within the Oxford region

Transcription

1 Journal of edical Genetics, 1984, 21, Tuberous sclerosis: a new estimate of revalence within the Oxford region A HUNT* AN R H LINENBAUt rom *the Human eveloment Research Unit, ark Hosital for Children, Old Road, Headington, Oxford; and teartment of edical Genetics, Churchill Hosital, Headington, Oxford. SUARY Within the counties administered by the Oxford Regional Health Authority (oulation ) the revalence of tuberous sclerosis was estimated as 1 in for ersons under 65 years of age. or the oulation below 30 years of age the revalence was in and for children under 5 years 1 in Cases were ascertained through the records of the eartment of edical Genetics at Oxford and the Tuberous Sclerosis Association of Great Britian and also by a questionnaire sent to selected consultants within the region. A revious estimate of revalence within the region was in This study suggests that the revalence at birth might be even higher than 1 in Although recognised and described by Bourneville' over a century ago, tuberous sclerosis may still be called 'a rare disorder'. What now seem to be low estimates of revalence were made by Stevenson and isher2 in Northern Ireland (1 in ) and by Nevin and earce3 working roughly within the bounds of the resent Oxford region (1 in ). ore recent estimates of revalence are higher, and include those of Zaremba4 (1 in ) based on a survey of institutionalised mentally retarded eole in oland, onegani et a15 (1 in ) estimated from routine necrosies in Switzerland, and leury et a16 (1 in ) in H4olland. aediatricians now recognise tuberous sclerosis as a significant cause of infantile sasms and develomental handica.7-9 The white skin macule, which usually aears before the facial angiofibroma (adenoma sebaceum), is established as a useful early sign of the disorder.'0 11 Use of comuterised tomograhic scanning imroves early detection and accurate diagnosis in both symtomatic and asymtomatic ersons. The autosomal dominant mode of transmission is well established. Although about 8000 of cases are estimated to be new mutations,'2 13 asymtomatic carriers of the gene without serious health roblems are often found among sibs or arents of severely handicaed children. No study can identify all the asymtomatic carriers in the general oulation. The resent one attemts to reassess the situation within the Oxford Received for ublication 29 November Acceted for ublication 4 January region with the hel of relatively 'new' hysical signs, such as white macules and enamel its,14 and new technology, such as CT scanning, combined with a family aroach and home visiting. The study drew on the records of the eartment of edical Genetics at Oxford and the Tuberous Sclerosis Association, and collected further cases by a questionnaire sent to consultants in nine secialities. Only at the end of the work was use made of the files of Nevin and earce, as a check against omissions. ethod An attemt was made to identify all cases of tuberous sclerosis within the geograhical limits of the Oxford Regional Health Authority who were alive on the survey date of Sufficient contact had been maintained with families to be sure that the cited ersons were alive on this date. Where doubt existed further enquiries were made. Of the 68 affected ersons, 51 were visited ersonally by one of the authors. Aart from the cases searately annotated (see aendix) all the cases seen satisfied the diagnostic criteria suggested by Gomez15 in 1979, having at least one rimary or two secondary signs of tuberous sclerosis. Gomez's criteria did not include eiletic seizures other than infantile sasms, mental retardation, gingival fibromata, or congenital enamel its, and the hyomelanotic macules are scored as a secondary sign only. urther cases were ascertained by a questionnaire 272 J ed Genet: first ublished as /jmg on 1 August ownloaded from htt://jmg.bmj.com/ on 13 ecember 2018 by guest. rotected by coyright.

2 Tiuberoius sclerosis: a new estimate of revalence within the Oxford region sent to all 79 of the regional consultants in aediatrics, dermatology, neurology, neurosurgery, neuroathology, mental handica, child sychiatry, ohthalmology, and renal medicine. Lastly the files of Nevin and earce's 1968 survey3 were re-examined and comared with the atients listed in this 1982 survey. The most recent information on the oulation of the Oxford region was obtained from OCS figures available through the Regional Health Authority. The latest figures related to 1981 and included a artitioning of the total oulation into age grous or cohorts, namely less than 1 year, I to 4 years, 5 to 14 years, and so on. Cases ascertained in this resent survey were artitioned into corresonding age grous and revalences searately estimated within these grous and for the total oulation ( ). Results A total of 68 cases was ascertained in all. any were ascertained indeendently from several sources (see aendix). There were 30 males and 37 females. In one family (case numbers 34, 35, and 65 in the aendix) it could not be decided which arent of three cases of tuberous sclerosis, one already dead, actually carried the gene. TABLE 1 Tuberouis sclerosis: revalence of mental handica by age. Age (yr) Aental handica Severe ild None Not known < All ages TABLE 2 Case numbers offamily members with tuberous sclerosis. 2 family members 3 family members 4 family members The numbers refer to cases listed in the aendix. TABLE 3 Tutberouis sclerosis: revalence by age ill Oxford region (as on ). orty-four cases were known to the eartmnent of edical Genetics (G), 28 cases were known to the Tuberous Sclerosis Association (),'6 and 13 cases were identified by questionnaire alone (relies were received from 62 of 79 consultants contacted). Nine cases from Nevin and earce were again identified in this survey. Only one had been referred again to G during the last 10 years, but four others were known to the and four were reidentified by questionnaire alone. The remaining nine cases of Nevin and earce had died meanwhile or were otherwise lost to follow-u. etails of referring consultants and of identifications made by questionnaire are listed in the aendix. aediatricians referred the greatest number of cases to G, a total of 17, with nine other cases recognised among family members through such referrals. Of the cases aged over 45, three out of five were identified only through referral of their ill or handicaed children. Nine of the 13 cases identified by questionnaire alone were older ersons, but four cases were under 15 years. ifty-one of the recorded cases were seen ersonally by one or both authors. The remaining 17 cases included eight reorted by questionnaire alone and three cases known also to Nevin and earce. In all cases not seen ersonally, the diagnosis was considered well established by secialist clinicians. Thirty-six ersons suffered severe mental handica, eight were mildly handicaed, and 20 not at all. There was no knowledge of the mental state in the remaining four cases. Table 1 shows that in the youngest age grous virtually all cases were severely mentally handicaed, while in the over 45s no case of severe handica was identified. The 68 cases comrised 48 unrelated subjects and seven families with more than one affected. The family grous consisted of one, two, or three affected sibs lus an affected arent (table 2). In one family there were three generations of eole with tuberous sclerosis, with only the child in the third generation showing mild mental handica. Thirty-four cases were thought to have arisen as new mutations and 17 received the tuberous sclerosis gene from an affected arent. In 17 cases it could not be decided whether the condition reresented a mutation or was transmitted from a arent. Very Born fromn * * bf/in Total To Age (yr) No of cases Regional oulation (looos) *6 491* revalence (looos/case) J ed Genet: first ublished as /jmg on 1 August ownloaded from htt://jmg.bmj.com/ on 13 ecember 2018 by guest. rotected by coyright.

3 274 A Hunt and R H Lindenbaum TABLE 4 Tuberous sclerosis: revalence by cumulative age grous in Oxford region (as on ). Age, cumulative years <1 <5 <15 <30 <45 <65 All ages No ofcases Regional oulation, cumulative (1000s) revalence, cumulative (oulation looos/case) often this uncertainty was due to insufficient investigation of the families concerned. Thus it was estimated that between 50% and 75% of cases reresent new mutations (34/68 to 51/68 cases). The ascertained cases were groued by age (aendix). Table 3 gives the revalence by age grous, using the OCS figures for the total oulation in the Oxford region. It is also of interest to consider revalence by cumulative age grous and this is given in table 4. iscussion The revalence of tuberous sclerosis in this study of the Oxford region was 1 in considering the whole oulation. However, for ersons under the age of 45 the revalence was 1 in , four times that found by Nevin and earce, and for ersons under the age of 15 the revalence was 1 in In children under 5 it was 1 in Incomlete ascertainment in 1968 may have arisen in a number of ways and ascertainment in 1982 is also likely to be incomlete. In the youngest age grous incomlete ascertainment may arise through lack of symtoms which may aear later, such as eilesy or mental retardation, or through lack of signs which can aear later such as facial angiofibroma or gingival fibromata. In the absence of clear hysical signs of tuberous sclerosis slight symtoms such as minimal fits or mild retardation may not suggest the diagnosis. Signs themselves may be hard to recognise, such as congenital forehead laques, hyoigmented macules on ale skin, and early or mild fibroadenomata. Symtoms and signs may be obvious, but the diagnosis of tuberous sclerosis may not have been considered or established. Table 1 shows that only severely handicaed children were likely to be identified below the age of 5 years. Older children and adults with tuberous sclerosis may suffer no neurological handica. In some the skin signs are oorly develoed or non-existent, or a facial rash is regarded as mere acne. Neurological handica, when mild, may be regarded as environmental or social in origin. Some ersons suffer serious roblems arising from tuberous sclerosis, such as renal angiomyolioma, but the diagnosis of tuberous sclerosis is not considered. amily asects of the disorder may be ignored and affected first degree relatives not identified. All these factors are likely to have oerated more strongly in 1968 than in 1982, but there is evidence that they are still oerating and resent ascertainment remains incomlete. The fullest ascertainment would be exected in the younger age grous where most of the diagnostic activity is concentrated. Tables 3 and 4 show clearly a higher revalence in the younger age grous; after the age of 30 the revalence dros considerably. This may reflect less accurate diagnosis within the older age grous, but the lower reorted revalence is robably also due in art to excess early mortality from related roblems, like renal, resiratory, or cardiac failure, brain tumour, or status eileticus, which may cause death in young or middle aged adults. Even our estimates of revalence in childhood are underestimates of birth revalence, since some children do die from tuberous sclerosis in the first years of life or, although affected, are not referred then. Given these difficulties in making a full ascertainment of tuberous sclerosis it is of some interest that the roortion of severely handicaed cases (36 out of 68, that is 53 %) is close to that of other ublished series.15 If it is assumed that nearly all of the incomletely investigated cases reresent new mutations then 51 of 68, that is 75% of cases, are new mutations. Thus the mutation rate can be calculated using 1 in as an estimate of revalence: 75/100 x 1/2 x 1/ = 2-5xlO-5 (SE = 3 2xlO-6). It aears that only severely handicaed children are diagnosed below the age of 5 years, but there are at least 20 out of 58 cases in the older age grous (5 years or over) who are without mental handica. This suggests that for the 10 cases diagnosed below 5 years there are in this age grou another five cases without handica, that is, the true revalence in the under 5s may not be I in but nearer to 1 in The method of estimating revalence by age grous, searately and cumulatively, seems articularly aroriate and useful when dealing with a condition associated with an increased risk of early mortality. This work was suorted by a grant from the Tuberous Sclerosis Association of Great Britain. J ed Genet: first ublished as /jmg on 1 August ownloaded from htt://jmg.bmj.com/ on 13 ecember 2018 by guest. rotected by coyright.

4 Tuberous sclerosis: a new estinmate cfrevalence within the Oxford region 275 References 9 O'onohue NV. Eilesies in childhood.- London: Butterworths, 1979: Bourneville. Sclerose tubereuse des circonvolutions 10 Critchley, Earl CJC Tuberous sclerosis and allied cerebrales: idiotie et eilesie hemilegique. Arch Neurol conditions. Brain 1932;55: (aris) 1880;1: Gold A, reeman J. eigmented nevi: the earliest 2Stevenson NC, isher O. requency of eiloia in sign of tuberous sclerosis. ediatrics 1965;35: Northern Ireland. BrJrev Soc ed 1956;10: Lagos JC, Gomez R. Tuberooss sclerosis: rearaisal of 3Nevin NC, earce G. iagnostic and genetical asects a clinical entity. roc ayo Clin 1967 ;42 : of tuberous sclerosis. J ed Genet 1968;5: Bundey S, Evans K. Tuberous sclerosis, a genetic study. Zaremba J. Tuberous sclerosis: a clinical and genetical JNeurolNeurosurgsychiatry 1969;32: investigation. J ent efic Res 1968 ;12: Ligidakis NA, Lindenbaum RH. Enamel defects in onegani G, Gratarolla R, Wildi E. Tuberous sclerosis. tuberous sclerosis: a clinical and scanning E study. In: Vinken J, Bruyn GW, eds. The hakomatoses. resentation at Symosium on Autosomal Heterozygosity, Handbook of Clinical Neurology. Vol 14. Amsterdam: Nijmegen, Holland, ay Summary in Clin Genet North-Holland, 1972: ;24: leury. de Groot, elleman JW, Verbeeten B Jr, 15 Gomez R. Clinical exerience at ayo Clinic. In: rankenmolen-witkiezwicz I. Tuberous sclerosis: the Gomez R, ed. Tuberous sclerosis. New York: Raven incidence of soradic versus familial cases. Brain ev ress, 1979: ;2: Hunt A. Tuberous sclerosis: a survey of 97 cases. ev 7amiglione G, ugh E. Infantile sasms and subsequent ed Child Neurol 1983 ;25 : aearance of tuberous sclerosis syndrome. Lancet 1975; 2:1046. Corresondence and requests for rerints to r R H 8 amiglione G, oynahan EJ. The tuberous sclerosis syndrome: clinical and EEG studies in 100 children. J Lindenbaum, eartment of edical Genetics, Neurol Neiurosiurg sychiatry 1976;39: Churchill Hosital, Headington, Oxford OX3 7LJ. AENIX Cases of tutberous sclerosis ascertained in survey of the Oxford region and mode of ascertainment. Case No S Hh OB Sex ascg asc ascque Nevea Seen by Born : age below 1 year 01 H 02 H Born : 1-4 years old 03 H 04 H 05 m H 06 H 07 H 08 H 09 H 10 S h Born : 5-14 years old ll H 12 m H S H h o H 19 H 20 s h 21 s o 22 s o 23 o 24 H 25 s h 26 H 27 h 28 H 29 o Born : years old 30 H 31 H H 34 S H 35 S H 36 m H 3/82 5/82 12/80 7/81 2/80 5/79 9/79 12/78 8/81 4/81 12/71 2/70 2/70 6/71 10/72 12/70 4/74 5/77 8/71 6/73 3/76 8/77 4/72 9/71 9/67 10/67 3/71 1/ /62 7/56 1/66 6/66 6/59 3/63 7/ () - - H, H - () () G - H S Nf - - H H - - G G , N,,, 2NS NS 2 H 2H 2H 21H J ed Genet: first ublished as /jmg on 1 August ownloaded from htt://jmg.bmj.com/ on 13 ecember 2018 by guest. rotected by coyright.

5 276 AENIX-continued H 2/64 H 5/60 H 12/62 S H 1/65 S H 5/66 o 8/63 h 10/66 H H /58 H 5/56 S o 7/65 H 1/66 m o 1/62 Born 9.37-q.52: years old 50 h 51 H 52 H 53 H H 56 o 57 s o 58 o 59 s o 60 S o 61 S o 62 S o 63 o Born : years old 64 S h 65 o 66 o 67 o 68 o Born u to and including 8.17: 65 years and over No cases 9/45 11/46 3/45 7/49 9/49 12/44 3/39 11/43 6/40 12/42 7/42 1/52 7/50 3/41 12/32 '23/'30? 9/ /24 A Hunt and R H Lindenbaum - - H, -, G , G, - -, H N+ N+ - -, H N+ S - S - - H S H N N N H N H N+ - 2H N H N+ () () N N - - () () () (G) N (Other) () = mutant m =?mutant S = segregant s? segregant H = severe mental handica h = mild mental handica o = no mental handica ascg = ascertainment by eartment of edical Genetics. asc = ascertainment by Tuberous Sclerosis Association (membershi list). ascque = ascertainment by questionnaire. Nevea = found also in Nevin and earce 1968 files. () means ascertained by family follow u with initial mode of referral in brackets. In ascg or ascque columns, referring doctor as follows: dermatologist G general ractitioner H mental handica hysician N neurologist NS neurosurgeon aediatrician S sychiatrist No cases were ascertained through ohthalmologists or renal hysicians. - N N J ed Genet: first ublished as /jmg on 1 August ownloaded from htt://jmg.bmj.com/ on 13 ecember 2018 by guest. rotected by coyright.

6 Tuberous sclerosis: a new estimate ofrevalence within the Oxford region Annotated cases Case 10 was referred for mild mental handica with macrocehaly and mildly dilated ventricles but no other signs of TS on the CT brain scan. On examination he had a few white macules. His father (62) had gingival fibromata as the only sign of TS, but the father's sister (61) and the father's mother (68) had classical adenoma sebaceum, subungual fibromata, and other signs of TS. In this family no-one had severe mental handica or had ever had a fit. The grandmother (68) was ascertained by questionnaire indeendently of the rest of the family and shortly before the grandchild (10) was seen in the eartment of edical Genetics. Case 14 had skin signs more suggestive of the linear sebaceus naevus syndrome, with severe retardation and eilesy roblems in the first 2 years of life and a few enamel its as seen in TS. Neurosurgery largely cured the eilesy and the retardation, and the neuroathological findings were reorted as tyical of TS. The father (58) had skin signs similar to those in the son, but to a lesser degree, with no eilesy or other handicas. Case 22 was referred by a aediatrician. He had suffered several grand mal convulsions at 3 years of age with no further fits in the following 2-year eriod. A sister (21) had a atch of shagreen skin, with tyical histological changes observed at biosy. She had no fits and no retardation, but there were one or ossibly two white macules somewhat suggestive of TS. Another sister (20) had suffered from mild retardation of unknown cause. There had been some twitching of a leg during the first 2 weeks of life, but no clear history of fits, and there were no obvious signs of TS. The mother (57) had no fits or handica, but was observed to have a few gingival fibromata as ints. The mother's brother, living outside the region, suffered from severe eilesy and mild retardation. He had undergone neurosurgery when aged 33 years 277 for a congenital arteriovenous malformation. Other maternal relatives were said to have suffered from fits and brain damage. Sisters 34 and 35 had classical skin signs of TS and were long term atients in hosital on account of severe mental handica and behaviour roblems. A brother had died almost 25 years reviously with rhabdomyoma and heart failure at 3 months of age. Another brother died several months after the survey date, suffering from severe mental retardation of unknown cause, with gross scoliosis but no clear signs of TS in life or at necrosy. The arents were first cousins and no signs of TS were detected in either. However, no CT brain scans were erformed and they were rather uncooerative in attemts to arrange other secial investigations, such as fundoscoy with mydriatics or skull x-rays. Either we accet arental gonadal mosaicism, autosomal recessive determination of TS, or trile extramarital concetion as exlanation of this constellation of cases, or one arent, signless and symtomless, was carrying the TS gene. We referred this latter exlanation and listed a arent, 'mother/father', as case 65. Case 67 would not be seen, but was reorted to have tyical adenoma sebaceum. Her daughter, dead at 20, was seen by and had skin signs of TS together with severe involvement of heart, lungs, and kidneys. Both mother and daughter had had arathyroidectomy for endocrine secreting tumours. Excluded from the survey was a child with intractable eilesy with onset at 2 to 3 months and gross develomental retardation. He had an oval 'bald atch', 1 x 1 5 cm, in the left arietal area, reddishbrown in colour, and resembling the congenital forehead laques sometimes seen in TS. There were no other signs of TS, and first degree relatives were also examined by with negative result. The child died of eilesy and neumonia at 18 months and ermission for necrosy was refused. He had been alive on the survey date. J ed Genet: first ublished as /jmg on 1 August ownloaded from htt://jmg.bmj.com/ on 13 ecember 2018 by guest. rotected by coyright.