We identified 379 confirmed cases of HEDS in the Dartmouth-Hitchcock Medical Center (Table 1). These patients were predominantly evaluated in the Rheumatology Clinic (53.3%) or Genetics Clinic (43.8%) for their musculoskeletal complaints, i.e. neck pain, back pain, or multiple joint pain. Only 2.9% of patients received a diagnosis of HEDS from a physician outside of these two clinics. Of these confirmed HEDS patients, 320 (84.4%) were female, and 59 (15.6%) were male. It is well-established that many rheumatic diseases, such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE), are more common in women. To ensure that the preponderance of female HEDS patients was not due to a sampling bias from the largely female patient population in the Rheumatology clinic, we compared the ratio of female to male HEDS patients with that of the overall patient population in both the Rheumatology and Genetics clinics (Table 2). While the general patient population of the Rheumatology clinic was biased towards females (66.9% female, 33.1% male), the female to male ratio of HEDS patients diagnosed at the Rheumatology Clinic was even more skewed (89.6% female, 10.4% male, p < 0.0001). Though the female to male ratio of the overall patient population of the Genetics clinic is 1:1 (50.1% female, 49.9% male), the HEDS patients diagnosed by this clinic were predominantly female as well (78.3% female, 21.7% male, p < 0.0001). Statistical analysis confirmed that the female predominance among HEDS patients was not a result of sampling bias (Table 2).

Table 1 Demographics of HEDS patients. Full size table

Table 2 Gender ratio of HEDS patients compared to general patient population by subspecialty. Full size table

Next, we classified patients according to the level of workup these HEDS patients received (Table 1). Most patients (240 total) received only a physical examination with no additional workup after a diagnosis of HEDS was made, and were categorized as “no workup” (NWU). Among this group, 21 patients (8.8%) were found to have at least one rheumatological condition in addition to HEDS. A total of 51 patients had limited serological or radiographic studies performed on their spine or joints in addition to the physical examination after a diagnosis of HEDS was made, and were classified as “limited workup” (LWU) patients. Significantly more patients (17, or 33.3%) in the LWU group were found to have at least one rheumatological diagnosis as compared to the NWU patients (adjusted p-value < 0.0001). The remaining 88 patients received a comprehensive workup (CWU), with detailed serological and radiographic studies, after a diagnosis of HEDS was made. Significantly more CWU patients (59, or 67.1%) had at least one rheumatological condition as compared to either the LWU or NWU groups (adjusted p-value < 0.0001). Additionally, patients in the CWU group tended to have more additional diagnoses than patients in either the LWU or NWU groups (Fig. 1); while only a very small percentage of NWU and LWU patients had two additional diagnoses (0.4 and 3.9%, respectively), 21.6% of CWU patients had two additional diagnoses. Furthermore, none of the patients in either the NWU or LWU groups had more than two additional diagnoses, but 12.5% of the CWU presented with three and 2.3% presented with four additional conditions following serological with or without radiographic studies.

Figure 1: Distribution of number of rheumatological diagnoses by workup status. NWU, no workup; LWU, limited workup; CWU, comprehensive workup. Full size image

Next, we quantified the number of patients who tested positive for serological markers of inflammation or autoimmunity (Table 3), such as ANA, RF, or anti-citrullinated protein antibodies (ACPA); however, it is difficult to determine the significance of these findings because not all patients in the limited workup group were tested for all of these markers. Interestingly, we found that 21 of the patients in the comprehensive workup group (23.9%) were tested positive for HLA-B27 (Table 3). A previous study found that the overall prevalence of the HLA-B27 antigen in the general population of the United States, was 6.1%10. Based on this observation, the prevalence of HLA-B27 in our patient population who received comprehensive workup was significantly higher than that of the general population (p-value = 2.2 × 10−8).

Table 3 Laboratory findings in HEDS patients. Full size table

Next, we catalogued all of the rheumatological conditions seen in our HEDS patients among all the different workup groups. These categories included structural defects (Table 4), non-inflammatory conditions (Table 4), and inflammatory conditions (Table 5). Of the 40 different conditions listed, ten were diagnosed solely on clinical grounds such as structural/physical abnormalities (club feet, developmental delay, occulocutaneous albinism type 1, pectus carinatum, and pectus excavatum) or physical examination (costochondritis, erythromelaliga, fibromyalgia, psoriasis, and Raynaud’s phenomenon); the majority of the conditions require further diagnostic workup, including serological studies (i.e. C3 hypocomplementemia), radiographic studies (i.e. inflammatory arthritis with erosive disease), or skin biopsy (i.e. small fiber sensory neuropathy). The five most common conditions were fibromyalgia (22 cases) and psoriasis (22 cases), followed by ankylosing spondylitis (AS) (11 cases), psoriatic arthritis (PsA) (11 cases), and then RA (9 cases). Interestingly, 27.3% of PsA patients and 33% of RA patients (both seronegative and seropositive) were diagnosed with advanced erosive disease, and without radiographic studies, these patients would have been missed solely based on physical examination. Of all the inflammatory conditions, only psoriasis and Kawasaki disease were diagnosed in the NWU group, as these two conditions require only physical examination for diagnosis. Although a limited workup allowed for six more inflammatory conditions to be diagnosed as compared to the NWU group, there were still ten fewer conditions diagnosed in the LWU than in the CWU group, which may be accounted for by the fact that these conditions require extensive serological and radiographic studies to diagnose.

Table 4 Structural defects and non-inflammatory conditions in HEDS patients. Full size table

Table 5 Inflammatory diseases in HEDS patients. Full size table

In an attempt to further quantitate the impact of HEDS on the prevalence of these rheumatological conditions, the prevalence of each rheumatological condition in our patient population was compared to the prevalence of these conditions in the general population, though such comparison does have the potential to produce a sampling bias of these subjects (Supplementary Figure S2). Only the patients in the CWU group were examined because, by definition, the patients in other groups did not receive a sufficient workup to rule out the possibility of rheumatic diseases. We found cases of nine different structural defects (Table 4), three non-inflammatory diseases (Table 4), and nineteen inflammatory diseases (Table 5), for a total of 31 different rheumatalogical conditions among CWU patients. The prevalence for ten of these conditions in the general population cannot be identified (Supplementary Table S2), either because these conditions are too rare or because epidemiological data do not exist. Among the remaining conditions, 15 were significantly more prevalent in our CWU patient population than in the general population (Supplementary Figure S2), including club foot deformity, hereditary angioedema, primary hypogammaglobulemia, fibromyalgia, erythromelalgia, psoriasis, PsA, AS, RA, inflammatory eye disease, autoimmune thyroiditis, SLE, Crohn’s disease, pernicious anemia, and TNF Receptor-Associated Periodic Fever Syndrome (TRAPS).