Persistent PTSD among Patients with Fragile X Syndrome: Case Series

Annals of Clinical and Medical
Case Reports
Case Series ISSN 2639-8109 Volume 12
Tak Y1
, Pinto IM2,3#
, Chi MH2,4#
, Schneider A2,5
, Tassone F2,6
, Bourgeois JA5
and Hagerman RJ2,5*
1
University of California, Davis School of Medicine, Sacramento, California, United States of America
2
Medical Investigation of Neurodevelopmental Disorders (M.I.N.D.) Institute, University of California, Davis, Sacramento, California,
United States of America
3
Department of Pediatrics, Gustavo Fricke Hospital, Viña Del Mar, Chile
4
Department of Psychiatry, National Cheng Kung University College of Medicine, Tainan, Taiwan
5
Department of Pediatrics, University of California, Davis, Sacramento, California, United States of America
6
Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, California, United States of Amer-
ica
7
Department of Psychiatry and Behavioral Sciences, University of California, Davis, Sacramento, California, United States of America
Persistent PTSD among Patients with Fragile X Syndrome: Case Series
*
Corresponding author:
Randi Hagerman MD,
Medical Director of the MIND Institute
Distinguished Professor, Endowed Chair in Fragile
X Research, UC Davis Health System, 2825 50th
Street Sacramento, CA 95817, USA
#These authors contributed equally to this work
Received: 22 Nov 2023
Accepted: 27 Dec 2023
Published: 01 Jan 2024
J Short Name: ACMCR
Copyright:
©2024 Hagerman RJ. This is an open access article
distributed under the terms of the Creative Commons
Attribution License, which permits unrestricted use, dis-
tribution, and build upon your work non-commercially
Citation:
Hagerman RJ, Persistent PTSD among Patients with
Fragile X Syndrome: Case Series. Ann Clin Med Case
Rep. 2024; V12(9): 1-7
United Prime Publications LLC., https://acmcasereport.org/ 1
Keywords:
Fragile X syndrome; posttraumatic stress disorder;
Behavioral regression; Intellectual disability;
Autism spectrum disorder
1. Abstract
1.1. Background: Posttraumatic stress disorder (PTSD) affects
about 3.6% of the US population and has clear diagnostic criteria
and treatment modalities. Individuals with autism spectrum dis-
order (ASD) and intellectual disabilities (ID) are at an elevated
risk for exposure to trauma and development of PTSD. Fragile X
syndrome (FXS) is the most common inherited cause of ID, and
there is currently need for further research regarding presentation
of PTSD among these individuals.
1.2. Case Presentation: We report three cases of individuals with
FXS and ID seen at a neurodevelopmental research center who
had traumatic experiences leading to severe PTSD symptoms. The
details of the traumatic event, patients’ social and communication-
al baselines and subsequent changes, manifestations of different
PTSD symptoms, and various psychopharmacological and non-
pharmacological interventions are discussed. Compared to PTSD
in neurotypical individuals, we find that post-traumatic symptoms
in FXS are more severe and very long lasting, even up to 10 years.
While the cases exhibited some classic symptoms of PTSD, there
were also non-classic behaviors involving significant developmen-
tal regression and exacerbation of pre-existing behavior problems
in response to trauma. In all cases, there was minimal improve-
ment with classic PTSD treatments, both psychopharmacological
and non-pharmacological.
1.3. Conclusion: There is a high risk of developing severe PTSD
among individuals with FXS. Given this risk, it is recommended
to take measures to avoid creating traumatic situations. Further re-
search regarding how PTSD manifests in FXS and effective treat-
ment modalities for these patients is merited.
2. Introduction
Posttraumatic stress disorder (PTSD) is defined by the American
Psychiatric Association as a disorder that may result after an indi-
vidual witnesses or lives through an event that presents a threat to
life and safety, and causes emotions of fear, terror or helplessness
[1] (Table 1). The current prevalence of PTSD in the United States

Volume 12 Issue 9 -2024 Case Series
is estimated to be about 3.6%, but for people with intellectual dis-
abilities (ID), the prevalence of PTSD has been reported to be up
to 10% [2]. Over the years, there has been concern that the preva-
lence of PTSD is underreported among those with ID, as measures
and screening tools had not been adapted to this population. The
Impact of Event Scale Questionnaire was modified for patients
with ID in a study by Hall et al in 2014, and a pilot study used
the Diagnostic Manual-Intellectual Disability (DM-ID) criteria for
PTSD, which showed that a greater number of study participants
with ID met criteria for PTSD under these modified guidelines
compared to use of the DSM-IV-TR guidelines [3, 4].
Individuals with autism spectrum disorders (ASD) and those with
IDs are at a higher risk of trauma exposure and development of
PTSD-spectrum symptoms [5]. Higher levels of anxiety, aggres-
sion, hyperactivity and social withdrawal were identified in youth
with ASD in response to traumatic experiences [6]. Additionally,
individuals with ASD demonstrated regressions in adaptive behav-
ior and exacerbation of behavioral problems in response to trauma
[7]. A case series by Santoro et al in 2020 identified unexplained
regression in patients with Down syndrome [8]. Among these pa-
tients, a significant number had other psychiatric co-morbidities
(including PTSD) and experienced more life stressors such as trau-
ma/loss/grief. Among individuals with 22q11.2 DS, it was identi-
fied that there was a higher risk of developing PTSD (8.0%) com-
pared to the general population (3.6%) [9]. While there is literature
regarding PTSD and response to traumatic experiences among in-
dividuals with ASD and in those with IDs, information remains
sparse for patients with fragile X syndrome. Fragile X syndrome
(FXS) is the most common inherited cause of ID. It is known that
individuals with FXS experience hyperarousal and greater anxiety
than normal patients at baseline and are at higher risk for develop-
ing a maladaptive stress response to traumatic or disruptive events.
Cordeiro et al. in 2011 identified the prevalence of formal anxie-
ty disorders in FXS. Among 58 males and 39 females with FXS,
86.2% of males and 76.9% of females met diagnostic criteria for
an anxiety disorder [10]. One case series described the psycholog-
ical and functional issues following traumatic experiences among
individuals with FXS and ID [11]. In this study, two individuals
with FXS and ID presented with severe PTSD symptoms follow-
ing motor vehicle accidents. Treatment with cognitive behavioral
therapy was provided for both patients, but minimal information
was discussed regarding treatments for PTSD with FXS. With
this in mind, we report three individuals with FXS and ID who
developed chronic psychological disturbances and behavioral re-
gression following various traumatic experiences. We also report
the different medications and treatment modalities the patients re-
ceived to address symptoms following their traumatic events, and
their effectiveness. Finally, we discuss safety planning and sugges-
tions for preventing traumatic events and improving well-being
among individuals with FXS and ID.
Table 1: DSM-V Criteria for PTSD
All the following criteria are required for a diagnosis of PTSD:
1.     Exposure to threatened death, serious injury, sexual violence one (or
more) different ways
·       Directly experiencing the event
·       Witnessing the event
·       Learning the event occurred to a close family member/friend
·       Indirect exposure to aversive details of the event
2.     Presence of one (or more) intrusive symptoms associated with the
traumatic event, beginning after the event occurred
·       Unwanted, disturbing memories
·       Nightmares
·       Flashbacks
·       Emotional distress to traumatic reminders
·       Physiological distress to traumatic reminders
3.     Persistent avoidance of stimuli associated with the event, one (or
more) of the following
·       Avoidance of distressing memories, feelings related to the event
·       Avoidance of external reminders of the event
4.     Negative changes in cognition and mood associated with the event,
one (or more) of the following
·       Inability to remember key aspects of the event
·       Persistent negative beliefs about oneself/world
·       Exaggerated self-blame, or blaming others for causing event
·       Persistent negative emotional state
·       Decreased interest in activities
·       Feeling isolated
·       Difficulty experiencing positive emotions
5.     Marked changes in arousal and reactivity associated with the event,
two (or more) of the following
·       Irritable behavior, angry outbursts
·       Reckless/self-destructive behavior

·       Hypervigilance
·       Exaggerated startle response
·       Concentration problems
·       Sleep disturbance
Additional criteria: ·       Duration of symptoms > 1 month
·       Disturbance causes significant distress/impairment in daily
functioning
·       Disturbance not attributed to effects of a substance or alternate
medical condition
3. Patient Cases
3.1. Case 1
Case 1 was a 31-year-old male with FXS and ASD. His DNA test-
ing demonstrated a full mutation in FMR1 that was unmethylated
in bands from 213 to 280 CGG repeats and methylated in bands
from 797 to 1063 CGG repeats. About 10 years prior to presenta-
tion, he returned home from work crying, agitated, and vomiting
with no clear precipitating event. He was urgently taken to the
emergency room by his father. When they arrived at the hospital,
the patient’s father informed the ED staff of the patient’s history of
FXS and associated excess sensitivity to sensory stimuli. Despite
this caution, an emergency department staff member at the front
desk closely approached the patient, and he became overwhelmed
and hit her. Police arrived and the patient was physically restrained
and tasered multiple times. He became apneic and was admitted
to the ICU for two days on mechanical ventilation. While admit-
ted, a urine toxicology screen showed traces of multiple drugs of
abuse. Per the patient’s parents, it was thought that someone at his
job (at a nonprofit organization for people with ID) was providing
him illicit drugs, and this could have caused his increased agita-
tion. Following discharge, the patient experienced severe anxiety
and global functional regression. He became unable to perform
his baseline tasks, such as showering and sleeping independently.
He experienced sleep disturbances, often waking multiple times a
night saying he “needed to shower”. He would avoid leaving home
for work and withdrew socially from his “favorite people,” like his
grandparents. The patient perseverated about his experience of be-
ing tasered and expressed a new fear of doctors, actively opposing
going to outpatient visits. He was trialed on multiple medications,
including citalopram 30 mg BID, guanfacine 2 mg TID, metformin
1000 mg BID, quetiapine 100 mg BID & 200 mg QHS, lithium
300 mg BID, minocycline 200 mg QD, alprazolam 1 mg BID, and
cannabidiol (CBD) capsules. Metformin 1000 mg BID was found
to slightly improve anxiety [12]. He also tried Eye Movement De-
sensitization and Reprocessing (EMDR) psychotherapy, received
regular individual psychotherapy, and participated in yoga. EMDR
was mildly helpful for his PTSD symptoms. Case 1 had previously
been friendly and outgoing, but following the incident he became
socially withdrawn and unable to carry out his activities of daily
life. Ten years following the event, he continued to have ongoing
symptoms of severe anxiety, disturbed sleep, and avoidance of so-
cial settings. The only improvement was absence of subsequent
violent interactions.
3.2. Case 2
Case 2 was a 21-year-old female with FXS, ADHD, and general-
ized anxiety disorder (GAD). Her FMR1 DNA testing demonstrat-
ed a full mutation that was 100% methylated with bands at 597
and 1030 on one X and 19 CGG repeats on the second X and her
activation ratio was 0.5. At age 20, the patient was on an airplane
with her father when a flight attendant asked her if she wanted to
have something to eat. She was very shy and turned her head away
while the flight attendant continued to address her, even though
her father said she was shy and did not want to respond. When
they landed, the police were present at the gate and arrested the
father on suspicion of human trafficking. The patient was placed in
another room for questioning, and she eventually communicated
that the man was her father. The situation was determined to be a
misunderstanding and the pair was released. Following this event,
the patient’s anxiety escalated substantially. She subsequently re-
fused to travel on airplanes and resisted leaving home. She experi-
enced sleep disturbances and nightmares, only falling asleep with
a parent by her side. She became unable to attend her special needs
academic classes and participate in recreational activities such as
swimming, because she could not be separated from her parents
for long periods of time. The patient received ongoing psychother-
apy and was trialed on metformin 1000 mg BID, sertraline 75 mg
QD, desvenlafaxine 100 mg QD, and baclofen 40 mg BID, which
all somewhat improved her anxiety. A trial of quetiapine 25 mg
QD was not helpful and was discontinued. After a year, the patient
was eventually able to attend classes at a secondary school, but
only half-time because she continued to exhibit parent separation
anxiety. She was not able to go on family trips due to her fear of
airplanes and continued to require parent presence to fall asleep.
3.3. Case 3
Case 3 was a 10-year-old male with FXS, ADHD and ASD. His
DNA testing demonstrated a full mutation in FMR1 with >200
CGG repeats. At age 9, he was scheduled for a dental procedure.
Prior to induction of anesthesia the patient’s mother attempted to
set expectations for the procedure; however, the patient panicked
with anesthetic mask placement and required five people to im-

mobilize him while sevoflurane was administered. Immediately
post-anesthesia, the patient aspirated vomit and required brief en-
dotracheal tube placement. After respiratory stabilization, the pa-
tient was extubated and discharged with prophylactic antibiotics.
Arriving home, he continued to vomit with minimal food intake,
and displayed significant behavioral changes and regression in lan-
guage and behavior. The patient became non-verbal, and parents
found him having moments of non-interactive, blank staring. After
two weeks of minimal nutritional intake, the patient was admit-
ted to a local children’s hospital, and a nasogastric feeding tube
was placed. Diagnostic workup including an EEG, ECG and CT
scan were unremarkable. The patient spent several more days in
the hospital before his nutritional status improved and he began
eating small amounts. However, his behavior changes persisted.
He became increasingly disruptive (e.g., opening cabinets, throw-
ing plates and other household items) and with parent intervention
he would scream and become physically violent. The patient could
not be taken to public spaces like department stores, because he
would knock items off shelves and damage property. He became
behaviorally oppositional and violent with peers in academic set-
tings, to the point he was not allowed to return to classes. The
patient became fearful of all medical settings. He could not sleep
more than 3 hours/night due to nightmares. He lost bowel control
(a developmental milestone he had gained at 12 months) and re-
quired restarting the use of diapers. The patient refused all forms
of therapy and continued to have episodes of minimal nutritional
intake, such that he eventually required G-tube placement. The
patient was previously treated with guanfacine 1.5 mg BID, cloni-
dine 0.2 mg QHS, melatonin 3 mg QHS, methylphenidate 27 mg
QD, and multivitamins. Two months following the event, he was
tried on sertraline 25 mg daily, which improved his behavior, sleep
quality and regaining of toilet training skills. Following G-tube
placement, he experienced improved nutritional and weight status.
4. Discussion
Through the cases presented in this report, we illustrated the var-
ying manifestations of traumatic experiences among individuals
with FXS and ID. All three patients experienced significant de-
velopmental regression and worsening behavior problems is sim-
ilar to the presentation of patients with ASD and PTSD described
by Mehtar and Mukaddes in 2011 [6]. In this study, patients with
ASD and PTSD were found to express increased anxiety, aggres-
sion, hyperactivity, and behavioral regression. It is notable that
both case 1 and case 3 had a prior co-diagnosis of ASD, and up to
67% of males and 23% of females with FXS are also diagnosed
with ASD [13]. Therefore, there may be significant overlaps in
how PTSD presents in patients with FXS+ASD and those with
ASD alone. Treatment modalities for patients with PTSD and ASD
could be considered for populations with FXS+ASD. All cases
also exhibited some classic symptoms of PTSD, including sleep
disturbances, avoidance of trauma-associated situations, anxiety,
and hyperarousal and they met diagnostic criteria for DSM-IV and
DSM 5. Compared to PTSD in neurotypical individuals, we find
that symptoms are more severe and persistent in these individuals
with FXS – even up to 10 years with minimal improvement from
standard therapies such as SSRIs, EMDR and psychotherapy. Case
1 and 2 experienced developmental and social regression and were
not able to attend school and go to work independently, nor leave
the home and be separated from their primary caregivers for ex-
tended periods of time.
4.1. Neurobiology of FXS and Trauma
There are molecular factors associated with FXS that increase vul-
nerability for developing a maladaptive stress response to trauma.
GABA receptors are involved in anxiety and stress responses, and
the GABAergic system (specifically the amygdala) has been found
to be disturbed and deficient in FXS [14]. Poor sensory gating with
abnormal processing of external stimuli in response to stress may
further magnify the impact of traumatic experiences in FXS [15,
16]. Studies have identified that the fragile X messenger ribonu-
clear protein (FMRP) and the FMR1 gene have a role in modulat-
ing PTSD and acute stress. In rodent models, FMRP and fragile
X related protein 1 (FXR1) was decreased in the hippocampus of
rats following a stressful stimulus, and miR132 was an upstream
modulator that regulated FMRP and FXR [17]. Response to acute
stress was assessed between a FMR1 knockout (KO) and wild-
type control mouse. Both were exposed to acute stress, and the KO
mice exhibited a longer corticosterone response compared to WT
mice, suggesting that the stress response is dysregulated in FMR1
KO mice as in FXS patients [18]. The Big Potassium (BK) channel
is dysregulated in the absence of FMRP. Therefore, in FXS, ex-
cess stimulation with trauma can lead to overactivation of the BK
channel, causing a more dramatic behavioral response and perhaps
amplifying PTSD symptoms [19].
4.2. Treatment of PTSD in FXS
Given that the pathophysiology of posttraumatic disorder involves
brain regions like the amygdala, hypothalamus and hippocampus,
along with changes in various neurotransmitters systems and the
inflammatory process, pharmacological interventions targeting
these areas provide positive effects in diminishing posttraumatic
symptoms [20]. Current monotherapy for treating PTSD involve
SSRI/SNRIs, as well as the antipsychotic quetiapine. Prazosin and
risperidone had positive effects for augmentation. There was no
evidence of superiority for these medications over one another
[21]. There is currently no information regarding effective phar-
macological interventions for individuals with commingled PTSD
and FXS. In regards to improving behavior and cognition in indi-
viduals with FXS alone, studies have identified the effectiveness of
sertraline, CBD, metformin and guanfacine [12, 22–25]. CBD has
been found to be useful in improving social avoidance and anxiety
among individuals with FXS [22, 26]. Research is recommended
to explore the role of these pharmacological treatments to improve

PTSD symptoms in FXS. A systemic review of non-pharmacolog-
ical interventions for individuals with ID and trauma symptoms
reported effectiveness of both cognitive behavioral therapy (CBT)
and EMDR, with greater benefit from EMDR [27]. Trauma-fo-
cused CBT(TF-CBT) could improve symptoms of aggression and
depression associated with trauma in some individuals with ID
[28–30]. However, it is worth noting that the self-awareness, cog-
nitive reconstruction, and imagination skills required for therapies
like CBT may limit the use of TF-CBT among individuals with
severe ID and FXS. EMDR may be particularly useful for some
people with ID, as it does not require identification or articulation
of a traumatic event to have a therapeutic effect. Adaptations to
EMDR interventions to increase accessibility for individuals with
ID have included splitting the traumatic event into smaller compo-
nents, increased verbal input by the psychotherapist, and the use
of bilateral tactile and auditory in addition to visual stimulation
[31]. Further research is required to assess the use of EMDR to
address PTSD symptoms among individuals with FXS, although it
was only minimally helpful in Case 1.
5. Conclusion
5.1. Safety Planning
The events surrounding our patients’ traumatic experiences are
notable. Two of the cases involved police intervention, and two in-
volved intensive hospitalization. Case 1 was tasered by police and
Case 2 witnessed her father arrested and interrogated. In both cas-
es, escalation could have been avoided with better understanding
and awareness of the behavioral and social deficits that individuals
with FXS experience. Escalation to a painful physical immobiliza-
tion with a taser by law enforcement has been frequently reported
among individuals with ID, with negative consequences that can
be lifelong. Aggressive “challenging behavior” in individuals with
ID leads to frequent contact with mental health services, ED ad-
missions, and involvement with law enforcement [32]. There have
been training programs designed for staff working at residential/
care facilities for individuals with ID. These programs were found
to improve understanding about people with ID, promote effec-
tive communication, and establish appropriate crisis intervention
plans [33, 34]. These interventions lead to not only the reduction
of traumatic crises, but also benefits in the well-being of the pa-
tient, family members and frontline workers. Therefore, further
training for frontline workers in the community such as police,
teachers, community care providers is warranted. Both Case 1
and 3 were acutely hospitalized for apneic and aspiration events
respectively and for Case 3 it is possible that the sevoflurane could
have contributed to toxic brain injury and exacerbation of PTSD
symptoms [35]. Intensive hospital experiences are a major form of
trauma for individuals with ID, and greater efforts need to be made
to optimize inpatient care and procedures (such as anesthesia) for
individuals with neurodevelopmental disorders. One approach is
to take the patient’s ID history early in hospitalization and estab-
lishing the baseline symptoms such as communication and social
abilities, sensory sensitivities and repetitive behaviors [36]. For
operative and other sedative procedures, the provider should con-
sider using alternative anesthetic agents to minimize impact on
cognitive function [35]. There is a large role for multi-disciplinary
special needs support teams and mental health expertise in hospi-
tal settings to improve experiences and outcomes for hospitalized
patients with ID [37].
5.2. Recommendations
For parents and caregivers, the initial steps for avoiding traumat-
ic experiences for individuals with FXS involve anticipation (Ta-
ble 2). Maintaining predictable routines and setting expectations
contributes significantly to emotional stability. It is important to
maintain consistent communication and allow space for frequent
questions. When entering new situations, we recommend provid-
ing abundant time for the event, and ensuring other aspects of life
remain routine. Development of PTSD in individuals with FXS
can occur even after what seems to be an innocuous event. If an
event leads to a posttraumatic stress response, the focus should be
on processing and healing. It is important to ensure that the indi-
vidual with FXS re-enters a familiar environment to comfortably
respond to the recent experience. It is important to recognize when
an individual with FXS has gone through a traumatic experience
and early therapeutic intervention is recommended. For those en-
countering individuals with FXS, their responses to stressful situ-
ations can manifest in different ways, including agitation, scream-
ing, and physical violence. We recommend avoiding immediate
immobilization, and creating a safe space where the individual
with FXS can eventually be calmed. Parents or close relatives are
the most ideal members to intervene and defuse these situations.
In all cases, we advise talking to the agitated individual in a calm
tone and approaching them slowly, being aware of their safety and
one’s own. Our strongest recommendation is to avoid violent inter-
vention whenever possible and never use immobilization measures
such as a taser unless faced with a life-threatening situation. For
psychiatrists, management of patients with FXS after traumatic ex-
periences is manifold. In patients with known FXS, ASD, and/or
ID, physicians need to be aware of a possible high risk of PTSD,
even following routine medical/surgical procedures. Diagnosis of
PTSD is difficult with any patient with communication barriers,
especially if the onset of PTSD further impairs communication.
For patients with neuropsychiatric conditions requiring operative
or sedative procedures, their responses to anesthetic agents may
be excessive and put them at risk for further compromise. Patients
with ID may not respond well to routine psychotherapy approach-
es. Creative use of off-label psychopharmacology may be needed
for both the neuropsychiatric symptoms of the baseline FXS as
well as new-onset PTSD due to subsequent, disruptive (including
medical-surgical) events.

Table 2: Recommendations for addressing PTSD in FXS
Parents, Caregivers, Family Members
Anticipation
Diverse methods of communication Verbally, visually with pictures/drawings
Allow space for numerous, frequent questions Leading up to the event, right before the event, following the event
Familiarize the new experience Visiting the new space, allowing family to stay with patient throughout hospitalization
Maintain routines Maintaining sleep schedule, meal times, school/work activities
Stress management
Place the individual in a familiar environment
Allow for various forms of expression, both verbal and non-verbal
Provide early therapeutic interventions
General Public
Avoid immediate immobilization
Create a safe space to reduce agitation
Allow for parents/caregiver intervention
Speak in a calm voice, and approach slowly
Avoid physical immobilization or tasers
Consultation-Liaison Psychiatrists
Recognize high risk for developing PTSD in FXS
Recognize varying presentations of PTSD in FXS
Caution in regards to anesthetic agents in FX related disorders
Awareness of the lack of evidence-based treatment for PTSD in FXS and consider creative use of off-label psychopharmacology
6. Acknowledgement
YT, IMP and MC conceptualized this manuscript, reviewed pri-
mary literature, collected patient case data, drafted the initial man-
uscript, and reviewed and revised the manuscript. AS proofread
the initial manuscript and critically reviewed the manuscript. FT
provided the molecular data of the cases, proofread the initial man-
uscript and critically reviewed the manuscript. RJH conceptual-
ized this manuscript, proofread the initial manuscript and critically
reviewed the manuscript. JAB critically reviewed and edited the
manuscript, adding psychiatry-specific content. All authors ap-
proved the final manuscript as submitted and agree to be account-
able for all aspects of the work.
7. Funding
This research was partially supported by the Azrieli Foundation
and private donors in addition to the MIND Institute Intellectual
and Developmental Disability Research Center funded by NICHD
(P50 HD103526)
8. Conflict of Interest/Disclosures
RJH has received funding from Zynerba for clinical trials of CBD
in FXS and from the Azrieli Foundation for a metformin study in
FXS. The other authors have no conflicts.
9. Patient Consent Statement
Parents/legal guardian of all cases provided verbal and written
consent for the writing of this case series.
10. Ethical Publication Statement
The study was approved by the local ethics committee and con-
ducted according to the principles of the Declaration of Helsinki.
All patients and their guardians gave written informed consent.
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