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).
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.
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).
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.
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).
Ehlers-Danlos syndrome (EDS) is a generalized disorder of one element of connective tissue manifesting clinically by fragility and hyperelasticity of the skin and joint laxity. It is a hereditary disorder, the inheritance being usually autosomal dominant with low penetrance. Autosomal recessive and X-linked recessive varieties are also known. First described by Hippocrates in 4th century B.C., the various clinical types with variable penetrance have been described lately. The number of cases EDS reported in the literature is very meagre. With the available information only about six publications of classic EDS in siblings had been reported in Indian literature.
Keywords: Cigarette paper scarring, Gorlin's sign, Reverse Namaskar sign
Ehlers-Danlos syndrome (EDS) is a heritary disorder of connective tissue characterized by fragility of skin and blood vessels, hyperextensibility of the skin and joint laxity. The diagnosis is mainly clinical. Milder variants of the classical mitis form of the EDS are common in the population and can be identified by a well-defined clinical scoring system.
A 17-year-old female born out of nonconsaguineous marriage attended the dermatology out-patient department with a history of laxity of skin and joints. A history of bruising of the skin and gaping wounds with even very trivial trauma could be easily ascertained, but no episode of a major hemorrhagic accident had ever occurred in the past. The patient was an outcome of a full term normal delivery with no neonatal or perinatal morbidity. The family history revealed no such complaints in parents and siblings.
On physical examination, the skin was soft, velvety and hyperextensible [Figure 3] but with normal recoil. Atrophic cigarette paper scars [Figure 1] were seen on forehead, cheeks, forearms, elbows, knees and both shin. Joints were hypermobile [Figure 2] with genu recurvatum of the knee and hallux valgus deformity of both great toes. Gorlin's sign and reverse Namaskar sign [Figure 4] could be elicited. There was no evidence of ecchymosis, cyanosis, digital clubbing, jaundice and lymphadenopathy. The fundus, routine blood test, urine, coagulogram, blood urea, sugar and echocardiogram were within the normal limits. X-ray of the spine and knee joints was normal except for feet which showed hallux valgus deformity. Histopathology with special stain for collagen and elastic fibers showed a decrease in collagen fibers with the relative increase in elastic fibers consistent with the diagnosis of EDS [Figures 5 and 6].
Cigarette paper scarring on forehead and lower limbs
Hyperelastic skin and palms touching the floor
Gorlin's sign and Reverse Namaskar sign
Van Giesons stain for collagen fibers under ×10 showing decrease in collagen bundles
Acid Orcein Giemsa stain for elastic fibres under ×10 showing relative increase in elastic fibres
EDS cases have been reported in previous literature.[1,2,3,6,7] It's a heterogenous group of inherited disorder of connective tissue manifesting clinically by fragility and hyperelasticity of the skin and joint laxity. It's a rare genetic disorder affecting 1:5000. The inheritance being usually autosomal dominant with low penetrance. Autosomal recessive and X-linked recessive varieties are also known. Van Meekeren described hyperelastic skin and Koop described hypermobility of joints. Ehler noticed the easy bruisability of the skin whereas; Danlos noted the peculiar cigarette paper scars and pseudotumour formation of the skin. Danlos also put forth four diagnostic criteria, namely, hyperelasticity of skin [Figure 3], fragility of skin, hypermobility of joints [Figure 4] and subcutaneous molluscus pseudotumour formation. More than ten clinical types have been described based on clinical, genetic and biochemical information.
In a recent consensus in Villefranche, in 1997, the classification of EDS was reorganized into six major subtypes. The diagnostic skin signs described in EDS includes Gorlins sign [Figure 4](ability to touch the tip of the nose with the tongue), Metenier sign (easy eversion of upper eyelid) and atrophic “cigarette paper” scarring [Figure 1]. Molluscoid pseudotumors and spheroids may occur in EDS. These are subcutaneous nodules due to herniation of subcutaneous fatty tissue and resemble lipomas histologically. The “reverse Namaskar sign” [Figure 4], a valuable diagnostic sign has been described by Premalatha in patients with EDS. Absence of ocular lesions, ecchymosis, large joint dislocations and periodontitis led us to classify our patient as EDS Type II (mitis). Treatment is highly unsatisfactory. Patients with EDS VI respond to oral ascorbic acid. We report this case because of the classical clinical signs present, which are depicted in the figures which will be helpful to diagnose the case of EDS in clinical practice.
Source of Support: Nil
Conflict of Interest: None declared.
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