Abstract
Clinical features of hypermobile Ehlers–Danlos syndrome (hEDS) and hypermobility syndrome (HMS) have classically focused on dysfunctions related to the musculoskeletal system. A growing body of literature suggests substantial multisystemic involvement, although this has not been recapitulated in a pediatric/young adult population. Leveraging a large United States healthcare claim database illuminates multisystem disorders among patients diagnosed with hEDS and HMS in the age range of 10 to 24. This was a retrospective review of patient records within the de-identified healthcare claims database, PearlDiver. Patients with a diagnosis of hEDS or HMS, and those without these diagnoses who were seen for their annual physical examination, between the ages of 10 and 24, were queried for the presence of additional medical conditions. Descriptive statistics were used to define the frequency of multisystem diagnoses. Nineteen thousand seven hundred ninety hEDS patients, 17,509 HMS patients, and 4,959,713 patients from the general population were analyzed. Within 2 years following hEDS or HMS diagnosis, digestive disorders were the most prevalent diagnosis, followed by cardiovascular conditions. Digestive disorders occurred in 54.6% of patients with hEDS and 41.6% of patients with HMS, compared to 28.5% of the general population. Cardiovascular disorders occurred in 43.6% of patients with hEDS and 21.8% of patients with HMS compared to 10.3% of the general population. Anxiety, respiratory disorders, and developmental disorders occurred in approximately 25% of the hEDS group and 20% of the HMS group, compared to ~15% of the general population, all statistically significantly higher in the hEDS and HMS groups. This study highlights multisystem diagnoses within the pediatric hEDS/HMS populations. hEDS patients had higher rates of multisystem diagnoses compared to HMS patients. These results suggest a high multisystem disease burden for young hEDS/HMS patients. Future research is needed to understand the timing and presentation of clinical symptoms for this population.
Keywords: anxiety, cardiovascular manifestations, digestive disorders, Ehlers–Danlos, PearlDiver, respiratory manifestations
1. Introduction
Hypermobile Ehlers–Danlos syndrome (hEDS) and other hypermobility syndromes (HMS) are a clinically variable and genetically heterogenous group of hereditary connective tissue disorders characterized by joint hypermobility, tissue fragility, and connective tissue frailty.[1–3] HMS is most often used to describe a cohort of patients who have complications associated with joint hypermobility when a heritable connective tissue disorder is not present.[4–6] Hypermobile hEDS is thought to be an autosomal dominant disorder with incomplete and variable expressivity,[7] which is likely caused by an alteration in the genes that synthesize and process collagen, resulting in structural changes that predispose individuals to greater than normal motion and laxity.[8] This increased laxity can lead to multiple organ dysfunction,[4] such as cardiac valve dysfunction, gastroesophageal reflux, or spontaneous pneumothorax. HMS may be a less severe phenotype within the hEDS spectrum. Even though HMS is sometimes considered to be a benign condition affecting only the joints and not leading to systemic manifestations,[5] this conclusion is not shown within the literature, and many patients report multisystem dysfunction.[9–11]
For many patients with hypermobile hEDS or HMS, the prominent complaint is pain, due to abnormal joint mechanics, which is often wide-spread and long lasting.[12] Patients also present with a high rate of concomitant fatigue, headaches, autonomic issues, anxiety, gastrointestinal, and genitourinary complaints.[7,13–15] Misdiagnosis of these disorders is common, with up to 56% of patients being misdiagnosed initially, and 70% of patients receiving inappropriate treatment.[16,17] It is very difficult to diagnose hypermobile hEDS and HMS in children under the age of 5 as they present with higher Beighton scores and exhibit more flexibility than adults.[10,18] Adults also tend to stiffen with age, which may hinder patient reporting of symptoms.[7,17] Additionally, the lack of familiarity and awareness about hEDS among physicians often results in delayed diagnosis, in some cases more than 28 years from initial consult.[16,17] As such, these disorders significantly impact quality of life for these patients[11] manifesting across physical, psychological, and social domains.[19] Although these conditions are not curable, recognizing the diverse symptoms and training healthcare professionals across specialties could improve early diagnosis and intervention.[14,19]
Currently, there is scarce data on hEDS due to limited research and lack of centers of excellence that specialize in care for these patients. Much of the medical literature uses small cohort studies consisting of samples with <100 adult patients.[17] Therefore, the purpose of this study was to explore the prevalence of systemic and multisystem disorders among pediatric and young adult patients with and without a diagnosis of hypermobile EDS and HMS by (1) describing the frequency of systemic and multisystem disorders in young patients (age 10–24) and (2) assessing if the frequency of these diagnoses differ between the general population and patients with a diagnosis of hEDS or HMS within a large US healthcare claims database.
2. Methods
2.1. Study design and database
This was a retrospective cohort study that used a de-identified healthcare claims database, PearlDiver Mariner Patient Claims Database (PearlDiver Technologies, Colorado Springs, CO), and was classified as exempt by the Institutional Review Board. PearlDiver is a proprietary web-based research platform that uses adjudicated medical claims from a large national repository of Commercial, Medicare, Medicaid, Government, and cash payer types. At the time of data query, there were 91 million distinct patients within the orthopedic subsection with access to de-identified medical, hospital, and prescription claims.
2.2. Patients
Data for this study was extracted from an orthopedic database, which was well-suited for the type of patient population, given the orthopedic nature of these conditions. Patient records were queried from January 2015, through October 2020, within the Mariner Database of PearlDiver. Three study samples were generated by querying records that were accessible through the database using International Classifications of Diseases (ICD-10) diagnosis codes. The first study sample queried for HMS patients using the ICD-10 code M35.7. The second study sample queried for hypermobile EDS patients using ICD-10 codes Q79.60 or Q79.62. Patients with ICD-10 codes for both HMS and hEDS were included in the hEDS sample. The third study sample queried for general population using the ICD-10 code for a routine child or adult health examination without abnormal findings (Z00.129 and Z00.00). Next, identified records were filtered to patients (1) between 10 and 24 years of age, and (2) those with continuous enrollment in the database for a year before and 2 years after their hEDS or HMS diagnoses, or health examination. Records were filtered a second time to exclude patients with a diagnosis of (1) cancer, or (2) a diagnosis of osteogenesis imperfecta. All samples were filtered a third time to exclude patients with a diagnosis of (1) fibromyalgia, (2) chronic fatigue, (3) hypothyroidism, (4) lupus, (5) multiple sclerosis, (6) sleep apnea, (7) polymyalgia rheumatica, or (8) Marfan syndrome (Fig. 1) to maintain a clearer focus on the multisystem nature of these disorders, as these diseases have been known to be misdiagnosed in the hypermobile EDS population. In addition, variables related to each patient’s demographics (sex [male, female], age [10–14, 15–19, 20–24 years of age], region of the country (Northeast, South, Midwest, West), and insurance status (Cash, Commercial, Government, Medicaid, or Medicare) were collected.
Figure 1.
Flow charts to determine populations based on ICD-10 codes.
2.3. Systemic and multisystem disorders
The primary outcome of interest was a concurrent diagnosis of systemic condition 1 year before or within 2 years after the initial diagnosis of hEDS or HMS, or routine health examination. Records for each study sample were queried for the initial diagnoses related to digestive disorders, respiratory dysfunction, anxiety, cardiovascular conditions, neurodevelopmental disorders, eating disorders, addictions, obsessive compulsive disorders, and depression (see Table 1).
Table 1.
ICD-10 codes used for concomitant conditions.
| Category | ICD-10 code |
|---|---|
| Digestive | R10.13 (epigastric pain) R11.0 (nausea) R13.10 (dysphagia) R19.7 (diarrhea) K13.84 (gastroparesis) K21 (gastroesophageal reflux) K44.9 (diaphragmatic hernia) K58.0, K58.9 (irritable bowel syndrome) K59.0 (constipation) K90.0 (Celiac disease) |
| Cardiovascular | I34.1 (mitral valve prolapse) I95.1 (orthostatic hypotension) R00.0 (tachycardia) R00.2 (palpitations) R01.1 (cardiac murmur) |
| Anxiety | F41.0 (panic disorder) F41.1, F41.3, F41.8, F41.9 (generalized anxiety disorder) |
| Respiratory | J30.0 (allergic rhinitis) J32.9 (chronic sinusitis) J38.0 (paralysis of vocal cords) J45.20, J45.21, J45.22, J45.30, J45.31, J45.32, J45.40, J45.41, J45.42, J45.50, J45.51, J45.52 (asthma) J90.0 (pleural effusion) J93.0 (spontaneous pneumothorax) |
| Neurodevelopmental | F90.0, F90.1, F90.2, F90.8, F90.9 (attention deficit hyperactivity disorder, ADHD) F84.0 (autistic disorder) F82 (developmental dyspraxia) |
| Eating disorders | F50.0, F50.01, F50.02 (anorexia nervosa) F50.2 (bulimia nervosa) R63.0 (anorexia) |
| Addictions | F10.10, F10.20 (alcohol abuse/ dependence) F17.220, F17.290 (nicotine dependence) F11.10, F11.20 (opioid abuse/ dependence) |
| Obsessive | F42, F42.8, F42.9 (obsessive compulsive disorder) F60.5 (obsessive compulsive personality) R46.81 (obsessive compulsive behavior) |
| Depression | F32.0, F32.1, F32.2, F32.3, F32.8, F32.89, F33.0, F33.1, F33.2, F33.3, F33.8, F33.9 (major depressive disorder) F34.1, F34.8, F34.81, F34.89, F34.9 (dysthymic disorder/ mood disorder) |
2.4. Statistical analysis
All statistical analyses were performed using PearlDiver native application. Descriptive statistics were used to describe the study samples’ demographics and prevalence of each systemic condition. Univariate testing was conducted to determine if demographic differences existed between study groups. To examine the frequency of systemic conditions between study samples, chi-square contingency tests with a Bonferroni correction was conducted. To examine the frequency of multisystem disorders in each study group, systemic conditions were grouped as the presence of 1 systemic condition (+1) to 6 systemic conditions (+6).
3. Results
The final study sample included 17,509 HMS patients, 19,970 hEDS patients, and 4,959,713 general population patients.
The demographics of these patients were further assessed, as seen in Table 2. Study samples were subdivided by sex, age, and region. Patients with hEDS or HMS come from all regions of the United States, however females are much more likely to be diagnosed with either hEDS (P < .0001, χ2 = 3762.39) or HMS (P < .0001, χ2 = 2852.18) than males as compared to the general population. Compared to the general population, hEDS patients (P < .001, χ2 = 200.0) and HMS patients (P < .001, χ2 = 138.8) tended to be older.
Table 2.
Demographics for all populations.
| hEDS diagnosis | HMS diagnosis | General population | ||||
|---|---|---|---|---|---|---|
| n = 19,790 | n = 17,509 | n = 4,959,713 | ||||
| Gender | ||||||
| Female | 15,303 | 77.3% | 13,256 | 75.7% | 2,758,827 | 55.6% |
| Male | 4487 | 22.7% | 4253 | 24.3% | 2,200,832 | 44.4% |
| Age | ||||||
| 10–14 | 4939 | 25.0% | 6845 | 39.1% | 2,197,567 | 44.3% |
| 15–19 | 8522 | 43.1% | 7307 | 41.7% | 1,740,210 | 35.1% |
| 20–24 | 6329 | 32.0% | 3357 | 19.2% | 1,021,936 | 20.6% |
| Region | ||||||
| Midwest | 6684 | 33.8% | 5005 | 28.6% | 1,192,343 | 24.0% |
| Northeast | 3481 | 17.6% | 3759 | 21.5% | 1,329,337 | 26.8% |
| South | 6710 | 33.9% | 5881 | 33.6% | 1,862,219 | 37.5% |
| West | 2833 | 14.3% | 2773 | 15.8% | 537,484 | 10.8% |
Within the 2 years following hEDS or HMS diagnosis, digestive disorders were the most prevalent system diagnosis for all study samples (see Table 3). Cardiovascular disorders are the second most common systemic disorder affecting the hEDS population. For HMS, anxiety is the second most common diagnosis. Respiratory disorders were also very common in hEDS (24.0%) and HMS (21.6%) compared to the general population, as were neurodevelopmental disorders.
Table 3.
Rates of concomitant disorders within the hEDS, HMS, and general populations.
| hEDS | HMS | General population | ||||
|---|---|---|---|---|---|---|
| Population: 19,790 | Population: 17,509 | Population: 4959,713 | ||||
| Cases | Percentage | Cases | Percentage | Cases | Percentage | |
| Digestive disorders | 10,817 | 54.6% | 7291 | 41.6% | 1,413,733 | 28.5% |
| Cardiovascular disorders | 8639 | 43.6% | 3811 | 21.8% | 509,261 | 10.3% |
| Anxiety | 5577 | 28.2% | 4375 | 25.0% | 826296.0 | 16.7% |
| Respiratory disorders | 4754 | 24.0% | 3780 | 21.6% | 803,512 | 16.2% |
| Neurodevelopmental | 4689 | 23.7% | 3411 | 19.5% | 759,924 | 15.3% |
| Eating disorders | 980 | 4.9% | 646 | 3.7% | 98,347 | 1.9% |
| Addictions | 786 | 3.9% | 313 | 1.8% | 116,208 | 2.3% |
| Obsessive | 792 | 4.0% | 424 | 2.4% | 50,733 | 1.0% |
| Depression | 713 | 3.6% | 660 | 3.7% | 190,844 | 3.8% |
Additionally, while under 5% of all populations had a diagnosed eating disorder, addiction or obsessive compulsive disorder, all showed an increased prevalence in hEDS and HMS. These comparisons between hEDS and the general population, hEDS and HMS, and HMS and the general population were statistically significant with P values < .0001 in all cases, except depression, as seen in Table 4. Equivalent rates of depression were seen in all groups (hEDS: 3.6% (P = .073), HMS: 3.7% (P = .590), general population: 3.8%(P = .780)).
Table 4.
hEDS, HMS, and the general populations P values and chi squared statistics for each diagnosis.
| Chi squared tests | hEDS vs general population | Chi squared statistic | HMS vs general population | Chi squared statistic | hEDS v HMS | Chi squared statistic |
|---|---|---|---|---|---|---|
| Digestive disorders | <0.00001 | 6601.95 | <0.00001 | 1476.11 | <0.00001 | 630.217 |
| Cardiovascular disorders | <0.00001 | 23575.71 | <0.00001 | 2494.78 | <0.00001 | 2001.31 |
| Anxiety | <0.00001 | 1880.15 | <0.00001 | 870.09 | <0.00001 | 48.44 |
| Respiratory disorders | <0.00001 | 886.84 | <0.00001 | 372.75 | <0.00001 | 31.17 |
| Neurodevelopmental | <0.00001 | 1062.93 | <0.00001 | 232.48 | <0.00001 | 96.96 |
| Eating disorders | <0.00001 | 888.85 | <0.00001 | 260.68 | <0.00001 | 35.51 |
| Addictions | <0.00001 | 227.89 | <0.00001 | 23.54 | <0.00001 | 154.96 |
| Obsessive | <0.00001 | 1708.35 | <0.00001 | 335.55 | <0.00001 | 73.57 |
| Depression | 0.073633 | 3.20 | 0.2989 | 0.59 | 0.39361 | 0.78 |
Tables 5 and 6 show additional breakdowns of the groups by age bracket and/or gender. This data breakdown shows a few interesting observations, as indicated in bold in Table 6. Digestive disorders (P = .081, χ2 = 3.0525), neurodevelopmental disorders (P = .483, χ2 = 0.4922), and eating disorders (P = .140, χ2 = 2.1806) are not different in the hEDS group and the general population in the 10 to 14 year old group. The rate of addictions is not different between any group in the 10 to 14 year old age bracket, and is not different in the HMS group as compared to the general population in the 15 to 19 year old age bracket as well (P = .102, χ2 = 2.6740). Obsessive disorders are not different in the 10 to 14 year old age bracket between HMS and hEDS (P = .439, χ2 = 0.5964), but are different compared to the general population. Depression was not statistically significantly different in any age group for HMS as compared to the general population, nor was it statistically significant for the 15 to 19 year group when comparing hEDS to the general population (P = .964, χ2 = 0.0021) or HMS to hEDS (P = .744, χ2 = 0.1059).
Table 5.
hEDS, HMS, and the general population striated by diagnosis, age range, and male:female ratio.
| hEDS | HMS | General population | ||||
|---|---|---|---|---|---|---|
| Population: 19,790 | Population: 17,509 | Population: 4,959,713 | ||||
| Cases | Percentage | Cases | Percentage | Cases | Percentage | |
| Digestive disorders | 10,817 | 54.6% | 7291 | 41.6% | 1,413,733 | 28.5% |
| Male:female | 1871:8946 | 17%:83% | 1482:5809 | 20%:80% | 502,426:911,295 | 35%:65% |
| 10–14 | 2269 | 21.0% | 2608 | 35.8% | 549,280 | 38.9% |
| 15–19 | 4758 | 44.0% | 3149 | 43.2% | 509,429 | 36.0% |
| 20–24 | 3790 | 35.0% | 1534 | 21.0% | 355,024 | 25.1% |
| Cardiovascular disorders | 8639 | 43.6% | 3811 | 21.8% | 509,261 | 10.3% |
| Male:female | 1299:7340 | 15%:85% | 717:3094 | 18%:82% | 176,970:332,285 | 35%:65% |
| 10–14 | 1433 | 16.6% | 1082 | 28.4% | 151,472 | 29.7% |
| 15–19 | 3872 | 44.8% | 1764 | 46.3% | 194,453 | 38.2% |
| 20–24 | 3334 | 38.6% | 965 | 25.3% | 163,336 | 32.1% |
| Anxiety | 5577 | 28.2% | 4375 | 25.0% | 826,296 | 16.7% |
| Male:female | 1110:4467 | 20%:80% | 954:3421 | 22%:78% | 292,770:533,518 | 35%:65% |
| 10–14 | 1421 | 25.5% | 1614 | 36.9% | 289,653 | 35.1% |
| 15–19 | 2417 | 43.3% | 1848 | 42.2% | 304,442 | 36.8% |
| 20–24 | 1739 | 31.2% | 913 | 20.9% | 232,201 | 28.1% |
| Respiratory disorders | 4754 | 24.0% | 3780 | 21.6% | 803,512 | 16.2% |
| Male:female | 1045:3709 | 22%:78% | 935:2845 | 25%:75% | 358,131:445,375 | 45%:55% |
| 10–14 | 1266 | 26.6% | 1618 | 42.8% | 385,205 | 47.9% |
| 15–19 | 2057 | 43.3% | 1523 | 40.3% | 275,002 | 34.2% |
| 20–24 | 1431 | 30.1% | 639 | 16.9% | 143,305 | 17.8% |
| Neurodevelopmental | 4689 | 23.7% | 3411 | 19.5% | 759,924 | 15.3% |
| Male:female | 1612:3077 | 34%:66% | 1303:2108 | 38%:62% | 456,004:303,918 | 60%:40% |
| 10–14 | 1552 | 33.1% | 1592 | 46.7% | 395,673 | 52.1% |
| 15–19 | 1922 | 41.0% | 1318 | 38.6% | 248,927 | 32.8% |
| 20–24 | 1215 | 25.9% | 501 | 14.7% | 115,324 | 15.2% |
| Eating disorders | 980 | 4.9% | 646 | 3.7% | 98,347 | 1.9% |
| Male:female | 122:858 | 12%:88% | 105:541 | 16%:84% | 31,543:66,803 | 32%:68% |
| 10–14 | 179 | 18.3% | 203 | 31.4% | 40,183 | 40.9% |
| 15–19 | 466 | 47.6% | 309 | 47.8% | 37,927 | 38.6% |
| 20–24 | 335 | 34.2% | 134 | 20.7% | 20,237 | 20.6% |
| Addictions | 786 | 3.9% | 313 | 1.8% | 116,208 | 2.3% |
| Male:female | 171:615 | 22%:78% | 82:231 | 26%:74% | 57,483:58,725 | 49%:51% |
| 10–14 | 39 | 5.0% | 39 | 12.5% | 12,815 | 11.0% |
| 15–19 | 289 | 36.8% | 143 | 45.7% | 46,418 | 39.9% |
| 20–24 | 458 | 58.3% | 131 | 41.9% | 56,975 | 49.0% |
| Obsessive | 792 | 4.0% | 424 | 2.4% | 50,733 | 1.0% |
| Male:female | 177:615 | 22%:78% | 106:318 | 25%:75% | 22,521:28,212 | 44%:56% |
| 10–14 | 165 | 20.8% | 159 | 37.5% | 18,624 | 36.7% |
| 15–19 | 337 | 42.6% | 178 | 42.0% | 18,766 | 37.0% |
| 20–24 | 290 | 36.6% | 87 | 20.5% | 13,343 | 26.3% |
| Depression | 713 | 3.6% | 660 | 3.7% | 190,844 | 3.8% |
| Male:female | 178:535 | 25%:75% | 146:514 | 22%:78% | 75,485:115,358 | 40%:60% |
| 10–14 | 159 | 22.3% | 234 | 35.5% | 74,590 | 39.1% |
| 15–19 | 297 | 41.7% | 270 | 40.9% | 74,630 | 39.1% |
| 20–24 | 257 | 36.0% | 156 | 23.6% | 41,624 | 21.8% |
Table 6.
hEDS, HMS, and the general populations P values and chi squared statistics for each diagnosis and each age range.
| Chi squared tests | hEDS vs general population | Chi squared statistic | HMS vs general population | Chi squared statistic | hEDS vs HMS | Chi squared statistic |
|---|---|---|---|---|---|---|
| Digestive disorders | ||||||
| 10–14 | 0.081 | 3.0525 | <0.0001 | 258.2956 | <0.0001 | 96.1506 |
| 15–19 | <0.0001 | 4036.94 | <0.0001 | 1123.8 | <0.0001 | 204.0503 |
| 20–24 | <0.0001 | 4240.00 | <0.0001 | 67.4164 | <0.0001 | 819.55 |
| Cardiovascular | ||||||
| 10–14 | <0.0001 | 1161.0 | <0.0001 | 573.706 | <0.0001 | 16.6420 |
| 15–19 | <0.0001 | 12615.8 | <0.0001 | 1745.0 | <0.0001 | 652.3344 |
| 20–24 | <0.0001 | 11192.9 | <0.0001 | 268.9403 | <0.0001 | 1170.6 |
| Anxiety | ||||||
| 10–14 | <0.0001 | 64.3350 | <0.0001 | 361.3557 | <0.0001 | 51.6057 |
| 15–19 | <0.0001 | 1080.9 | <0.0001 | 589.224 | <0.0001 | 25.2373 |
| 20–24 | <0.0001 | 742.0501 | 0.001 | 11.0912 | <0.0001 | 179.5493 |
| Respiratory disorders | ||||||
| 10–14 | <0.0001 | 51.6418 | <0.0001 | 52.9058 | <0.0001 | 105.3069 |
| 15–19 | <0.0001 | 882.211 | <0.0001 | 330.7045 | <0.0001 | 30.7874 |
| 20–24 | <0.0001 | 1316.5 | <0.0001 | 35.8998 | <0.0001 | 227.3175 |
| Neurodevelopmental | ||||||
| 10–14 | 0.483 | 0.4922 | <0.0001 | 29.5189 | <0.0001 | 18.8093 |
| 15–19 | <0.0001 | 907.4836 | <0.0001 | 229.9381 | <0.0001 | 55.8855 |
| 20–24 | <0.0001 | 1254.7 | <0.0001 | 22.0672 | <0.0001 | 227.4486 |
| Eating disorders | ||||||
| 10–14 | 0.140 | 2.1806 | <0.0001 | 26.4370 | 0.014676 | 5.9549 |
| 15–19 | <0.0001 | 651.3563 | <0.0001 | 228.9212 | <0.0001 | 15.8894 |
| 20–24 | <0.0001 | 790.7854 | <0.0001 | 54.6432 | <0.0001 | 64.3597 |
| Addictions | ||||||
| 10–14 | 0.089 | 2.878 | 0.354 | 0.860 | 0.588 | 0.2934 |
| 15–19 | <0.0001 | 58.3435 | 0.102 | 2.6741 | <0.0001 | 33.614 |
| 20–24 | <0.0001 | 234.87 | <0.0001 | 24.6833 | <0.0001 | 146.6 |
| Obsessive | ||||||
| 10–14 | <0.0001 | 110 | <0.0001 | 131.64 | 0.439 | 0.5964 |
| 15–19 | <0.0001 | 904.86 | <0.0001 | 187.45 | <0.0001 | 32.1302 |
| 20–24 | <0.0001 | 1000 | <0.0001 | 33.66 | <0.0001 | 87.091 |
| Depression | ||||||
| 10–14 | <0.0001 | 65.41 | 0.069 | 3.3044 | <0.0001 | 25.316 |
| 15–19 | 0.964 | 0.0021 | 0.685 | 0.1641 | 0.744887 | 0.1059 |
| 20–24 | <0.0001 | 49.8796 | 0.454 | 0.5609 | 0.0002 | 14.0994 |
Values which were not statistically significant between groups are bolded.
The rate of multisystem disorders was also assessed in this population. Among patients with an hEDS or HMS diagnosis, 15.3% and 26.9%, respectively, had no additional systemic diagnosis, compared to 41% of the general population with no systemic diagnoses. Multisystem diagnoses were identified in 57.2% of patients with an hEDS diagnosis, 40.7% of patients with a HMS diagnosis, and 24.8% in the general population. Figure 2 shows the breakdown of the number of multisystem diagnoses by each study group.
Figure 2.
Rate of multiple diagnoses in the hEDS and HMS population as compared to the general population. hEDS patients are represented by orange bars, HMS patients by yellow bars, and the general population by green bars. Dx = diagnosis.
4. Discussion
This study explored the multisystem disorders in patients with hEDS and HMS by describing the prevalence of the different clinical manifestations, and the cumulative disease burden within this population. All conditions assessed herein are known comorbidities of hEDS and HMS. Patients with hEDS have a higher percentage of all comorbid conditions assessed, with the exception of depression. Likewise, HMS patients also have a higher percentage of all comorbid conditions assessed, albeit with lower rates than those diagnosed with hEDS.
Results from our study indicate that 54.6% of hEDS and 41.6% of HMS patients were diagnosed with a gastrointestinal related condition. Gastrointestinal disorders in hEDS/HMS patient population have been well described in the literature.[20] Similarly to our study, Alomari et al which described patients with high frequencies of nausea (49.5%), constipation (45.4%), diarrhea (37.6%), and epigastric pain (49.8%).[13] The pathophysiological explanation for the occurrence of these symptoms is likely rooted in altered gastrointestinal function. In hEDS/HMS, excessive connective tissue elasticity causes an enlargement of the gastrointestinal wall which activates the mechanoreceptors responsible for the sensation of bloating.[20] In addition to causing pain from abdominal distention, this phenomenon alters abdominal motility and delays transit of gas.[21]
In our cohort, approximately 43.6% of hEDS and 21.8% of HMS patients were evaluated for at least one cardiac condition, with the most common being tachycardia, followed by palpitations, and orthostatic hypotension. Autonomic nervous system dysregulation responsible for postural orthostatic tachycardia syndrome (POTS) may present a more severe disease phenotype when occurring alongside hEDS.[22] Our trends are consistent with prior studies that cite the prevalence of POTS-like phenotype in hEDS/HMS cohorts between 5% and 41%.[23] This number is likely higher as diagnosis for POTS often takes years.[23] Connective tissue laxity and the inability to vasoconstrict observed in hEDS/HMS cause orthostatic blood pooling and orthostatic intolerance, which in combination with peripheral neuropathy, frequently seen in hEDS/HMS, may contribute to autonomic impairment.[22]
The very high percentage of individuals with hEDS who also had anxiety (28.2%) or neurodevelopmental disorders like autism or attention deficit hyperactivity disorder (ADHD) (23.7%), similar to Kindgren et al.[24] For patients with HMS, a quarter (25%) had a diagnosis of anxiety and 19.5% had a developmental disorder. Hypermobile EDS patients are at higher risk of mood disorders and developmental disorders than the general population,[25] though the studies looking at prevalence were performed on individuals over the age of 18 or used self-reports. Prevalence for anxiety disorders ranges from 9%[26] to 51.2%.[27] Our data falls more in line to the 26.6% prevalence found by Wasim et al.[28] The reason for the high rate of anxiety in the hEDS/ HMS population is not known. Perceived quality of life may be contributory to high levels of anxiety. A high rate of neurodevelopmental disorders has been found in patients with hEDS,[27,29] but prevalence varies considerably. Additionally, generalized joint laxity has been associated with developmental disorders, perhaps due to difficulties in motor planning associated with poor proprioception and motor coordination,[30] or perhaps due to the autonomic dysfunction seen in this population.[31] Interestingly, we did not see a high rate of depression in our cohort.
Respiratory manifestations have been inconsistently described as sequela of hEDS and HMS in literature.[4] Morgan et al observed asthma in 23% of hEDS and 37% of HMS patients,[32] which is comparable to our population at 24% and 21.6%, respectively. Symptoms of asthma in hEDS/HMS may be attributed to aberrant mast cell activation which may contribute to dysfunction of multiple organ systems.[33]
Our study found that females were diagnosed more frequently with hEDS (77.3%) or HMS (75.7%) than males, which is often reported.[16] Most of the patients in our cohort received their diagnoses between the ages of 15 to 19, and those who were diagnosed younger had fewer comorbidities. Possible explanations for this phenomenon are the influence of hormones and puberty on joint hypermobility and the higher predominance of chronic pain syndromes in women.[7,17,34] Therefore, pediatricians should be aware of hEDS/HMS presenting around puberty. No geographic differences were noted in these populations.
Additionally, we found a very high rate of multiple diagnoses within the hEDS and HMS cohorts as compared to the general population.[9,35] Over 25% of the hEDS group have more than 3 diagnoses, which accounts for a huge disease burden in this population. This number of additional diagnoses is not surprising as a recent study by Halverson et al, showed that the average hEDS patient goes through more than 10 alternative diagnoses before a formal diagnosis of hEDS is reached, and it takes approximately 5 years before the patient is officially diagnosed.[36] As hEDS has the tendency to resemble symptoms of other medical conditions, it is important to consider a potential diagnosis in a patient with multiple extra-articular manifestations, especially in a young population. We excluded fibromyalgia and chronic fatigue from our cohort due to the overlap of these conditions with hEDS/HMS, though recent research[10] suggests that including these comorbidities within our population groups would be insightful.
There are several limitations within this investigation. Firstly, our study utilized an insurance database, which limits our patient population to only those with insurance coverage, and limited conclusions to the statistical analyses and patient breakdowns available within the database. As a retrospective analysis, our study does not include follow-ups, the severity of the presentation for each disorder assessed, nor does it include date of diagnosis. Consequently, we lack significant information regarding the impact of the diagnosis on the quality of life of each patient and their comorbidities. Given that a large portion of patients are misdiagnosed,[17] it is possible that the lack of definitive diagnostic criteria for hEDS/HMS resulted in a much higher number of HMS and a much lower number of hEDS cases than in reality. Additionally, the subjective nature of symptom reporting by patients, may affect the accuracy of utilization of ICD-10 codes to represent these disorders. The ICD-10 code for HMS is an imperfect proxy for the variability of presentation seen within hypermobile patients.
5. Conclusions
In conclusion, hEDS is a relatively rare genetic disorder, and as such it is difficult to find large pools of patients to assess. The true prevalence of comorbid conditions within this population is unknown. This study highlights the growing number of hEDS/HMS diagnoses in younger populations. Patients diagnosed with hEDS also had higher rates of multisystem diagnoses compared to HMS patients. These results suggest a high multisystem disease burden for younger hEDS/HMS patients. Future research is needed to understand the timing of onset and presentation of clinical symptoms in these patients.
Author contributions
Conceptualization: Monika Kozyra, Regina Kostyun, Sara Strecker.
Data curation: Regina Kostyun, Sara Strecker.
Formal analysis: Regina Kostyun, Sara Strecker.
Investigation: Monika Kozyra, Regina Kostyun, Sara Strecker.
Methodology: Regina Kostyun, Sara Strecker.
Resources: Monika Kozyra.
Visualization: Regina Kostyun, Sara Strecker.
Writing – original draft: Monika Kozyra, Regina Kostyun, Sara Strecker.
Writing – review & editing: Monika Kozyra, Regina Kostyun, Sara Strecker.
Abbreviations:
- ADHD
- attention deficit hyperactivity disorder
- Dx
- diagnosis
- hEDS
- hypermobile Ehlers–Danlos syndrome
- HMS
- hypermobility syndromes
- ICD-10
- International Classifications of Diseases
- POTS
- postural orthostatic tachycardia syndrome
The PearlDiver subscription was a philanthropic gift to HH & BJI from the Beverly Buckner Baker Foundation.
This study has been reviewed by the Hartford Healthcare IRB and been classified as exempt (HHC-2022-0104).
The authors have no conflicts of interest to disclose.
The data that support the findings of this study are available from a third party, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available.
How to cite this article: Kozyra M, Kostyun R, Strecker S. The prevalence of multisystem diagnoses among young patients with hypermobile Ehlers–Danlos syndrome and hypermobility spectrum disorder: A retrospective analysis using a large healthcare claims database. Medicine 2024;103:41(e39212).
Level of Evidence: Level III; Case–Control Study.
Contributor Information
Monika Kozyra, Email: kozyra@uchc.edu.
Regina Kostyun, Email: regina.kostyun@hhchealth.org.
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