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	Recurrent laryngeal dislocation in Ehlers-Danlos Syndrome

Andrew F. Goodall, E. H. Qureshi, M. A. Siddiq
Department of Otolaryngology, St Helens & Knowsley Hospitals NHS Trust, UK.
Correspondence author: Andrew F. Goodall MBChB MRCS, Department of Otolaryngology, St Helens & Knowsley Hospitals NHS Trust, St Helens Hospital, Marshalls Cross Road, St Helens, WA9 3DA,  Tel: 01744 646621; Fax 01744 646331; Email:  HYPERLINK "mailto:agoodall@doctors.org.uk" agoodall@doctors.org.uk

Abstract
Introduction: Ehlers Danlos Syndrome (EDS) is an inherited connective tissue disorder affecting collagen synthesis.  Common symptoms are skin laxity, joint hypermobility and easy bruising.  Patients may suffer recurrent skeletal joint dislocations that are frequently managed conservatively but sometimes require surgery.  Patients with Ehlers Danlos Syndrome may present with a range of ENT disorders including dysphonia, difficulty swallowing, and globus sensation.  We report an unusual case of recurrent laryngeal dislocation in EDS.
Methods: Case report and literature review.
Results: A 43 year-old female patient with hypermobility-type Ehlers-Danlos syndrome (EDS) and recurrent skeletal joint dislocations was referred to ENT clinic in April 2013 with episodes of recurrent and spontaneous dislocation of the larynx towards the left, which caused brief airway obstruction and respiratory distress before spontaneously resolving.  Examination revealed a highly mobile laryngeal framework but nasolaryngoscopic examination was normal.  All episodes have been self-limiting and treatment focused on helping the patient deal with the stress of an episode, as well as self-laryngeal manipulation to more rapidly relocate the larynx to the midline.
Conclusion: We report a case of recurrent and spontaneous lateral dislocation of the larynx in a patient with hypermobility-type EDS. It is proposed that the tissue laxity attributed to EDS allows the larynx to rotate spirally causing reversible airway obstruction.  This is the first reported instance in the scientific literature.

Keywords: Ehlers Danlos Syndrome; Larynx; Laryngeal dislocation; Laryngeal manipulation; Humans� 

Introduction
Ehlers Danlos Syndrome (EDS) is a group of inherited connective tissue disorders affecting collagen synthesis.  Common symptoms are skin laxity, joint hypermobility and easy bruising [1].  Patients may suffer recurrent skeletal joint dislocations that are frequently managed conservatively but sometimes require surgery.  Patients with Ehlers Danlos Syndrome may present with a range of ENT disorders including dysphonia, difficulty swallowing, and globus sensation.  We report a case of recurrent and spontaneous lateral dislocation of the larynx in a patient with Ehlers Danlos syndrome.  This is the first reported case in the scientific literature.

Case report
In April 2013, a 43 year-old patient with a history of recurrent, spontaneous skeletal joint dislocations and hypermobility-type Ehlers-Danlos Syndrome (the patient had a historic and now defunct diagnosis based on clinical criteria, which becomes hypermobility-type EDS using the updated nosology [2]) was reviewed in the ENT clinic with a six-week history of recurrent and distressing episodes of spontaneous dislocation of the larynx towards the left side, associated with acute airway obstruction and respiratory distress.  These episodes were associated with extreme right-sided neck pain radiating to the right ear and tongue base.  The first episode occurred in March 2013 whilst the patients� neck was at rest; she was facing forwards with her head in the midline, washing her hands.  Whilst observing herself in the mirror, the patient experienced an acute movement of her laryngeal complex towards the left side, which she could see in the mirror.  The episode spontaneously resolved within 40 seconds.  Several episodes occurred over the next six weeks with the patient losing consciousness at home on one occasion, and presenting to the Emergency Department with cyanosis on another occasion.  Following each episode the patient experienced odynophagia and dysphonia for the subsequent few days.  Each episode has been self-limiting although the patient is distressed and is fearful of further episodes. 
Examination revealed a highly mobile laryngeal framework but there was no cervical lymphadenopathy or palpable masses.  Nasoendoscopic examination of the larynx and pharynx was unremarkable giving no targets for biopsy.  Whilst in retrospect, biopsies would have confirmed the specific collagen abnormality in our patient, EDS patients typically have poor wound healing and a bleeding diathesis that risks biopsy site morbidity and haematoma formation [2], and given the large overlap in clinical features amongst EDS subtypes, histological analysis would not inform management or affect patient outcome.
It is proposed that the underlying tissue laxity attributed to abnormal collagen in Ehlers Danlos Syndrome allows the entire laryngeal complex to rotate spirally towards the left side, causing reversible occlusion of the trachea.  Since these episodes have been self-limiting, management has focused on helping the patient develop a coping strategy to deal with the stress of an episode, as well as advice regarding external laryngeal manipulation [3] to relocate the larynx to the midline.

Discussion
Ehlers-Danlos syndrome is an inherited group of connective tissue disorders affecting collagen synthesis that affects skin, ligaments, joints, blood vessels and organs [1].  
Electron microscopy demonstrates structural abnormalities within collagen fibres, including disorganised layout, bizarre shapes, diminished collagen formation, and fewer small-diameter fibrils [4,5].  There is an equal gender distribution and it affects all ethnic groups.  The prevalence of EDS is thought to be 1 in 5000, which equates to 60 affected patients in the catchment area of a typical District General Hospital that serves a population of 300,000 [6]. 
The currently used Villfranche nosology describes 6 subtypes according to major and minor diagnostic criteria [2].  It is important to note that overlap between the subtypes is common and one-third of patients do not fit neatly into only one subtype [7].  Hypermobility type EDS (formerly type III) EDS is inherited in an autosomal dominant pattern and is associated with frequent joint subluxations and dislocations, that lead to chronic pain and early arthrosis [8].  These can become debilitating and whilst arthrodesis had historically been a commonly performed treatment, current management focuses on supportive and preventative measures such as physiotherapy, rehabilitation and avoiding contact sports [6].  It has been associated with reduced muscle tone and even delayed motor development.  Vascular type EDS (formerly type IV) has autosomal dominant inheritance and leads to abnormal type III collagen formation [9].  This affects arteries and leads to potentially fatal spontaneous arterial rupture affecting the aorta, the cerebral vessels as well as the viscera.  Theses patients are advised to avoid contact sports and isometric exercises to minimise the risk of these injuries [1].  Patients tend to have a characteristic �pinched face� [9].  The dermatosparaxis type (previously type VIIC) causes pronounced skin fragility and a tendency to hernias.  The majority of patients (from all subtypes) have a bleeding diathesis which is relevant especially to surgical management.  This may manifest simply as a tendency to bruise easily, or in more severe instances causes haematoma formation or bleeding from the nose, gastrointestinal tract, lungs and urinary tract [2].  However, laboratory investigations of clotting factors, platelet aggregation and bleeding time are often normal [1].  Tranexamic acid postoperatively has been used to reduce episodes of bleeding [9].  
Head and neck symptoms associated with EDS include eyelid extensibility (Metenier sign), mucosal and gingival fragility in the oral cavity, early onset periodontitis, excessive haemorrhage, weak teeth, hypoplasia of the enamel and a vaulted palate [11].  Although voice problems are not a recognised symptom of any subtype of EDS, multiple authors have concluded that the larynx is similarly afflicted by the widespread collagen defects seen throughout the body [6, 12, 13, 14].  
Richmon et al. [12] reported two cases of dysphonia associated with EDS, which was attributed to hypermobility of the tongue (both patients demonstrated the ability to retroflex the tongue behind the soft palate, and one patient could even traverse the posterior choana to enter the nasal cavity) and both patients had normal laryngeal appearances on laryngoscopy and videostroboscopy, respectively.
Desuter et al. [13] investigated a female patient with confirmed hypermobility-type EDS for sudden-onset aphonia in the absence of a triggering event.  Indirect laryngoscopy showed the larynx to have normal mobility but the right vocal fold was injured, with ruptured epithelium that exposed the underlying ligament and haemorrhagic infiltration of Reinke�s space.  Narrow band imaging allowed vascular enhancement which demonstrated microvascular aneurysms within the subepithelial tissue and thyroarytenoid muscle.  Electron microscopy of a biopsy specimen confirmed the presence of abnormal collagen.  The patient responded to voice rest with complete recovery of voice and normalisation of endoscopic appearances after 5 days. Desuter et al. [13] concluded that the well-established propensity for tissue fragility in EDS was responsible for the laryngeal abnormalities in this patient.
Rimmer et al. [7] reported two cases of dysphonia in childhood attributed to EDS (one patient had classical-type EDS and the other had hypermobility-type EDS, formerly type II and III respectively).  Both patients developed dysphonia before 18 months of age, which had proved intractable to voice therapy, which had triggered the referral to ENT services.  Indirect laryngoscopy and videostroboscopy revealed an immobile hemilarynx with absent mucosal wave in one patient, and reduced mobility of the left cricoarytenoid joint in the other patient (subsequent microlaryngoscopy excluded fixation of the cricoarytenoid joint). Both patients had been referred to an adult Otolaryngologist for surgical augmentation of the affected vocal fold at the time of publication.
Hunter et al. [14] surveyed 200 patients with EDS using a self-reported questionnaire, with a large proportion of this cohort reporting various symptoms that fall within the remit of head and neck surgery.  28% reported difficulty sustaining voice (persistent in 54% and self-limiting in the remaining 46%), 39% reported difficulties with swallowing, especially a globus sensation or difficulty clearing their throat after one swallow, and 25% reported difficulties chewing from temporomandibular joint problems or misalignment of the upper and lower jaws.  
Ultrastructural abnormalities of the larynx may explain the propensity for dysphonia in EDS patient.  The lamina propria of the vocal fold allows the overlying epithelium to vibrate freely without restriction from the underlying bulky muscle.  It comprises 3 layers (superficial, intermediate and deep) with differing mechanical properties afforded by varying densities of elastic and collagenous fibres.  The deep layer (the vocal ligament) contains the greatest concentration of collagen fibres and abnormalities here may result in altered properties and dysphonia.  Additionally, dysphonia may result from laxity of the arytenoids and a loss of tension in the membranous cord [12].
A MEDLINE/ PUBMED search confirmed that recurrent laryngeal dislocation has not previously been reported in Ehlers Danlos Syndrome (of any subtype).  We believe that the underlying tissue laxity attributed to Ehlers Danlos syndrome allowed the entire laryngeal complex to rotate spirally causing reversible occlusion of the trachea.  Our patient was advised regarding external laryngeal manipulation techniques to relocate the larynx to the midline and align the airway.  A number of laryngeal manipulation techniques have been previously described for use by Anaesthetists to align the airway and facilitate endotracheal intubation; applying posterior pressure to the thyroid or cricoid cartilage has been advocated for almost 30 years but more recent updates include external laryngeal manipulation [15], �BURP� [16] and �laryngeal lift� [17] techniques.  Each advocates slightly different directions, magnitudes, and locations where to apply pressure to align the larynx, elevate the epiglottis and reduce anterior laryngeal tilt [15], but posterior and cephalad displacement of the larynx is central to all.  A study designed to establish the optimal direction and magnitude of manipulation to facilitate airway alignment for endotracheal intubation [3] established that there was no universal prescriptive standardized movement (a �one size fits all�) for all patients, but was overwhelmingly via the thyroid cartilage (88% thyroid, 11% cricoid, 1% hyoid) and most commonly cephalad and posterior, but occasionally cephalad alone, or posterior alone vectors [3].  In our patient, with left-sided laryngeal dislocation, we suggest that cephalad, posterior and rightward manipulation, applied to the thyroid cartilage using pressure from the fingers and thumbs of her hands will relocate the larynx and align the airway.  Although the larynx has always spontaneously returned to the midline in previous episodes, by manipulating her larynx the events will be shorter and less distressing for her.    

Conclusion
We report an unusual case of recurrent lateral dislocation of the larynx in a patient with hypermobility-type Ehlers Danlos syndrome that has always spontaneously resolved but caused temporary airway obstruction, respiratory distress and psychological upset.  We believe that the underlying tissue laxity attributed to Ehlers Danlos syndrome allowed the entire laryngeal complex to rotate spirally causing reversible occlusion of the trachea.  This is the first instance reported in the scientific literature of recurrent laryngeal dislocation associated with any EDS subtype.  

Financial support: This research received no specific grant from any funding agency, commercial or not-for-profit sectors.

Conflicts of interest: None

References
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Summary
Ehlers Danlos syndrome (EDS) is a group of inherited connective tissue disorders of disordered collagen synthesis yielding abnormal collagen fibres that skin, ligaments, blood vessels, and organs [1].  It affects 1 in 5000 patients, which equates to 60 affected patients in the typical catchment area of a district general hospital [6].
Although laryngeal problems are not described in the major clinical criteria for diagnosis of any subset in the Villefranche nosology [2], EDS patients often present in ENT clinics with a range of head and neck symptoms, including dysphonia, difficulty swallowing and globus sensation [14].
Additionally reported head and neck symptoms have included eyelid extensibility (Metenier sign), gingival fragility in the oral cavity, a vaulted palate, enamel hypoplasia and early onset periodontitis [11].
We report a case of recurrent laryngeal dislocation in a patient with hypermobility-type EDS that caused episodes of temporary airway obstruction that always resolved spontaneously but caused the patient psychological distress.  We attribute this lateral spiralling of the entire laryngeal complex to the underlying tissue laxity of Ehlers Danlos syndrome.  This is the first such case reported in the scientific literature.

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