A Novel Psychiatric Phenotype of Chromosome 4q

Deletion: A case report

Sarah L Vaithilingam (  [email protected] )
Rogers Behavioral Health
Sheldon Garrison
Rogers Behavioral Health
Julia Krantz
Medical College of Wisconsin
Aman Mahajan
Rogers Behavioral Health
John Diener
Rogers Behavioral Health

Case Report

Keywords: Hyperphagia, ADHD, rare disease, sleep, ASD, autism, parasomnia, hallucinations

Posted Date: September 22nd, 2023

DOI: https://doi.org/10.21203/rs.3.rs-3317958/v1

License:   This work is licensed under a Creative Commons Attribution 4.0 International License.
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Abstract
Background

Chromosome 4q deletion is a rare genetic disorder affecting an estimated 1 out of 100,000 people,
although there are relatively few reports in the literature. It is characterized by microdeletions of the long
arm of chromosome 4 with variable clinical presentations including heart defects, craniofacial and
skeletal abnormalities, short stature, and developmental delays. While behavioral and psychiatric
symptoms have been reported in a small number of Chromosome 4q deletion patients, none of these
reports have described the hyperphagia or parasomnia symptoms that are presented in the current case.

Case presentation

A 7-year-old male patient presented with a microdeletion of the long arm of chromosome 4 that resulted
in psychiatric symptoms and neurodevelopmental delays. Notable manifestations included aggression,
hyperphagia, parasomnias, functional encopresis and speech delays. At inpatient admission, a
multidisciplinary approach to diagnosis and treatment was adopted, encompassing pharmacological and
behavioral interventions. His initial treatment was markedly delayed due to limited genetic testing at age
one, which led to a misdiagnosis of childhood aggression. This limited the care team involvement for
neurologic evaluation and appropriate school interventions that would have otherwise been indicated.

Conclusion

Chromosome 4q deletion -related behaviors parallel that of children with autism spectrum disorder (ASD),
and treatment is primarily focused on behavioral interventions. In the current case, the patient’s attention-
deficit/hyperactivity disorder (ADHD) was treated, and his individualized education plan (IEP)
recommendations included a functional behavioral assessment, the Behavioral Assessment System for
Children, occupational therapy services and speech and language services. Following a 4-day inpatient
stay, the patient demonstrated a significant decrease in aggressive behaviors.

BACKGROUND
Chromosome 4q deletion is a rare genetic finding marked by terminal or interstitial deletions on the long
arm of chromosome 4. It is estimated to occur in 1 out of 100,000 people and affects males and females
equally [5]. Chromosome 4q deletion is characterized by a vast range of phenotypic presentations,
including developmental delays, short stature, congenital heart defects and facial abnormalities. It also
has varied psychiatric presentations including developmental delay, ADHD, autism spectrum disorder
(ASD) and schizoaffective disorder. The large phenotypic variation of chromosome 4q deletion makes it
challenging to characterize specific genotype-phenotype relationships for varying 4q deletions in children
with psychiatric symptoms [6]. The rarity of chromosome 4q deletions and the incomplete penetrance of
its symptoms have been highlighted as major obstacles in outlining candidate genes for specific
phenotypes [6, 7].

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In the present report, a child with 4q deletion presented with aggressive behavior, parasomnias, cognitive
impairment, speech disorder, functional encopresis and hyperphagia. While aggression, intellectual
disability and speech delay have been previously described in the literature on 4q microdeletions,
parasomnias and hyperphagia have not. The maladaptive behaviors in this case were linked to sleep-
related hallucinations, hyperphagia and food-seeking behaviors.

CASE PRESENTATION
A 7-year-old boy presented to the child and adolescent inpatient psychiatric unit in a large behavioral
health care system with aggressive behaviors, hyperphagia and parasomnias. He was born to
nonconsanguineous parents, and there were no complications during pregnancy or delivery. Prior to
hospitalization, the patient did not undergo any psychiatric evaluations and there was no history of home
medications.

The patient had a 7-year medical history of developmental delays and behaviors, including hyperphagia,
encopresis, speech and articulation problems and problems with fine motor skills. His history included
concerns of malnutrition and suspected failure to thrive at the age of 1. At the age of 1, a nasogastric
(NG) tube was initiated due to concerns of failure to thrive. Routine lab work did not show any
abnormalities. Following weeks without gaining weight, and due to the complexity of the presentation,
genetic testing was performed to determine genetic disease involvement. This initial testing revealed a
microdeletion of chromosome 4 and he was subsequently diagnosed with a chromosome 4q
microdeletion. Further genetic analysis determined that his mother was the carrier.

At the time of admission, the 7-year-old patient’s general physical examination showed short stature, 25th
percentile for weight, microcephaly, gastroesophageal reflux disease (GERD), lactose intolerance and
unspecified neurocognitive disorder. Other psychiatric complaints included parasomnia, particularly
hypnogogic hallucinations, where he often described the “snakes and monsters” that would attempt to
eat him. The patient’s parent reported that these daily hallucinations would cause the patient to lock
himself in the bathroom screaming and crying. Additionally, he had hyperphagia that led to atypical
behaviors. His food-seeking behaviors were excessive, with his parent reporting that he would hoard food,
consume large quantities of food to the point of emesis, consumed food throughout the night and day
and was reported to obtain discarded food items taken from the outdoors.

A connection between the hyperphagia and aggressive behaviors was suspected, particularly at times
when his demands for food were not met. These behaviors were at times dangerous to the patient and
those around him. For example, his parent reported that he intentionally set the microwave on fire when
his food demands were not met. The patient also had daily parasomnias, as defined by the International
Classification for Sleep Disorders [11]. This would cause significant behavioral dysregulation. The
patient’s parents reported that at home he would also urinate in cups and hide them in his room.

The patient’s parents also provided historical reports of aggressive behaviors that included flipping
tables, pulling his sibling out of bed and burning the targeted sibling. At the time of admission for
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psychiatric hospitalization, the patient demonstrated physically aggressive behaviors towards objects
and others, selective mutism and poor eye contact. The patient also regularly displayed self-injurious
behaviors that included punching himself or repeatedly hitting his head against the wall to the point he
would bleed. The patient continued to urinate in inappropriate places in the hospital, typically in the
corner of his room and in cups.

After psychiatric inpatient admission, the patient was evaluated and stabilized for acute aggression.
Given the neurodevelopmental and behavioral concerns, much of the treatment course focused on
presenting symptoms and setting up an appropriate medical work up including cardiology, child
development, gastroenterology (for hyperphagia and encopresis), sleep medicine for non-REM (rapid eye
movement) sleep disorder and neurocognitive evaluation. Community support that included a case
manager, therapist and psychiatrist was also established in advance of discharge. Poor reality testing
was not initially demonstrated, and therefore he was not diagnosed with psychosis or started on
antipsychotic medications. The patient was diagnosed with other specified neurodevelopmental disorder,
ADHD and non-REM sleep disorder. He was started on clonidine extended release, 0.1mg twice daily
(b.i.d.), to treat his sleep, impulsivity and aggression. The patient received daily dialectical behavioral
group therapy.

The patient was discharged following 4 days of treatment after demonstrating decreased aggressive and
self-injurious behaviors. He denied experiencing perceptual disturbances, including parasomnias, and
was calm and cooperative. He continued to present with ASD-related symptoms. He had poor eye contact
and was easily distracted by objects in the room. His verbal skills were limited, using 3–5 word
sentences. He described his mood as “good” although his affect appeared blunted, with minimal facial
expression. Thought content reflected questions about animals and when he would be able to talk to his
mother. His thought process was concrete and underdeveloped for chronological age. He had very little
insight into why he was at the hospital and his judgment was limited.

After discharging, the patient continued to be followed by child psychiatry and pediatrics. His
neurodevelopmental evaluation came back confirming ADHD and other specified neurodevelopmental
disorder. His cardiology report came back normal with no concerns for structural or electrical
abnormalities that could affect the prescribing of atypical antipsychotics for treating his aggressive
behaviors. Recommendations included continuation on 0.1mg clonidine b.i.d., IQ-testing, functional
behavioral assessment, speech and language assessment, occupational therapy, consult with a
nutritionist and completion of a sleep study.

DISCUSSION AND CONCLUSIONS

This case report is focused on a unique presentation of chromosome 4q deletion. To the best of our
knowledge, there are no previous reports of the association of parasomnia and hyperphagia with
chromosome 4q deletion. The patient’s preoccupation with food and problems with REM sleep are
suspected to have contributed to the complexity of his behavioral presentation, particularly his

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aggression, which became difficult to quell without psychiatric intervention. Importantly, adverse food-
related behaviors are not uncommon in children; however, the extent to which this child was behaving
around food was comparable to children with Prader-Willi syndrome [12]. Collectively, these features
highlighted the 7-year diagnostic delay that placed substantial burden on both the patient and his family.

Adding to this complexity, the correlation between cognitive impairment and the psychiatric symptoms
observed in the reported case remains unclear. Moreover, the severity of the intellectual disability varies
broadly in individuals with confirmed 4q deletions. Consequently, a critical avenue for future investigation
entails examining the interplay between intellectual disabilities and the diverse array of psychiatric
features within this patient population.

The large phenotypic variation of chromosome 4q deletion makes it challenging to characterize specific
genotype-phenotype relationships for varying 4q deletions in children with psychiatric symptoms such as
such as developmental delay, ASD, ADHD and schizoaffective disorder. Developmental delay, which
included language, encopresis and fine motor skills in our patient, is a particular phenotype of
chromosome 4q deletion that has been closely evaluated in critical regions in the chromosome to
determine the genotype-phenotype relationship [13]. Deletion of the terminal region of the long arm of
chromosome 4 results in common features of chromosome 4q deletion, including developmental delay,
learning difficulties, and craniofacial, digital, skeletal and cardiac anomalies [14]. Phenotypic differences
between patients with a terminal deletion seems to largely be based on breakpoint locations starting at
4q33 vs 4q34, 4q33, which is suggested to be the critical region for the 4q terminal deletion [13, 14].

The genetic underpinnings of ASD presentation in children with chromosome 4q deletion continues to be
explored, with some genotype—phenotype correlations previously reported. For example, a 19 MB deletion
spanning from 4q32 to 4q34 was identified in a young boy with chromosome 4q deletion and resulting
ASD [15]. By examining the deletion region and associated genes, five candidate autism-specific genes
were identified [15]. One goal of this line of work is to continue to individualize treatment planning. The
patient in the current case report had limited verbal expression, which limited the assessment and
identification of his social impairment. To address this limitation, neuropsychological testing for autism
was recommended to enhance the depth of understanding of the patient’s social reciprocity, despite his
language deficits. Specifically, it was recommended that either the Autism Diagnostic Observation
Schedule (ADOS) [16] or the Autism Diagnostic Interview-Revised (ADI-R) [17] be used.

ADHD is also common in children with chromosome 4q microdeletions. In a study of a multigenerational

family who was genetically isolated, linkage was determined at certain chromosomal regions, including
4q13.2. Results were consistent across multiple forms of linkage analysis and indicate that chromosome
4 does contain ADHD susceptibility genes [18]. ADHD is often associated with the DAT1 dopamine
transporter gene that has been mapped to chromosome 5p15. It codes for a solute carrier protein
responsible for the reuptake of dopamine from the synaptic cleft back to the presynaptic neuron. Other
genes such as Mastermind Like Transcriptional Coactivator 3 (MAML3; chromosomal 4 at 4q28.3) and
the DRD5 dopamine D5 receptor (DRD5; chromosome 4 at 4p15.3) have been explored as potential

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contributors to ADHD and disruptive behavioral disturbances [19, 20]. Although their role in the
presentation of chromosome 4q deletion is not well understood.

Studies have also begun to explore the potential presentation of schizoaffective disorder in patients with
chromosome 4q deletion. This relationship was first described in an individual with a 4q deletion who
had a learning disability and psychosis [21]. It has been established that those with intellectual
disabilities may be at a significantly higher risk of developing schizoaffective disorder [22]. Indeed, to
help improve the lives of patients diagnosed with cognitive impairment, screening for symptoms of
schizophrenia, bipolar disorder and other mental health conditions may be best practice [21, 23]. It
remains unclear if individuals with 4q deletions and accompanying intellectual disabilities would
specifically be at increased risk for psychosis and mood disorders; however, the current report suggests
that these should be assessed when treating patients with chromosome 4q deletion.

The challenging range of psychiatric symptoms faced by patients with chromosome 4q deletion, and
their families and caregivers, can be substantial. Parents of children diagnosed with 4q deletion have
reported feeling overwhelmed and concerned about the dearth of information and training on the
condition that is available to medical professionals [5]. Delayed genetic testing is common for rare
diseases, which can subsequently delay comprehensive psychiatric testing and optimal therapeutic
approaches. It is important for additional studies to be published that continue to characterize this
debilitating condition. With an estimated 3300 people diagnosed in the United States alone [5], yet fewer
than 200 cases reported worldwide [6], there is likely to be a significant number of undiagnosed patients,
highlighting an urgent need to inform the broader medical community.

Without a clear constellation of psychiatric symptoms that define 4q deletion, identifying patients with
this condition remains challenging. This specific case contributes to the characterization of chromosome
4q deletion, as the patient had a unique psychiatric presentation that included hyperphagia and
parasomnia. Once the diagnosis is made, and aside from crisis stabilization in an acute psychiatric
setting, we strongly recommend an IEP that includes a functional behavioral assessment, the Behavioral
Assessment System for Children [24], the National Institute for Children's Health Quality (NICHQ)
Vanderbilt Assessment Scales [25], occupational therapy, social skills training, and speech and language
services (Fig. 1). To successfully manage the psychiatric features of this complex condition, we also
recommend the involvement of a multidisciplinary team that includes a psychiatrist, pediatrician, medical
geneticist, dietician, speech and language therapist, physical therapist, occupational therapist,
psychologist, and special education teacher to reduce the need for crisis intervention.

Abbreviations
ADOS Autism Diagnostic Observation Schedule

ADI-R Autism Diagnostic Interview-Revised

ADHD Attention-deficit/hyperactivity disorder

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ASD Autism spectrum isorder

BDNF Brain-derived neurotrophic factor

b.i.d. Twice a day

GERD Gastroesophageal reflux disease

IEP Individualized education plan

IQ Intelligence quotient

MAML3 Mastermind-like transcriptional coactivator 3

NG Nasogastric

REM Rapid eye movement

Declarations
ACKNOWLEDGEMENTS

The authors wish to acknowledge the patient and his family for their assistance. The authors also wish to
acknowledge Isaac Siegel for his comments on the manuscript.

FUNDING

The authors thank the Rogers Behavioral Health Foundation for their support on this project.

Data availability

Not applicable.

Ethics approval and consent to participate.

This case study was determined to be non-human subjects research by the Rogers Behavioral Health
Institutional Review Board.

Consent for publication

A HIPAA waiver was provided, and the patient and parent signed a consent to use data contained in the
electronic medical records.

Competing interests

The authors declare that there is no conflict of interest regarding the publication of this article.

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Figures

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Figure 1

Flowchart of recommended testing and management for children presenting with developmental delays
when genetic disease is suspected that may increase detection of chromosome 4q deletion.

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