Li XC, Babic M, Lin M, Carmagnac A, Lee YK, Kok CH, Gagliardi L, Friend KL, Ekert PG, Butcher CM, Brown AL, Lewis ID, To LB, Timms AE, Storek J, Moore S, Altree M, Escher R, Bardy PG, Suthers GK, D'Andrea RJ, Horwitz MS, Scott HS. Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat Genet. 2011 Sep 4. [Epub ahead of print]
[30] Liew E, Owen CJ. Familial myelodysplastic syndromes - a review of the literature.Haematologica. 2011 May 23. [Epub ahead of print]
[31] Bödör C, Renneville A, Smith M, Charazac A, Iqbal S, Etancelin P, Cavenagh J, Barnett MJ, Kramarzova K, Krishnan B, Matolcsy A, Preudhomme C, Fitzgibbon J, Owen C. Germ-line GATA2 p.THR354MET mutation in familial myelodysplastic syndrome with acquired monosomy 7 and ASXL1 mutation demonstrating rapid onset and poor survival. Haematologica. 2012 Jan 22. [Epub ahead of print]