Otorhinolaryngological manifestations of the 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.

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 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.

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 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).

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.

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

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.