Case Report: A Novel Pathogenic Missense Mutation in FAS: A Multi-Generational Case Series of Autoimmune Lymphoproliferative Syndrome

Abstract

Autoimmune Lymphoproliferative Syndrome (ALPS), commonly caused by mutations in the FAS gene, is a disease with variable penetrance. Subjects may be asymptomatic, or they may present with lymphadenopathy, splenomegaly, cytopenias, or malignancy. Prompt recognition of ALPS is needed for optimal management. We describe a multi-generational cohort presenting with clinical manifestations of ALPS, and a previously unreported heterozygous missense variant of uncertain significance in FAS (c.758G >T, p.G253V), located in exon 9. Knowledge of the underlying genetic defect permitted prompt targeted therapy to treat acute episodes of cytopenia. This cohort underscores the importance of genetic testing in subjects with clinical features of ALPS and should facilitate the reclassification of this variant as pathogenic.

Full text

CASE REPORT
published: 18 March 2021
doi: 10.3389/fped.2021.624116
Frontiers in Pediatrics | www.frontiersin.org 1March 2021 | Volume 9 | Article 624116
Edited by:
Ivan K. Chinn,
Baylor College of Medicine,
United States
Reviewed by:
Oskar A. Haas,
St. Anna Children’s Cancer Research
Institute (CCRI), Austria
Nicholas L. Rider,
Baylor College of Medicine,
United States
*Correspondence:
Jolan Eszter Walter
jolanwalter@usf.edu
†These authors share first authorship
Specialty section:
This article was submitted to
Pediatric Immunology,
a section of the journal
Frontiers in Pediatrics
Received: 30 October 2020
Accepted: 25 January 2021
Published: 18 March 2021
Citation:
Gaefke CL, Metts J, Imanirad D,
Nieves D, Terranova P, Dell’Orso G,
Gambineri E, Miano M, Lockey RF,
Walter JE and Westermann-Clark E
(2021) Case Report: A Novel
Pathogenic Missense Mutation in FAS:
A Multi-Generational Case Series of
Autoimmune Lymphoproliferative
Syndrome. Front. Pediatr. 9:624116.
doi: 10.3389/fped.2021.624116
Case Report: A Novel Pathogenic
Missense Mutation in FAS: A
Multi-Generational Case Series of
Autoimmune Lymphoproliferative
Syndrome
Claudia L. Gaefke 1†, Jonathan Metts 2† , Donya Imanirad 1, Daime Nieves 3,
Paola Terranova 4, Gianluca Dell’Orso 4, Eleonora Gambineri 5, Maurizio Miano 4,
Richard F. Lockey 1, Jolan Eszter Walter 3, 6
*and Emma Westermann-Clark 1,3
1Department of Medicine, University of South Florida, Tampa, FL, United States, 2Cancer and Blood Disorders Institute,
Johns Hopkins All Children’s Hospital, Saint Petersburg, FL, United States, 3Department of Pediatrics, University of South
Florida, Saint Petersburg, FL, United States, 4Hematology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy,
5NEUROFARBA, Meyer Children’s Hospital, Florence, Italy, 6Massachusetts General Hospital and Harvard Medical School,
Boston, MA, United States
Autoimmune Lymphoproliferative Syndrome (ALPS), commonly caused by mutations in
the FAS gene, is a disease with variable penetrance. Subjects may be asymptomatic,
or they may present with lymphadenopathy, splenomegaly, cytopenias, or malignancy.
Prompt recognition of ALPS is needed for optimal management. We describe a
multi-generational cohort presenting with clinical manifestations of ALPS, and a
previously unreported heterozygous missense variant of uncertain significance in FAS
(c.758G >T, p.G253V), located in exon 9. Knowledge of the underlying genetic defect
permitted prompt targeted therapy to treat acute episodes of cytopenia. This cohort
underscores the importance of genetic testing in subjects with clinical features of ALPS
and should facilitate the reclassification of this variant as pathogenic.
Keywords: ALPS (autoimmune lymphoproliferative syndrome), novel mutation, Fas, cytopenia, lymphoproliferation
INTRODUCTION
Autoimmune lymphoproliferative syndrome (ALPS) is characterized by lymphadenopathy,
splenomegaly, autoimmunity, especially autoimmune cytopenias, and an increased risk of
lymphoma. Lymphoproliferation and autoimmunity result from failure of effector T-cells to
undergo programmed cell death. The most common mutation associated with ALPS lies in the
FAS gene, and is labeled as ALPS-FAS; other known mutations that cause ALPS include Fas ligand
(FAS-L) and caspase 10 (CASP 10) (1,2). Germline mutations in FAS, inherited in an autosomal
dominant manner, comprise the largest group of ALPS cases, while somatic mutations in FAS
are the second most common genetic cause of ALPS (2,3). There is an expanding spectrum
of ALPS-like disorders, including caspase 8 deficiency state (CEDS, resulting from a germline
mutation in caspase 8 [CASP8]); RAS-associated autoimmune leukoproliferative disease (RALD),
resulting from gain of function somatic mutation of the neuroblastoma RAS viral oncogene (NRAS)
or proto-oncogene Kirsten Rat Sarcoma virus (KRAS); X-linked lymphoproliferative syndrome
(XLP1) resulting from mutation or deletion of the SH2D1A gene; heterozygous loss of function
mutation in nuclear factor kappa light chain enhancer of activated B cells (NFKB-1), heterozygous
loss of function mutation of cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and mutations
of the FAS-associated protein with death domain (FADD), among others. Approximately one-third

Gaefke et al. Case Report: Novel FAS Mutation in ALPS
of subjects with clinical features of ALPS have unidentified
genetic defects (1,2,4). Patients with unknown genetic
defects but clinical features of ALPS are classified as Dianzani
autoimmune lymphoproliferative disease (DALD) (2).
Children with confirmed genetic findings and clinical features
of ALPS require monitoring for cytopenias, splenomegaly, and
malignancy as they age. A sizeable proportion of subjects
with ALPS-FAS (74%) require medical/surgical intervention
during their lifetime, and intervention is often initiated
due to autoimmune cytopenias, massive splenomegaly, or
adenopathy (3).
The variable clinical phenotype of ALPS contributes to
the complexity of management. Affected subjects can carry
a pathogenic variant but be relatively asymptomatic, and
biomarkers for development of lymphoproliferation and
autoimmunity have not been fully established. It is challenging
to determine when to initiate immunomodulating therapy
with milder disease, such as intermittent thrombocytopenia.
Targeted therapy, including T-cell modulation with sirolimus,
can be beneficial, but timing and duration of therapy is unclear
(5,6). Splenectomy should be avoided because of the high risk
of subsequent sepsis, increased risk of death, and failure to
prevent recurrence of autoimmune cytopenia in many subjects
(3,7). Here we describe a family with a novel FAS mutation
FIGURE 1 | Pedigree of kindred. On left axis, generations are labeled with Roman numerals I-V. Individual members of the family are labeled with italicized Arabic
numerals. Family members related only by marriage are not numbered. Detailed family history was obtained from subject II-2, the maternal great-grandmother of the
proband V-1. Subject II-2 postulates that the FAS variant stems from her father’s side of the family (I-1) because his sister (not depicted) died of leukemia at age 17.
found across several generations and discuss challenges in
long-term management.
DEFINITION OF ALPS
For this study, ALPS was defined as proposed by Oliveira
et al. (2). These diagnostic criteria divide symptoms and
laboratory values into required and accessory criteria. Required
criteria include chronic (>6 months), non-malignant, non-
infectious lymphadenopathy or splenomegaly or both, and
elevated CD3+T-cell receptor (TCR)αβCD4-CD8- double
negative cells (DNTCs) (≥1.5% of total lymphocytes or
2.5% of CD3+lymphocytes) in the setting of normal or
elevated lymphocyte counts. Accessory criteria are divided
into primary accessory [(1) defective lymphocyte apoptosis
in two separate assays; (2) somatic or germline pathogenic
mutation in FAS, FASLG, or CASP10] and secondary accessory
criteria which include useful biomarkers (elevated soluble FAS-
ligand [sFASL], interleukin-10 (IL-10), vitamin B12, interleukin-
18 (IL-18) levels, elevated immunoglobulin G (IgG) levels),
typical immuno-histological findings, autoimmune cytopenias
(which must be accompanied by elevated IgG), or family
history of non-malignant/non-infectious lymphoproliferation
with or without autoimmunity. A definitive diagnosis is based
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Gaefke et al. Case Report: Novel FAS Mutation in ALPS
TABLE 1 | Immunophenotypic evaluation of pediatric subjects.
Subject Subject
Evaluation (units) Normal values for
age 12 mo
V-1 V-2 Normal values for age
6-8 years
V-3 V-4
Age at evaluation 13 months 12 months 6 years 8 years
IgG [mg/dL] 246–904 895
IgA [mg/dL] 27–66 73
IgM [mg/dL] 40–143 56
IgE [IU/mL] 0–200 5.2
Pneumococcal Titers >50% protective 5/10
Diphtheria [IU/mL] ≥0.01 1.83
Tetanus [IU/mL] ≥0.01 2.83
Hib [mg/dL] 1 0.81
WBC [10*3/mm3] 6.4–13.0 9.9 6.14 4.4–9.58 6.73 6.2
Hgb [g/dL] 10–13.2 11.2 10.1 10.9–14.9 13.5 14.8
MCV [fL] 70–90 80 30.3 76–98 78 85
PLT [10*3/mm3] 150–450 214 129 150–450 250 264
ANC [cells/mm3] 500–9500 2400 1140 1500–7500 3810 3420
Abs Lymph [cells/mm3] 3400–9000 7131 6387 1900–3700 2513 2300
Abs CD3 [cells/mm3] 1900–5900 5027 4747 1200–2600 2042 1754
CD4:CD8 [cells/mm3] 1.34–3.04 2.20 1.23 1.18–2.65 0.97 1.2
Abs CD4 [cells/mm3] 1400–4300 3170 2417 650–1500 844 877
Abs CD8 [cells/mm3] 500–1700 1397 1956 370–1100 867 738
Abs CD56 [cells/mm3] 160–950 267 243 110–480 205 197
Abs CD19 [cells/mm3] 610–2600 1745 1369 270–860 261 441
Ig, immunoglobulin; Hib, Haemophilus influenzae type b; WBC, white blood cell; Hgb, hemoglobin; MCV, mean cell volume; PLT, platelets; ANC, absolute neutrophil count; Abs, absolute;
Lymph, lymphocytes. Age-appropriate ranges were identified for immunoglobulins (9), CBC (10), lymphocyte subsets (11) and CD4:CD8 ratio (12).
on the presence of both required criteria plus one primary
accessory criterion; a probable diagnosis is based on the
presence of both required criteria plus one secondary accessory
criterion (2).
CASE PRESENTATION
The proband (V-1) (Figure 1) is a 7-month-old female who
presented to clinic with greater than 6 months of mild anterior
and posterior cervical and axillary lymphadenopathy, with the
largest lymph node measuring 1 cm in diameter in the neck. She
also had a spleen of 7.5 cm in length, slightly larger than normal
for age, with the upper limit being 7 cm in length for a 12-month
old (8). She had a history of asthma triggered by viral respiratory
tract infections and no history of recurrent or severe bacterial
sinopulmonary infections. She was normal developmentally for
her age. Complete blood count (CBC) with differential was
normal at presentation, but at 2 years of age she experienced
an episode of autoimmune hemolytic anemia, with hemoglobin
nadir of 5.3 g/dL and mild thrombocytopenia (platelets 108,000).
Immune evaluation was notable for normal immunoglobulin
levels and normal diphtheria and tetanus antibody titers;
however, pneumococcal titers were only protective for 50% of a
10-serotype panel, and patient had a low Haemophilus influenzae
type B (Hib) titer (Table 1).
Her mother (IV-1 in Figure 1) reported a personal history
of splenomegaly, which had been diagnosed along with “kidney
enlargement” during her pregnancy, and a family history of
splenomegaly, lymphadenopathy, and hematologic malignancy
in prior generation maternal relatives. The grandmother of
subject IV-1, subject II-2, reported a personal history of neck
lymphadenopathy requiring excision during her late teenage
years. Subject II-2 suspected that she had inherited her tendency
toward lymphadenopathy from her father (I-1 in Figure 1),
whose sister had died of leukemia at age 17.
Among living family members with suspected ALPS, a
17-month-old male second cousin (V-2) was also seen in
the clinic for persistent lymphadenopathy. Subject V-2 had
posterior cervical lymphadenopathy, splenomegaly, and history
of thrombocytopenia. There was no history of recurrent or
severe infections, bleeding, or other illnesses. His mother (IV-
2) reported a personal history of recurrent lymphadenopathy,
splenomegaly since childhood, and chronic anemia with no
formal history or testing for ALPS. Subject IV-1 and IV-2
(mothers to proband and V-2, respectively) share a maternal
grandmother (II-2), who reported neck lymphadenopathy in
her teenage years, as mentioned previously. This maternal
grandmother (II-2) had a sister (II-1) who was healthy, and a
brother (II-3) who required splenectomy at age 15 and often had
abnormal blood cell counts in childhood. A child of II-1, (male
child III-1), was healthy. II-3 had a son, III-6, who was healthy,
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Gaefke et al. Case Report: Novel FAS Mutation in ALPS
TABLE 2 | Family members evaluated based on ALPS Criteria.
Subject
ALPS Criteria V-1 V-2 V-3 V-4 IV-1 IV-2
Required:
TCR αβDNTcs >2% or >68
cells/µL
Present Present Present Absent N/A N/A
Clinical: LAD and/or
Organomegaly
Present Present Absent Absent Present Present
Primary accessory:
Genetic
sequencing
HMM HMM Declined Testing Declined Testing HMM HMM
FAS c.758 G>T
(p. Gly253 Val)
FAS c. 758 G>T
(p. Gly253 Val)
N/A N/A FAS c. 758 G>T
(p. Gly253 Val)
FAS c. 758 G>T
(p. Gly253 Val)
Apoptosis assay
(normal 68-93%)
38% N/A N/A N/A 41% N/A
Secondary accessory:
IL-18 (normal <540 pg/mL) 1513 958 714 260 N/A N/A
IL-10 (normal <2 pg/mL) 300 186 40.5 <1.6 N/A N/A
sFAS-L (normal 69-492 pg/mL) 5952 4825 1601 169 N/A N/A
Vitamin B12 (normal
200-1100 ng/mL)
>2000 >2000 1892 675 N/A N/A
Clinical manifestations AIHA ITP Absent Absent History of anemia History of Anemia
Family history LP, AI LP, AI LP, AI LP,AI LP, AI LP, AI
AI, autoimmunity; AIHA, autoimmune hemolytic anemia; DNTCs, double negative T cells; HMM, heterozygous missense mutation; IL, interleukin; ITP, immune thrombocytopenia; LAD,
lymphadenopathy; LP, lymphoproliferation; N/A, not applicable; sFAS-L, soluble FAS ligand.
but his grandson IV-3 required splenectomy at 1 year of age due
to splenomegaly. Subject II-2 also had four children (subjects III-
2, III-3, III-4, and III-5) who did not show notable signs of ALPS.
Based upon this information, further evaluation was pursued
in available family members, which included two half-siblings
of subject V-2: subjects V-3 and V-4. Subject V-3, a 6-year-old
female, had a history of recurrent oral lesions resembling herpes
simplex virus with no clinical evidence of ALPS. Subject, V-4, an
8-year-old female, had a history of recurrent ear infections and
otherwise no clinical history suggestive of ALPS.
LABORATORY EVALUATION AND
RESULTS
Given this clinical multi-generational history, laboratory
evaluation of the kindred was undertaken to identify a possible
shared mutation leading to ALPS.
The proband and her mother were evaluated for ALPS. As
noted above, the proband had a relatively normal immune
phenotype except for low recall response to certain vaccine
antigens. Proband’s mother (IV-1) had mild leukocytosis on
CBC but normal absolute lymphocytes (3100 cells/µL), and full
immune phenotyping was not performed. Both proband and
mother had an abnormal apoptosis assay; proband (V-1) had FAS
activity of 38% of control, and mother (IV-1) had FAS activity
41% of control (normal 68–93%). Flow cytometry in V-1 showed
>2% TCR αβDNTcs (Cincinnati’s Children’s Hospital ALPS
Flow Cytometry panel, Cincinnati, OH) which prompted further
evaluation for accessory criteria. Secondary accessory criteria,
including clinical and serological markers, were met as noted
on Table 2. For confirmation, genetic sequencing was pursued
using a 207-gene Primary Immunodeficiency Panel (Invitae, San
Francisco, CA). Genetic sequencing confirmed a mutation in
FAS, c.758G>T (p.G253V), exon 9, in the death domain. This
mutation was identified in both the proband and her mother.
This sequence change replaces glycine with valine at codon 253 of
the FAS protein (p.Gly253Val). The glycine residue is moderately
conserved and there is a moderate physicochemical difference
between glycine and valine. This variant is not reported in the
literature with FAS-related conditions and is not present in
Genome Aggregation Databases (gnomAD June 2020, no allele
frequency). The Genome Aggregation Database (gnomAD), also
known as ExAC in its first release, does not include individuals
with G253V amino acid substitution mutations. It does include 5
individuals with a nearby p.His285Arg mutation among 251,308
alleles sequenced.
Laboratory evaluation for subjects V-2, V-3, and V-4 (second
cousins of the proband) and their mother (IV-2) was performed.
Subjects V-2, V-3, and V-4 did not undergo full immune
phenotyping, but CBC and lymphocyte subsets, along with
age-appropriate normal ranges, are reported in Table 1. ALPS
panel testing was performed in V-2, V-3, and V-4. V-2 and V-
3 had >2% TCR αβDNTcs and serological markers consistent
with ALPS, while subject V-4 did not meet criteria for ALPS
(Table 2). Subject IV-2 declined genetic sequencing for subject
V-3 and V-4, but genetic sequencing in subject V-2 confirmed
the same variant. Both mothers (subjects IV-1 and IV-2) did
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Gaefke et al. Case Report: Novel FAS Mutation in ALPS
FIGURE 2 | Timeline of proband’s clinical course, including clinical and laboratory diagnosis, treatment and response to therapy.
not wish to undergo immune phenotyping, serologic markers, or
ALPS panel, but chose to pursue genetic testing; the same genetic
variant was confirmed.
EVOLUTION OF CLINICAL PHENOTYPE
AND TREATMENT
One year after initial presentation, the proband developed an
acute episode of autoimmune hemolytic anemia, initially treated
with corticosteroids and high dose intravenous immunoglobulin
(IVIG). Since she had an established diagnosis of ALPS, targeted
therapy with sirolimus was initiated at 2 mg/m2. She was able
to discontinue corticosteroids and has not required further high
dose IVIG or hospitalization (Figure 2). The family elected
to discontinue sirolimus after 1 year of treatment, and she
is currently being monitored for recurrence of cytopenias or
progression of ALPS.
Subject V-2, who met criteria for ALPS, was also found
to have intermittent thrombocytopenia, with platelet counts
between 84,000 and 200,000/µL. He is being monitored with
plans to initiate sirolimus for platelet counts <50,000/µL or other
persistent cytopenias.
Subject V-3 is being monitored for clinical manifestations of
ALPS, as she meets required and secondary accessory criteria, but
parents have declined genetic sequencing.
Subject V-4 did not manifest clinical or laboratory features of
ALPS, and parents declined genetic sequencing.
Subjects IV-1 and IV-2, both of whom carry the VUS in
FAS, are being monitored for further clinical manifestations
of ALPS.
DISCUSSION
Autoimmune lymphoproliferative syndrome is a disease with
variable penetrance from asymptomatic to lymphadenopathy,
splenomegaly, cytopenias, and malignancy. Though most
patients develop lymphoproliferation at a median age
of 11.5 months, seemingly unaffected family members
with heterozygous FAS pathogenic variants are also
predisposed to malignancy, most commonly non-
Hodgkin lymphoma later in life, with a lifetime risk of
up to 20% (13,14). This underscores the importance
of recognizing ALPS promptly to appropriately manage
complications and to monitor asymptomatic kindred for
prompt recognition of malignancy which may present later
in life.
When the proband met criteria for ALPS, it was decided to
pursue screening for willing kindred. By doing this, a second
family member (subject V-2) was found to meet criteria for ALPS.
A third family member (V-3) has not developed the required
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Gaefke et al. Case Report: Novel FAS Mutation in ALPS
clinical manifestations of ALPS but does meet many laboratory
benchmarks for ALPS diagnosis, including elevated DNTCs, IL-
18, IL-10, sFAS-L, and vitamin B12. In total, four of the six family
members agreed to genetic testing, and all four were found to
share the same VUS in FAS.
The missense mutation identified by the genetic testing
company (Invitae) that performed the 207-gene primary
immunodeficiency panel was labeled as a “variant of uncertain
significance (VUS)” because symptomatic individuals with this
specific variant have not previously been reported in the literature
or in population databases. The absence of the variant in
population sequence databases increases the likelihood that
it is pathogenic. A stop codon in the same residue G253V
has been previously reported, with a FAS-induced apoptosis
of 25% of control, slightly less than the apoptosis activity
reported in this study (38–41%) (15). There have been multiple
FAS mutations reported in the death domain of exon 9, and
these mutations can show clinical variability among family
members, including asymptomatic members with the mutation
and diminution of signs and symptoms with increasing age
(15,16). The cohort described in this paper shows a similar
pattern of clinical presentation, with the most affected subjects
presenting during childhood. Taken together, the novel missense
mutation, apoptosis assay/ALPS panel, and absence of the variant
in population databases provide moderate to strong evidence that
this variant should be reclassified as pathogenic, according to
published guidelines for the interpretation of sequence variants
(17). The clinical phenotype and cosegregation of the gene in
multiple affected family members provide additional supporting
evidence (17).
Confirmation of ALPS with genetic sequencing facilitates
clinical use of targeted therapies for complications of ALPS.
Several potential therapies exist, including corticosteroids, IVIG,
rituximab, mycophenolate mofetil (MMF), and mammalian
target of rapamycin (mTOR) inhibitor therapy such as sirolimus
(18). While the proband’s autoimmune hemolytic anemia
was initially treated with corticosteroids and intravenous
immunoglobulin, due to the genetic diagnosis, she was
successfully transitioned to sirolimus, minimizing steroid
exposure. This is not surprising given published reports of
durable complete response of autoimmunity, lymphadenopathy,
and splenomegaly within 3 months of sirolimus initiation in
ALPS subjects, as well as no detection of DNTCs in most subjects
(19). Though rituximab is often used as a second-or third line
option for pediatric subjects with autoimmune cytopenia, the
risk of B-cell depletion and prolonged hypogammaglobulinemia
is a concern, and long-term management with corticosteroids
is not ideal. Splenectomy for autoimmune cytopenia is a
last resort, given the risk of sepsis and failure to prevent
recurrence of cytopenias in many subjects post-splenectomy
(7). Mycophenolate mofetil (MMF) is generally well-tolerated
and inactivates a key enzyme in purine synthesis required
for lymphocyte proliferation (20,21). However, MMF does
not reduce DNTCs, which may account for suboptimal
results such as a partial response or relapse in some ALPS
subjects (13). Sirolimus shows good responses in ALPS
subjects with autoimmune cytopenias, with possible side effects
including hypercholesteremia, hypertension, and mucositis (22).
Monitoring of clinical symptoms and ALPS biomarkers can be
used to decide when and how treat patients with confirmed
disease, as these biomarkers can increase as disease becomes
active. DNTCs tend to decrease when patients are treated with
sirolimus, and monitoring of DNTC percentage can therefore
be useful. Additional serological biomarkers to monitor disease
activity and treatment response include vitamin B12 levels,
soluble FAS ligand, interleukin-10, and interleukin-18 levels. It
is important to note that achieving the target plasma levels of
sirolimus is not necessary to control the disease, as levels can
be below 5 ng/mL and still be effective for disease control
(23,24). Additionally, in pediatric subjects who show decreased
disease activity and eventually go into remission as they reach
adolescence, sirolimus discontinuation can be considered, and
the medication can be restarted if relapses occur.
We trust that this report will facilitate reclassification of
this FAS variant as pathogenic and underscore the importance
of genetic testing, which is useful for targeted therapy, family
planning, and monitoring patients for malignancy.
DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included
in the article/supplementary material, further inquiries can be
directed to the corresponding author/s.
ETHICS STATEMENT
The studies involving human participants were reviewed
and approved by Johns Hopkins Institutional Review Board
IRB00103900. Written informed consent to participate in this
study was provided by the participants’ legal guardian/next of kin.
Written informed consent was obtained from the individual(s),
and minor(s)’ legal guardian/next of kin, for the publication of
any potentially identifiable images or data included in this article.
AUTHOR CONTRIBUTIONS
CG, JM, and JEW conceived the presented idea. CG, EW-C,
JEW, and JM verified the methods used and reviewed the clinical
information presented. CG, JM, DI, EW-C, and JEW assisted
with data collection and manuscript review and editing. EG
provided guidance regarding long-term management of subjects
and serologic monitoring. EW-C oversaw the writing, data
collection, and editing process. RFL provided critical review of
the manuscript. MM, PT, and GD performed apoptosis assay on a
research basis. JEW encouraged to describe this cohort’s findings
and supervised the findings of this work. All authors discussed
the results and contributed and agreed to the final manuscript.
FUNDING
This research was partly funded by Johns Hopkins All Children’s
Hospital (JHACH) Institutional Grant entitled Feasibility study
to assess the role of T and B cells in refractory cytopenias in
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Gaefke et al. Case Report: Novel FAS Mutation in ALPS
children (JEW), the Jeffrey Modell Foundation, Jeffrey Modell
Diagnostic and Research Center at JHACH and the Robert A.
Good Endowment at the University of South Florida. The Jeffrey
Modell Foundation funds supported genetic testing. The JHACH
Institutional Grant supported a larger study on autoimmune
cytopenia, in which the ALPS subjects were enrolled.
ACKNOWLEDGMENTS
Alina Ramirez as liaison for the study who assisted with
coordination of patient care. Maryssa Ellison and Sumai Gordon
for research/sample coordination. Earle Trott for assistance with
publication documents.
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Conflict of Interest: The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be construed as a
potential conflict of interest.
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Frontiers in Pediatrics | www.frontiersin.org 7March 2021 | Volume 9 | Article 624116