Otorhinolaryngological manifestations of the mucopolysaccharidoses

International Journal of Pediatric Otorhinolaryngology (2005) 69, 589—595

www.elsevier.com/locate/ijporl

Otorhinolaryngological manifestations of the mucopolysaccharidoses M.A. Simmons a,*, I.A. Bruce a, S. Penney a, E. Wraith b, M.P. Rothera a a

Department of Otorhinolaryngology, The Royal Manchester Childrens’ Hospital (Pendlebury), Hospital Road, Pendlebury, Manchester M27 4HA, UK b Willink Biochemical Genetics Unit, The Royal Manchester Childrens’ Hospital (Pendlebury), Hospital Road, Pendlebury, Manchester M27 4HA, UK Received 23 September 2004; received in revised form 30 December 2004; accepted 1 January 2005

KEYWORDS Otolaryngology; Mucopolysaccharidoses

Summary The mucopolysaccharidoses (MPS) are a family of related inherited metabolic disorders where, due to specific lysosomal enzyme deficiencies, partially degraded glycosaminoglycans (GAGs) accumulate in the body’s cells. Due to the ubiquitous nature of GAGs in the body this deposition can occur in many tissue types and may interfere with cellular function. Although these conditions are rare, there is a propensity for the disease process to cause problems with the function of the ears, noses and throats of affected patients. In this review, we present an overview of the clinical manifestations of MPS in general and highlight the problems specifically presenting in the field of otorhinolaryngology. # 2005 Published by Elsevier Ireland Ltd.

1. Introduction Although the mucopolysaccharidoses (MPS) are rare there is a propensity for the children with this condition to suffer from ear, nose, throat and airway problems. The Willink Biochemical Genetics Unit based at the Royal Manchester Children’s Hospital is a specialist unit diagnosing and treating patients with these disorders, taking referrals both nationally and from a large portion of Europe. Over 500 children and adults with this diagnosis have been * Corresponding author. Present address: Manchester Royal Infirmary, Manchester M13 9WL, UK. Tel.: +44 161 276 4639; fax: +44 161 276 5003. E-mail address: [email protected] (M.A. Simmons).

seen and assessed at the hospital and as a result the hospital’s ENT department has become involved in the care of these children both for routine childhood ENT conditions and those specifically caused by the MPS disease process. This review aims to summarize the ENT manifestations of the mucopolysaccharidoses and describe our experiences treating this challenging group of patients.

1.1. Pathophysiology and nomenclature of MPS disorders Glycosaminoglycans (GAGs) are complex, branching, protein—carbohydrate polymers which form a major constituent of the ground substance found in most connective tissues. There is a constant slow

0165-5876/$ — see front matter # 2005 Published by Elsevier Ireland Ltd. doi:10.1016/j.ijporl.2005.01.017

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Fig. 1 Female child with MPS type 1H (Hurler’s syndrome) following tracheostomy.

physiological background cycling of these molecules dependant upon lysosomal enzymes. Should one or more of these enzymes be deficient, the normal recycling process cannot occur and an excess of partially degraded mucopolysaccharide molecules accumulates. These molecules are excreted into the urine and also accumulate in cells. These partially degraded breakdown products affect cellular function and can thus also cause alteration of function at the tissue and organ level [1,2]. The resulting storage disorders were originally classified according to the syndromic physical manifestations observed (see Fig. 1). Seven distinct MPS syndromes have now been classified according to the particular enzyme deficiency [3]. All are inherited in a recessive manner: MPS II (Hunter syndrome) being X-linked, whereas the other types are autosomal. Within each type there is considerable heterogeneity at both a clinical and genetic level. For example, the more severe variant of MPS type I is known as ‘Hurler syndrome’ (and is often considered the archetypal MPS disorder) whereas the more attenuated or chronic variant is known as ‘Scheie syndrome’. The ‘Hurler—Scheie compound’ is the term given to an intermediate phenotype not conforming to either of the standard syndromic definitions and probably reflects the reality that there is in fact a spectrum of severity seen in most types of the disease. Different enzyme deficiencies may cause the accumulation of the same stored material, but the disease may manifest in differing ways (See Table 1).

Table 1 The biochemical basis of the different MPS types MPS type

Eponym

Enzyme deficiency

Stored material

MPS I H

Hurler

Iduronidase

MPS I S

Scheie

Iduronidase

MPS I H/S

Hurler—Scheie compound

Iduronidase

MPS II

Hunter

Iuronidate sulphate sulphatase

MPS III A MPS III B MPS III C

Sanfilippo

Maroteaux-Lamy Sly

Heparan-N-sulphatase N-acetylglucosaminidase Acetyl-CoA-glucosaminidase acetyltransferase N-acetylglucosamins-6-sulphatase Galactosamine-6-sulphatase B-galactosidase N-acetylgalactosamine-4-sulphatase B-glucuronidase

Dermatan sulphate, heparan sulphate Dermatan sulphate, heparan sulphate Dermatan sulphate, heparan sulphate Dermatan sulphate, Heparan sulphate Heparan sulphate Heparan sulphate Heparan sulphate

Natowicz

Hyaluronidase

MPS MPS MPS MPS MPS

III D IV A IV B VI VII

MPS IX

Morquio

Heparan sulphate Keratan sulphate Keratan sulphate Dermatan sulphate Dermatan sulphate, heparan sulphate, chondroitin sulphate Hyaluronic acid

Otorhinolaryngological manifestations of the mucopolysaccharidoses

1.2. Presentation, diagnosis and progression Presentation of the disorder in these patients may be at birth or later as the conditions proceed. MPS I, MPS II and MPS VII normally present in early childhood as dysmorphic syndromes. Childhood behavioural abnormalities and dementia may point towards a diagnosis of MPS III. Moderate dysmorphism with normal intellect in association with severe bony dysplasia will suggest MPS IV or MPS VI. The rare MPS IX has not occurred in a sufficient number of patients to know the phenotype with certainty but ear, nose and throat disease has not been a feature of the reported case [4]. Initial diagnosis is suggested by the pattern of GAGs in urine. Confirmation of the diagnosis is possible by analysis of lysosomal enzymes in blood, or skin fibroblasts, in a specialist centre [5]. Preterm diagnosis is now available for those families with an affected child who may be planning further children.

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The ubiquitous nature of GAGs in the body’s connective tissues means a number of different organ systems may become affected. Many of the physical manifestations–—skeletal changes, mental retardation, organomegaly, and abnormal facies–— are common to several of the MPS types, albeit with differing degrees of severity. In addition to this, other, more unique, phenotypes are associated with certain types of MPS but not others. The pathogenesis of altered organ function secondarily to the deposition of the storage products is poorly understood. In many cases the physical bulk of tissues distended by the storage products is in itself problematic (Fig. 2). These conditions are unrelenting, progressive and normally cause death before adulthood due to cardiac or respiratory failure. In some cases, especially in MPS IIIA (Sanfilippo syndrome) neuronal degeneration is more likely to cause death. A comprehensive account of each syndrome is beyond the scope of this review and has documented

Table 2 Summary of general and ENT features of the MPS syndromes MPS type

General features

ENT problems

Other problems

MPS I (Hurler/Scheie)

Characteristic dysmorphism (coarse facies and gum hypertrophy, macroglossia), initial intellectual development normal, then deteriorates

Airway problems, sleep apnoea, upper and lower respiratory tract infections, otitis media, sensorineutral hearing loss

MPS II (Hunter)

Coarse facies, X linked inheritance, classic nodular rash (rare), normal intellect initially

MPS III (Sanfilippo)

Most common MPS disorder, mild dysmorphism, severe behavioural disturbance Normal intellect, severe bony dysplasia

Adenotonsillar hypertrophy, airway problems, otitis media, sensorineural hearing loss Otitis media, adenotonsillar hypertrophy

Cardiomyopathy, aortic and mitral valve disease, hydrocephalus (often requiring shunt), thoracolumbar kyphosis, spondylolisthesis and spinal cord compression, short neck, progressive joint stiffness, hepatosplenomegally, mandibular prognathism G I dysfunction, progressive neurodegeneration, cervical myelopathy, stiff joints

MPS IV (Morquio)

MPS VI (Maroteaux-Lamy)

MPS VII (Sly)

Otitis media, adenotonsillar hypertrophy

Progressive diffuse airway narrowing, adenotonsillar hypertrophy, otitis media Very rare, mild Hurler type phenotype

Short stature, odontoid hypoplasia, unstable craniocervical junction, cervical myelopathy, aortic valve incompetence Carpal tunnel syndrome, cardiomyopathy, endocardial fibroelastosis, cervical myelopathy, macroglossia

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elsewhere [1,2]. A brief synopsis of general features of each syndrome is shown in Table 2.

1.3. Treatment options Traditionally, this group of conditions was regarded as incurable, with treatment aimed solely at symptomatic relief. More recently however, enzyme replacement therapy and bone marrow transplantation have had some limited success in selected cases [6]. Current surgical treatment is not curative, but is undertaken either in response to current problem symptoms or to pre-empt predictable future ones. Irrespective of the age at death of patients with MPS, the judicious use of ENT surgery has the ability to greatly improve the quality of life for the patients by reducing the persistent rhinorrhoea, reducing the frequency and severity of ear infections and by relieving the symptoms of upper airway obstruction.

affects other body systems before contemplating any–—even seemingly routine–—ENT intervention.

2.1. Otological disorders Due to deposition of MPS deposits in the post-nasal space, eustachian tubes and middle ear these patients have an increased risk for otitis media with effusion and acute otitis media. Once diagnosis has been secured symptomatic treatment with ventilation tubes or hearing aids is undertaken. A number of children present with a mixed hearing loss. It is not known whether the sensorineural element has a congenital basis or whether there has been acquired secondary to deposition of partly degraded glycosaminoglycans in the inner ear or central nervous system. A degree of sensorineural loss is common in MPS types I and II.

2.2. Adenotonsillar hypertrophy

2. Otolaryngological problems ENT manifestations of MPS disorders may be considered in three broad groups: otological problems, adenotonsillar hypertrophy, and airways problems. Minor ENT problems–—such as otitis media with effusion are near universal in this group of patients. Indeed, in our institution automatic review in the ENT department is arranged for each new diagnosis. Because of the systemic nature of the disease process, is important to consider how the MPS condition

Fig. 2

Adenotonsillar hypertrophy is almost universal in this group of patients due to the deposition of GAGs. These deposits may also be seen in the pharyngeal wall. In conjunction with the macroglossia and the mandibular abnormalities sometimes seen in MPS, these patients are at risk of progressive upper airways obstruction and obstructive sleep apnoea. Recurrent upper respiratory tract infections may also cause tonsil pathology. When sleep apnoea is suspected, overnight pulse oximetry should be undertaken in the usual manner.

MPS deposits distending the arytenoid mucosa and causing partial airway obstruction.

Otorhinolaryngological manifestations of the mucopolysaccharidoses

Fig. 3

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Festoons of MPS deposits seen in the pharynx and larynx causing deformity of the laryngeal architecture.

An ascending ladder of treatment modalities is used in the management of airway obstruction: initially adenotonsillectomy is performed and in many cases is all that is required; for those in whom it is inadequate or who later develop further airways compromise nasal CPAP is used; in extreme cases tracheostomy is required (Fig. 1). Care needs to be taken when undertaking tonsillar surgery because of potential neck instability. This is universal in MPS IV (Morquio’s syndrome) but also may manifest in other MPS types. For this reason we undertake tonsillectomy using a modified Boyle—Davis gag but without extending the neck or using draffin rods.

Temporomandibular (TM) joint stiffness, and the short stiff neck found in other MPS types (e.g. MPS I) can also pose problems with access. Such is the propensity for adenotonsillar hypertrophy that in cases of MPS IV (Morquio’s syndrome) patients with borderline tonsillar hypertrophy may have prophylactic tonsillectomy before undergoing the crainiocervical fusion that most patients eventually require for their odontoid peg instability.

2.3. Progressive airway compromise In addition to adenotonsillar hypertrophy there may be deposition of the GAGs in the walls of

Fig. 4 Excess arytenoid mucosa, distended by MPS deposit, that was prolapsing into the airway with each inspiration (excess retracted by suction tube).

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the pharynx and larynx. We have seen several cases where there are festoons of excessive tissue associated with substance deposition over the arytenoid cartilages and the aryepiglottic folds (Figs. 2 and 3). In extreme cases these may prolapse into the laryngeal inlet and cause stridor and severe airways compromise (see Fig. 4). There may also be narrowing of the tracheal lumen due to GAG deposition in the wall. In these cases investigation is primarily by direct laryngotracheobronchoscopy under general anaesthesia. In some cases tracheostomy has been necessary to secure a safe airway. We have had some success at performing per oral laser excision of the excess tissue using a microscope and micromanipulator or laser bronchoscope.

2.4. General surgical and anaesthetic considerations As these conditions may affect any organ system, the systemic effects of the disease process must be borne in mind before considering even seemingly minor surgical intervention [7]. Indeed, such is the risk of anaesthesia in severely affected patients that anaesthesia would be unwise for non-life threatening procedures. Cardiovascular manifestations together with difficult airway access mean that these children have far greater risks for general anaesthesia than others [8—11]. The short, immobile or unstable necks found in this group of patients combined with stiffening of the TM joint, macroglossia or mandibular prognathism means that normal anaesthetic intubation may be impossible. Generally the airway may be secured by means of a laryngeal mask airway, and should formal intubation be required this may be facilitated using a modified ‘Seldinger’ technique utilising a guidewire placed under endoscopic control and an airways exchange catheter [12]. Patients with Hunter, Hurler and Maroteaux-Lamy syndromes tend to have more difficult airways [13,14]. Anaesthesia following formal cervical fusion for the odontoid peg instability commonly found in MPS type IV A (Morquio’s syndrome) poses particular challenges. Surgery to relieve airway obstruction may precipitate post-obstructive pulmonary oedema [15]. Reversal of anaesthesia is not without risk. In some cases post-anaesthetic respiratory obstruction has been reported and on occasion has been fatal [16].

3. Summary We hope that this brief overview has highlighted the range of the otorhinolaryngological problems found

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commonly associated with patents suffering with one of the mucopolysaccharidoses and hope that our experience in dealing with these might be interesting and educational to ENT surgeons in general. We would like to emphasise that these patients often have complicated and multisystemic manifestations of their mucopolysaccharidosis. For this reason we would advocate that this special group of patients be treated in a specialist Children’s Hospital, with prior experience of these conditions, to allow the multidisciplinary and holistic approach needed to treat these patients as this often requires input from specialist paediatric medical, surgical and anaesthetic and intensive care services.

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[16] R. Hopkins, J.A. Watson, J.H. Jones, M. Walker, Two cases of Hunters syndrome–—the anaesthetic and operative difficulties in oral surgery, Br. J. Oral Surg. 10 (1973) 286—299.