MINI REVIEW

published: 11 January 2022

doi: 10.3389/fpsyt.2021.803898

Ehlers-Danlos Syndrome in the Field

of Psychiatry: A Review
Hiroki Ishiguro 1,2,3*, Hideaki Yagasaki 1 and Yasue Horiuchi 1,4
1
Center of Genetic Medicine, Hospital, University of Yamanashi, Kofu, Japan, 2 Cancer Counseling and Support Center,
Hospital, University of Yamanashi, Kofu, Japan, 3 Department of Neuropsychiatry, Graduate School of Medicine, University of
Yamanashi, Kofu, Japan, 4 Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical
Science, Tokyo, Japan

Ehlers-Danlos syndrome (EDS) comprises a series of rare hereditary connective tissue

diseases characterized by joint hypermobility, joint dislocation, and hyperextensibility of
the skin, as well as cardiovascular involvement. EDS is often associated with chronic
widespread physical pain, which can lead to psychological pain. Poor awareness
and limited diagnosis of EDS and related symptoms result in decreased self-esteem
and confusion regarding physical sensation. Furthermore, EDS imposes substantial
psychological burden on patients due to exercise restriction, scars, keloids, and
subcutaneous fat accumulation on the extremities, which leads to parental overprotection
and bullying experiences from other children at school age. Recent large-scale studies
have suggested that patients with EDS have a higher risk of mood disorders than
the general population. Other cohort studies indicated high prevalence of anorexia
nervosa, addiction, obsessive compulsive disorder, and anxiety disorder were found
Edited by:
Vincent Guinchat, in patients with EDS. Case reports instead indicated that some psychiatric disorders
Hôpitaux Universitaires Pitié were secondary symptoms due to physical problems from EDS. Therefore, psychiatrists
Salpêtrière, France
must be more knowledgeable and proactive about EDS in their practice. We review the
Reviewed by:
Cora Cravero,
previous case reports and literature for patients with EDS, along with our own case of
Service de Psychiatrie de l’Enfant et complicated psychiatric problems, which are strongly related to early stressful situations
de l’Adolescent, GHU Pitie-Salpetriere
through childhood and adolescence. This is to aid general psychiatrists in the discussion
Charles Foix, APHP, France
Massimo Pasquini, of appropriate medical management in such infrequent, yet challenging conditions.
Sapienza University of Rome, Italy
Keywords: Ehlers Danlos syndrome, pain, self-esteem, psychiatric disorders, psychiatrist, clinical geneticist,
*Correspondence: psychotropic drugs, counseling
Hiroki Ishiguro
[email protected]

INTRODUCTION
Specialty section:
This article was submitted to Ehlers-Danlos syndrome (EDS) comprises a series of hereditary connective tissue diseases,
Psychosomatic Medicine,
which is often characterized by musculoskeletal, dermatological, and cardiovascular problems.
a section of the journal
Frontiers in Psychiatry
While EDS had been classified into more than 10 types in the past, it was reclassified into 13
types in 2017 based on symptomatic features: Classical (cEDS), Classical-like (clEDS), Cardiac-
Received: 28 October 2021
vascular (cvEDS), Vascular (vEDS), Hypermobile (hEDS), Arthrochalasia (aEDS), Dermatosparaxis
Accepted: 16 December 2021
Published: 11 January 2022
(dEDS), Kyphoscoliotic (kEDS), Brittle Cornea syndrome (BCS), Spondylodysplastic (spEDS),
Musculocontractural (mcEDS), Myopathic (mEDS), and Periodontal (pEDS) (1). EDS has an
Citation:
Ishiguro H, Yagasaki H and Horiuchi Y
overall prevalence of 1/5,000, and multiple causative genes involved in each type have been
(2022) Ehlers-Danlos Syndrome in the identified, although some implicated genes remain elusive (2). The inherited form is mostly
Field of Psychiatry: A Review. autosomal dominant in the classical, hypermobile, and arthrochalasia types, while it is autosomal
Front. Psychiatry 12:803898. recessive in the dermatosparaxis and kyphoscoliotic types. EDS mainly involves physical symptoms,
doi: 10.3389/fpsyt.2021.803898 and there is little evidence of central nervous system involvement in affected patients.

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Ishiguro et al. EDS and Psychiatric Disorders

Although it has been established that joint hypermobility associated with spondylodysplastic-type spEDS. The common
syndrome (JHS) is a connective tissue disorder that primarily symptoms of this type of EDS include progressive short stature
affects the musculoskeletal system, while EDS comprises from childhood, hypotonia, and bowing of limbs, and some
connective tissue disorders with multisystem manifestations, the minor symptoms include skin hyperextensibility, pes planus,
2017 International Classification of the EDS replaced previous delayed motor development, and mild intellectual disabilities
terms for symptomatic joint hypermobility with hypermobile (11). One of the patients we reported on (12) had moderate
EDS, since there was a lack of clinical distinction between intellectual disabilities and did not have some of the clinical
the hEDS (3, 4). Thus, the term JHS is no longer used symptoms, such as short stature and sparse scalp hair and
according to Ehlers-Danlos Support UK (https://www.ehlers- eyebrows. Therefore, we diagnosed his condition as cEDS.
danlos.org/what-is-eds/information-on-eds/types-of-eds/). EDS As EDS is a rare disease, when patients with EDS present
are the most common hereditary, non-inflammatory disorders neurodevelopmental disorders, it is difficult to distinguish the
of connective tissues, and the hypermobile type of EDS inevitable symptoms or coincidences without proof of genetic
(hEDS) may present with common symptoms comparable to findings that could explain both physiological EDS symptoms
joint hypermobility, including joint pain, swelling, instability, and CNS symptoms.
dislocation, and back pain (3, 4). Children with hEDS have a high rate of developmental
Many psychiatrists are unfamiliar with the medical care of coordination disorder (DCD) with learning disability and
genetic disorders, as they especially avoid the despairing history attention deficit hyperactive disorder (ADHD), which can
of discrimination against mentally ill persons under the former affect their well-being and the development of the nervous
Eugenic Protection Law. However, many clients with genetic system. Further clinical research is necessary to explore the
and chromosomal diseases are likely to have mental problems, pathogenesis and management of patients with EDS (13–15).
including neurodevelopmental, anxiety, and mood disorders. Patients with hEDS may favor behavioral atypism with both
Some of these may occur due to congenital brain mechanisms hypoactivity and hyperactivity. Some patients use endurance
and various socio-psychological burdens in the life of patients to cope with pain, which is persistence in an unhealthily
with EDS. Thus, doctors in Japan who are both certified as clinical high level of activity despite pain. In addition, pain disrupts
geneticists and psychiatrists have the opportunity to treat patients the attentional performance. These psychological reactions
with EDS complicated by mental disorders. By listening to their may contribute to ADHD (16). A high prevalence of ADHD
complaints and understanding their psychological problems, we and autism spectrum disorder (ASD) has been found in
believe that more psychiatrists should cooperate in the treatment patients with hEDS (17). However, whether the prevalence
and support of such patients. of ADHD in patients with hEDS is higher than that in
Chronic pain is a common symptom of EDS, which damages the general population is inconclusive because the study did
the quality of life and causes psychological disability (5, 6). The not have a matched control group (18). However, another
combination of anxiety, depression, and pain can be thought of study reported that ADHD was significantly enriched in the
as an alternate interaction of physical and emotional distress in hypermobility spectrum disorders but not in the EDS group
humans (7–9) and in rodents (10). Therefore, patients with EDS than in general population (19). Casanova et al. suggested
often experience anxiety and depression caused by chronic pain, comorbidity and familial co-occurrence between EDS and autism
as well as stress from surrounding incomprehension regarding (as defined by the authors) (20). Baeza-Velasco et al. reported the
their physical restrictions and social disability. A history of overrepresentation of ASD in patients with EDS (21). Regarding
recurrent joint dislocation and major bleeding poses a fear in the biological interaction between hEDS and ASD, elevation of
the daily lives of patients with EDS. EDS has a huge impact serum tyrosine and hydroxyproline levels in patients with ASD
on physical and psychological development. Many patients have may provide evidence for a link between them, considering the
several cognitive distortions regarding themselves due to the lack association between hydroxyproline levels and collagen damage
of early psychological support. In this review, we summarize the (22). Although shared clinical features and phenotypes between
clinical psychiatric endophenotypes caused by and from hEDS, as EDS and ASD are not rare, we need to specify the possible
many of them have been more or less neglected in the past. common causative genetic factors for both disorders to arrive at
a conclusion.
On the contrary, few studies have reported specific learning
NEURODEVELOPMENT DISORDERS AND disorders, such as dyslexia, dysgraphia, and dyscalculia, in
EDS patients with EDS, and these aspects are poorly explored.
Baeza-Velasco recently summarized that physical disabilities in
The current EDS classification (major types I–VII) patients with hEDS could increase learning and communication
does not include specific disease types associated with disorders from an early age (16). The diagnosis of learning
neurodevelopmental disorders. The older classification (in disorders is difficult because of the overlap with several EDS
the 1990s and thereafter) included a certain subtype with criteria associated with proprioception and pronounced fatigue.
intellectual developmental disorder. However, few evidences However, child and adolescent psychiatrists should be aware of
reported genetic factors could explain brain hypofunction the importance of identifying and handling these comorbidities
and physical symptoms in EDS. Wang et al. performed when they exist. Notably, children with hEDS may need to
whole-genome low-coverage sequencing and medical exome be routinely screened for neuropsychiatric symptoms, such as
sequencing and found a case with B4GALT7 gene variants specific learning disorders.

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Ishiguro et al. EDS and Psychiatric Disorders

ANOREXIA NERVOSA AND EDS ANXIETY DISORDERS AND EDS

With regard to eating disorders in hEDS, growing clinical A high prevalence of anxiety was found in patients with EDS
evidence has been reported in the previous years. hEDS presents (35–37). Similar to EDS, panic disorder is also found more
with gastrointestinal problems, temporomandibular disorders, frequently in patients with hEDS as reported by recent research
and smell and taste abnormalities, thereby producing significant and meta-analysis (38–40), while others have reported a different
implications for eating, which are commonly experienced by result (41).
those affected (23). There are two reported cases of hEDS and In a study by Pasquini et al. symptom severity was assessed
anorexia nervosa complications (24, 25). Although Miles et using the Hamilton Anxiety Rating Scale (HAM-A) and the
al. reported their case as a coincidental event (25), Lee and Hamilton Depression Rating Scale (HAM-D) in an hEDS patient
Strand discussed in detail how patients with EDS can develop group and healthy controls. The study indicated higher scores
anorexia nervosa. The patient suffered from various recurrent of HAM-D and HAM-A in the hEDS patient group than in the
gastrointestinal complaints, such as diffuse pain, bloating, and controls (42). More clinical evidence is needed to determine what
nausea, for ∼10 years. Such gastrointestinal symptoms, in types of anxiety or anxiety-related disorders may be associated
addition to persistent fatigue, muscle cramps, and joint pain, with hEDS. Based on the Symptom Check List revised 90 (SCL-
can primarily be attributed to anorexia nervosa (24). Indeed, 90-R) that is a widely used self-report measure assessing the
gastrointestinal symptoms and esophagitis are very common in severity of current psychological symptoms and distress, high
patients with hEDS, resulting in nausea and vomiting (26–28). percentage of patients with EDS reported their somatization
Dysphagia, fragility of the oral mucosa, and smell and taste and obsessive-compulsivity. Severe levels of those symptoms are
abnormalities as EDS complications, can lead to food selectivity observed more than depressiveness, general anxiety, hostility,
and disordered eating patterns (23). and phobic anxiety (43). We have been treating a patient with
In addition to the psychological causes, we encountered clEDS, due to a homozygous null mutation in the TNXB gene.
a Japanese woman with EDS, who had anorexia nervosa It phenotypically resembles the classical form of EDS, although
(restriction type), in addition to dissociative identity disorder, it lacks atrophic scarring (44). As an example of somatization,
gender dysphoria, and dysthymia (12). She had classical EDS the patient is suffering from general pain, part of which cannot
symptoms with skin hyperextensibility and atrophic scarring, be explained by joint dislocation, internal bleeding, and other
generalized joint hypermobility, easy bruising, soft and doughy physiological damages; however, it is enhanced by anxiety caused
skin, skin fragility, traumatic splitting, and pain, which is a by incomprehension from family members and surroundings
complication of joint hypermobility. The patient was brought up regarding EDS symptoms.
as an older sister in contrast to another twin sister, although they
were monozygotic twins. The younger sister had EDS, however,
she had no psychiatric symptoms. A meta-analysis revealed that MOOD DISORDERS, SCHIZOPHRENIA,
being victimized by bullying and teasing is a risk factor that AND EDS
contributed to eating disorders (29, 30); hence, the patient was
likely to develop anorexia nervosa by being frequently bullied Depressive symptoms in patients with EDS were first reported
for her facial scars caused by EDS at elementary school age. In in 2003 (45). Moreover, patients with EDS are at a relatively
addition, we have to focus on the assumption that her anorexic high risk of mental disorders, such as mood disorders, and
symptoms in this case could have been influenced by insufficient suicidal behavior accompanied by pain, including headache,
maternal separation from early childhood, on account of her muscle pain, neuralgia, abdominal pain, and malaise (17, 37,
mother’s overprotectiveness and excessive interference driven by 46–50). The overall use of psychotropic drugs to treat these
her concern for the high risk of trauma associated with EDS conditions was 41.4% in patients with EDS compared with 13.9%
(31, 32). in controls (37).
Since patients with depression frequently experience pain
(51, 52), some of the pain reported by patients with EDS could
ADDICTION AND EDS be either attributable to physical symptoms, due to dislocation
or depression. Additionally, chronic pain in such patients may
Since chronic pain is highly observed in patients with EDS, lead to negative emotions due to the psychological burden
research should be focused on pain relief for these patients. A (47). Furthermore, a large-scale study on a Swedish population
study indicated that opioid use among children was double in found that patients with EDS have a higher risk of mood and
an EDS cohort compared to a control group (27.5 vs. 13.5%), developmental disorders than that of the general population (17).
while in adults, it was nearly double in patients with EDS (62 Tenascin-X (TNX) deficiency had been well-reported to
vs. 34.1%) (33). However, to the best of our knowledge, there has be associated with EDS (53–60). While a single nucleotide
been no research on the misuse of analgesics among patients with polymorphism in TNX gene had been indicated to be associated
EDS. While increases in tobacco and alcohol use were found in with schizophrenia by Tochigi (61), the replication studies from
hEDS (34), not much is known about the ratio of their misuse other researchers could not find the association (62, 63). To
in the EDS population, although patients are thought to use both the best of our knowledge, there has been no research on high
substances to cope with distress and anxiety. prevalence of the schizophrenia among patients with EDS.

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Ishiguro et al. EDS and Psychiatric Disorders

TABLE 1 | Neuropsychiatric disorders associated with EDS. of effective drugs is important, as is understanding the
patient’s pain.
Disease References
Besides pharmaceutical therapy, psychiatrists should
Neurodevelopment disorders (11–22) understand and find ways to support the holistic pain of patients
Anorexia nervosa (12, 23–30) with EDS. In the case introduced above, our patient with
Addiction (33, 34) cEDS had complex psychiatric symptoms, including dysthymia,
Anxiety disorders (35–43) dissociative identity disorder, gender dysphoria, and anorexia
Mood disorders (17, 37, 45–50) nervosa (12). It took years for her condition to be diagnosed by a
Personality disorder (42, 49, 64) psychiatrist, and the patient was enduring these symptoms with
insufficient support from a general clinical geneticist. During
those years, multiple personalities have deteriorated due to self-
care for undernutrition risk brought about by anorexia nervosa
and social discomfort due to gender dysphoria. We believe
PERSONALITY DISORDER AND EDS
that the cooperation of clinical geneticists and psychiatrists can
The patients with hEDS had obsessive-compulsive personality provide sufficient support to such patients.
disorder (OCPD) with an observed prevalence rate of >10%
(42). With regard to other personality disorders, borderline CONCLUSION
personality disorder along with depression, emotionally unstable
personality disorder was observed in each patient with EDS Since the lifespan of patients with EDS is not affected,
(49, 64). However, there is still not much information about psychiatrists must recognize the need for medical assistance
personality disorders that are common in EDS. in the course of psychological problems and mood disorders.
Their pain and early disability could be the modulators of the
psychiatric manifestations. To date, there is no evidence that
PSYCHIATRIC TREATMENT the causative gene of EDS is expressed in the brain and that it
is involved in changes of the central nervous system function.
As summarized above, it has been found that various psychiatric Moreover, it is difficult to assume that the symptoms of EDS are
disorders can coexist either biologically or psychologically with psychiatrically detailed and accurately categorized.
EDS (Table 1). However, there is minimal information regarding Patients with EDS are often disappointed and dissatisfied with
the management of treatment-resistant psychiatric symptoms in not knowing the causative gene of the disease. All the causes
patients with EDS. Therefore, we have discussed some successful of EDS are genetics based; although, various genes are involved
management strategies for anxiety in patients with EDS who in different types of EDS, which needs to be considered, given
use psychotropic drugs. Since some chronic pain symptoms may that they may have varying implications for the patient and their
be aggravated by anxiety, therapeutic alliances with patients’ families. Therefore, genetic counseling and psychological support
physicians may allow for better coping strategies for pain. Drug are also important (69, 70).
therapy may be effective in addition to supportive psychotherapy. In addition, psychiatric care can contribute to the genetic
Benzodiazepines are useful in managing acute anxiety symptoms counseling of patients with EDS and the medical management
and pain relief. However, if drugs are used for a longer period of EDS psychiatric symptoms, as well as in the development
to treat chronic pain, patients are at a risk of dependence, of clinical research. Both psychiatrists and clinical psychologists
withdrawal, and cognitive changes (65); therefore, information should be aware that these patients have a variety of physical,
on alternative medicines is needed. Niedt et al. reported the social, and psychological distresses associated with EDS, resulting
efficacy of risperidone in patients with anxiety symptoms (66). in secondary psychiatric symptoms and in social hypoactivity.
A patient with borderline personality disorder reported a
reduction in suicidal ideation after taking selective serotonin AUTHOR CONTRIBUTIONS
reuptake inhibitor and lithium as its enhancer (49). Another
patient with emotionally unstable personality disorder treated HI and HY contributed to make diagnosis for EDS. HI and
with duloxetine, quetiapine, lamotrigine and with Dialectical YH contributed to the writing of the manuscript. HI treats the
Behavioral Therapy reported self-harm free and stable emotion patients’ psychiatric symptoms. All authors read and approved
(64). In our patient with clEDS, described above, who is the final manuscript.
suffering from general pain in the whole body, duloxetine, an
antidepressant that targets pain, was dramatically effective for ACKNOWLEDGMENTS
both pain relief and anxiety/depressiveness. This is because
duloxetine has an analgesic effect, such as in fibromyalgia and This article has been edited by a professional language editing
other chronic pain (67, 68). For psychiatrists, the selection service at Editage, a division of Cactus Communications.

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Ishiguro et al. EDS and Psychiatric Disorders

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Frontiers in Psychiatry | www.frontiersin.org 6 January 2022 | Volume 12 | Article 803898