https://orcid.org/0000-0002-9353-5535
Key Points
The type of genetic variant is a predictive biomarker for disease severity and survival in WAS.
Less severe variants entail a later onset of disease-related complications but patients remain prone to morbidity and premature mortality.
Abstract
Wiskott-Aldrich syndrome (WAS) is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (range, 0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% confidence interval, 78-87) at age 15 years and 70% (61-80) at 30 years. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hot spot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared with 71% (62-81) and 48% (34-68) in patients with any other variant (class II; P < .0001). The cumulative incidence rates of disease-related complications such as severe bleeding (P = .007), life-threatening infection (P < .0001), and autoimmunity (P = .004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (P = .6) was not different between classes I and II. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of the variant is a biomarker to predict the outcome for patients with WAS.
References
1.
Sullivan
KE
, Mullen
CA
, Blaese
RM
, Winkelstein
JA
. A multiinstitutional survey of the Wiskott-Aldrich syndrome
. J Pediatr
. 1994
;125
(6 pt 1
):876
-885
.2.
Albert
MH
, Notarangelo
LD
, Ochs
HD
. Clinical spectrum, pathophysiology and treatment of the Wiskott-Aldrich syndrome
. Curr Opin Hematol
. 2011
;18
(1
):42
-48
.3.
Wiskott
A
. Familiärer, angeborener Morbus Werlhofii?
. Montasschr Kinderheilkd
. 1937
;68
:212
-216
.4.
Aldrich
RA
, Steinberg
AG
, Campbell
DC
. Pedigree demonstrating a sex-linked recessive condition characterized by draining ears, eczematoid dermatitis and bloody diarrhea
. Pediatrics
. 1954
;13
(2
):133
-139
.5.
Derry
JM
, Ochs
HD
, Francke
U
. Isolation of a novel gene mutated in Wiskott-Aldrich syndrome
. Cell
. 1994
;78
(4
):635
-644
.6.
Bach
FH
, Albertini
RJ
, Joo
P
, Anderson
JL
, Bortin
MM
. Bone-marrow transplantation in a patient with the Wiskott-Aldrich syndrome
. Lancet
. 1968
;2
(7583
):1364
-1366
.7.
Braun
CJ
, Boztug
K
, Paruzynski
A
, et al. Gene therapy for Wiskott-Aldrich syndrome--long-term efficacy and genotoxicity
. Sci Transl Med
. 2014
;6
(227
):227ra33
.8.
Worth
AJ
, Thrasher
AJ
. Current and emerging treatment options for Wiskott-Aldrich syndrome
. Expert Rev Clin Immunol
. 2015
;11
(9
):1015
-1032
.9.
Zhu
Q
, Watanabe
C
, Liu
T
, et al. Wiskott-Aldrich syndrome/X-linked thrombocytopenia: WASP gene mutations, protein expression, and phenotype
. Blood
. 1997
;90
(7
):2680
-2689
.10.
Albert
MH
, Bittner
TC
, Nonoyama
S
, et al. X-linked thrombocytopenia (XLT) due to WAS mutations: clinical characteristics, long-term outcome, and treatment options
. Blood
. 2010
;115
(16
):3231
-3238
.11.
Imai
K
, Morio
T
, Zhu
Y
, et al. Clinical course of patients with WASP gene mutations
. Blood
. 2004
;103
(2
):456
-464
.12.
Jin
Y
, Mazza
C
, Christie
JR
, et al. Mutations of the Wiskott-Aldrich syndrome protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation
. Blood
. 2004
;104
(13
):4010
-4019
.13.
Mahlaoui
N
, Pellier
I
, Mignot
C
, et al. Characteristics and outcome of early-onset, severe forms of Wiskott-Aldrich syndrome
. Blood
. 2013
;121
(9
):1510
-1516
.14.
Dupuis-Girod
S
, Medioni
J
, Haddad
E
, et al. Autoimmunity in Wiskott-Aldrich syndrome: risk factors, clinical features, and outcome in a single-center cohort of 55 patients
. Pediatrics
. 2003
;111
(5 pt 1
):e622
-e627
.15.
Rivers
E
, Worth
A
, Thrasher
AJ
, Burns
SO
. Bleeding and splenectomy in Wiskott-Aldrich syndrome: a single-centre experience
. J Allergy Clin Immunol Pract
. 2019
;7
(3
):1042
-1044.e1
.16.
Magnani
A
, Semeraro
M
, Adam
F
, et al. Long-term safety and efficacy of lentiviral hematopoietic stem/progenitor cell gene therapy for Wiskott-Aldrich syndrome
. Nat Med
. 2022
;28
(1
):71
-80
.17.
Albert
MH
, Slatter
MA
, Gennery
AR
, et al. Hematopoietic stem cell transplantation for Wiskott-Aldrich syndrome: an EBMT Inborn Errors Working Party analysis
. Blood
. 2022
;139
(13
):2066
-2079
.18.
Burroughs
LM
, Petrovic
A
, Brazauskas
R
, et al. Excellent outcomes following hematopoietic cell transplantation for Wiskott-Aldrich syndrome: a PIDTC report
. Blood
. 2020
;135
(23
):2094
-2105
.19.
Cavannaugh
C
, Ochs
HD
, Buchbinder
D
. Diagnosis and clinical management of Wiskott-Aldrich syndrome: current and emerging techniques
. Expert Rev Clin Immunol
. 2022
;18
(6
):609
-623
.20.
Ferrua
F
, Marangoni
F
, Aiuti
A
, Roncarolo
MG
. Gene therapy for Wiskott-Aldrich syndrome: history, new vectors, future directions
. J Allergy Clin Immunol
. 2020
;146
(2
):262
-265
.21.
Gerrits
AJ
, Leven
EA
, Frelinger
AL
, et al. Effects of eltrombopag on platelet count and platelet activation in Wiskott-Aldrich syndrome/X-linked thrombocytopenia
. Blood
. 2015
;126
(11
):1367
-1378
.22.
Moratto
D
, Giliani
S
, Bonfim
C
, et al. Long-term outcome and lineage-specific chimerism in 194 patients with Wiskott-Aldrich syndrome treated by hematopoietic cell transplantation in the period 1980-2009: an international collaborative study
. Blood
. 2011
;118
(6
):1675
-1684
.23.
Ferrua
F
, Cicalese
MP
, Galimberti
S
, et al. Lentiviral haemopoietic stem/progenitor cell gene therapy for treatment of Wiskott-Aldrich syndrome: interim results of a non-randomised, open-label, phase 1/2 clinical study
. Lancet Haematol
. 2019
;6
(5
):e239
-e253
.24.
Albert
MH
, Freeman
AF
. Wiskott-Aldrich syndrome (WAS) and dedicator of cytokinesis 8- (DOCK8) deficiency
. Front Pediatr
. 2019
;7
:451
.25.
Shah
AJ
, Sokolic
R
, Logan
B
, et al. Quality of life of patients with Wiskott Aldrich syndrome and X-linked thrombocytopenia: a study of the Primary Immune Deficiency Consortium (PIDTC), Immune Deficiency Foundation, and the Wiskott-Aldrich Foundation
. J Clin Immunol
. 2019
;39
(8
):786
-794
.26.
Worth
AJ
, Metelo
J
, Bouma
G
, et al. Disease-associated missense mutations in the EVH1 domain disrupt intrinsic WASp function causing dysregulated actin dynamics and impaired dendritic cell migration
. Blood
. 2013
;121
(1
):72
-84
.27.
Richards
S
, Aziz
N
, Bale
S
, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology
. Genet Med
. 2015
;17
(5
):405
-424
.28.
Franklin by Genoox
. Accessed 24 December 2023. https://franklin.genoox.com.29.
Oken
MM
, Creech
RH
, Tormey
DC
, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group
. Am J Clin Oncol
. 1982
;5
(6
):649
-655
.30.
Team RC
. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing
; 2017
.31.
Bourne
HC
, Weston
S
, Prasad
M
, Edkins
E
, Benson
EM
. Identification of WASP mutations in 10 Australian families with Wiskott-Aldrich syndrome and X-linked thrombocytopenia
. Pathology
. 2004
;36
(3
):262
-264
.32.
Brooimans
RA
, van den Berg
AJ
, Tamminga
RY
, Revesz
T
, Wulffraat
NM
, Zegers
BJ
. Identification of six novel WASP gene mutations in patients suffering from Wiskott-Aldrich syndrome
. Hum Mutat
. 2000
;15
(4
):386
-387
.33.
El-Hakeh
J
, Rosenzweig
S
, Oleastro
M
, et al. Wiskott-Aldrich syndrome in Argentina: 17 unique, including nine novel, mutations
. Hum Mutat
. 2002
;19
(2
):186
-187
.34.
Liu
DW
, Zhang
ZY
, Zhao
Q
, et al. Wiskott-Aldrich syndrome/X-linked thrombocytopenia in China: clinical characteristic and genotype-phenotype correlation
. Pediatr Blood Cancer
. 2015
;62
(9
):1601
-1608
.35.
Proust
A
, Guillet
B
, Picard
C
, et al. Detection of 28 novel mutations in the Wiskott-Aldrich syndrome and X-linked thrombocytopenia based on multiplex PCR
. Blood Cells Mol Dis
. 2007
;39
(1
):102
-106
.36.
Amarinthnukrowh
P
, Ittiporn
S
, Tongkobpetch
S
, et al. Clinical and molecular characterization of Thai patients with Wiskott-Aldrich syndrome
. Scand J Immunol
. 2013
;77
(1
):69
-74
.37.
Gulácsy
V
, Freiberger
T
, Shcherbina
A
, et al. Genetic characteristics of eighty-seven patients with the Wiskott-Aldrich syndrome
. Mol Immunol
. 2011
;48
(5
):788
-792
.38.
Imai
K
, Nonoyama
S
, Ochs
HD
. WASP (Wiskott-Aldrich syndrome protein) gene mutations and phenotype
. Curr Opin Allergy Clin Immunol
. 2003
;3
(6
):427
-436
.39.
Li
W
, Liu
D
, Zhang
X
, Ding
Y
, Zhao
X
. Clinical features and genotype analysis of 132 patients with Wiskott-Aldrich syndrome [in Chinese]
. Zhonghua Er Ke Za Zhi
. 2015
;53
(12
):925
-930
.40.
Oshima
K
, Imai
K
, Albert
MH
, et al. Hematopoietic stem cell transplantation for X-linked thrombocytopenia with mutations in the WAS gene
. J Clin Immunol
. 2015
;35
(1
):15
-21
.41.
Safaei
S
, Fazlollahi
MR
, Houshmand
M
, et al. Detection of six novel mutations in WASP gene in fifteen Iranian Wiskott-Aldrich patients
. Iran J Allergy Asthma Immunol
. 2012
;11
(4
):345
-348
.42.
Suri
D
, Rikhi
R
, Jindal
AK
, et al. Wiskott Aldrich syndrome: a multi-institutional experience from India
. Front Immunol
. 2021
;12
:627651
.43.
Suri
D
, Singh
S
, Rawat
A
, et al. Clinical profile and genetic basis of Wiskott-Aldrich syndrome at Chandigarh, North India
. Asian Pac J Allergy Immunol
. 2012
;30
(1
):71
-78
.44.
Thompson
LJ
, Lalloz
MR
, Layton
DM
. Unique and recurrent WAS gene mutations in Wiskott-Aldrich syndrome and X-linked thrombocytopenia
. Blood Cells Mol Dis
. 1999
;25
(3-4
):218
-226
.45.
Chan
KW
, Lee
TL
, Chung
BH
, Yang
X
, Lau
YL
. Identification of five novel WASP mutations in Chinese families with Wiskott-Aldrich syndrome
. Hum Mutat
. 2002
;20
(2
):151
-152
.46.
Haskoloğlu
Ş
, Öztürk
A
, Öztürk
G
, et al. Clinical features and outcomes of 23 patients with Wiskott-Aldrich syndrome: a single-center experience
. Turk J Haematol
. 2020
;37
(4
):271
-281
.47.
Kwan
SP
, Hagemann
TL
, Blaese
RM
, Knutsen
A
, Rosen
FS
. Scanning of the Wiskott-Aldrich syndrome (WAS) gene: identification of 18 novel alterations including a possible mutation hotspot at Arg86 resulting in thrombocytopenia, a mild WAS phenotype
. Hum Mol Genet
. 1995
;4
(10
):1995
-1998
.48.
Landrum
MJ
, Lee
JM
, Benson
M
, et al. ClinVar: public archive of interpretations of clinically relevant variants
. Nucleic Acids Res
. 2016
;44
(D1
):D862
-D868
.49.
National Center for Biotechnology Information (NCBI) NLoM
. ClinVar:ClinVar is a freely accessible, public archive of reports of the relationships among human variations and phenotypes, with supporting evidence
. https://ncbi.nlm.nih.gov/clinvar/.50.
Albert
MH
, Sirait
T
, Eikema
DJ
, et al. Hematopoietic stem cell transplantation for adolescents and adults with inborn errors of immunity: an EBMT IEWP study
. Blood
. 2022
;140
(14
):1635
-1649
.51.
Wada
T
, Schurman
SH
, Jagadeesh
GJ
, Garabedian
EK
, Nelson
DL
, Candotti
F
. Multiple patients with revertant mosaicism in a single Wiskott-Aldrich syndrome family
. Blood
. 2004
;104
(5
):1270
-1272
.2024
You do not currently have access to this content.
This feature is available to Subscribers Only
Sign In or Create an Account Close Modal