Abstract
SUMMARY The clinical features are described in 31 cases of the mild form of Hunter's syndrome (mucopolysaccharidosis II) ascertained in the British Isles. The mean age at onset was 49 3 years and at death was 21-7 years. Each patient had a large head and short stature. Umbilical and inguinal herniae were recorded in 95 % and 61 % of the cases. Evidence of cardiac disease was found in 91 %; this was the most common cause of death. All of the patients suffered from frequent upper or lower respiratory tract infection. Middle airways obstruction proved to be a particular hazard. A high incidence of sensorineural deafness and unexplained papilloedema was noted. The importance of regular health care for these individuals is stressed.

The demonstration of heterogeneity within the gene.ic mucopolysaccharidoses marks one of the major landmarks in contemporary knowledge of hereditary disease in man. There is now abundant evidence to suggest that Hunter's syndrome, first described in 19171 and subsequently shown to be sex-linked,2 is heterogeneous, with patients falling into two groups, labelled 'mild' and 'severe' depending upon the presence or absence of progressive mental retardation.3 4 We have recently completed a national survey of Hunter's syndrome, the genetic aspects of which have been presented elsewhere.56 This paper describes the clinical features in a large group of patients with the fairly rare mild form of the disease.
Patients ascertained
Following an approach by letter to paediatricians throughout the British Isles, details were obtained concerning 22 definite and 9 probable cases of mild Hunter's syndrome. The diagnosis in the former was based upon reduced activity of iduronate sulphatase,7 and in the latter upon a characteristic phenotype, with clear corneae, and excessive mucopolysacchariduria.
Patients ascertained
At the time of ascertainment, 14 of the patients were dead. Ten patients were personally examined: details of the remainder were obtained from hospital records and discussion with living relatives. Photographs of 10 All the patients were male and none had reproduced at the time of the study.
Results
Clinical features of the 31 patients are summarised in Table 1 . During the period of maximum ascertainment the incidence of the disorder was 1 in 579 282 male live births (0.173 per 100 000) and the prevalence 1 in 3-17 million males and females (0-065 per 100 000 males). These data show the rarity of the condition.
Results
General appearance. As shown (Fig. 1) Growth parameters. All of the patients had large head circumferences which became more apparent as they became older (Fig. 2) . Linear growth began to decline at 4 to 6 years so that by 12 years all of the study patients had fallen below the 3rd centile (Fig. 3) at ages 5 and 2j years. The importance of cardiac disease in this disorder is reflected by the fact that it was the most common cause of death among the study patients, several of whom had been treated with digoxin and diuretics with only limited success.
Results
Respiratory system. All of the study patients had a history of frequent upper respiratory infections including rhinitis, tonsillitis, laryngitis, and otitis media, with chronic muco-purulent nasal discharge. Tonsils and adenoids were removed from 14 of 19 patients at a modal age of 4 years. Lower respiratory infections tended to be less frequent in these patients, but when present proved life threatening. Often an element of cardiac failure supervened. During these dyspnoeic episodes the expectoration of profuse secretions proved a major hazard.
Results
A curious finding, possibly related to the rigidity of the chest wall, was the presence of bronchial breathing in 4 cases, in the absence of other signs of active pulmonary disease. All of the patients showed reduced chest expansion due to the splinting effect of a rigid rib cage and abdominal distension. Two of the older patients spontaneously volunteered that they were unable to swim and in particular float.
Results
One of the most sinister problems in these patients was their propensity to middle airways obstruction. Serious problems had occurred during attempted intubation in 4 cases, one of whom died. Of the 10 cases personally examined, all but one, the youngest, had a husky or hoarse low pitched voice which became more noticeable with advancing years. In these patients there was no other evidence of relevant cranial nerve disturbance.
Results
Hearing. Deafness was common (Table 1 ) and in 3 this was the main complaint. The hearing deficit, often first noted in early childhood, consisted of both conductive and sensorineural components. This is well illustrated in Fig. 4 which shows audiograms recorded from Case 17 at age 7 years, shortly before and after bilateral myringotomy and insertion of grommets. These audiograms clearly show the benefit gained by regular drainage of the chronic glue ear occurring as a result of persistent Eustachian tube dysfunction associated with adenoidal hypertrophy. Prompt Spinal involvement tended to be minor with loss of normal curvature. Four patients showed a mild thoraco-lumbar kyphosis, non-progressive in nature.
Results
The joints showing most severe involvement in decreasing order of severity were those in the hands, elbows, shoulders, hips, knees, wrists, and ankles. The well recognised 'claw-like' changes were apparent by 5 years, and with advancing age the hands took on a spade-like appearance being broad and thick with stubby clawed digits. These features are apparent in Fig. 5 which shows the hands of the oldest encountered living patient at the age of 31 years. This picture also shows early atrophy of the thenar musculature.
Discussion
It is evident that individuals with this disorder are subject to extensive multi-system disease, due primarily to the functional disturbance generated by the cellular accumulation of excessive oligosaccharides. However the pathogenesis of some of the more insidious and invidious complications is not entirely clear. The explanation for the macrocephaly may also be multifactorial, and include thick skin, bushy scalp hair, calvarial thickening with frontal bossing, meningeal hypertrophy, cerebral enlargement, and possibly mild hydrocephaly. Computerised tomography in Case 1 at age 31 years showed normal lateral and 3rd ventricles with a dilated 4th ventricle. In his cousin (Case 2) examination at necropsy showed the brain to be enlarged (1800 g) with 'congested' meninges but no other apparent abnormality. Reports suggest that hydrocephalus does not normally occur in mild Hunter's syndrome, the exception being a child,'7 in whom there was failure of reabsorption of cerebrospinal fluid because of leptomeningeal thickening.
Discussion
The high incidence of inguinal and umbilical herniae in Hunter's syndrome may be due at least in part to underlying abnormalities in connective tissue. An increased quantity of mucopolysaccharide has been noted in the connective tissue from bone, cartilage, and respiratory tract obtained from a 32-year-old man with probable mild Hunter's syndrome who died in a road accident.18 It was also noted that collagen-mucopolysaccharide bonds in his bone, cartilage, skin, and mitral valve differed appreciably from normal and that the collagen itself showed an increased number of free hydroxyl groups. 25 Nor is the peripheral nerve entirely spared in this disease. Sural nerve biopsy in a 20-year-old proved case showed multivacuolated endoneurial fibroblasts and perineurial cells with 'zebra bodies' in the Schwann cells.26 Similar changes were noted in sural nerve from 3 brothers with an unusually mild form of the disease manifesting as multiple nerve entrapments. 27 The progressive quadriparesis noted in the 27-year-old patient in this study may be due to a myelopathy secondary to meningeal thickening in the cervical region as has been documented in at least one other adult with mild Hunter's syndrome. 22 This disorder is sufficiently rare for it to be unusual for more than a single case to be encountered in a lifetime. Yet its complications are so extensive as to merit the fullest possible medical attention. This paper is presented in the hope that those who do encounter 'such a case may-be alerted to the many problems which may lie ahead.
Discussion
The observations in this paper are drawn from a thesis submitted to the University of London for the degree of Doctor of Medicine by I D Y.
Discussion
We thank the patients and their families for their hospitality and co-operation; Dr P F Benson and Dr R Stephens for allowing us to study their patients; Dr I M Archer for performing assaysof iduronate sulphatase activity; Mr R G S Mills for invaluable assistance with interpretation of the audiograms; Dr R Marshall and his staff for help and enthusiastic production of the illustrations; the following physicians for allowing us 

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