ANNOTATIONS

ordination. Support for this co-operation is easily voiced, but it is not sufficient unless it leads on to the devising of practical steps to tackle the problem.

In the meantime, as long as the present state of doubt and ignorance exists, a more restrictive attitude to prescribing and self-treatment in pregnancy is mandatory, especially in the many conditions for which the benefits of treatment are judged to be marginal.

Department of Pharmacology and Therapeutics, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY.

L. J. CHRISTOPHER

REFERENCES 1 . McBride, W. G. (1961) ‘Thalidomide and congenital abnormalities.’Lancet, 2,1358. 2. Lenz, W. (1962) ‘Thalidomide and congenital abnormalities.’ Lancet, 1, 271. 3. Burrow, G. N. (1965) ‘Neonatal goitre after maternal propylthiouracil therapy.’ Journal of Clinical

Endocrinology and Metabolism, 25, 403408. 4. Kemball, M. L., McIver, C., Milner, R. D. G., Nourse, C. H., Schiff, D., Tiernan, J. R. (1970) ‘Neonatal

hypoglycaemia in infants of diabetic mothers given sulphonylurea drugs in pregnancy.’ Archives of Disease in Childhood, 45,696-701.

5. Owen, J. R., Irani, S. F., Blair, A. W. (1972) ‘Effect of diazepam administration to mothers during labour on temperature regulation of neonate.’ Archives of Disease in Childhood, 47,107-1 10.

6. Moya, F., Thorndike, V. (1963) ‘The effects of drugs used in labour on the fetus and newborn.’ Clinical

7. Fisher, D. E., Paton, J. B. (1974) ‘The effect of maternal anaesthetic and analgesic drugs on the fetus and newborn.’ Clinical Obstetrics and Gynecology, 17, 275-287.

8. Desmond, M., Schwanecke, R. P., Wilson, G. S., Yasunaga S., Burgdorff, I. (1972) ‘Maternal barbiturate utilization and neonatal withdrawal symptomatology.’ Journal of Pediatrics, 80,190-197.

9. Herbst, A. L., Ulfelder, H., Poskanzer, D. C. (1971) ‘Adenocarcinoma of the vagina; association of maternal stilbestrol therapy with tumor appearance in young women.’ New England Journal of Medicine, 284, 878-881.

10. Greenwald, P., Barlow, J. J., Nasca, P. C., Burnett, W. S. (1971) ‘Vaginal cancer after maternal treat- ment with synthetic estrogens.’ New EnglandJournalof Medicine, 285,390-392.

1 1 . Ashton. H. (1971) ‘Drugs and the foetus and neonate.’ Adverse Drun Reaction Bulletin. No. 28. 80-83.

Pharmacology and Therapeutics, 4, 628-653.

12. Schardein, J. L. (1976)’Drugs as teratogens,’ Cleveland, Ohio: C:R.C. Press Inc., Chapter 1, 1-8. 13. Christopher, L. J., Crooks, G. (unpublished). 14. Forfar, J. 0.. Nelson, M. M. (1973) ‘Epidemiology of drugs taken by pregnant women: drugs that may

15. Peckham. C. H.. King. R. W. (1963) ‘A studv of intercurrent conditions observed during uregnancv.’ affect the fetus adversely.’ Clinical Pharmacology and Therapeutics, 14, 632-641.

- _ - ~

American JournalofObstetrics and Gynecology, 87,609-624. 16. Hill, R. M., Craig, J. P., Chaney, M. D., Tennyson, L. M., McCulley, L. B. (1977) ‘Utilization of over

the counter drugs during pregnancy.’ Clinical Obstetrics and Gynecology, 20,381-394. 17. Boethius, G. (1977) ‘Prescription of drugs 1970-75 in the county of Jamtland, Sweden: epidemiological

and clinical pharmacological aspects.’ (Chapter IV, Ph.D. thesis.) Ostersund : Department of Internal Medicine, Ostersund Hospital.

18. Kelly, J. V. (1977) ‘Drugs used in toxemia of pregnancy.’ Clinical Obstetrics andGynecology, 20,395-410. 19. Shapiro, S., Slone, D., Hartz, S. C., Rosenberg, L., Siskind, V., Monson, R. R., Mitchell, A. A., Heino-

nen, 0. P., Idanpaan-Heikkila, J., Haro, S., Saxen, L. (1976) ‘Anticonvulsants and parental epilepsy in the development of birth defects.’ Lancet, 1,272-275.

20. Greenberg, G., Inman, W. H. W., Weatherall, J. A. C., Adelstein, A. M., Haskey, J. C. (1977) ‘Maternal drug histories and congenital abnormalities.’ British MedicalJournal, 2,853-856.

THE PSEUDO - HURLER SYNDROMES

The clinical picture of the child with a disorder of mucopolysaccharide metabolism is usually easy enough to identify. Typically in Hurler’s disease there will be severe retardation after the first year of life. The facies will be coarse with thick skin, a flattened nasal bridge and widely-spaced eyes. There is dwarfing with kyphosis, enlargement of the liver and spleen,

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DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY. 1978, 20

and clouding of the cornea. x-rays show a hook-shaped deformity of the lower thoracic and upper lumbar vertebral bodies, with thoraco-lumbar kyphosis. The bones of the hands and feet are short and broad and the ribs are widened. The pelvis has narrow iliac wings and the skull an enlarged sella turcica. Sometimes there is also evidence of hydrocephalus1. With minor variations, Hunter’s disease shows a similar clinical picture. Deafness and nodular skin lesions are common. and usually-but not always-the deterioration is slower. Cloud- ing of the cornea, lumbar gibbus or cardiovascular complications do not occur.

Other syndromes showing excess excretion of mucopolysaccharides in the urine and evidence of specific enzyme deficiencies-such as that of Sanfilippo-may be harder to recognise as the clinical and radiological changes are not so marked. However, they are almost always suggestive enough to raise the possibility of a mucopolysaccharide disorder, so the necessary investigations can be instigated. The trouble arises when the diagnosis of a mucopolysaccharide disorder seems likely but the tests do not confirm this.

There are a number of diseases in which it is justifiable to consider a clinical diagnosis of Hurler’s syndrome, although subsequent investigations will prove this not to be the case. Gml gangliosidosis, first described in 19642, is one of the more common examples. Develop- ment is slow, with hypotonia. There is a coarse facies with a depressed nasal bridge and internal strabismus. Vision gradually fails and corneal opacities and a cherry-red spot at the macula may be observed. Other features are seizures, deafness, short fingers with flexion contractures, dorsolumbar kyphosis and hepatosplenomegaly. These children do not usually survive their second year of life.

X-ray examination shows distended irregular diaphyses, hook-shaped deformities of the verebral bodies, supra-acetabular overconstriction of the pelvic bones and coxae valgae3. Neurones of the cerebral cortex, brain stem and spinal cord are distended by a PAS-positive substance. Chemical analysis shows abnormal amounts of Gm 1 ganglioside in the brain and viscera, but an excess of mucopolysaccharide-probably keratin sulphate-is also found in the viscera4. The enzyme deficiency, inherited as an autosomal recessive trait, involves D-galactosidase A, Band C5.

There is another type of Gml gangliosidosis in which there is a lack of D-galactosidase B and C only. This shows none of these clinical features of gargoylism but on x-ray examination there may be mild dysostosis with beaking of the vertebrae and abnormal metacarpal bones.

Glycoprotein storage diseases such as fucosidosis and mannosidosis offer a number of examples of pseudo-Hurler syndromes. Although the clinical picture seems to show con- siderable variation, Hurler-like appearances are described in fucosidosis. This disease is caused by a lack of z-fucosidase, resulting in storage of a fucose-containing substance6. In the first few years of life there is progressive mental and physical deterioration, with death before the age of six. There may be coarseness of the facies, restricted joint-movements and hepatosplenomegaly, but the fundi and cornea are normal. It is also probably transmitted in an autosomal recessive manner.

Patients have been described with mannosidosis and features of Hurler’s syndrome’. In the first year or two of life there are acromegalic features, but also developmental retardation with hypotonia and brisk tendon-jerks. There is enlargement of the liver and spleen. With increasing age the facies coarsens, the tongue enlarges, anterior lens opacities are seen, and a lumbar kyphosis develops. There is a marked sensitivity to infections, which may be related to hypogammaglobulinaemia. x-rays show enlargement of the ribs, coarse bone trabeculation and slight changes at the wrists and ankles suggestive of rickets. The urinary excretion of mucopolysaccharides is normal, but the activity of a-mannosidase is low in the

384

ANNOTATIONS

brain, liver and spleen. The activity of other lysosomal enzymes, particularly 13-galactosidase is increased6. This results in the accumulation of storage material containing mannose, although its exact nature is unknown.

Children with the rare variant of the late infantile type of metachromatic leucodystrophy, first described in 19659, may present a facial appearance which is at least suggestive of gargoylism. Their development is slow and soon starts to regress, with myoclonic seizures. From being hypotonic, the muscles become spastic but with diminished tendon jerks. The liver and spleen are not enlarged, and there are no corneal opacities or atrophic changes in the retina. On x-ray examination there are globoid vertebral bodies, coxae valgae and shortening, swelling and proximal pointing of the metacarpals. Increased amounts of sulphatides are found in the urine, and also an excess of heparan and dermatan sulphatelo. As in the more classical type of metachromatic leucodystrophy, there is raised CSF protein and delayed conduction velocity in the peripheral nerves. The increased amounts of muco- polysaccharides in the brain and kidneys are mainly heparan sulphate. The cortical cells con- tain abnormal amounts of gangliosidesll. There is a lack of arylsulphatases A, B and C in the liver, kidney and brain, and the disease is now referred to as ‘multiple sulphatase deficiency’ or ‘mucosulphatidosis’. The multiple deficiency leads to an accumulation of many types of sulphate ester, including cerebroside sulphate and polysaccharides resembling dermatan and heparan sulphate. The associated metabolic disturbance may be secondary to the ac- cumulation of mucopolysaccharides, because these inhibit or alter lysosomal hydrolases, including sulphatases12.

The mucolipidoses are storage diseases with features of both the mucopolysaccharidoses and the sphingolipid~ses~. Lipomucopolysaccharidosis, or mucolipidosis I, is characterised by slow development and the appearance of symptoms like those of Hurler’s syndrome in the second year of life13. There are coarse features, macrocephaly, stiffness of the joints, herniae and hepatic enlargement. Muscle tone is reduced and there is marked inco- ordination. Corneal opacities and cherry-red spots in the retinae have been reported. x-ray examination shows changes similar to those of Hurler’s syndrome, but of a milder degree except that the posterior skull bones may be thickened. There is an accumulation of storage material in the cells of the liver and brain and an increased activity of p-galactosidase, but no enzyme deficiency has been demonstrated.

Children with I-cell disease, mucolipidosis 11, show an appearance from the early months more like Hurler’s syndrome than does the genuine article at that age14. In fact if an infant in the neonatal period is suspected of having Hurler’s syndrome the diagnosis is most probably I-cell disease. Development is severely retarded, and growth as well. There is hepatosplenomegaly but no corneal clouding. The child dies within a few years, sometimes with evidence of cardiac failure. Changes shown on x-ray are also those of Hurler’s syndrome but often more severe in degree. Cultured fibroblasts contain inclusions which react posi- tively with PAS and Sudan Black BT5. Storage material in the fibroblasts is composed of mucopolysacharides, particularly dermatan sulphate and hyaluronic acid, and of lipid substances.

In I-cell disease there are a bewildering number of possible enzyme disturbances, such as the low level of a-L-iduronidase and a gross deficiency of 13-D-galactosidase and a-L- fucosidase, as well as a lessened activity of other enzymes. The explanation may be an inability of the lysosomal enzymes to stay within the lysosomal compartment, due to a recognition defect. It is postulated that the enzymes flow normally out of the cells, but are unable to re-enterla.

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DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY. 1978, 20

Mucolipidosis 1 I1 or pseudo-Hurler polydystrophy, like other mucolipidoses, is most probably inherited as an autosomal recessive trait". Early in life dwarfing becomes apparent, with thoracic deformity and restricted joint mobility. The facies is soon suggestive of Hurler's syndrome and the liver and spleen enlarge. There are fine corneal opacities and hearing is impaired. The intellect gradually deteriorates. x-rays show changes of dysostosis multiplex but mainly confined to the long bones and pelvis. Vacuolated plasma cells found in the bone marrow contain abnormal amounts of glycolipids and finely granular material, with staining characteristics of acid mucop~lysaccharides~.

Other conditions in individual families with a suggestive recessive mode of inheritance are described from time to time. In Winchester's syndrome there is a progressive skeletal dysplasia. In the first few months of life there is limitation of movement of spine and knees, the proximal interphalangeal joints enlarge and the wrists are painful. Subsequently extensive contractures and corneal opacities develop. The facies begin to suggest Hurler's syndrome and there is gum hypertrophy and evidence of myocardial damage, but no exces- sive mucopolysaccharidurialJ.

Other skeletal dyspasias such as Kniest's syndrome may combine dwarfism, deformities of the limbs and mental retardation in early life, but should not be confused with the mucopolysaccharidoses'". It should not be forgotten that children on long-term treat- ment with phenytoin may develop coarse facies not unlike those of the diseases being discussed. This also applies to babies born of mothers taking phenytoin during pregnancy20.

The appearance of the children suffering from these various conditions, suggesting as it does the patient with Hurler's syndrome, is certainly intriguing. Presumably it indicates a common effect on skin and connective tissue early in gestation. There is much to be learnt of the biochemical basis of these disorders and the effect this has on various tissues, and until this knowledge is increased the clinician must often be responsible for the diagnosis. Only then will the biochemist have the opportunity to carry out investigations and further research. Therefore. whenever the appearance of the child has even the suggestion of gargoylisni combined with other anomalies, tests should be directed towards demonstrating a possible disorder of both mucopolysaccharide and sphingolipid metabolism. These will include radiological examinations, examination of the urine for excessive excretion of mucopolysaccharides, sometimes bone marrow puncture, the checking of leucocyte enzymes, the culture of skin fibroblasts and, if the facilities are available, more complicated procedures such as radioisotope studies.

I n the absence of any effective treatment at present, the main reason for making as exact a diagnosis as possible of these diseass, apart from the opportunties for research, is the ability to give reliable genetic advice.

Booth Hall Children's Hospital, Manchester M9 2AA.

NEIL GORDON

REFEREhrCES I . Fwnicr, T. M;. (1975) Pc~clicrttYc~ h'ertrok?gj,. h i ' edn. Hagerstown, Maryland: Harper & Row. 2. L.anding, B. H., Silverman, F. N., Craig, J. M., Jacohy, M. D.. Lahey. M. E., Chadwick, D. L. (1964)

'Faniilial neurovisceral lipidosis.' ~ / ~ ~ f ~ ~ i ~ ~ / ~ i ~ ~ ~ r t ~ ~ i t ~ ~ of Disetrsrs of Cliikdreri, 108, 503-522. 3 . Spninger. J. W., Wiedernann, H. R. ( I 970) 'The genetic mucopolvsacchal.ido~es.' NeuropZldirrtr.ie, 2,3-16. 4. XTacHrinn. M. C . , Okada, S., Ho, M. W., Hu. C. C.. O'Brien, J. S. (1969) 'Generalized gangliosidiosis:

in:paired cleavage of galactose from a niucopolysaccharide and a glycoprotein.' Science, 103, 946-947.

386

ANNOTATIONS

5. O’Brien, J. S. (1969) ‘Generalized gangliosidosis.’Journal ofPediatrics, 75,167-186. 6. van Hoof, F., Hers, H. G . (1968) ‘Mucopolysaccharidosis by absence of m-fucosidase.’Lancet, 1, 1198. 7. Kjellman, B., Gamstorp, I., Brun, A., bckerman, P. A., Palmgren, B. (1969) ‘Mannosidosis: a clinical

8. Ockerman, P. A. (1967) ‘A generalised storage disease resembling Hurler’s syndrome.’ Lancet, 2, 239-

9. Austin, J. H., Armstrong, D., Shearer, L. (1965) ‘Metachromatic form of diffuse cerebral sclerosis. V:

10. Thieffry, S., Lyon, G., Maroteaux, P. (1967) ‘Enckphalopathie metabolique associant une mucopoly-

11. Austin, J. H. (1965) ‘Mental retardation. Metachromatic leucodystrophy.’ In Carter, C. H. (Ed.)

12. Roy, A. B. (1977) ‘Sulphatase deficiencies.’ In Harkness, R. A., Cockburn, F. (Eds.) The Cultured Cell

13. Sanfilippo, S . J., Yunis, J., Worthen, H. G. (1962) ‘An unusual storage disease resembling the Hunter-

14. Gordon, N. (1973) ‘I-Cell disease-mucolipidosis 11.’ Postgraduate Medical Journal, 49,359-361. 15 Leroy, J. G., Spranger, J. W., Feingold, M., Opitz, J. M., Crocker, A. C. (1971) ‘I-Cell disease.

16. Weismann, U. N. (1975) In Holton, J. B., Ireland, J. T. (Eds.) Inborn Errors of Skin, Hair and Con-

17. Maroteaux, P., Lamy, M. (1966) ‘La pseudo-polydystrophie de Hurler.’ Presse Medicale, 74,2889-2892. 18. Kelly, T. E. (1976) ‘Hurler-like disorders in infancy.’ ClinicalPerinatology, 3,115-132. 19. Siggers, D. C., Rimoin, 0. L., Dorst, J. P. (1974) ‘The Kniest syndrome.’ Birth Defects, Original Article

20. Hanson, J. W., Smith, D. W. (1975) ‘The fetal hydantoin syndrome.’JournalofPediatrics, 87,285-290.

and histopathologic study.’ Journal of Pediatrics, 75, 366-373.

241.

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saccharidose et un sulfatidose.’ Archives Frangaises de PediatriC, 24,425-432.

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and Inherited Metabolic Disease. Lancaster: M.T.P. Press.

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A clinical picture.’ Journal of Pediatrics, 79, 360-365.

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H 387