Abstract

Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders characterized by clonal hematopoiesis with a propensity to evolve into acute myeloid leukemia. MDS presenting in children and young adults is associated with features clinically and biologically distinct from MDS arising in older adults. MDS presenting in children and young adults is associated with a higher likelihood of an underlying genetic predisposition; however, genetic predisposition is increasingly recognized in a subset of older adults. The diagnosis of a genetic predisposition to MDS informs clinical care and treatment selection. Early diagnosis allows a tailored approach to management and surveillance. Genetic testing now offers a powerful diagnostic approach but also poses new challenges and caveats. Clinical expertise in these disorders together with scientific expertise regarding the affected genes is essential for diagnosis. Understanding the basic mechanisms of genetic predisposition to myeloid malignancies may inform surveillance strategies and lead to novel therapies. The cases presented in this article illustrate challenges to the diagnosis of germline genetic predisposition to MDS and how the diagnosis affects clinical management and treatment.

References

References
1.
Sperling
AS
,
Gibson
CJ
,
Ebert
BL
.
The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia
.
Nat Rev Cancer
.
2017
;
17
(
1
):
5
-
19
.
2.
Babushok
DV
,
Bessler
M
.
Genetic predisposition syndromes: when should they be considered in the work-up of MDS?
Best Pract Res Clin Haematol
.
2015
;
28
(
1
):
55
-
68
.
3.
Arber
DA
,
Orazi
A
,
Hasserjian
R
, et al
.
The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia [published correction appears in Blood. 2016;128:462-463]
.
Blood
.
2016
;
127
(
20
):
2391
-
2405
.
4.
Lindsley
RC
,
Saber
W
,
Mar
BG
, et al
.
Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation
.
N Engl J Med
.
2017
;
376
(
6
):
536
-
547
.
5.
Keel
SB
,
Scott
A
,
Sanchez-Bonilla
M
, et al
.
Genetic features of myelodysplastic syndrome and aplastic anemia in pediatric and young adult patients
.
Haematologica
.
2016
;
101
(
11
):
1343
-
1350
.
6.
Savage
SA
,
Dufour
C
.
Classical inherited bone marrow failure syndromes with high risk for myelodysplastic syndrome and acute myelogenous leukemia
.
Semin Hematol
.
2017
;
54
(
2
):
105
-
114
.
7.
Schwartz
JR
,
Ma
J
,
Lamprecht
T
, et al
.
The genomic landscape of pediatric myelodysplastic syndromes
.
Nat Commun
.
2017
;
8
(
1
):
1557
.
8.
Bluteau
O
,
Sebert
M
,
Leblanc
T
, et al
.
A landscape of germ line mutations in a cohort of inherited bone marrow failure patients
.
Blood
.
2018
;
131
(
7
):
717
-
732
.
9.
Muramatsu
H
,
Okuno
Y
,
Yoshida
K
, et al
.
Clinical utility of next-generation sequencing for inherited bone marrow failure syndromes
.
Genet Med
.
2017
;
19
(
7
):
796
-
802
.
10.
Ghemlas
I
,
Li
H
,
Zlateska
B
, et al
.
Improving diagnostic precision, care and syndrome definitions using comprehensive next-generation sequencing for the inherited bone marrow failure syndromes
.
J Med Genet
.
2015
;
52
(
9
):
575
-
584
.
11.
Donadieu
J
,
Beaupain
B
,
Fenneteau
O
,
Bellanné-Chantelot
C
.
Congenital neutropenia in the era of genomics: classification, diagnosis, and natural history
.
Br J Haematol
.
2017
;
179
(
4
):
557
-
574
.
12.
Shimamura
A
,
Alter
BP
.
Pathophysiology and management of inherited bone marrow failure syndromes
.
Blood Rev
.
2010
;
24
(
3
):
101
-
122
.
13.
Kallen
ME
,
Dulau-Florea
A
,
Wang
W
,
Calvo
KR
.
Acquired and germline predisposition to bone marrow failure: diagnostic features and clinical implications
.
Semin Hematol
.
2019
;
56
(
1
):
69
-
82
.
14.
Furutani
E
,
Shimamura
A
.
Germline genetic predisposition to hematologic malignancy
.
J Clin Oncol
.
2017
;
35
(
9
):
1018
-
1028
.
15.
Babushok
DV
,
Bessler
M
,
Olson
TS
.
Genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia in children and young adults
.
Leuk Lymphoma
.
2016
;
57
(
3
):
520
-
536
.
16.
DiNardo
CD
,
Bannon
SA
,
Routbort
M
, et al
.
Evaluation of patients and families with concern for predispositions to hematologic malignancies within the hereditary hematologic malignancy clinic (HHMC)
.
Clin Lymphoma Myeloma Leuk
.
2016
;
16
(
7
):
417
-
428.e2
.
17.
Kennedy
AL
,
Shimamura
A
.
Genetic predisposition to MDS: clinical features and clonal evolution
.
Blood
.
2019
;
133
(
10
):
1071
-
1085
.
18.
McReynolds
LJ
,
Savage
SA
.
Pediatric leukemia susceptibility disorders: manifestations and management
.
Hematology Am Soc Hematol Educ Program
.
2017
;
2017
:
242
-
250
.
19.
West
AH
,
Churpek
JE
.
Old and new tools in the clinical diagnosis of inherited bone marrow failure syndromes
.
Hematology Am Soc Hematol Educ Program
.
2017
;
2017
:
79
-
87
.
20.
Ebens
CL
,
MacMillan
ML
,
Wagner
JE
.
Hematopoietic cell transplantation in Fanconi anemia: current evidence, challenges and recommendations
.
Expert Rev Hematol
.
2017
;
10
(
1
):
81
-
97
.
21.
Dietz
AC
,
Savage
SA
,
Vlachos
A
, et al
.
Late effects screening guidelines after hematopoietic cell transplantation for inherited bone marrow failure syndromes: consensus statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects After Pediatric HCT
.
Biol Blood Marrow Transplant
.
2017
;
23
(
9
):
1422
-
1428
.
22.
Barbaro
P
,
Vedi
A
.
Survival after hematopoietic stem cell transplant in patients with dyskeratosis congenita: systematic review of the literature
.
Biol Blood Marrow Transplant
.
2016
;
22
(
7
):
1152
-
1158
.
23.
Guha
T
,
Malkin
D
.
Inherited TP53 mutations and the Li-Fraumeni syndrome
.
Cold Spring Harb Perspect Med
.
2017
;
7
(
4
):
a026187
.
24.
Bougeard
G
,
Renaux-Petel
M
,
Flaman
JM
, et al
.
Revisiting Li-Fraumeni syndrome from TP53 mutation carriers
.
J Clin Oncol
.
2015
;
33
(
21
):
2345
-
2352
.
25.
Furutani
E
,
Newburger
PE
,
Shimamura
A
.
Neutropenia in the age of genetic testing: advances and challenges
.
Am J Hematol
.
2019
;
94
(
3
):
384
-
393
.
26.
Obrochta
E
,
Godley
LA
.
Identifying patients with genetic predisposition to acute myeloid leukemia
.
Best Pract Res Clin Haematol
.
2018
;
31
(
4
):
373
-
378
.
27.
University of Chicago Hematopoietic Malignancies Cancer Risk Team
.
How I diagnose and manage individuals at risk for inherited myeloid malignancies
.
Blood
.
2016
;
128
(
14
):
1800
-
1813
.
28.
Kratz
CP
,
Achatz
MI
,
Brugières
L
, et al
.
Cancer screening recommendations for individuals with Li-Fraumeni syndrome
.
Clin Cancer Res
.
2017
;
23
(
11
):
e38
-
e45
.
29.
Churpek
JE
,
Lorenz
R
,
Nedumgottil
S
, et al
.
Proposal for the clinical detection and management of patients and their family members with familial myelodysplastic syndrome/acute leukemia predisposition syndromes
.
Leuk Lymphoma
.
2013
;
54
(
1
):
28
-
35
.
30.
Peffault de Latour
R
,
Soulier
J
.
How I treat MDS and AML in Fanconi anemia
.
Blood
.
2016
;
127
(
24
):
2971
-
2979
.
31.
Loyola
VP
,
Panda
PK
,
Sahoo
SS
, et al
.
Monosomy 7 as the initial hit followed by sequential acquisition of SETBP1 and ASXL1 driver mutations in childhood myelodysplastic syndromes [abstract]
.
Blood
.
2018
;
132
(
suppl 1
):
105
.
32.
Wlodarski
MW
,
Sahoo
SS
,
Niemeyer
CM
.
Monosomy 7 in pediatric myelodysplastic syndromes
.
Hematol Oncol Clin North Am
.
2018
;
32
(
4
):
729
-
743
.
33.
Sanders
MA
,
Chew
E
,
Flensburg
C
, et al
.
MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML
.
Blood
.
2018
;
132
(
14
):
1526
-
1534
.
34.
Tesi
B
,
Davidsson
J
,
Voss
M
, et al
.
Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms
.
Blood
.
2017
;
129
(
16
):
2266
-
2279
.
35.
Pastor
VB
,
Sahoo
SS
,
Boklan
J
, et al
.
Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7
.
Haematologica
.
2018
;
103
(
3
):
427
-
437
.
36.
Chen
DH
,
Below
JE
,
Shimamura
A
, et al
.
Ataxia-pancytopenia syndrome is caused by missense mutations in SAMD9L
.
Am J Hum Genet
.
2016
;
98
(
6
):
1146
-
1158
.
37.
Buonocore
F
,
Kühnen
P
,
Suntharalingham
JP
, et al
.
Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans
.
J Clin Invest
.
2017
;
127
(
5
):
1700
-
1713
.
38.
Padron
E
,
Ball
MC
,
Teer
JK
, et al
.
Germ line tissues for optimal detection of somatic variants in myelodysplastic syndromes
.
Blood
.
2018
;
131
(
21
):
2402
-
2405
.
39.
Jongmans
MCJ
,
Verwiel
ETP
,
Heijdra
Y
, et al
.
Revertant somatic mosaicism by mitotic recombination in dyskeratosis congenita
.
Am J Hum Genet
.
2012
;
90
(
3
):
426
-
433
.
40.
Gregory
JJ
Jr
,
Wagner
JE
,
Verlander
PC
, et al
.
Somatic mosaicism in Fanconi anemia: evidence of genotypic reversion in lymphohematopoietic stem cells
.
Proc Natl Acad Sci USA
.
2001
;
98
(
5
):
2532
-
2537
.
41.
Hsu
AP
,
Johnson
KD
,
Falcone
EL
, et al
.
GATA2 haploinsufficiency caused by mutations in a conserved intronic element leads to MonoMAC syndrome
.
Blood
.
2013
;
121
(
19
):
3830
-
3837
.
42.
Weitzel
JN
,
Chao
EC
,
Nehoray
B
, et al
.
Somatic TP53 variants frequently confound germ-line testing results
.
Genet Med
.
2018
;
20
(
8
):
809
-
816
.
43.
Faivre
L
,
Meerpohl
J
,
Da Costa
L
, et al
.
High-risk pregnancies in Diamond-Blackfan anemia: a survey of 64 pregnancies from the French and German registries
.
Haematologica
.
2006
;
91
(
4
):
530
-
533
.
44.
Zhang
MY
,
Keel
SB
,
Walsh
T
, et al
.
Genomic analysis of bone marrow failure and myelodysplastic syndromes reveals phenotypic and diagnostic complexity
.
Haematologica
.
2015
;
100
(
1
):
42
-
48
.
45.
Kennedy
JA
,
Ebert
BL
.
Clinical implications of genetic mutations in myelodysplastic syndrome
.
J Clin Oncol
.
2017
;
35
(
9
):
968
-
974
.
46.
Zahid
MF
,
Patnaik
MM
,
Gangat
N
,
Hashmi
SK
,
Rizzieri
DA
.
Insight into the molecular pathophysiology of myelodysplastic syndromes: targets for novel therapy
.
Eur J Haematol
.
2016
;
97
(
4
):
313
-
320
.
You do not currently have access to this content.