Main text word count: 777
Number of supporting files: 1 Table, 1 Figure
Running title: ALL in a patient with Bainbridge-Ropers
Syndrome
Keywords : ASXL3 , malignancy, BRPS, cancer,
germline ASXL3 mutation
To the editor,
The Additional Sex Combs Like (ASXL) gene family is comprised of theASXL1 , ASXL2 , and ASXL3 genes which encode proteins
involved in epigenetic regulation, embryogenesis, and
carcinogenesis1-3. Despite the implication of somaticASXL mutations in a variety of malignancies, germline ASXLmutations do not appear to have an association with increased malignancy
risk. Bainbridge-Ropers Syndrome (BRPS) is a rare autosomal dominant
genetic disorder that results from de novo mutations in the ASXL3gene4, characterized by poor growth, hypotonia,
intellectual disability, language delay, and dysmorphic facial
features5. Many affected patients have autism
disorder, and epilepsy is seen in approximately one-third of
patients6, 7. The few published reports of cancer in
patients with germline ASXL mutations are limited to patients
with ASXL1 mutations, implicating Bohring-Opitz Syndrome (BOS), a
phenotypically similar neurodevelopmental syndrome to BRPS. These
include two patients with bilateral Wilms tumor8, and
a father and son with identical germline ASXL1 mutations with
acute myeloid leukemia9. Unlike BOS, there have been
no reported cases of malignancy in patients with BRPS. Here we report
the clinical course of a 3-year-old male with known BRPS found to have
precursor B-cell acute lymphoblastic leukemia (ALL).
At 10-months-old, the patient underwent neurologic evaluation due to
developmental delay, feeding difficulties, and growth failure. He was
hypotonic and had subtle dysmorphic features, including arched eyebrows
and anteverted nares. An Autism/ID Xpanded Panel demonstrated a de novo
pathogenic variant of the ASXL3 gene (c.4678C>T;
p.R1560X), consistent with BRPS.
At 3-years-old, he presented with acute feeding intolerance, fatigue,
and abdominal pain. Laboratory analysis showed: white blood cell (WBC)
12.7/mm3 with 27% peripheral blasts,
hemoglobin 8.3 g/dL, and platelet count 69,000/mm3.
Peripheral flow cytometry identified an immature lymphoid population
consistent with precursor B-cell ALL (Table 1). Bone marrow analysis
showed no detectable clonal abnormalities on standard cytogenetics and
fluorescence in situ hybridization (FISH) analysis showed tetrasomy of
chromosomes 4, 8q, 10, 12p, 21q, 22q sequences, trisomy of chromosome 9
and 11 sequences, and homozygous deletion of 9p21 (CDKN2A ).
He underwent standard-risk three-drug induction therapy with
dexamethasone, vincristine, and peg-asparaginase. Post-induction bone
marrow evaluation was morphologically negative for malignancy and
negative by FISH. Minimal residual disease (MRD) testing revealed a
persistent immature clonal B-cell population representing 0.056% of
nucleated cells prompting escalation to high-risk consolidation
therapy10, which was complicated by several
toxicities. This included a prolonged episode of altered mental status
with magnetic resonance imaging (MRI) findings suggestive of intrathecal
methotrexate toxicity, and a subsequent episode requiring ICU admission
for refractory status epilepticus. Notably, neither the timing of
seizure onset nor the MRI findings were consistent with methotrexate
toxicity during this episode, and there was no identifiable etiology for
his new-onset seizure activity.
Repeat marrow evaluation following consolidation therapy was negative
for malignancy by morphology, FISH, and MRD. He began interim
maintenance therapy with intravenous (IV) high-dose methotrexate,
vincristine, 6-mercaptopurine, and intrathecal methotrexate, and again
suffered numerous toxicities and treatment delays. Following his second
dose of IV methotrexate, he presented with increased irritability,
fatigue, and new petechiae. Laboratory analysis showed: WBC
52.9/mm3 with 37% blasts, 2% myelocytes, and 2%
reactive lymphocytes, concerning for relapsed disease versus lineage
switch (Fig. 1).
Bone marrow immunophenotyping revealed a persistent clonal immature
B-cell population with increased myelomonocytic marker expression (CD13:
57%, CD33: 58%, MPO: 2%) compared to initial diagnosis. Homozygous
loss of CDKN2A sequences in 74.3% was detected by FISH as
observed in his original clone, as well as gain of 8q21.3
(RUNX1T1 ) sequences, consistent with relapsed pre-B ALL with
aberrant myeloid marker expression. Shortly thereafter, he developed
respiratory failure, severe electrolyte derangements, and his mental
status declined. Due to his poor prognosis and concerns regarding poor
tolerability of additional therapy, his family elected to forego further
treatment. He was discharged on hospice care and ultimately succumbed to
his disease.
Somatic ASXL3 mutations have been reported in a subset of solid
tumors but unlike ASXL1 mutations, they are infrequently seen in
hematologic malignancies11, 12, potentially due to a
more restricted pattern of ASXL3 expression compared toASXL1 and ASXL2 in hematopoietic
cells12-14. To our knowledge, this case of pre-B ALL
in a patient with a known germline ASXL3 mutation represents the
first report of malignancy in a patient with BRPS. His initial oncologic
presentation followed a typical clinical course for a pediatric patient
with new-onset ALL, however his disease proved to be highly aggressive
and poorly responsive to standard therapy. He endured several
complications during therapy, including neurotoxicity which he may have
been predisposed to in the setting of by his underlying genetic
disorder. While an isolated case cannot determine cancer risk for an
entire group of patients, the potential for malignancy should be
considered in patients with this rare genetic diagnosis.
Conflict of Interest: The authors have no conflicts of
interest to disclose.
Acknowledgements: n/a
References:
1. Balasubramanian M, Willoughby J, Fry AE, et al. Delineating the
phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with
de novo, heterozygous, loss-of-function mutations in ASXL3 and review of
published literature. J Med Genet . Aug 2017;54(8):537-543.
doi:10.1136/jmedgenet-2016-104360
2. Katoh M. Functional proteomics of the epigenetic regulators ASXL1,
ASXL2 and ASXL3: a convergence of proteomics and epigenetics for
translational medicine. Expert Rev Proteomics . Jun
2015;12(3):317-28. doi:10.1586/14789450.2015.1033409
3. Christopher J. Gibson BLE, David P. Steensma.
. In: Ronald Hoffman EJB, Leslie E. Silberstein, Helen E. Heslop,
Jeffrey I. Weitz, John Anastasi, Mohamed E. Salama, Syed Ali Abutalib,
ed. Hematology . 7 ed. 2018:944-969:chap 60 - Myelodysplastic
Syndromes.
4. Bainbridge MN, Hu H, Muzny DM, et al. De novo truncating mutations in
ASXL3 are associated with a novel clinical phenotype with similarities
to Bohring-Opitz syndrome. Genome Med . 2013;5(2):11.
doi:10.1186/gm415
5. Russell B, Graham JM, Jr. Expanding our knowledge of conditions
associated with the ASXL gene family. Genome Med . 2013;5(2):16.
doi:10.1186/gm420
6. Myers KA, White SM, Mohammed S, et al. Childhood-onset generalized
epilepsy in Bainbridge-Ropers syndrome. Epilepsy Res . Feb
2018;140:166-170. doi:10.1016/j.eplepsyres.2018.01.014
7. Yu KP, Luk HM, Fung JLF, Chung BH, Lo IF. Further expanding the
clinical phenotype in Bainbridge-Ropers syndrome and dissecting
genotype-phenotype correlation in the ASXL3 mutational cluster regions.Eur J Med Genet . Jan 2021;64(1):104107.
doi:10.1016/j.ejmg.2020.104107
8. Russell B, Johnston JJ, Biesecker LG, et al. Clinical management of
patients with ASXL1 mutations and Bohring-Opitz syndrome, emphasizing
the need for Wilms tumor surveillance. Am J Med Genet A . Sep
2015;167A(9):2122-31. doi:10.1002/ajmg.a.37131
9. Seiter K, Htun K, Baskind P, Liu Z. Acute myeloid leukemia in a
father and son with a germline mutation of ASXL1. Biomark Res .
2018;6:7. doi:10.1186/s40364-018-0121-3
10. National Cancer Institute and Children’s Oncology Group. Children’s
Oncology Group (COG); [cited 2021 Nov]. Available
from:www.childrensoncologygroup.org/.
11. Duployez N, Micol JB, Boissel N, et al. Unlike ASXL1 and ASXL2
mutations, ASXL3 mutations are rare events in acute myeloid leukemia
with t(8;21). Leuk Lymphoma . 2016;57(1):199-200.
doi:10.3109/10428194.2015.1037754
12. Micol JB, Abdel-Wahab O. The Role of Additional Sex Combs-Like
Proteins in Cancer. Cold Spring Harb Perspect Med . Oct 3
2016;6(10)doi:10.1101/cshperspect.a026526
13. LaFave LM, Beguelin W, Koche R, et al. Loss of BAP1 function leads
to EZH2-dependent transformation. Nat Med . Nov
2015;21(11):1344-9. doi:10.1038/nm.3947
14. Fisher CL, Randazzo F, Humphries RK, Brock HW. Characterization of
Asxl1, a murine homolog of Additional sex combs, and analysis of the
Asx-like gene family. Gene . Mar 15 2006;369:109-18.
doi:10.1016/j.gene.2005.10.033