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	Title page

Recurrent laryngeal dislocation in Ehlers-Danlos Syndrome

Andrew F. Goodall MRCS, Department of Otolaryngology, St Helens & Knowsley Hospitals NHS Trust, UK.

E. H. Qureshi, FRCS (Edin) FRCS (Glasg), Department of Otolaryngology, St Helens & Knowsley Hospitals NHS Trust, UK.

M. A. Siddiq FRCSE (ORL-HNS), 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: agoodall@doctors.org.uk

Abstract and key words

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 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 known Ehlers-Danlos syndrome (EDS) and other joint dislocations was referred to ENT clinic in April 2013 with episodes of recurrent and spontaneous dislocation of 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 relocating the larynx to the midline.
Conclusion: We report a case of recurrent and spontaneous lateral dislocation of the larynx in a patient with Ehlers Danlos syndrome. 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.


Key words

Ehlers Danlos Syndrome; Larynx; Laryngeal dislocation; Humans  Text

Introduction

Ehlers Danlos Syndrome (EDS) is an inherited connective tissue disorder affecting collagen synthesis.  Common symptoms are skin laxity, joint hypermobility and easy bruising [1].  Patients may suffer recurrent 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

A 43 year-old female patient with known Ehlers-Danlos syndrome (EDS) and a history of spontaneous joint dislocations was seen in the ENT clinic in April 2013 with a 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 the 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 experiences 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.  
It is proposed that the underlying tissue laxity attributed to 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 relocating 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 [2,3].  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 [4]. 
The currently used Villfranche nosology describes 6 subtypes according to major and minor diagnostic criteria [5].  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 [6].  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 [7].  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 [4].  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 [8].  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� [8].  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 tract5.  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 [10].  

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. [6] 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 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 TMJ 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].

Conclusion

We report a case of recurrent lateral dislocation of the larynx in a patient with 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.

Financial support

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


Conflicts of interest

None


References

Parapia L, Jackson C, Ehlers-Danlos syndrome � a historical review (2008), British journal of haematology 141: 32-35

Wechsler H, Fisher E, Ehlers-Danlos syndrome. Pathologic, histochemical and electron microscope observations (1964), Arch Pathol 77: 613-19

Black C, Gathercole L, Bailey A, Breighton P, The Ehlers-Danlos syndrome: an analysis of the structure of the collagen fibres of the skin (1980), Br J Dermatol 102: 85-96

Dabbas N, Saker R, Blakeley C, Multiple spontaneous dislocations in a patient with Ehlers-Danlos syndrome (2008) Emergency Medicine Journal 25: 175-6

Breighton P, De Paepe A, Steinmann B, Tsipouras P, Ehlers-Danlos syndrome: revised nosology, Villfranche, 1997. Ehlers-Danlos National foundation (USA) and Ehlers-Danlos Support Group (UK) (1998), American Journal of Medical Genetics 77: 31-37

Rimmer J, Giddings C, Cavalli L, Hartley B, Dysphonia � a rare early symptom of Ehlers-Danlos syndrome? (2008), Int J Pediatr Otorhinolaryngology 72: 1889-92

Kivirikko K, Collagens and their abnormalities in a wide spectrum of diseases (1993), Ann Med 25: 113-26

Callewaert B, Malfait F, Loeys B, De Paepe A, Ehlers-Danlos syndromes and Marfan syndromes (2008), Best Pract Res Clin Rheumatol 22: 165-89

Breighton P, The Ehlers-Danlos Syndrome (1970), William Heinemann Medical Books Ltd, pp1-194

Bolton-Maggs PH, Perry DJ, Chalmers EA, Parapia LA, Wilde JT, et al., The rare coagulation disorders - review guidelines for management from the United Kingdom Haemophilia Centre Doctors Organisation (2004), Haemophilia 10: 593 

Letourneau Y, Perusse R, Buithieu H, Oral manifestations of Ehlers-Danlos syndrome (2001), J Can Dent Assoc 67: 330-4

Richmon J, Wang-Rodriguez J, Thekdi A, Ehlers-Danlos syndrome presenting as dysphonia and manifesting as tongue hypermobility: report of 2 cases (2009), Ear Nose Throat J 88: 8-12

Desuter G, Gardiner Q, Dahan K, Laryngeal signs of Ehlers Danlos syndrome in an adult: the first case reported (2009), Otolaryngology � Head and Neck Surgery 141: 428-9

Hunter A, Morgan A, Bird H, A survey of Ehlers-Danlos syndrome: hearing, voice, speech and swallowing difficulties.  Is there an underlying relationship? (1998), Br J Rheumatol 37: 803-4


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 [4].
Although laryngeal problems are not described in the diagnostic criteria for any subset in the Villefranche nosology [5], EDS patients often present in ENT clinics with a range of head and neck symptoms, including dysphonia, difficulty swallowing and globus sensation.
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 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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