TUBEROUS SCLEROSIS: A SURVEY OF 97 CASES, I l l : FAMILY ASPECTS

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Ann Hunt

Tuberous sclerosis can occur sporadically, but it is also dominantly inherited, so when a case is diagnosed there are implications for all members of the family. In severely affected cases the epileptic seizures usually receive treatment, but the mental retard- ation and difficult behaviour can cause more problems for the family and eventually lead to institutional care.

Method Among the sample of 97 cases (see Part I ) there were 13 families with 31 affected individuals, for 25 of whom questionnaire data were available (Fig. I ) . Six parents had themselves been treated for adenoma sebaceum at some time during childhood, but their condition was diagnosed only after the birth of a severely affected child. Two grandfathers also were known to have tuberous sclerosis. By a conservative estimate, therefore, 18 individuals (16 children and two of the mothers) have inherited the disorder. The incidence of 79 sporadic cases must be viewed with caution, however: 35 were diagnosed as sporadic, but a full family investigation had not been done in 52 cases, which included some of the 13 families in Fig. 1.

Results Genetic asp ec f s When asked if the genetic implications of tuberous sclerosis had caused any family

problems, 16 parents said they had caused them personal concern, and eight were worried about their children's situations. It has been suggested that in diseases with dominant inheritance, when mothers are the carriers the children are more severely affected. Harper (1975) reported that severe cases of childhood myotonic dystrophy, which, like tuberous sclerosis, is transmitted by a n autosomal dominant gene, invariably were transmitted matern- ally. However, in the present study 14 of the 16 children with inherited tuberous sclerosis were mentally retarded with seizures, but there was no relationship between the sex of the carrier parent and severity of handicap.

To determine the possible relationship between the occurrence of new mutations and parental age, the ages of the parents at the time of birth of their affected children were compared in subgroups known by investigation to have inherited the disorder (18), the documented sporadic cases (35) and those not adequately investigated (44). The average parental ages in the three groups did not differ significantly (Table I), and were strikingly similar to the average U K ages of maternity (27 .8 years) and paternity (3 1 . 5 years) cited by Bundey and Evans (1969).

Because the birth of a severely handi- capped child tends to curtail family size, the data were reviewed to determine 353

Not inc luded in sample of 97

0 Seizure-free, n o r m a l in te l l igence

Seizures, menta l retardat ion

Fig. 1. Families with two or more members with tuberous . d e r m i s (unaffei,ted individuals omitted)

TABLE 1

Average parental ages at birth of children with tuberous sclerosis

Average parental axe

Aetiology No. cases (91) Mother Father

Inherited 18 2 8 . 0 31 .2 Sporadic 35 27 .8 30 .4 Not known 41 27 .9 31.3

3 N o information on age

TABLE 11

Genetic counselling and birth order

Genetic coun reNinc~

Birth order Ye 5 N O

Not last-born I6 ( I ) * 21 (4) Last-born 29 (9) 30 (4) Adopted 1

Total 45 (10) 52 (8)

*Inherited cases in parentheses

TABLE 111

Ages at achieving developmental milestones

< 2 2 -4

31 2 3 7 5 5 5 I 5

4 6 I 4 5 2 2 I

6-10 1 1 2 Not reported 3 12 1

Total 61 29 21 354

whether the affected person was the, last- born, whether the tuberous sclerosis was inherited, and whether other family members had received genetic counselling. For the families with inherited cases who had not been given genetic counselling, perhaps it had been assumed that the risk of further affected children was obvious, but siblings had not been investigated, and they could be carriers. In both counselled and uncounselled families the affected individual was more likely to be the last- born (Table 11). In one of the uncounselled families tuberous sclerosis was diagnosed in a child and the mother when the mother was pregnant again, fortunately with a non-affected child: subsequent counselling was given. Among the uncounselled families was one with an adopted child.

Developmental problems Parents answered questionnaires for the 82 individuals with seizures, 81 of whom were also mentally retarded, and for the two seizure-free children (see Table I, Part I ) . The retrospective data, admittedly, are prone to inaccuracies in parental recall. At the time of the study, 53 children could not speak, 51 were neither bowel nor bladder trained, and 21 were unable to walk. However, seven children were under two years of age and would be expected to master additional skills in the future, but the presence of seizures among all seven does not augur well.

The ages at which the children who were walking, talking and continent achieved those milestones are shown in Table 111. Talking was defined as the production of single words (10 children) or short sentences (15), as well as normal speech (four).

TABLE 1V

Behaviour problems

Problems Frequency ( 5 8 children)

Hyperactivity Screaming Destructiveness Temper tantrums Aggressiveness Sleeplessness Self-mutilation Expelled from school Masturbation N o problems reported

22 14 9 9 9 7 7 3 2

24

TABLE V

Most pressing problems for parents

Problem (82 children)

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Frequency

Behaviour, including communication problems 29

Epilepsy 20 Child’s future 10 Physical management 9 Lack of friends 1 ‘Everything’ 1 No response 12

Behaviour problems As would be expected, the brain lesions in tuberous sclerosis increase the likelihood of behaviour problems. Varied and multiple problems were reported in 58 children (Table IV). Several children were unable to tolerate frustration and respond- ed by self-mutilation, head-banging or biting themselves, or turned their aggression outward by being noisy, hyperactive, or biting or hitting others. One mother reported that her son’s conduct was so bad between the ages of five and eight years that she woke each morning in fear of his life. He smashed, wrecked, hit, kicked and swore. Nothing seemed to frighten him, and at six years of age he deliberately ran into a moving car. He was expelled from his first special school because of his behaviour. After tuberous sclerosis had been diagnosed he was helped by means of behaviour modification. Another hyper- active child was strong and violent when

thwarted and rarely went to bed before midnight.

Although only seven parents com- plained of their children’s sleeplessness, 17 had been given medication for sleeping problems. 16 had also received psycho- tropic medications such as thioridazine, haloperidol and diazepam for behaviour problems.

Only two children were reported as sitting and rocking. One was living in a mental-handicap hospital, the other had been hyperactive when young-climbing out of windows and eating furnishing materials-but by 17 years of age the major problem was reported to be masturbation.

Because many of the children were severely mentally retarded, it was difficult to assess any deterioration in behaviour with age: nevertheless, deterioration was reported for five children. For example one 16-year-old girl had attended a normal school until she was nine, a special school from nine to 12 years, but had then remained at home without further tuition. Her mother described her as ‘detached from reality, with unpredictable extremes of exhilaration and depression and fre- quent periods of confabulation and phobic ranting’.

Parents of 24 children reported no problems. Nine of these children were profoundly handicapped in that they neither walked nor spoke, although more than five years old. One mother commen- ted ‘She does not behave as such’.

Parents’ most pressing problems When asked what problems were of greatest concern, parents most often mentioned their children’s behaviour, including the lack of communication and speech (Table V). One mother worried that her eight-year-old son’s behaviour would affect the quality of care that could be offered him in the future: ‘What happens when I can no longer manage. He cannot go to the subnormality hospital as he is too difficult, so I cope!’. Another mother stated: ‘It was the behaviour problems, but now I think the fact that he has no friends upsets me most. The epilepsy we have learned to accept.’ However, 20 parents said their major problem was the manage- ment of their children’s seizures.

Physical management such as lifting and

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b r carrying older and heavier children, kidney s w M

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problems and menstruation hygiene con- cerned nine parents. 10 parents worried most about their children’s future, and one

Of the 12 parents who did not respond t o

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parent merely replied ‘Everything’.

this question, five had children under 2% years of age, when handicaps caused by

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$ tuberous sclerosis may not yet be ac- knowledged. Four children were over 16 years old, three of them profoundly handicapped. Of the remaining three children, one had presented no behaviour problems at the time of the questionnaire but she has since developed such severely aggressive and self-mutilating behaviour that she has been placed in a residential school; another is in a mental-handicap hospital, and the last is profoundly retarded.

D

Discussion For diseases such as tuberous sclerosis, in which a dominant gene can cause severe handicap, it is important that families be given sufficient advice about the implic- ations of the condition. Parents who learned of their own tuberous sclerosis after the birth of an affected child are likely to have a n increased feeling of the guilt which many parents experience following the birth of a handicapped child. However, unless there were signific- ant facial lesions, these parents were unlikely to have been diagnosed before their affected children were born. Inherited tuberous sclerosis was identified con- servatively in 18 cases, yet the other 79 cannot all be regarded as sporadic since more than half the cases had not received a full family investigation. Parents and siblings therefore were left in considerable doubt about the occurrence of tuberous sclerosis in future generations. Wilson and Carter (1978) have reported a family with more than one affected child but no signs of the condition in either parent on full examination. A glance at the parents’ faces for obvious skin rash and a n enquiry about familial epilepsy and retardation are not sufficient to detect carriers of the tuberous sclerosis gene. Of the cases in this sample, 95 per cent showed white skin macules (see Part II) , which indicates the importance of

356 examining family members with ultra-

violet light. The genetic implications of tuberous sclerosis should be explained t o individuals showing only the common skin problems of tuberous sclerosis-depig- mented areas, adenoma sebaceum and raised skin (shagreen) patches.

Of the 97 people in the sample, 90 were over the age of two, and of these 16 were of normal intelligence, including the 15 who were free of seizures. Thus, 74 of the 90 (82 per cent) showed some degree of mental retardation. This is higher than the 60 per cent reported by Gomez (1979), but the motivation for parents of severely handi- capped children to be in contact with a group such as the Tuberous Sclerosis Association is greater than for parents of children with average intelligence, and this is reflected in the sample of parents who responded to the questionnaire. Further- more, the response rate of 65 per cent limits the ability to generalize from these findings.

Of the 82 children with seizures, 46 of the 75 (61 per cent) over the age of two did not speak a meaningful word. All the children unable to speak had experienced infantile spasms, which occurred in 66 (80 per cent) of these 82. This lack of speech, coupled with psychotic behaviour patterns, some- times follows infantile spasms (Ounsted 1970).

The children’s behaviour was the parents’ greatest concern. The behaviour included screaming, a form of vocal activity that might be expected in non- verbal children, and hyperactivity. There were also worries about the management of intractable seizures. Children with organic brain lesions are a t risk of developing behaviour problems (Rutter ct a/. 1970), and with a condition such as tuberous sclerosis not all behaviour problems can be directly attributable to the parents’ interactions and management. The families of children with tuberous sclerosis often need considerable help on a continuing basis after the initial diagnosis is made, and there is little wonder that these parents are concerned about their children’s future.

Author’ \ Appointmrnt A n n Hunt . H.A. , Kcsearch Worker, Human Development Research [init. Park Hospital for Children. Old Road. Hcadington, Oxford OX3 7LQ.

SUMMARY Although tuberous sclerosis is transmitted through a dominant gene, less than half the parents and siblings of the 97 individuals surveyed had received genetic counselling. There was no apparent difference in severity of handicaps in relation to whether the gene was transmitted by the father or the mother. The majority of the sample were mentally retarded, and speech was more affected than gross motor development. Behaviour problems were of more concern to parents than their children’s seizures or worries about the future.

RESLIME SclProte tubPrcuse: Ptude de 97 cas. I l l . Aspects ,familiau.u Bien que la sclProse tubereuse soit transmise sur le mode dominant, moins de la moitie des parents et des fratries des 97 cas itudies ont beneficie d’un conseil gknetique. I I n’est apparu aucune difference dans la gravitt. du handicap que le gkne ait CtC transmis par le pkre ou par la mere. La majorit6 de I’Cchantillon etait mentalement retardke. le langage plus atteint que le dkveloppement moteur. Les problimes de comportement preoccupaient davantage les parents que les crises de leurs enfants ou des prboccupations du futur.

ZUSAMMENFASSUNG Tuberose Sklerose: ein Uberblick uber 97 Falle. IlI: Familiare Aspekre Obwohl die tuberose Sklerose dominant vererbt wird, erfolgte nur bei weniger als der Halfte der Eltern und Geschwister dieser 97 Patienten eine genetische Beratung. Der Schweregrad der Behinderung war unabhangig davon, ob das Gen vom Vater oder von der Mutter ubertragen worden war. Der GroDteil dieser Patienten war geistig retardiert und die Sprache war starker betroffen als die motorische Entwicklung. Die Eltern machten sich groBere Sorgen wegen der Verhaltensprobleme als wegen der Krampfe und um die Zukunft der Kinder.

RESUMEN E.derori.s ruberma: revision dr 97 casos. 111: Aspectos ,familiares Aunque la esclerosis tuberosa se transmite por un gen dominante, menos de la mitad de 10s padres y hermanos habian recibido un consejo genktico. No habia diferencia aparente en la gravedad del handicap en relacion con el hecho de si el gen habia sido transmitido por el padre o la madre. La mayor parte de la muestra era mentalmente retrasado y el lenguaje estaba mas afectado que el desarrollo motor. Los problemas de comportamiento originaban mas preocupacion a 10s padres que las convulsiones o 10s problemas del futuro de 10s n i b s .

References Bundey, S., Evans, K. (1969) ‘Tuberous sclerosis: a

genetic study.’ Journal of Neurology, Neurosurgery and Psychiatry, 32, 591-603.

Gomez, M. R. (1979) ‘Clinical experience at the Mayo Clinic.’ In Gomez, M. R. (Ed.) Tuberous Sclerosis. New York: Raven Press. pp. 16-20.

Harper, P. S. (1975) ‘Congenital myotonic dystrophy in Britain. 11. Genetic basis.’ Archives of Disease in Childhood, 50, 5 14-52 1.

Ounsted. C. (1970) ‘A biological approach to

autistic and hyperkinetic syndromes.’ In Apley, J. (Ed.) Modern Trends in Paediatrics. London: Butterworths. pp. 286-316.

Rutter, M., Graham, P., Yule, W. (1970) A Neuropsychiatric Study in Childhood. Clinics in Developmental Medicine Nos. 35/36. London: SIMP with Heinemann Medical; Philadelphia: Lippincott.

Wilson, J., Carter, C. 0. (1978) ‘Genetics of Tuberous sclerosis.’ Lancer, 1. 340.

pp. 7-8.

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