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A Cohort Study Comparing Women with Autism Spectrum Disorder with and without Generalized Joint Hypermobility

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  • Autism Research Institute

Abstract and Figures

Reports suggest comorbidity between autism spectrum disorder (ASD) and the connective tissue disorder, Ehlers-Danlos syndrome (EDS). People with EDS and the broader spectrum of Generalized Joint Hypermobility (GJH) often present with immune-and endocrine-mediated conditions. Meanwhile, immune/endocrine dysregulation is a popular theme in autism research. We surveyed a group of ASD women with/without GJH to determine differences in immune/endocrine exophenotypes. ASD women 25 years or older were invited to participate in an online survey. Respondents completed a questionnaire concerning diagnoses, immune/endocrine symptom history, experiences with pain, and seizure history. ASD women with GJH (ASD/GJH) reported more immune-and endocrine-mediated conditions than their non-GJH counterparts (p = 0.001). Autoimmune conditions were especially prominent in the ASD/GJH group (p = 0.027). Presence of immune-mediated symptoms often co-occurred with one another (p < 0.001-0.020), as did endocrine-mediated symptoms (p < 0.001-0.045), irrespective of the group. Finally, the numbers of immune-and endocrine-mediated symptoms shared a strong interrelationship (p < 0.001), suggesting potential system crosstalk. While our results cannot estimate comorbidity, they reinforce concepts of an etiological relationship between ASD and GJH. Meanwhile, women with ASD/GJH have complex immune/endocrine exophenotypes compared to their non-GJH counterparts. Further, we discuss how connective tissue regulates the immune system and how the immune/endocrine systems in turn may modulate collagen synthesis, potentially leading to higher rates of GJH in this subpopulation.
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behavioral
sciences
Article
A Cohort Study Comparing Women with Autism
Spectrum Disorder with and without Generalized
Joint Hypermobility
Emily L. Casanova 1, 2, *ID , Julia L. Sharp 3, Stephen M. Edelson 4, Desmond P. Kelly 2
and Manuel F. Casanova 1,2
1
Department of Biomedical Sciences, University of South Carolina School of Medicine Greenville, Greenville,
SC 29605, USA; mcasanova@ghs.org
2Department of Pediatrics, Greenville Health System Children’s Hospital, Greenville, SC 29605, USA;
dkelly@ghs.org
3
Department of Statistics, Colorado State University, Fort Collins, CO 80523, USA; julia.sharp@colostate.edu
4Autism Research Institute (ARI), San Diego, CA 92116, USA; director@autism.com
*Correspondence: casanove@greenvillemed.sc.edu
Received: 23 November 2017; Accepted: 15 March 2018; Published: 17 March 2018
Abstract:
Reports suggest comorbidity between autism spectrum disorder (ASD) and the connective
tissue disorder, Ehlers-Danlos syndrome (EDS). People with EDS and the broader spectrum of
Generalized Joint Hypermobility (GJH) often present with immune- and endocrine-mediated
conditions. Meanwhile, immune/endocrine dysregulation is a popular theme in autism research. We
surveyed a group of ASD women with/without GJH to determine differences in immune/endocrine
exophenotypes. ASD women 25 years or older were invited to participate in an online survey.
Respondents completed a questionnaire concerning diagnoses, immune/endocrine symptom
history, experiences with pain, and seizure history. ASD women with GJH (ASD/GJH) reported
more immune- and endocrine-mediated conditions than their non-GJH counterparts (
p= 0.001
).
Autoimmune conditions were especially prominent in the ASD/GJH group (
p= 0.027
). Presence of
immune-mediated symptoms often co-occurred with one another (p< 0.001–0.020), as did
endocrine-mediated symptoms (p< 0.001–0.045), irrespective of the group. Finally, the numbers of
immune- and endocrine-mediated symptoms shared a strong inter-relationship (p< 0.001), suggesting
potential system crosstalk. While our results cannot estimate comorbidity, they reinforce concepts of
an etiological relationship between ASD and GJH. Meanwhile, women with ASD/GJH have complex
immune/endocrine exophenotypes compared to their non-GJH counterparts. Further, we discuss
how connective tissue regulates the immune system and how the immune/endocrine systems in turn
may modulate collagen synthesis, potentially leading to higher rates of GJH in this subpopulation.
Keywords:
connective tissue diseases; autoimmunity; mast cells; immunity; humoral; endocrine
system diseases; neurodevelopmental disorders
1. Introduction
Ehlers-Danlos syndrome (EDS) is a group of phenotypically-related disorders subtyped according
to variations in underlying genetic pathology, primary symptom severity, and secondary symptom
associations. All of these conditions are typified by deficits in collagen production and maintenance,
leading to structural changes within the connective tissues of the body. These changes are most evident
within the joints and skin, although many other systems can be affected.
Generalized joint hypermobility (GJH) is a major feature of Hypermobile EDS (hEDS) and
other connective tissue disorders. In addition, GJH can either be benign or associated with
Behav. Sci. 2018,8, 35; doi:10.3390/bs8030035 www.mdpi.com/journal/behavsci
Behav. Sci. 2018,8, 35 2 of 16
significant musculoskeletal impairment; the latter of which is often affected by an individual’s age,
leading to changes in diagnosis over time. According to newer nosology [
1
], when GJH occurs in
conjunction with significant impairment and other criteria for hEDS are not met, it is diagnosed as
“Generalized Hypermobility Spectrum Disorder (G-HSD).” Studies have shown that hEDS and GJH
often co-segregate within families, indicating linked etiologies in some cases [reviewed in 1].
Neuropsychiatric manifestations are common secondary symptoms in EDS/GJH. In particular,
anxiety and mood disorders are prominent and probably the best studied to date [
2
,
3
]. However,
a thorough review of the literature by Baeza-Velasco et al. [
4
] suggests significant links between EDS
and autism, as well as other neurodevelopmental and psychiatric conditions such as attention-deficit
hyperactivity disorder (ADHD), schizophrenia, eating disorders, personality disorders, and even
substance abuse. Interestingly, work by Shetreat et al. [
5
] and Eccles et al. [
6
] indicates that joint
hypermobility is significantly more common in children and adults with autism than age- and
gender-matched controls, suggesting etiological links between some cases of autism and connective
tissue disorders.
Immune & Endocrine Dysregulation in ASD & GJH
Immune and neuroendocrine crosstalk is a well-established phenomenon. These systems are
linked via two primary pathways through which that crosstalk is achieved: (1) the sympathoadrenal
system and (2) the hypothalamo-pituitary-adrenal axis [
7
]. The immune system can also have a direct
effect on oogenesis through the presence of innate and adaptive immune cells located within the ovarian
germ cell pool, which release morphoregulatory signals that stimulate or suppress ovulation [8].
Immune dysregulation has been a popular area of study in autism research, whose foci center around
topics of maternal immune activation (MIA), prevalence of autoimmunity, and other aspects of general
immune dysfunction [
9
]. In regards to the latter, Careaga et al. [
10
] have identified two non-overlapping
Th1- and Th2-skewed endophenotypes that are especially prominent in children with ASD.
Hormonal exophenotypes, in contrast, have been less well-studied in ASD. One study by
Ingudomnokul et al. [
11
] found that high-functioning women on the autism spectrum and their
mothers reported high rates of endocrine disorders. However, most endocrine research to date has
focused on maternal disorders with an emphasis on etiological risk factors, such as diabetes, hirsutism,
and polycystic ovary syndrome (PCOS) [1214].
High rates of immune- and endocrine-mediated disorders have also been reported in EDS,
though they are currently viewed as secondary symptoms to what are traditionally seen as “collagen
disorders” [
15
17
]. While it has previously been difficult to explain links between immune and
collagen dysfunction, research into the connective tissue disorders, Marfan and Loeys-Dietz Syndromes,
which share features of overlap with EDS, may help to guide future EDS research.
In order to study the frequency and relationship of immune and endocrine exophenotypes in
adult women with ASD, with or without GJH, we have utilized self-reports covering a range of
clinical symptoms, including features of chronic allergies, autoimmunity, irritable bowel syndrome
(IBS)/gastrointestinal (GI) dysfunction, and menstrual irregularities.
2. Methods
2.1. Study Population
The vast majority (94%) of respondents were affected persons themselves, rather than family
members responding for adult wards. As such, it is assumed that the majority of our study population
was composed of women with an IQ > 70 due to their abilities to answer a series of complex questions
about general health.
Our study group was composed of two English-speaking subpopulations: (1) women 25 years
and older with a diagnosis of ASD (referred to here as simply “ASD”) (N= 85); and (2) women 25 years
or older with dual ASD and EDS, G-HSD, or Joint Hypermobility Syndrome (JHS) diagnoses (referred
Behav. Sci. 2018,8, 35 3 of 16
to here as “ASD/GJH”) (N= 20) (Figure 1). Individuals who were male, were under the age of 25,
or did not have a diagnosis of ASD were excluded. In the ASD group, further exclusionary criteria
were applied: (a) An individual’s responses were removed from the data pool if she suspected the
presence of GJH but was currently undiagnosed, and/or (b) reported double-jointedness across two or
more types of joints [
18
]. The majority of women reporting EDS diagnosis had hEDS, although a small
minority reported diagnosis of Classical EDS. (See Table 1for descriptions of terms and definitions.)
Our groups were sex-matched and did not differ significantly by age (t=
0.327, df = 28.451,
p= 0.7459
). Full data are presented in Supplementary File 2, Tables S1–S7. All data were complete,
with the exception of two respondents’ answers on the topic of “Other Chronic Pain”.
Due to the biased manner in which respondents were recruited [i.e., specifically targeting both
ASD and ASD/GJH subgroups via respective web fora (see Section 2.2 under Methods)], we are unable
to estimate the prevalence of GJH in the female ASD population. However, this method allowed us to
collect a larger pool of ASD/GJH respondents, which might otherwise be underrepresented. In doing
so, we are able to study group differences more easily.
Behav. Sci. 2018, 8, x FOR PEER REVIEW 3 of 17
Our study group was composed of two English-speaking subpopulations: (1) women 25 years
and older with a diagnosis of ASD (referred to here as simply “ASD”) (N = 85); and (2) women 25
years or older with dual ASD and EDS, G-HSD, or Joint Hypermobility Syndrome (JHS) diagnoses
(referred to here as “ASD/GJH”) (N = 20) (Figure 1). Individuals who were male, were under the age
of 25, or did not have a diagnosis of ASD were excluded. In the ASD group, further exclusionary
criteria were applied: (a) An individual’s responses were removed from the data pool if she
suspected the presence of GJH but was currently undiagnosed, and/or (b) reported
double-jointedness across two or more types of joints [18]. The majority of women reporting EDS
diagnosis had hEDS, although a small minority reported diagnosis of Classical EDS. (See Table 1 for
descriptions of terms and definitions.)
Our groups were sex-matched and did not differ significantly by age (t = -0.327, df = 28.451, p =
0.7459). Full data are presented in Supplementary File 2, Tables S1S7. All data were complete, with
the exception of two respondents’ answers on the topic of “Other Chronic Pain.”
Due to the biased manner in which respondents were recruited [i.e., specifically targeting both
ASD and ASD/GJH subgroups via respective web fora (see Section 2.2 under Methods)], we are
unable to estimate the prevalence of GJH in the female ASD population. However, this method
allowed us to collect a larger pool of ASD/GJH respondents, which might otherwise be
underrepresented. In doing so, we are able to study group differences more easily.
Figure 1. Flow chart illustrating group allocation according to reported diagnoses.
Figure 1. Flow chart illustrating group allocation according to reported diagnoses.
Table 1. Terms and diagnoses related to the connective tissue disorders discussed in the manuscript.
Generalized Joint Hypermobility-Related Diagnoses Description
Hypermobile Ehlers-Danlos Syndrome
(hEDS)—Formerly known as EDS, Hypermobile Type,
or EDS Type III.
Generalized joint hypermobility
Musculoskeletal involvement
(arthralgia, instability)
Involvement of other organ systems (skin,
Marfanoid features, etc.)
No consistently associated gene mutations
Behav. Sci. 2018,8, 35 4 of 16
Table 1. Cont.
Generalized Joint Hypermobility-Related Diagnoses Description
Classical Ehlers-Danlos Syndrome (cEDS)—Also
known as EDS Type I. Skin hyperpextensibility and atrophic scarring
Generalized joint hypermobility
Minor features: e.g., easy bruising, skin fragility,
hernias, etc.
Associated gene mutations: COL1A1,COL5A1,
and COL5A2
Generalized Hypermobility Spectrum Disorder
(G-HSD) - Formerly known as “non-benign” JHS. Generalized joint hypermobility
Musculoskeletal involvement
(arthralgia, instability)
Other minor criteria associated with hEDS may
be present but to a comparatively lesser extent
* Joint Hypermobility Syndrome (JHS)—Divided into
“benign” and “non-benign” forms. Diagnosis now in
disuse as of 2017.
Generalized joint hypermobility
Optional: musculoskeletal involvement
(arthralgia, instability)
Hypermobility Spectrum Disorders (HSD) Composed of:
G-HSD (formerly known as “non-benign” JHS)
Peripheral HSD (P-HSD)
Localized HSD (L-HSD)
Historical HSD (H-HSD)
Asymptomatic Joint Hypermobility
Asymptomatic Generalized Joint Hypermobility
(A-GJH) (formally known as “benign” JHS)
Asymptomatic Peripheral Joint Hypermobility
(A-PJH)
Asymptomatic Localized Joint Hypermobility
(A-LJH)
Marfan Syndrome (MFS) Aortic root dilation
Ectopia lentis (dislocated lenses of the eye)
Minor features: Marfan habitus, generalized
joint hypermobility
Associated gene mutations: FBN1
Loeys-Dietz Syndrome (LDS) Enlargement of the aorta
Aneurysms
Hypertelorism
Bifid uvula or cleft palate
Minor features: Marfanoid habitus, immune
disorders (allergy, asthma, rhinitis, eczema)
Associated gene mutations: TGFBR1,TGFBR2,
SMAD3,TGFB2, and TGFB3
* indicates terminology that is no longer in use as of the recent nosological changes enacted [1].
2.2. Survey
This study was approved by the Institutional Review Board (IRB) of the Greenville Health System
(GHS) (ID: Pro00061122). The survey utilized in this study was designed by our research group
based in part on previous informal survey studies performed by the Autism Research Institute (ARI).
These questions were further adapted and expanded according to an additional literature search of
relevant clinical symptomology for our topics of interest. (See Supplementary File 1 for full survey.)
The survey was built on and hosted by the website, SurveyGizmo.com, and was advertised
via the ARI newsletter; the ASD forum, Wrong Planet; and a variety of FaceBook ASD- and
Behav. Sci. 2018,8, 35 5 of 16
EDS-specific webcommunities, such as the Autism Women’s Network (AWN), the Autism Spectrum
Women’s Group, AutismTalk, the Ehlers-Danlos Support Group, and Ehlers-Danlos Worldwide.
The administrative teams of all participating web communities were informed that the survey was
IRB-approved and were given access to the survey and, when requested, a copy of the IRB protocol
prior to approval. Following administrator approval, either ELC posted the survey announcement
or administrators posted it themselves. The survey weblink (www.autismwomensstudy.com) led
potential respondents to a description of the purpose and expectations of the study, potential risks
and benefits, investigator contact information, and a waiver of consent. The survey was open and
participants were actively recruited for approximately three months.
Survey questions focused on topics concerning ASD and EDS/GJH diagnoses; symptoms
involving the immune and endocrine systems; chronic pain; GI dysfunction such as IBS; seizures;
and limited aspects of medication history (hormone treatment, antiseizure medications). Additional
topics were covered but were not used for the current study.
Questions on immune symptomology included items concerning hospitalization history;
respiratory disorders like asthma, allergies, sinusitis/rhinitis, and reactions to medications or
environmental chemicals; and autoimmunity [
19
21
]. Hormone-mediated symptoms included items
such as chronic irregularities in menstruation and associated pain syndromes; PCOS; and other
clinical symptoms indicative of the metabolic syndrome, such as type 2 diabetes/insulin resistance,
hypertension, and high cholesterol [
11
,
22
]. The data of respondents who agreed to participate but
failed to complete the survey were discarded.
2.3. Statistical Analyses
When assessing group differences for quantitative variables (e.g., age, immune- and
endocrine-mediated symptoms), Welch two-sample t-tests were conducted unless the distributions
were heavily skewed, in which case the Wilcoxon rank sum test with continuity correction was
used. Two sample tests of proportions were used to compare groups for binary categorical data
(e.g., presence/absence of diabetes, infertility, etc.). Fisher’s Exact Test was used in cases of small
sample sizes. Where appropriate, a false discovery rate adjustment was used to account for multiple
comparisons. A significance level of 0.05 was used for all analyses.
3. Results
3.1. Immune-Mediated Disorders
Although women with ASD and ASD/GJH did not differ in the presence of one or more
immune-mediated symptoms (
χ2
= 1.162, p= 0.281), ASD/GJH women were, however, more likely
to report multiple symptoms (t=
3.860, df = 30.981, p= 0.001), an effect that differed by age
(
W= 534.5–563
,p= 0.009–0.017) (Figure 2A). Women with ASD and ASD/GJH also reported similar
proportions of specific immune exophenotypes (
χ2
= 0.788–4.744, p= 0.137–0.375), with an overall trend
towards higher proportions in the ASD/GJH group. However, one exception concerned autoimmune
disorders: while 13% of the ASD group had an autoimmune disorder, 45% of women with ASD/GJH
reported the same (χ2= 8.813, p= 0.027) (Table 2).
The presence of most immune exophenotypes exhibited a significant association with one another,
suggesting that a similar etiological background underlies many of these symptoms. Allergies, rhinitis,
sinusitis, asthma, ear infections, reaction to medications, and reaction to environmental chemicals
all seemed to share a strong interrelationship (p< 0.001–0.020). Meanwhile, autoimmunity was
significantly associated with ear infections (CI = 1.509–18.898, p= 0.014) and showed a trend towards
significance with asthma (CI = 1.003–9.582, p= 0.059) (Figure 2B).
Behav. Sci. 2018,8, 35 6 of 16
Table 2.
Reported rates of various immune-related symptoms according to group, as well as estimated
general prevalence rates.
Immune Symptomology ASD
(N= 85)
ASD/EDS
(N= 20) General Prevalence
Allergies 45% 60% 30% in adults [23]
Asthma 33% 60% 8.4% in general population [24]
Autoimmunity 13% 45% * 7.6–9.4% in general population [25]
Chronic Ear Infections 40% 65%
83% with 1 incidents between 0–3
years of age [26] 11% with 1
incidents of all ages [27]
Chronic Rhinitis 38% 60% 8% in adults [28]
Chronic Sinusitis 46% 60% 8% in adults [28]
Severe Reaction to Medications 35% 65%
10–15% of hospitalized patients [
29
]
Severe Reaction to
Environmental Chemicals 39% 65% 13–16% in adults [30]
* indicates a significant difference between groups.
Behav. Sci. 2018, 8, x FOR PEER REVIEW 7 of 17
Figure 2. (A) Number of immune-mediated symptoms across ASD and ASD/GJH groups. ‘Any
immune’ = 1 or more immune symptoms. (B) Network of immune-mediated symptoms. (C) Number
of endocrine-mediates symptoms across ASD and ASD/GJH groups. ‘Any endocr.’ = 1 or more
endocrine symptoms. (D) Network of endocrine-mediated symptoms.
Interestingly, the proportions of IBS/GI dysfunction did not differ significantly between groups,
though the ASD/GJH group reported modestly higher rates (χ2 = 0.648, p = 0.946). In spite of IBS’
links with immunity, it did not share a significant relationship with immune exophenotypes in
general (CI = 0.2827.60, p = 0.717), although our study may have been too underpowered to glean an
effect [31]. Yet in spite of modest numbers, IBS/GI dysfunction was significantly linked with
hormonal exophenotypes: individuals with IBS/GI dysfunction had more hormone-mediated
symptoms on average than those without (W = 811, p = 0.002).
In spite of the previously reported relationship between hormones and seizure propensity, the
presence of complex hormonal exophenotypes was not associated with epilepsy in our cohort (W =
274, unadj. p = 0.3742) [32]. However, despite the small number of women reporting epilepsy (N = 7),
epilepsy shared a modest positive relationship with the number of immune-mediated disorders
irrespective of the group (W = 166, unadj. p = 0.022). While the average number of immune-mediated
disorders reported across the entire cohort was approximately 3.6 (SD = 2.45), women with epilepsy
averaged approximately 5.7 (SD = 2.43).
Finally, joint pain was reported in all cases of ASD/GJH compared to 29% in the ASD group (χ2
= 30.122, p < 0.001). Meanwhile, differences in joint pain were not accounted for by age (W = 559.5, p =
0.101) or obesity (χ2 = 0, p = 1.000). Other types of chronic pain were also reported more often in
ASD/GJH (75% vs. 31%) (χ2 = 11.072, p < 0.001), including conditions such as fibromyalgia [33].
3.2. Hormone Disorders
Though the ASD/GJH and ASD groups did not differ in the presence of one or more
hormone-mediated disorders (χ2 = 0.728, p = 0.394), ASD/GJH women reported significantly more
Figure 2.
(
A
) Number of immune-mediated symptoms across ASD and ASD/GJH groups. ‘Any
immune’ = 1 or more immune symptoms. (
B
) Network of immune-mediated symptoms. (
C
) Number
of endocrine-mediates symptoms across ASD and ASD/GJH groups. ‘Any endocr.’ = 1 or more
endocrine symptoms. (D) Network of endocrine-mediated symptoms.
Interestingly, the proportions of IBS/GI dysfunction did not differ significantly between groups,
though the ASD/GJH group reported modestly higher rates (
χ2
= 0.648, p= 0.946). In spite of
IBS’ links with immunity, it did not share a significant relationship with immune exophenotypes in
general (CI = 0.282–7.60, p = 0.717), although our study may have been too underpowered to glean an
effect [
31
]. Yet in spite of modest numbers, IBS/GI dysfunction was significantly linked with hormonal
Behav. Sci. 2018,8, 35 7 of 16
exophenotypes: individuals with IBS/GI dysfunction had more hormone-mediated symptoms on
average than those without (W= 811, p= 0.002).
In spite of the previously reported relationship between hormones and seizure propensity,
the presence of complex hormonal exophenotypes was not associated with epilepsy in our cohort
(
W= 274
,unadj. p = 0.3742) [
32
]. However, despite the small number of women reporting epilepsy
(
N= 7
), epilepsy shared a modest positive relationship with the number of immune-mediated disorders
irrespective of the group (W= 166, unadj. p = 0.022). While the average number of immune-mediated
disorders reported across the entire cohort was approximately 3.6 (SD = 2.45), women with epilepsy
averaged approximately 5.7 (SD = 2.43).
Finally, joint pain was reported in all cases of ASD/GJH compared to 29% in the ASD group
(
χ2= 30.122
,p< 0.001). Meanwhile, differences in joint pain were not accounted for by age (W= 559.5,
p= 0.101) or obesity (
χ2
= 0, p= 1.000). Other types of chronic pain were also reported more often in
ASD/GJH (75% vs. 31%) (χ2= 11.072, p< 0.001), including conditions such as fibromyalgia [33].
3.2. Hormone Disorders
Though the ASD/GJH and ASD groups did not differ in the presence of one or more
hormone-mediated disorders (
χ2
= 0.728, p= 0.394), ASD/GJH women reported significantly
more symptoms than their non-GJH counterparts (W= 434, p= 0.001) (Figure 2C). On a
symptom-by-symptom basis, ASD/GJH women reported higher rates of endometriosis (
χ2
= 9.265,
p= 0.018
), dysmenorrhea (
χ2
= 19.599, p< 0.001), and severe teen acne (
χ2
= 7.817, p= 0.026) (Table 3).
Dysmenorrhea, in particular, was reported three times more often (85% vs. 28%) in ASD/GJH
compared to ASD (
χ2
= 19.60, p< 0.001), a frequency similar to that reported in previous EDS research
(see Table 3). In its extreme form, dysmenorrhea is typically associated with endometriosis and both
share links with immune dysfunction in the general population [34,35].
Table 3.
Reported rates of various endocrine-related symptoms according to group, as well as estimated
general prevalence rates.
Endocrine Symptomology ASD
(N= 85)
ASD/EDS
(N= 20) General Prevalence
Adult Acne 21% 35%
35% in women ages 30–39 [
36
]
Amenorrhea 39% 45%
4.6% in women ages 15–44 [
37
]
Diabetes/Insulin Resistance 6% 10% 7.9% in adults [38]
Dysmenorrhea 28% 85% * 2–29% in adult women [39]
Endometriosis 5% 30% * 4% in women [40]
High LDL Cholesterol 14% 30% 28% in adults [41]
Hirsutism 19% 30% 10% in adult women [42]
Hypertension 14% 20% 29.1% in adults [43]
Infertility 8% 15% 6% [44]
Irregular Menstruation 27% 55% 18.2% in adult women [45]
Overweight/Obesity 36% 45% 70.7% aged 20+ years [46]
Polycystic Ovary Syndrome
(PCOS) 8% 25% 7.3% in adult women [47]
Premenstrual Dysphoric
Disorder (PMDD) 21% 30% 3–8% of premenopausal
women [48]
Severe Teen Acne 14% 45% * 12.1% in males and females
aged 17 [49]
Uterine Fibroids 9% 5%
4.5–9.8% in adult women aged
40–49 [50]
* indicates a significant difference between groups.
We found no significant interaction between group and birth control/hormone treatment in
relation to the average number of hormone-mediated symptoms, indicating that such treatment is an
unlikely group confound in this study. There was, however, a significant relationship between the
Behav. Sci. 2018,8, 35 8 of 16
number of hormone-mediated symptoms reported and whether an individual was receiving some
form of hormonal treatment (t(101) = 2.75, p= 0.004). While we cannot rule out a potential confound,
instead, we conclude that this is likely a reflection of the severity of endocrine disorders in our cohort
and their prescribed treatments [51].
Like immune symptoms, individual hormone-mediated symptoms were often associated with
one another (Figure 2D). PCOS shared links with other symptoms, including diabetes, adult acne,
irregular menses, and hirsutism, all of which are either diagnostic of or commonly reported in
PCOS (p= 0.005–0.045). In contrast, infertility, overweight/obesity, amenorrhea, hypertension,
and high low-density lipoprotein (LDL) cholesterol did not associate with PCOS in our groups
(
p= 0.073–0.809
) [
52
]. There was, however, a trend towards significance between PCOS and infertility,
suggesting our data may have been underpowered, requiring a larger pool of respondents in the future
(OR 95% CI = 1.20–37.800, p= 0.073). Endometriosis and dysmenorrhea were also associated with one
another (CI = 2.229–785.323, p= 0.013).
3.3. The Relationship between Immune- & Hormone-Mediated Symptoms
There was no significant association between the general presence of immune- and
endocrine-mediated disorders across our cohort (OR 95% CI = 0.538, 21.119, p= 0.098). However,
the number of immune-mediated symptoms per individual greatly predicted the number of
hormone-mediated symptoms (Spearman’s rho = 0.35, p< 0.001). This suggests that the complexity and
severity of immune- and endocrine-mediated disorders share a strong positive relationship with one
another in autism and potentially within the general population, e.g., [53].
4. Discussion
The present study attempts to address phenotypic differences between ASD women with and
without GJH. This research supports a growing body of literature indicating that immune-mediated
disorders are a common comorbid feature in hEDS and GJH. In addition, we have also shown that
this dysfunction may be paired with endocrine dysregulation, leading to complex immune and
hormonal exophenotypes, such as autoimmune disorders, allergic rhinitis, asthma, endometriosis,
and dysmenorrhea. While we have not addressed autism and GJH comorbidity rates in this study,
their co-occurrence in the adult ASD female population suggests links between the dysfunction of
connective tissue and the immune and endocrine systems in this subpopulation.
As discussed, the immune system has been a popular area of investigation in autism research.
However, reports of clinical manifestations in the child population seem to vary [
54
57
]. Some clinical
manifestations arise during or progress in severity with the advent of puberty, highlighting the role the
endocrine system plays in immune function, e.g., [
58
]. In addition, women are more frequent targets
of such dysfunction, suggesting that studying immune dysregulation in prepubertal individuals with
autism, while also ignoring gender confounds, dramatically underrepresents the frequency of clinical
symptoms in the autism population [
19
]. For these reasons, we limited our study population to women
aged 25 years or older on the autism spectrum.
4.1. Immune-Mediated Disorders in Association with Connective Tissue Disorders
Loeys-Dietz Syndrome (LDS) is a connective tissue disorder caused by mutations directly targeting
the TGF-
β
pathway and is characterized primarily by enlargement of the aorta. People with LDS
have high rates of immune-mediated disorders such as respiratory and food allergies and occasionally
present with Hyper-IgE Syndrome, a type of primary immunodeficiency [
59
]. In addition, they also
share many of the same dysmorphic features as those seen in the connective tissue disorder, Marfan
Syndrome (MFS) [60].
Although MFS is associated with mutations in the Fibrillin-1 (FBN1) gene whose protein
product is a component of the extracellular matrix (ECM), FBN1 mutations lead to marked TGF-
β
dysregulation [
61
63
]. Fibrillin appears to control the activity of TGF-
β
by acting as a structural
Behav. Sci. 2018,8, 35 9 of 16
platform for the Latent TGF-
β
Binding Protein (LTBP) that sequesters and inactivates TGF-
β
, acting as
a reserve pool for rapid injury response [
64
]. Given its role as a foundational morphogen, it is believed
this overlap in TGF-βpathway dysregulation leads to the overlapping features of MFS and LDS [65].
Like LDS, some individuals with hEDS present with a Marfanoid (Marfan-like) habitus [
66
].
However, unlike MFS that results from dysfunctional fibrillin, EDS is typically linked with dysfunction
of the ECM protein, collagen. Marfan and Marfanoid features in all three of these disorders suggest
considerable overlap and interaction between the ECM and the TGF-
β
pathway. In addition, TGF-
β
serves as a link between the ECM and immune system disruption as it is a key immunomodulator,
implicated not only within the joints in these connective tissue disorders, but also in other organ
systems such as the lungs [
65
]. Interestingly, several studies have consistently found lower TGF-
β
1
levels in autism, which according to Ashwood et al. [
67
], may help explain some of the immune
dysregulation in the condition [
67
,
68
]. For these reasons, the TGF-
β
pathway and upstream networks
may be prime areas of study for future work into the overlapping etiologies of both connective tissue
disorders and autism.
4.2. The Effects of Estrogen on Collagen Production & the Immune System
Similar to certain immune disorders like autoimmunity, GJH and hEDS preferentially target
women for reasons not well understood [
69
]. One possibility may stem from sex differences in
muscle mass, in which stronger muscles help to counteract joint laxity and ensuant pain [
16
]. For this
reason, one of the foci of physical therapy in the treatment of GJH/hEDS centers around improved
muscle strength surrounding problem joints [
70
]. However, female-specific effects may result not only
from low testosterone levels, but also estrogen metabolites that either suppress collagen production
directly, particularly within the skin, or result in a more rapid turnover of collagen within tendons and
ligaments [7173].
Estrogen is also a major immunomodulator. It is capable of driving activation of the Th2 branch
of the immune system, boosting humoral immunity and the ability of the body to target parasites and
other extracellular infections. Estrogen also stimulates mast cell degranulation, prompting a release
of chemicals such as histamines, TNF-
α
, various amines, chymase, and tryptase [
74
,
75
]. Mast cell
activation, in turn, may drive both Th1/Th2 immune responses depending on the invading pathogen,
the target tissue, and other variable factors [76].
Interestingly, estrogen also increases the synthesis of TGF-
β
within numerous cell types, the latter
of which is itself a key morphogen and immunodulator. In addition, estrogen further interacts with the
TGF-
β
pathway by forming a complex with Smad 3/4, redirecting TGF-
β
target genes. Finally, TGF-
β
and estrogen are able to interact at the level of various Ras complexes, by which TGF-
β
enhances
estrogenic action [
77
]. All of these data together suggest significant interaction of estrogen with various
networks implicated in connective tissue disorders and their secondary symptoms.
4.3. Autism & Generalized Joint Hypermobility
Results of this study indicate that the ASD/GJH phenotype in women is characterized not only
by classic symptoms of EDS/G-HSD such as generalized hypermobility and chronic pain, but that
immune and endocrine system involvements may be extensive. In addition, phenotypic expression of
this immune disorder is mediated by the endocrine system and the ongoing presentation of symptoms
throughout life are guided by immune-endocrine crosstalk.
In support of this, all 20 ASD/GJH women in our study group reported
2 immune-mediated
symptoms, with an average reporting of 5.3 symptoms per person compared to 3.2 in the ASD group.
Likewise, 90% of ASD/GJH women reported
2 hormone-mediated symptoms, with an average of
5.1, compared to 2.7 in ASD. Therefore, the vast majority of ASD/GJH women in this study reported
multiple immune- and endocrine-mediated symptoms, the extent of which appears to vary with
one another.
Behav. Sci. 2018,8, 35 10 of 16
Mast Cell Activation Syndrome (MCAS), a newly recognized diagnostic entity with growing
clinical significance, may be relevant to immune exophenotypes reported by our participants [
15
].
While the traditional slew of MCAS impairments include analphylaxis, syncope, flushing, urticaria,
and GI distress (e.g., diarrhea, nausea, vomiting), continued study of this condition reveals a broader
spectrum of physical ailments relative to the locations of mast cells involved, the extent of stimulation,
and the specific mediators released.
Although MCAS can mimic many localized diseases, its defining feature is chronic mast cell
activation across two or more organ systems, which is reminiscent of the complex combination of
respiratory, connective tissue, and GI symptoms reported by some of our participants [
78
,
79
]. Interestingly,
MCAS is also a common comorbid feature of EDS and postural orthostatic syndrome (POTS), reinforcing
this emerging pattern [
15
,
80
]. Current prevalence rates of this newly recognized entity (14–17%) also
suggest it is far more common in the general population than originally believed [78].
While GJH can occur without complications, many cases involve extensive inflammation at the
affected joints, suggesting a potential immune component in the disorder as is seen in TGF-
β
pathway
involvement in LDS and MFS. As Afrin [78] suggests in reference to the MCAS-/hEDS relationship:
. . .
chronic aberrant elaboration of a particular set of mediators (drawn from amongst the mast cell’s
repertoire of more than 200 such molecular signals) not only [influences] virtually every other system
and organ in the body but also [influences] connective tissue development to yield the “hyperextensible”
phenotype long associated with EDS Type III [(hypermobile type)]. (p. 138)
4.4. The Etiology of Autism
While this study cannot address rates of ASD and GJH co-occurrence because of the way in which
respondents were recruited, the comorbidity itself reinforces etiological links between autism and
connective tissue disorders. Both cytokines and hormones play recognized roles in neurogenesis,
neuritogenesis, synaptogenesis, and ongoing plasticity [
81
84
]. In addition, some researchers have
proposed that autoantibodies to brain-specific proteins may also disrupt neurodevelopment, leading to
increased autism risk [
85
]. Finally, endocrine disruption, either via endogenous or exogenous effectors,
is likewise a growing area of research into autism’s etiology [
12
,
86
]. All of these topics highlight the
crosstalk between the immune and endocrine systems and strengthen their combined links to ASD.
4.5. Limitations
According to recent changes in nosology, hEDS, the most common of the Ehlers-Danlos
Syndromes, lies on a continuum with Hypermobility Spectrum Disorders (HSD), including what
was once known as Joint Hypermobility Syndrome (JHS) (see Table 1). Previous studies have shown
that hEDS and JHS often co-segregate within families, suggesting that in some cases, JHS/HSD may
be a lighter variant of hEDS (reviewed in [1]).
As of last year, the criteria for hEDS have become more stringent, placing greater focus on the
additional involvement of tissue systems outside that of the musculoskeletal system, e.g., skin and
other organs [
1
]. It is therefore possible and probable that some individuals in this study who had a
previous diagnosis of EDS, Hypermobile Type, no longer reach the cut-off for hEDS and would instead
be given a diagnosis of Generalized HSD (G-HSD) were they reassessed.
Due to the nature of online surveys and our inability to reassess participants for appropriate
recategorization, it is therefore assumed that the ASD/GJH group in this study contains a mix of
individuals who would currently be defined as G-HSD and hEDS. For these reasons, our results may
not be fully applicable to hEDS and must therefore be interpreted with caution.
Other limitations of our study concern the reliability of data derived from self-reports, which is
vulnerable to reporting bias. In particular, the similarity between rates of clinical presentation in our
ASD group and the general population suggests reporting reliability (Tables 2and 3). Meanwhile,
similarly high rates of immune- and endocrine-mediated disorders in our ASD/GJH group compared
to the general HSD/EDS population also support the veracity of their reports [17,33,69].
Behav. Sci. 2018,8, 35 11 of 16
A related vulnerability of our data hinges on ASD and GJH diagnostic reliability. While the data
is dependent upon self-reports, we did however offer respondents the opportunity to specify whether
they were professionally diagnosed or suspected a diagnosis. Those who indicated a suspicion of
hEDS or some type of HSD were initially included in the first round of analyses as an additional
group of interest. However, their data varied too dramatically from the diagnosed group and were not
included in the final analysis. Therefore, while the diagnostics are not standardized in this study, those
reporting professional diagnoses of ASD or GJH were assumed to be truthful.
Another limitation concerns small sample sizes, particularly of the ASD/GJH group. Given the
rarity of EDS (1:5000) and the infrequency of its overlap with ASD (3%), a sample size of 20 could
be considered quite large [
87
,
88
]. There are unfortunately no current estimates of G-HSD prevalence
under the new nosology; however, our results indicate that we have had ample power for this study.
We selectively surveyed ASD women aged 25 years or older to study specific immune and
endocrine exophenotypes. However, we cannot generalize our results to the broader autism spectrum,
though previous studies indicate that related endo- and exophenotypes exist in ASD males and
individuals under the age of 25. Likewise, we cannot generalize our data to the full EDS and GJH
spectrums, though previous research supports our findings [
17
,
79
,
80
,
89
]. Instead, future research is
needed to explore a potential clinical spectrum that spans the sexes and the lifespan to determine to
what extent our findings apply to the broader autism spectrum and GJH.
Finally, our results suggest there may be a relationship between epilepsy and immune
symptomology, which is supported by the recognized roles that cytokines and other immune factors
play in epileptogenesis [
90
]. However, due to small participant numbers, further investigation is
necessary to address this potential and is a topic we will be addressing in future studies.
Supplementary Materials:
The following are available online at http://www.mdpi.com/2076-328X/8/3/35/s1,
Table S1: immune symptoms: hospitalization history, asthma, ear infections, rhinitis, and sinusitis.
0 = no
symptom reported; 1 = symptom reported, Table S2: immune symptoms: allergies, reaction to medications
(med react), reaction to environmental chemicals (env react), autoimmunity, and sum of all immune symptoms.
0 = no symptom reported
; 1 = symptom reported, Table S3: endocrine symptoms: polycystic ovary syndrome
(PCOS), amenorrhea, diabetes 2/insulin resistance (diabetes, endometriosis, and adult acne. 0 = no symptom
reported; 1 = symptom reported, Table S4: Endocrine symptoms: infertility, dysmenorrhea, irregular menses,
high LDL cholesterol, and hypertension. 0 = no symptom reported; 1 = symptom reported, Table S5: Endocrine
symptoms: hirsutism, overweight/obesity, premenstrual dysphoric disorder (PMDD), severe teen acne, uterine
fibroids, and sum of all endocrine symptoms. 0 = no symptom reported; 1 = symptom reported, Table S6: Sum
of immune symptoms by age range (child, teen, and adult). 0 = no symptom reported; 1 = symptom reported,
Table S7: Symptoms of irritable bowel syndrome/gastrointestinal dysmotility (IBS), joint pain, other chronic pain,
epilepsy, and birth control/hormone treatment (BC Tx). 0 = no symptom reported; 1 = symptom reported.
Acknowledgments:
We would like to give the warmest of thanks to Jeanne Winstead, without whose advice
and help in advertising this survey our study would not have been possible. We would also like to thank the
many websites, both autism- and EDS-specific, that allowed us to advertise the survey and collect respondents.
Thank you to the respondents themselves and their willingness to participate in this study. And finally, thank you
to Lawrence Afrin who took time from his busy clinical schedule to read this article and offer valuable critique.
This work was supported by the National Institutes of Health [grant number R01 HD-65279].
Author Contributions:
E.L.C. conceived of the study. E.L.C. and S.M.E. designed the survey and E.L.C., along with
help from the autism and Ehlers-Danlos/Hypermobility Spectrum Disorder communities, worked to advertise
the study online. J.L.S. performed the statistical analyses. M.F.C. and D.P.K. provided expertise on autism and
were integral in helping to design the overall study. All authors contributed substantially to the drafts and have
read and approved the final manuscript.
Conflicts of Interest:
E.L.C. reported no biomedical financial interests or potential conflicts of interest.
J.L.S. reported no biomedical financial interests or potential conflicts of interest. S.M.E. reported no biomedical
financial interests or potential conflicts of interest. D.P.K. reported no biomedical financial interests or potential
conflicts of interest. M.F.C. reported no biomedical financial interests or potential conflicts of interest.
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2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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... Most population-based reports indicated an estimated severe PMS/PMDD prevalence between 3% and 8% across all age groups in the general population (Sáenz-Herrero et al., 2019;Liao et al., 2017;Tadakawa et al., 2016), while those with mild to moderate PMS occurring in 20-80% (Kyrkou, 2005). Evidence suggests that the prevalence of PMDD among women with ASD can range as high as 92% (Obaydi and Puri, 2008) and as low as 21% (Casanova et al., 2018;Lever & Geurts, 2016). Other studies reported findings that over 75% (Kyrkou, 2005) and even 86% (Hamilton et al., 2011) of women with ASD experienced moderate to severe PMS/PMDD. ...
... It is probable that the severity of PMS symptoms/PMDD occurrence is higher in ASD participants with other comorbidities (Casanova et al., 2018;Kyrkou, 2005). However, this does not negate the fact that even among women with ASD only, the percentage of severe PMS/PMDD is very high -86% of ASD participants consisting of autism, Asperger's syndrome, and PDD-NOS diagnosis reported moderate to severe PMS/PMDD (Hamilton et al., 2011). ...
Thesis
Full-text available
Adolescent girls and adult women with ASD who experience severe PMS symptoms may be unrecognized by mental health professionals and thus not treated appropriately. The purpose of the study is to engage in an extensive literature review and critical analysis to explore the nature of menstruation experiences in women diagnosed with ASD, statistical evidence to support the comorbid nature of PMS/PMDD in ASD, and possible comorbidity mechanisms involved. A qualitative systematic review approach was carried out following the PRISMA framework. Results indicated that many women with ASD, either with a single diagnosis or other comorbidities, experienced PMS/PMDD symptoms that affect their daily life functioning. Shared etiopathophysiological findings from ASD and PMS/PMDD revealed several potential theoretical pathways for the comorbidity occurrence. Increase awareness, education, and support, including a proper investigation on reported distress related to menstruation for this specific population, are implicated for professional practice. As the study acts as a starting point of new theoretical constructs, future primary investigations of the comorbidity condition are warranted to assist early identification, diagnosis, and intervention for ASD and PMDD among women.
... Moreover, brain heterotopia, which refers to brain malformations resulting from deficits of neuronal migration, has been described in autism (Wegiel et al., 2010) and in EDS (Sheen & Walsh, 2005) providing another clue in understanding the overlap between these conditions. In addition, as highlighted by Casanova, Sharp, Edelson, Kelly, and Casanova (2018) Hsiao, 2013) and are also present in EDS (Hugo-Rodin, Lebègue, Becourt, Hamonet, & Gompel, 2016;Seneviratne, Maitland, & Afrin, 2017). Consistently, the survey by Casanova et al. (2018) showed that women with ASD and JHM presented with significantly more immune and endocrine mediated conditions than those without JHM. ...
... In addition, as highlighted by Casanova, Sharp, Edelson, Kelly, and Casanova (2018) Hsiao, 2013) and are also present in EDS (Hugo-Rodin, Lebègue, Becourt, Hamonet, & Gompel, 2016;Seneviratne, Maitland, & Afrin, 2017). Consistently, the survey by Casanova et al. (2018) showed that women with ASD and JHM presented with significantly more immune and endocrine mediated conditions than those without JHM. ...
Article
Joint hypermobility (JHM), defined as an increased range of joint motion, is a frequent somatic trait in the general population but also the hallmark of many of the hereditary disorders of connective tissue. Ehlers-Danlos syndromes (EDS) belong to this group of diseases and are characterized by tissue fragility, skin abnormalities and JHM. Between JHM and EDS there are the so-called Hypermobility Spectrum Disorders (HSD) which is an umbrella term referring to people with symptomatic JHM who do not fulfill criteria for a syndromic connective tissue disorder such as EDS. Among the variety of clinical correlates of JHM/HSD/EDS, neurodevelopmental atypisms are common although often not screened for and identified in the clinical setting. This article reviews the pertinent literature concerning neurodevelopmental conditions for which there is some evidence of an association with JHM/HSD/EDS. These include hyperactivity and attention deficit, learning, communication, and motor problems including tic disorders such as Tourette syndrome, and autism spectrum disorders. Underlying mechanism hypotheses for such interconnections are also reviewed. The coexistence of connective tissue-altered conditions and neurodevelopmental atypisms increases disability in patients from an early age. Thus, increased awareness among clinicians and researchers is necessary to promote assessment, diagnosis and develop management strategies to meet the specific needs of those affected.
... Paediatric studies have highlighted a higher incidence of neurodevelopmental disorders in children with chronic pain [16,17] or CSS [18,19], but there is little equivalent research in adults. There is, however, growing awareness of a link between neurodivergence and genetic connective tissue disorders, particularly joint hypermobility-related disorders [20,21] and the Ehlers-Danlos syndromes [22]. These conditions often co-occur with CSS [23][24][25], but more research is needed into whether this directly translates to an association between autism and CSS. ...
... Autism and CSS may also be related through neuroimmune and genetic differences, particularly the recently recognised "trifecta" of conditions, and are increasingly found to be co-morbid with or underly CSS diagnoses [25]. They have also been recognised to be associated with autism and other neurodevelopmental conditions [20,22], particularly through the work of Eccles et al [21,25,68,69], and Casanova et al (2019) recently theorised that some forms of autism could even be hereditary connective tissue disorders [70]. Autism and bromyalgia are directly associated through the FRM1 gene mutation [71] associated with Fragile X syndrome [72], the most common single gene cause of autism. ...
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Full-text available
Background Autistic adults, particularly women, are more likely to experience chronic ill health than the general population. Central sensitivity syndromes (CSS) are a group of related conditions that are thought to include an underlying sensitisation of the central nervous system; heightened sensory sensitivity is a common feature. Anecdotal evidence suggests autistic adults may be more prone to developing a CSS. This study aimed to investigate the occurrence of CSS diagnoses and symptoms in autistic adults, and to explore whether CSS symptoms were related to autistic traits, mental health, sensory sensitivity, or sex. Methods Participants included 982 autistic adults (male = 409, female = 563, other = 9, mean age = 44.5) registered at the Netherlands Autism Register, who completed questionnaires assessing autistic traits, sensory sensitivity, CSS, physical and mental health symptoms. The reliability and validity of the Central Sensitization Inventory (CSI) in an autistic sample was established using exploratory and confirmatory factor analyses. Chi2 analyses, independent t-tests, ANOVA, hierarchical regression analysis and path analysis were used to analyse relationships between CSS symptoms, autistic traits, measures of mental health and wellbeing, sensory sensitivity, age and assigned sex. Results 21% of participants reported one or more CSS diagnoses, and 60% scored at or above the clinical cut-off for a CSS. Nonbinary and female autistics were more likely to report a CSS diagnosis and experienced more CSS symptoms than males. Sensory sensitivity, anxiety, age and sex were significant predictors of CSS symptoms, with sensory sensitivity and anxiety fully mediating the relationship between autistic traits and CSS symptoms. Limitations Although this study included a large sample of autistic adults, we did not have a control group or a CSS only group. Conclusions CSS diagnoses and symptoms appear to be very common in the autistic population. Increased awareness of an association between autism and CSS should inform clinicians and guide diagnostic practice, particularly for females where CSS is common and autism under recognised.
... Given the observed association between neurodevelopmental conditions and hypermobility, neurodivergent individuals may have an increased likelihood of experiencing pain (38). For instance, an online survey of autistic females found that 100% of those with joint hypermobility (n = 85) experienced joint pain, compared to only 29% of those without joint hypermobility [n = 20; (39)]. Chronic pain has a detrimental effect on the quality of life of neurodivergent individuals (40), highlighting a need to further characterize these associations within a more representative sample including males (38). ...
Article
Full-text available
Objectives: Autism, attention deficit hyperactivity disorder (ADHD), and tic disorder (Tourette syndrome; TS) are neurodevelopmental conditions that frequently co-occur and impact psychological, social, and emotional processes. Increased likelihood of chronic physical symptoms, including fatigue and pain, are also recognized. The expression of joint hypermobility, reflecting a constitutional variant in connective tissue, predicts susceptibility to psychological symptoms alongside recognized physical symptoms. Here, we tested for increased prevalence of joint hypermobility, autonomic dysfunction, and musculoskeletal symptoms in 109 adults with neurodevelopmental condition diagnoses. Methods: Rates of generalized joint hypermobility (GJH, henceforth hypermobility) in adults with a formal diagnosis of neurodevelopmental conditions (henceforth neurodivergent group, n = 109) were compared to those in the general population in UK. Levels of orthostatic intolerance and musculoskeletal symptoms were compared to a separate comparison group (n = 57). Age specific cut-offs for GJH were possible to determine in the neurodivergent and comparison group only. Results: The neurodivergent group manifested elevated prevalence of hypermobility (51%) compared to the general population rate of 20% and a comparison population (17.5%). Using a more stringent age specific cut-off, in the neurodivergent group this prevalence was 28.4%, more than double than the comparison group (12.5%). Odds ratio for presence of hypermobility in neurodivergent group, compared to the general population was 4.51 (95% CI 2.17-9.37), with greater odds in females than males. Using age specific cut-off, the odds ratio for GJH in neurodivergent group, compared to the comparison group, was 2.84 (95% CI 1.16-6.94). Neurodivergent participants reported significantly more symptoms of orthostatic intolerance and musculoskeletal skeletal pain than the comparison group. The number of hypermobile joints was found to mediate the relationship between neurodivergence and symptoms of both dysautonomia and pain. Conclusions: In neurodivergent adults, there is a strong link between the expression of joint hypermobility, dysautonomia, and pain, more so than in the comparison group. Moreover, joint hypermobility mediates the link between neurodivergence and symptoms of dysautonomia and pain. Increased awareness and understanding of this association may enhance the management of core symptoms and allied difficulties in neurodivergent people, including co-occurring physical symptoms, and guide service delivery in the future.
... Paediatric studies have highlighted a higher incidence of neurodevelopmental disorders in children with chronic pain [47,48] and/or CSS [49,50], but there is little equivalent research in adults. There is, however, growing awareness of a link between autism and genetic connective tissue disorders, particularly joint hypermobility-related disorders [51,52] and the Ehlers-Danlos syndromes [53]. These conditions often co-occur with CSS [54][55][56], but more research is needed to determine whether this directly translates to an association between autism and CSS. ...
Article
Full-text available
Background Autistic adults, particularly women, are more likely to experience chronic ill health than the general population. Central sensitivity syndromes (CSS) are a group of related conditions that are thought to include an underlying sensitisation of the central nervous system; heightened sensory sensitivity is a common feature. Anecdotal evidence suggests autistic adults may be more prone to developing a CSS. This study aimed to investigate the occurrence of CSS diagnoses and symptoms in autistic adults, and to explore whether CSS symptoms were related to autistic traits, mental health, sensory sensitivity, or gender. Methods The full sample of participants included 973 autistic adults (410 men, 563 women, mean age = 44.6) registered at the Netherlands Autism Register, who completed questionnaires assessing autistic traits, sensory sensitivity, CSS, physical and mental health symptoms. The reliability and validity of the Central Sensitization Inventory (CSI) in an autistic sample was established using exploratory and confirmatory factor analyses. Chi2 analyses, independent t-tests, hierarchical regression and path analysis were used to analyse relationships between CSS symptoms, autistic traits, measures of mental health and wellbeing, sensory sensitivity, age and gender. Results 21% of participants reported one or more CSS diagnosis, and 60% scored at or above the clinical cut-off for a CSS. Autistic women were more likely to report a CSS diagnosis and experienced more CSS symptoms than men. Sensory sensitivity, anxiety, age and gender were significant predictors of CSS symptoms, with sensory sensitivity and anxiety fully mediating the relationship between autistic traits and CSS symptoms. Limitations Although this study included a large sample of autistic adults, we did not have a control group or a CSS only group. We also could not include a non-binary group due to lack of statistical power. Conclusions CSS diagnoses and symptoms appear to be very common in the autistic population. Increased awareness of an association between autism and central sensitisation should inform clinicians and guide diagnostic practice, particularly for women where CSS are common and autism under recognised.
... Concerning HSD and EDS, the study by Cederlöf et al. (2016) reported an increased risk of autism spectrum disorders in people with these syndromes. Explanatory hypotheses about the overlap/comorbidity between autism and collagen altered conditions includes brain heterotopias, immune, endocrine and metabolic alterations have been proposed to understand the comorbidity with autism (Baeza-Velasco et al., 2018c;Casanova et al., 2018Casanova et al., , 2019Casanova et al., , 2020Skalny et al., 2020). ...
... This factor should be further investigated with a multi-disciplinary assessment for ASD, the gold standard for autistic traits in adulthood [34]. If confirmed, the high prevalence of ASD in EDS should suggest a shared etiological hypothesis [35,36]. Moreover, the co-occurrence of EDS and ASD have a clinical implication. ...
Article
Full-text available
Background: Ehlers-Danlos syndromes (EDS) have been associated with psychological distress, comorbid psychiatric disorders, and worsening in quality of life (QoL). Among the neurodevelopmental disorders, autism spectrum disorders (ASD) have shown the highest rates of co-occurrence with EDS. The reasons for these associations are unknown and a possible role of pain in increasing the risk of psychiatric disorders in EDS has been suggested. However, a detailed picture of an Italian EDS sample is still lacking. Methods: We conducted a web-based survey in a third level center for the diagnosis of EDS in northern Italy, to investigate psychological distress, QoL, and the presence of autistic traits. Furthermore, we correlated the psychometric data with some clinical variables. Results: We observed a high rate of psychological distress with 91% of the responders at high risk of common mental disorders, low QoL, and high prevalence of autistic traits in EDS patients. Specifically, patients lacking a specific genetic test, diagnosed as suspects of EDS appeared to be at greater risk and reported worse psychological QoL. Pain was significantly associated with both psychological distress and worse QoL. Conclusions: Our findings support the need of further research and of a multi-disciplinary approach to EDS including psychological and psychiatric liaison.
Article
Background Ehlers-Danlos Syndromes (EDS) comprise a group of heterogeneous hereditary connective tissue disorders [1, 2]. Psychiatric disorders such as depression, anxiety, panic disorder, agoraphobia, schizophrenia, neurodevelopmental disorders, personality disorder, eating disorders, substance misuse and interpersonal issues have been reported in the literature to be associated with EDS [1-3]. Objectives The case of a 15-year -old male who was hospitalized after a suicide attempt by gunshot was discovered to have symptoms suggestive of EDS is presented in this paper along with the results of a literature search of psychiatric manifestations of EDS in children and adolescents. Methods Literature review was conducted on the UpToDate website on March 11, 2020 to review symptoms of EhlersDanlos Syndrome for the purpose of preliminary diagnosis of this patient. Additional literature search was conducted on PubMed on 4/2/20 at 12:10 P.M. and on 4/9/20 at 10:51 P.M. and on the search engine Google on 4/2/20 at 12:25 P.M. On May 11, 2020 at 2 P.M., another web search was conducted with review of 6 different websites pertaining to EhlersDanlos Syndrome. Results A systematic review of psychiatric manifestations of Ehlers-Danlos Syndromes revealed a strong incidence of psychiatric symptoms. Conclusion Our patient’s psychiatric symptoms of depression, suicidal ideations, anxiety and social and educational struggles may have been at least partially due to chronic pain- abdominal, headache and musculoskeletal, and social ostracization associated with Ehlers-Danlos Syndrome. Education regarding this illness helped our patient’s recovery as he came to understand why he was so “odd” and the cause of his multisystemic chronic pain.
Article
Full-text available
The Ehlers Danlos Syndromes (EDS) are a group of heritable, connective tissue disorders characterized by joint hypermobility, skin hyperextensibility and tissue fragility. There is phenotypic and genetic variation among the thirteen subtypes. The initial genetic findings on EDS were related to alterations in fibrillar collagen, but the elucidation of the molecular basis of many of the subtypes revealed several genes not involved in collagen biosynthesis or structure. However, the genetic basis of the hypermobile type of EDS (hEDS) is still unknown. hEDS is the most common type of EDS and involves generalized joint hypermobility, musculoskeletal manifestations, and mild skin involvement along with the presence of several co-morbid conditions. Variability in the spectrum and severity of symptoms and progression of patient phenotype likely depend on age, gender, lifestyle and expression domains of the EDS genes during development and postnatal life. In this review, we summarize the current molecular, genetic, epidemiologic and pathogenetic findings related to Ehlers-Danlos Syndromes with a focus on the hypermobile type. This article is protected by copyright. All rights reserved.
Article
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This study examines medical conditions diagnosed prior to the diagnosis of autism spectrum disorder (ASD). Using a matched case control design with 3911 ASD cases and 38,609 controls, we found that 38 out of 79 medical conditions were associated with increased ASD risk. Developmental delay, mental health, and neurology conditions had the strongest associations (ORs 2.0–23.3). Moderately strong associations were observed for nutrition, genetic, ear nose and throat, and sleep conditions (ORs 2.1–3.2). Using machine learning methods, we clustered children based on their medical conditions prior to ASD diagnosis and demonstrated ASD risk stratification. Our findings provide new evidence indicating that children with ASD have a disproportionate burden of certain medical conditions preceding ASD diagnosis. Electronic supplementary material The online version of this article (doi:10.1007/s10803-017-3130-4) contains supplementary material, which is available to authorized users.
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Well known for their role in allergic disorders, mast cells (MCs) play a key role in homeostatic mechanisms and surveillance, recognizing and responding to different pathogens, and tissue injury, with an array of chemical mediators. After being recruited to connective tissues, resident MCs progenitors undergo further differentiation, under the influence of signals from surrounding microenvironment. It is the differential tissue homing and local maturation factors which result in a diverse population of resident MC phenotypes. An abundance of MC reside in connective tissue that borders with the external world (the skin as well as gastrointestinal, respiratory, and urogenital tracts). Situated near nerve fibers, lymphatics, and blood vessels, as well as coupled with their ability to secrete potent mediators, MCs can modulate the function of local and distant structures (e.g., other immune cell populations, fibroblasts, angiogenesis), and MC dysregulation has been implicated in immediate and delayed hypersensitivity syndromes, neuropathies, and connective tissue disorders (CTDs). This report reviews basic biology of mast cells and mast cell activation as well as recent research efforts, which implicate a role of MC dysregulation beyond atopic disorders and in a cluster of Ehlers-Danlos Syndromes, non-IGE mediated hypersensitivity disorders, and dysautonomia. © 2017 Wiley Periodicals, Inc.
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Background: To assess the risk of psychiatric disorders in Ehlers-Danlos syndrome (EDS) and hypermobility syndrome. Methods: Nationwide population-based matched cohort study. EDS, hypermobility syndrome and psychiatric disorders were identified through Swedish national registries. Individuals with EDS (n = 1,771) were matched with comparison individuals (n = 17,710). Further, siblings to individuals with EDS who did not have an EDS diagnosis themselves were compared with matched comparison siblings. Using conditional logistic regression, risk of autism spectrum disorder (ASD), bipolar disorder, attention deficit hyperactivity disorder (ADHD), depression, attempted suicide, suicide and schizophrenia were estimated. The same analyses were conducted in individuals with hypermobility syndrome (n = 10,019) and their siblings. Results: EDS was associated with ASD: risk ratio (RR) 7.4, 95 % confidence interval (95 % CI) 5.2-10.7; bipolar disorder: RR 2.7, CI 1.5-4.7; ADHD: RR 5.6, CI 4.2-7.4; depression: RR 3.4, 95 % CI 2.9-4.1; and attempted suicide: RR 2.1, 95 % CI 1.7-2.7, but not with suicide or schizophrenia. EDS siblings were at increased risk of ADHD: RR 2.1, 95 % CI 1.4-3.3; depression: RR 1.5, 95 % CI 1.1-1.8; and suicide attempt: RR 1.8, 95 % CI 1.4-2.3. Similar results were observed for individuals with hypermobility syndrome and their siblings. Conclusions: Individuals with EDS and hypermobility syndrome are at increased risks of being diagnosed with psychiatric disorders. These risk increases may have a genetic and/or early environmental background as suggested by evidence showing that siblings to patients have elevated risks of certain psychiatric disorders.
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