Expanding Clinical Spectrum of Female X-linked
Lymphoproliferative Syndrome 2
Shruthi Suryaprakash, MD1, Mohammad
El-Baba2, MD, Kelly J. Walkovich,
MD3, Süreyya Savaşan, MD4
1Children’s Hospital of Michigan
2Division of Gastroenterology, Children’s Hospital of
Michigan
3Division of Hematology/Oncology, Immuno-Hematology
Comprehensive Program, C.S. Mott Children’s Hospital, University of
Michigan
4Division of Hematology/Oncology and Blood and Marrow
Transplant Program, Children’s Hospital of Michigan, Carman and Ann
Adams Department of Pediatrics, Barbara Ann Karmanos Cancer Center,
Central Michigan University College of Medicine
Correspondence: Süreyya Savaşan, MD
3901 Beaubien Blvd.
Division of Hematology/Oncology
Blood and Marrow Transplant Program
Children’s Hospital of Michigan
Detroit, Michigan 48201
E-mail: savas1s@cmich.edu
Phone: 313-745-5516
Fax: 313-745-5237
Text word count: 495
Reference count: 4
Tables and figures: 1
Short running title: Spectrum of Symptomatic Female XLP2
Key words: Female XLP2, EBV reactivation, Vitamin B12
deficiency, B-cell lymphopenia, clonal T-LGL proliferation
Dear Editor:
X-linked lymphoproliferative syndrome type 2 (XLP2) due to pathogenic
variants in the X-linked inhibitor of apoptosis (XIAP) gene is a rare
cause of primary immunodeficiency. Symptomatic patients, primarily
males, present with hemophagocytic lymphohistiocytosis (HLH),
inflammatory bowel disease (IBD) and/or transient
hypogammaglobinaemia.1 However, XLP2 in female
patients is complicated with the rarity of symptomatic cases and
clinical heterogeneity.2 We report a female affected
by XLP2 with previously unreported findings.
A currently 18-year-old female presented with fever, abdominal pain,
diffuse lymphadenopathy, splenomegaly, and pancytopenia three years ago.
She was diagnosed with HLH, treated with steroids and found to have low
B-cells and borderline hypogammaglobinemia. Additionally, a single
pathogenic variant in XIAP (c.389_392delACAG
[p.Asp130Glyfs*11]) was identified. Further workup showed presence
of EBV IgG, and normal expression of XIAP protein in only 8-19% of
various white blood cell types by flow cytometry indicating skewed X
chromosome inactivation. She had intermittent infections, one resulting
in an additional HLH flare with elevated IL-18 and CXCL9 levels that was
treated with steroids and intravenous immunoglobulin (IVIG). Repeated
EBV PCR testing had been negative.
However, she was found to have EBV reactivation with positive EBV
VCA-IgM, high titer VCA-IgG and EA-IgG levels while EBV-PCR was negative
when she presented to our clinic with diarrhea. There was ongoing
history of headaches, abdominal pain, joint pain, and ADHD at that time.
Later, she underwent work up for recurrent abdominal pain, diarrhea,
urgency and elevated fecal calprotectin. MRI-enterography and capsule
endoscopy were negative. Endoscopy was remarkable for chronic active
proctitis. She was prescribed mesalamine with significant improvement in
abdominal pain and resolution of mucuosy stools.
Due to persistent knee/ankle pain, she was investigated for peripheral
neuropathy and was found to have low vitamin B12 levels (112-145pg/mL;
N:180-914) without dietary restrictions, absent anti-intrinsic factor
antibodies and negative family history. Her pain improved significantly
on vitamin B12 injections and gabapentin with normalization of vitamin
B12 levels.
She continued to have fluctuating and borderline low levels of serum
immunoglobulins with persistently low B-cells. She was given IVIG
supplementation when serum IgG levels were low. No additional HLH flares
have occurred. Mild increase in CD5-dim T-cells (9%) representing
T-large granular lymphocytes (T-LGL) and clonal T-cell receptor (TCR)
rearrangement pattern were identified in peripheral blood. She continues
to have migraine episodes and very high EA-IgG at >150U/mL
(N <9).
Female carriers are at risk for extra hematopoietic manifestations, if
they have an extremely skewed X chromosome
inactivation.3 She was EBV-PCR negative, but EBV
VCA-IgM positive repeatedly suggesting a recent reactivation at
presentation to our institution. Persistent high EBV EA-IgG titers is
suggestive of ongoing EBV challenge due to immune deficiency and
emphasizes the significance of EBV serology testing. Clonal T-LGL
expansion may be related to EBV and/or immune
deficiency.4 Low vitamin B12 raises the possibility of
impairment in absorption; the presence of proctitis raises possible
subclinical inflammation in the distal ileum. Observed conditions in
this case add to the spectrum of this rare entity (Table1).