Discussion

Ehlers–Danlos syndrome is usually diagnosed in young adults, although clinical manifestations of the disease, including laryngological symptoms, may begin in childhood.^{Reference Rimmer, Giddings, Cavalli and Hartley9} Textbooks often report the prevalence of Ehlers–Danlos syndrome as 1 in 5000 births. A recent study in the Danish population also reported a prevalence of 1 in 5000 births.^{Reference Søborg, Leganger, Mortensen, Rosenberg and Burcharth21} However, this incidence increases with increased awareness amongst physicians, and a 2019 study found that diagnoses of Ehlers–Danlos syndrome and joint hypermobility syndrome have been steadily increasing over the past 27 years.^{Reference Callewaert, Malfait, Loeys and De Paepe2,Reference Demmler, Atkinson, Reinhold, Choy, Lyons and Brophy22} Our findings are consistent with this trend, as we report a substantial increase in the number of Ehlers–Danlos syndrome cases that presented to the laryngology clinic in 2019 compared with previous years (Figure 1).

In our case series, there was a large range in the ages of the patients presenting to the laryngology clinic, with a median age of 47 years. Of the 21 patients in our case series, 18 (85.7 per cent) were female and 3 (14.3 per cent) were male; in comparison, there were 73.9 per cent females and 26.1 per cent males in the Danish study.^{Reference Søborg, Leganger, Mortensen, Rosenberg and Burcharth21} In our literature review, Rimmer et al. reported two paediatric cases of Ehlers–Danlos syndrome with reported symptoms of dysphonia within 18 months of birth; these patients first presented to the paediatric voice clinic at ages 14 years and 6 years, respectively.^{Reference Rimmer, Giddings, Cavalli and Hartley9} Hunter et al. reported a mean age of 45.5 years (range = 1.5–80 years) in their study which asked patients with Ehlers–Danlos syndrome about difficulties with their voice.^{Reference Hunter, Morgan and Bird10} These examples in the literature suggest that whilst Ehlers–Danlos syndrome is usually diagnosed in young adults, clinicians should be aware of early laryngological signs of Ehlers–Danlos syndrome presenting in childhood, as well as late presentations, as demonstrated by the large age range.

In our case series, swallowing and voice symptoms were reported in 71.4 per cent and 42.9 per cent of patients, respectively (Figure 3). This is higher than previous figures reported in the literature.^{Reference Hunter, Morgan and Bird10} The third most common group of presenting symptoms were hyolaryngeal skeletal complex problems (28.6 per cent). Ehlers–Danlos syndrome patients commonly experience musculoskeletal issues, which in the throat manifest as hyolaryngeal skeletal complex problems, as collagen defects are found throughout the body (Figure 4). The vocal folds are composed of epithelium, vocal muscle, and three layers of lamina propria consisting of different distributions of collagen, including collagen type I and type III, which are adversely affected in Ehlers–Danlos syndrome.^{Reference Bühler, Sennes, Tsuji, Mauad, Ferraz Da Silva and Saldiva23} Ehlers–Danlos syndrome may also affect synovial joints in the larynx, such as the cricoarytenoid joints, which have been reported to be affected in rheumatoid arthritis.^{Reference Kamanli, Gok, Sahin, Kaygusuz, Ardicoglu and Yalcin24}

Fig. 4.

Image showing wide excursion of the arytenoids on sniffing in one of the patients in our case series.

Our literature review included case reports that also mention hyolaryngeal skeletal complex problems. Chatzoudis et al. reported a case of a 44-year-old woman with classical Ehlers–Danlos syndrome presenting with recurrent airway obstruction because of hypermobility of the suprahyoid suspensory soft tissues.^{Reference Chatzoudis, Kelly, Lancaster and Jones11} Ali et al. reported a case of a 48-year-old woman with Ehlers–Danlos syndrome type III (hypermobility type) presenting with dyspnoea and aphonia 1 day after anterior cervical discectomy.^{Reference Ali, Al Ahwel, Milad, Rehman, Safi and Assaly25} On direct laryngoscopy, the vocal folds appeared normal, but on inspiration, the arytenoids were observed to have hyperlaxity and obstruct the airway.^{Reference Ali, Al Ahwel, Milad, Rehman, Safi and Assaly25} However, neither of these studies reported patient-reported outcome measures data. In our case series, six patients (28.6 per cent) reported hyolaryngeal skeletal complex problems, including arytenoid prolapse, arytenoid subluxation and hyoid subluxation (Table 1). We had patient-reported outcome measures data for four of these patients, with median values of 29 (range = 0–33) on the Reflux Symptom Index, 28.5 (range = 0–35) on the Eating Assessment Tool and 21.5 (range = 0–32) on the Voice Handicap Index.

The term ‘Patient Reported Outcome Measures’ was indexed in the Ovid version of the Medline database in 2017, and was previously indexed under the term ‘Patient Outcome Assessment’. This perhaps explains the small number of studies reporting laryngological patient-reported outcome measures in patients with Ehlers–Danlos syndrome. In total, we had patient-reported outcome measures data for 8 of the 21 patients included in our study, showing a median Reflux Symptom Index of 25.5 (range = 0–33), median Eating Assessment Tool score of 21.5 (range = 0–35) and median Voice Handicap Index of 21.5 (range = 0–104). The large range in our patient-reported outcome measures data may suggest that our patients presented with varying degrees of symptom severity or that these symptoms had different effects on our patients’ quality of life. It could also be reflective of possible limitations of the Reflux Symptom Index, Eating Assessment Tool and Voice Handicap Index tools at assessing symptom severity in the Ehlers–Danlos syndrome population.

At present, no patient-reported outcome measure tools characterising laryngological symptoms have been validated in the Ehlers–Danlos syndrome patient cohort. This is important, as living with Ehlers–Danlos syndrome has a significant impact on a patient's quality of life. In one study, females with Ehlers–Danlos syndrome rated their physical functional health status as being worse than those with fibromyalgia on the Sickness Impact Profile.^{Reference Berglund and Nordström26} With the number of Ehlers–Danlos syndrome patients presenting to laryngology clinic possibly increasing (Figure 1), accurate tools to characterise symptom severity and its effects on patients’ quality of life are needed urgently.

Our study limitations include the small number of patients and the incomplete patient-reported outcome measures dataset from our patient cohort. The retrospective nature of our study does not allow us to monitor symptom progression, and future prospective studies involving patient-reported outcome measure assessments at multiple points in time are recommended. Furthermore, we used three different patient-reported outcome measure tools in our study that have not been validated in the Ehlers–Danlos syndrome patient cohort; hence, the effectiveness of these tools for characterising symptom severity is unknown.