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Frequency of tuberous sclerosis in san-in district (Japan) and birth weight of patients with tuberous sclerosis
Frequency of Tuberous Sclerosis In San-In District (Japan) and Birth Weight of Patients with Tuberous Sclerosis Kousaku Ohno, MD, Kenzo Takeshita, MD, and Masataka Arima, MD
Fifty-two patients with tuberous sclerosis including 44 propositi were collected from 11 hospitals and 20 institutions in the San-in district. Of the 52 patients 44 were alive at the time of the study and the prevalence of tuberous sclerosis among the general population of the San-in district in October 1979 was estimated to be one in 31,000 (3.2 x 10-5 ), which was the highest value among the surveys in certain geographical areas. The frequency of tuberous sclerosis in live-births was estimated to be one in 24,000 (4.0 x 10- 5 ). The frequency of the sporadic cases in live-births was one in 31,000 (3.2 x 10- 5 ) and the mutation rate was directly estimated to be 1.6 x 10-5 per gene per generation. A difference between the parental age or birth order of the sporadic cases and those of controls was not detected. The mean birth weight for the tuberous sclerosis group was 2,834 g which was slightly less than the 2,985 g for their normal sibs. The frequency of low birth weight, less than 2,500 g, among the children with tuberous sclerosis was 30% (7/23), which was 4 times that in the general population (p < 0.005). These facts suggest that the intrauterine growth is affected in a considerable number of the patients. Ohno K, Takeshita K, Arima M. Frequency of tuberous sclerosis in San-in District (Japan) and birth weight of patients with tuberous sclerosis. Brain Dev 1981;3:57-64
Tuberous sclerosis is one of the most frequent genetic disorders which causes epilepsy and mental retardation in early childhood. The prevalence of tuberous sclerosis has been estimated to range between one in 100,000 and one in From the Division of Child Neurology, Institute of Neurological Science, Tottori University School of Medicine, Tottori (KO, KT); Division of Child Neurology, National Center for Nervous, Mental and Muscular Disorders, Tokyo (MA).
170,000 in the general population of Caucasians [1, 2] or Chinese [3] , but there is no report on its frequency in the Japanese population. The present study was mainly devoted to estimating the prevalence of tuberous sclerosis in the Japanese population of the San-in district. At the same time, the effects of the parental age and birth order on mutation rate and the effects of the tuberous sclerosis gene on the growth and activity of the affected fetus were evaluated.
Received for Publication: November 20, 1980. Accepted for pUblication: February 9, 1981.
Subjects and Methods
Key words: Tuberous sclerosis, prevalence rate, frequency in live-births, mutation rate, birth weight. Correspondence Address: Kenzo Takeshita, MD, Division of Child Neurology, Institute of Neurological Science, Tottori University School of Medicine, Nishimachi 36, Yonago 683, Japan.
The San-in district is located in the western part of Honshu, i.e. the main island of Japan, and consists of Shimane and Tottori Prefectures. Persons with tuberous sclerosis were collected from Tottori University Hospital by surveying
the clinical records (for about the previous 10 years) of the Divisions of Child Neurology and Neurology of the Institute of Neurological Science, and the Departments of Pediatrics, Psychiatry, Dermatology, and Urology; from 10 hospitals in Shimane and Tottori Prefectures by asking pediatricians, psychiatrists, neurologists and dermatologists; and from 20 institutions for retarded children and adults in this area by examining all institutionalized patients. Diagnosis of tuberous sclerosis was made on the basis of either (a) angiofibroma of the face, (b) circumscribed hypomelanosis (naevi or hair) and nodular calcific density on skull X-ray or computer assisted tomography, or (c) cerebral biopsy specimens. This revealed 44 propositi. All propositi were classified into familial cases (familials) or sporadic cases (sporadics) depending on the presence or absence of the conditions in their parents. The relatives of familials and the children of the propositi who had married were examined as far as possible. In every case information including present address, birth place, parental age, sibships, prenatal history, and birth weight from census registers, hospital records, and/or questionnaires was obtained. The prevalence in the general population of the San-in district was evaluated by ascertaining the patients living in this area in October 1979. The frequency in live-births was calculated by ascertaining the patients born in this area. The birth order effect was studied by HaldaneSmith's method. The information on prenatal history and birth weight of affected cases was compared with that of their normal sibs and that of the general population. Result
All of the propositi, except case No 5 whose diagnosis was made on a biopsied specimen of a cerebral tumor, had clinical manifestations corresponding to the diagnostic criteria. Among the 44 propositi, there were 23 males and 21 females with a sex ratio of 1.10, and 37 patients (84%) were classified as sporadics (Table 1) and the other 7 (16%) as familials. In one family (No 38), it was very probable that the father, now dead, had angiofibroma of the face and we classified this family as a familial. In another family (No 40) the father was an epileptic and demented man with depigmented naevi on the back. Although he did not have angiofibroma 58 Brain & Development, Vol 3, No 1, 1981
of the face, retinal phacoma or calcification on skull X-rays, we considered him as a "forme fruste" and classified this family as a familial. By surveying the offspring of 4 sporadics who had children and the relatives of 6 familials, 8 patients including an affected parent were diagnosed to have tuberous sclerosis (Fig 1). A total of 52 affected individuals were ascertained in the San-in district. Age of the ascertained 49 living cases ranged between 2 years and 65 years and one or more patients were found in each five-year age group between 0 and 55 years old (Table 2). This shows the patients in this series were almost equally collected from all age groups. Mental retardation was present in 34 (65%) of the total 52 cases and 31 (70%) of the 44 propositi. Forty-two patients (81 %) of the total 52 cases and 38 (86%) of the 44 propositi presented convulsions. According to published reports [2-6] , in which the patients were collected not only from institutions for the mental defective or epileptic but also derrnatologic and ophthalmologic clinics, the frequency of mental retardation among the patients with tuberous sclerosis ranged between 61% and 73%, and that of epilepsy between 83% and 93%. The frequencies of mental retardation and epilepsy in our series are in good comparison with those of previous reports. This shows that the patients in this survey were reasonably collected also from the non-epileptic or normal intelligence population. These findings show that the results of this survey represent the general population reasonably.
Clinical Features These are summarized in Table 1 and Fig 1. Skin and hair manifestations of 26 personally examined cases and computer assisted tomographic findings of 7 affected children in this series have already been reported in detail [7, 8]. Prevalence of Living Cases in a Population Of the 52 patients 44 were living in the San-in district, which has a population of 1,380,000 (October 1979). The prevalence in the general population was 3.2 x 10-5 • Thirty-two patients out of the 44 living cases were sporadic cases (Table 2), so that the prevalence of sporadics was 2.3 x 10-5 • Taking into consideration the presence of patients who were not ascertained
by this survey and the presence of "forme fruste" cases who had been overlooked in hospitals, these values are regarded as a minimal estimation of the prevalence.
1945 (after World War II) coincided with the present address except for one case (No 25, born in Tottori and living in Shimane) and the 10 institutionalized children who moved in the district. The number of live-births in this area between 1945 and 1946 was not known because of World War II, and between 1947 and 1978 there were about 840,000 live-births in this area.
Frequency of Tuberous Sclerosis in a Series of Births The birth place of each sporadic born after Table 1 Summary of clinical data in sporadics Case No 1 (T) No 2 (0) No 3 (T) No 4 (S) No 5 (T) No 6 (T) No 7 (S) No 8 (T) No 9 (0) No 10 (S) No 11 (S) No 12 (T) No 13 (T) No 14 (T) No 15 (S) No 16 (S) No 17 (S) No 18 (T) No 19 (T) No 20 (S) No 21 (0) No 22 (T) No 23 (T) No 24 (T) No 25 (S) No 26 (S) No 27 (T) No 28 (T) No 29 (T) No30(T) No 31 (T) No 32 (T) No 33 (T) No 34 (T) No 35 (T) No 36 (T) No 37 (S)
Sex Birth M 1977 F 1977 M 1977 M 1977 F 1977 F 1976 M 1974 M 1974 F 1971 M 1971 M 1968 F 1966 M 1966 M 1965 F 1963 F 1962 M 1960 F 1959 F 1958 M 1957 M 1957 F 1957 M 1955 F 1952 F 1952 M 1952 F 1951 F 1949 M 1949 F 1948 M 1943 F 1942 F 1941 F 1936 M 1936 M 1930 M 1927
Parental age M F 27 32 21 43 26 36 29 22 40 31 31 30 26 35 31 27 28 40 27 30 19 25 23 31 31 25 33
24 26 22 26 24 29 28 21 36 30 30 30 31 34 28 30 23 34 28 28 23 29 22 26 27 21 31
37 23 34
38 23 32
22
19
Sibships P NP P NPN SPN NAAP PN P NAP P NPA NPN PNN ANP NPAAN PN PAN NNP NP ANP PN NP PN NPN P NPN NNP NP NAAAPN P NNP P NPNN PNNNN NP PNNNN NPNNNNN
AF ND MR EP CA + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+ + + + + + + + + + + + + + + + + + + + + + NR NR NR
+
+ + + + + + + + + + + + +
+ + + + + + + + + + + + + + + + +
+
+ + + + + + + + + + + + +
+
+
+ + + + + + + + +
-
+ + NR NR
-
+ + + + + + + + + + + + + + NE + + NE NE + NE + NE + + + NE NE NE NE NE NE NE NE NE
Others
Giant ,?ell astro. (brain, 1978) Paresis Giant cell astro. (brain, 1978)
Giant cell astro. (eye, 1973) Dwarfism
Urinary stone
Cystoadenoma (mamma, 1977) Paresis Paresis Dwarfism, Death 1970 (pneumonia) Death 1969 (accident)
Dwarfism Fibrolipoma (Kidney, 1972) Angiolipoma (Kidney, 1977)
(T) = living in Tottori, (S) = living in Shimane, (0) = living in other places, M = male, F = female, N = normal sib, P = patients, S = stillbirth, A = abortion, AF = angiofibroma of face, ND = naevus depigmentosum, MR = mental retardation, EP = epilepsy, CA = calcifications on skull X-ray or computed tomography, Giant cell astro. (brain, 1978) = operation of brain tumor in 1978 and histology revealed giant cell astrocytoma. Cystoadenoma (mamma, 1977) = operation of mammary tumor in 1977 and histology revealed cystoadenoma. NR = not recorded, NE = not examined.
Ohno et al: Frequency of tuberous sclerosis 59
No. 38 (S)
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Fig 1 Pedigrees of familial cases and sporadic cases who had children, (8), (T), (0) =living in 8himane (8),
Tottori (T), or others (0). 0 = male, 0 = female, .,.0 = propositus, Dt =deceased, ~ =angiofibroma of face, ~ = naevus depigmentosum, ~ = epilepsy, Iil = febrile convulsion during childhood, I!J =severe mental retardation, EJ = mild mental retardation,
Except for the 7 sporadic cases born before 1946, there were 27 births of sporadics between 1947 and 1978. In addition, 2 children borne by a mother with tuberous sclerosis (No 33) had angiofibroma and 5 propositi of familials (Nos 39 to 43) were born in this area during this period. Then a total of 34 births occurred between 1947 and 1948, and the frequency of tuberous sclerosis in the series of live-births was 4.0 x 10-5 and that of sporadics was 3.2 x 10- 5 (Table 3). This is also considered to be minimal.
Table 2 Age distribution of ascertained living cases Age (years)
0- 5 6-10 11-15 16-20 21-25 26-30 31-35 36-40 41-45 46-50 51-55 56Total
60 Brain & Development, Vol 3, No 1,1981
No of case (sporadics) Living in 8himane and Tottori 7
2
7
4 5 5 3 3 2 1 3
2 44
(7)
(1) (4) (4) (4) (5)
Living in others
1 2
(1)
1
(1)
5
(3)
(1)
(1)
(2) (2) (1) (1) (32)
Table 3 Frequency of tuberous sclerosis in live-births (1947-1978, Shimane and Tottori) Year of birth
No of cases (sporadics)
Total live· births (Shimane and Tottori)
1947-50 1951-60 1961-70 1971-78
5 (3) 11 (10) 9 (6) 9 (8)
192,378 293,411 198,525 156,679
34 (27)
1947-78
Frequency (sporadics) 2.6 3.7 4.5 5.7 4.0
840,993
x x x x x
10-5 10-5 10-5 10-5
(1.6 (3.4 (3.0 (5.1
x
x
10-5 ) 10-5 ) 10-5 ) 10-5 )
5
(3.2
x
10-5 )
10-
x x
Table 4 Maternal age of sporadics Maternal age -19 Sporadics
= 31) (N = 31)
(N
Controls (517816)
0.31 (5153)
40-
20-24
25-29
30-34
35-39
9
10
9
2
0
8.86 (147954)
14.40 (240521)
5.80 (96965)
1.45 (24183)
0.18 (3040)
Mutation Rate The sporadics who are indistinguishable clinically from the familials are regarded as a fresh mutation that arose in the germ cell of a parent. A direct estimation of mutation rate results in % x 3.2 X 10-5 = l.6 X 10-5 per gene per gene· ration. This is also minimal. Birth Order and Parental Age Contrary to the findings for other dominant diseases such as neurofibromatosis (9), the role of increased parental age in the occurrence of tuberous sclerosis mutants had not been demonstrated [2, 10]. Maternal ages at birth of 31 sporadics were compared with those of the general population in the San-in district between 1954 and 1976 (Table 4). The maternal age for children born before 1953 was not registered in this area and the ratios of the five-year age groups were almost the same in the period from 1954 to 1976, so we used the maternal age between 1954 and 1976 as a control. The frequency of the sporadics borne by mothers over 30 years of age was slightly higher than that of the controls, but not signifi· cantly (X2 = 2.256, P < 0.1). The mean mater· nal age at birth of the sporadics (N = 29: Nos 1-28 and No 30) was 27 .65 and that of their
Table 5 Prenatal history and birth weight Affected Normal sibs (N = 32) (N = 32) Poor fetal movement* Threatened abortion . Early rupture of amnion Asphyxia Low birth weight <2,500 g Mean birth weight
4 3 4 3 8 2,834 g
o 1 1 1
2,985 g
*A1though fetal mpvements are subjective feeling, in questionnaires three types of answer were indicated: 1) felt movements with or without kicking of fetus; 2) did not feel any movements of fetus; 3) stopped movements during course of pregnancy. We defined the latter two answers as poor.
normal sibs (N = 30) was 27.23 with a difference of + 0.42. The mean birth paternal age of sporadics was 29.62 and that of the normal sibs was 30.10 with a difference of -0.48. These results were considered to be inSignificant. Birth order was obtained for all sporadics and the birth order effect was examined by HaldaneSmith's test [11], which indicated no significant deviation from the theoretical expectation, i.e. observed 6A =420 and theoretical 6A = Ohno et al: Frequency of tuberous sclerosis 61
+1. 5
3500g
...........•.
3000g
2500g
.......
...............
2000g
1500g
..a:a . .... ~
",-
. .....
..
.~
... ,.
.... ,
sn*
1.-· """:1:';' SD'"
•....
--.- .....
........... 34
35
36
37
38
39
40
41
42
43
44
45
weeks
term of pregnancy
*
by Funakawa 1964
(22)
Fig 2 Birth weigh t and length of gestation
426 ± 31.89. Prenatal History and Birth Weight To determine the prenatal effects of the tuberous sclerosis gene on the fetus, exact information on prenatal history and birth weight was obtained for 32 patients and 32 normal sibs including 3 familials. Histories of threatened abortion, poor fetal movements, early rupture of the amnion and neonatal asphyxia were high in children with tuberous sclerosis (Table 5). The mean birth weight for the tuberous sclerosis group was 2,834 g, which is slightly less than the mean birth weight for normal sibs; 2,985 g (Table 5). The incidence of low birth weight, less than 2,500 g, was 25% (8/32) (Fig 2). The incidence of low birth weight for the general population of Tottori between 1956 and 1977, which had not been registered before 1955, was 7.5% (about 15,000/198,000 live-births). Except for the patients born before 1955, the frequency of low birth weight in patients with tuberous sclerosis was 30% (7/23), which was 4 times greater than that of the general popUlation (X2 = 22.98, p < 0.005). These results appeared to indicate that the intrauterine growth and activity were affected in a considerable number of the patients, which may explain the high frequency of dwarfism among the children with tuberous sclerosis, Le. 9% (4/44 propositi).
Discussion The problem in the genetic study of tuberous sclerosis is the variable expression of this con62 Brain & Development, Vol 3, No 1, 1981
dition, especially the presence of a milder form, "forme fruste." Detection of the milder form or diagnosis in early childhood are necessary to allow precise genetic study. Hypomelanotic macules have been recognized as an important early sign of tuberous sclerosis [12-14]. This lesion has occasionally a characteristic shape, oval or leaf-shaped, and histology reveals distinctive features; number of melanocyte normal, decrease in size of melanosome, decrease in melanization of melanosome and so on [14, 15]. This is of considerable diagnostic value, however, without histology, the usefulness in the diagnosis of isolated cases who have no other signs of tuberous sclerosis remains uncertain. Intracranial calcification has been reported to be another characteristic finding of tuberous sclerosis. The calcifications at the walls of the ventricular system seen on computer assisted tomography have been reported to be useful for early diagnosis of patients and for the detection of milder forms [8, 16]. Similar calcifications may be found in other diseases which cause epilepsy and mental retardation such as congenital toxoplasmosis. The diagnosis of an isolated case who has intracranial calcification without any other signs of tuberous sclerosis also remains uncertain. However, we considered a case with periventricular calcification and circumscribed hypomelanosis during childhood was most probably tuberous sclerosis, and we used this combination of features as a diagnostic criterion for ascertaining affected children before the appearance of angiofibroma of the face. As another possibility for early diagnosis or detection of milder forms, Rundle [17] reported that serum alpha-2-macroglobulin is significantly high in affected cases and suggested it to be useful for genetic counceling. We have preliminarily measured serum alpha-2macroglobulin of 17 affected children under 15 years old. There is no significant difference between patients and age-matched controls (data unpublished). Serum alpha-2-macroglobulin is considered to be of no use for the early diagnosis or the detection of milder forms during childhood. There have been several popUlation studies of tuberous sclerosis in the past. Population surveys in certain geographical areas were conducted by Stevenson and Fisher [1] , Nevin and Pearce [2] and Singer [3]. Their estimates of prevalence were one in 150,000 of the general
population of Northern Ireland, one in 100,000 of that of the Oxford Regional Hospital area, and one in 170,000 of the Chinese population of Hong Kong, respectively. The prevalence in the general population of the San-in district was about one in 31,000 (3.2 x 10-5 ), which was the highest value among the surveys in certain geographical areas. However, all these rates represent minimal estimates of true prevalence since many cases with mild or no clinical manifestations were undoubtedly overlooked in these surveys and, due to this, the prevalence rates for comparative purposes may not always be meaningful. Indeed, the prevalence rates indirectly estimated by the incidence of tuberous sclerosis among mental deficients were higher than these prevalence rates observed by actual population surveys; one in 30,000 of the general population of England [18], one in 20,000 to 40,000 in North Carolina [19] and one in 23,000 in Poland [10]. The prevalence rate in this study on the Japanese population is rather comparable to these indirectly estimated prevalence rates of Caucasians. Although the first sign of tuberous sclerosis usually appears during childhood, affected cases have been found among stillbirths and newborns. All cases detected within the first week after birth were pathologically diagnosed by the typical tubers on the brain [20, 21]. Periventricular tubers can occasionally be detected by computer assisted tomography even in infancy. These facts ·suggest that the brain lesion of tuberous sclerosis is formed in the embryonic life or in the early stage of life. Because of this we are interested in the condition of affected cases during the prenatal and perinatal periods. The present data revealed that the frequency of low birth weight, less than 2,500 g, was significantly high among patients with tuberous sclerosis and the frequency of prenatal and perinatal troubles of affected cases was higher than that of normal sibs. These facts may suggest that the tuberous sclerosis gene tends to interfere with fetal growth and activity. Acknowledgments We are grateful to the many doctors and teachers who provided us with the facilities for surveying and examining the patients under their care. Index patients were collected from many sources as follows: Division of Neurology (Nos 24, 25, 30, 39), Department of Psychiatry (Nos 23, 26, 29, 31, 38, 41), Pediatrics
(Nos 18, 24, 26), Dermatology (Nos 12, 15, 19, 26, 29, 31, 33, 34), Urology (Nos 36, 37), Division of Child Neurology (Nos 1-15,17,21,44), Tottori Univ. Hosp.; Izumo Prefectural Central Hosp. (Nos 4, 20, 40); Koryo Hosp. (No 43); Matsue Red Cross Hosp. (No 26); Hamada National Hosp. (No 10); Tottori Prefectural Central Hosp. (No 14); Kurayoshi Kousei Hosp. (No 3); Yonago National Hosp., Kurayoshi Hosp. (Nos 18, 32, 35); Tottori Red Cross Hosp., San-in Rosai Hosp., National Sanatorium Matsue Hosp. (Nos 15, 28); National Sanatorium Tottori Hosp. (Nos 12, 27, 28); Sazanami-Gakuen (Nos 16, 17,42); Matsue-Gakuen, Yasugi-Gakuen, Suginoko-Gakuen, Kurumi-Gakuen, Hamada-Gakuen, Kokubu-Gakuen, Kaisei-Gakuen, 1st and 2nd Shikano-Kachimien (No 22); Matsuno-Seibo-Gakuen (No 14); Mominokien, Kezin-Kaikan (No 35); Kibohno-Ie, Kohfuen, Kuwanokien, Ryokufuen, and Oh-hiraen (No 32). And we are also grateful to the many patients and their parents for answering our questions and questionnaires, and for giving their permission for examination. This investigation was aided by a grant from the Ministry of Health and Welfare of Japan for the Handicapped Children.
References 1. Stevenson AC, Fisher OD. Frequency of epiloia in Northern Ireland. Br J Prev Soc Med 1956;10: 134-5. 2. Nevin NC, Pearce WG. Diagnostic and genetical aspects of tuberous sclerosis. J Med Gent 1968; 5:273-80. 3. Singer K. Genetic aspects of tuberous sclerosis in a Chinese population. Am J Hum Genet 1971; 23:3340. 4. Borberg A. Clinical and genetic investigations into tuberous sclerosis and Recklinghausen's neurofibromatosis: contribution to elucidation of interrelationship and eugenics of the syndromes. Acta Psychiatr Scand [Suppl] 1951;71: 11-239. 5. Lagos JC, Gomez MR. Tuberous sclerosis: reappraisal of a clinical entity. Mayo Clin Proc 1967; 42:2649. 6. Bundey S, Evans K. Tuberous sclerosis: a genetic study. J Neurol Neurosurg Psychiatry 1969;32: 591-603. 7. Ohno K, Takeshita K. Tuberous sclerosis: a clinical study of the cutaneous manifestations. Brain Dev (Domestic Ed) (Tokyo) 1979;11: 394-9. 8. Ohno K, Eda I, Suzuki Y, Yano E, Ochiai Y, Arima M. Tuberous sclerosis: cranial computerized tomographic observation. Brain Nerv (Tokyo) 1978;30:172-7. 9. Sergeyev AS. On the mutation rate of neurofibromatosis. Hum Genet 1975;28:128-38. 10. Zaremba J. Tuberous sclerosis: a clinical and genetical investigation. J Ment Defic Res 1968; 12:63-80. 11. Haldane JBS, Smith CAB. A simple exact test for birth order effect. Ann Eugen 1948;14:117-24. 12. Tamura E, Suzuki M, Kamoshita S, Arirna M,
Ohno et al: Frequency of tuberous sclerosis 63
13. 14.
15.
16.
Fukuyama Y. Clinical observation of phacomatosis in infancy and childhood. Pediatr Univ Tokyo 1964;10:3541. Gold AP, Freeman JM. Depigmented naevi: the earliest sign of tuberous sclerosis. Pediatrics 1965 ;35: 1003-5. Fitzpatrick TB, Szabo G, Hori Y, Shimone AA, Reed WB, Greenberg MH. White leaf-shaped macules. Earliest visible sign of tuberous sclerosis. Arch DermatoI1968;98:1-6. Jimbow K, Fitzpatrick TB, Szabo G, Hori Y. Congenital circumscribed hypomelanosis: a characterization based on electron microscopic study of tuberous sclerosis, naevus depigmentosum, and piebaldism. J Invest Dermatoll975;64:50-62. Gomez MR, Mellinger JF, Reese DF. The use of computerized transaxial tomography in the diagnosis of tuberous sclerosis. Mayo Clin Proc 1975; 50:553-6.
64 Brain & Development, Voll, No 1, 1981
17. Rundle AT, Atkin J. Serum a.2 macroglobulin levels in tuberous sclerosis. J Ment Defic Res 1976;20:231-6. 18. Gunther M, Penrose LS. The genetics of epiloia. J Genet 1935;31 :413-30. 19. Paulson GW, Lyle CB. Tuberous sclerosis. Dev Med Child NeuroI1966;8:571-86. 20. Thibault JH, Manuelidis EE. Tuberous sclerosis in a premature infant. Report of a case and review of the literature. Neurology 1970;20:13946. 21. Oster AG, Fortune DW. Tuberous sclerosis initially seen as hydrops fetalis. Report of a case and review of the literature. Arch Pathol Lab Med 1978;102:34-9. 22. Funakawa H. Statistical observation of low birth weight newborns and the standard body height and weight at different gestational periods. Jpn J Pediatr (Tokyo) 1964;17:872-7.
Fifty-two patients with tuberous sclerosis including 44 propositi were collected from 11 hospitals and 20 institutions in the San-in district. Of the 52 patients 44 were alive at the time of the study and the prevalence of tuberous sclerosis among the general population of the San-in district in October 1979 was estimated to be one in 31,000 (3.2 x 10-5 ), which was the highest value among the surveys in certain geographical areas. The frequency of tuberous sclerosis in live-births was estimated to be one in 24,000 (4.0 x 10- 5 ). The frequency of the sporadic cases in live-births was one in 31,000 (3.2 x 10- 5 ) and the mutation rate was directly estimated to be 1.6 x 10-5 per gene per generation. A difference between the parental age or birth order of the sporadic cases and those of controls was not detected. The mean birth weight for the tuberous sclerosis group was 2,834 g which was slightly less than the 2,985 g for their normal sibs. The frequency of low birth weight, less than 2,500 g, among the children with tuberous sclerosis was 30% (7/23), which was 4 times that in the general population (p < 0.005). These facts suggest that the intrauterine growth is affected in a considerable number of the patients. Ohno K, Takeshita K, Arima M. Frequency of tuberous sclerosis in San-in District (Japan) and birth weight of patients with tuberous sclerosis. Brain Dev 1981;3:57-64
Tuberous sclerosis is one of the most frequent genetic disorders which causes epilepsy and mental retardation in early childhood. The prevalence of tuberous sclerosis has been estimated to range between one in 100,000 and one in From the Division of Child Neurology, Institute of Neurological Science, Tottori University School of Medicine, Tottori (KO, KT); Division of Child Neurology, National Center for Nervous, Mental and Muscular Disorders, Tokyo (MA).
170,000 in the general population of Caucasians [1, 2] or Chinese [3] , but there is no report on its frequency in the Japanese population. The present study was mainly devoted to estimating the prevalence of tuberous sclerosis in the Japanese population of the San-in district. At the same time, the effects of the parental age and birth order on mutation rate and the effects of the tuberous sclerosis gene on the growth and activity of the affected fetus were evaluated.
Received for Publication: November 20, 1980. Accepted for pUblication: February 9, 1981.
Subjects and Methods
Key words: Tuberous sclerosis, prevalence rate, frequency in live-births, mutation rate, birth weight. Correspondence Address: Kenzo Takeshita, MD, Division of Child Neurology, Institute of Neurological Science, Tottori University School of Medicine, Nishimachi 36, Yonago 683, Japan.
The San-in district is located in the western part of Honshu, i.e. the main island of Japan, and consists of Shimane and Tottori Prefectures. Persons with tuberous sclerosis were collected from Tottori University Hospital by surveying
the clinical records (for about the previous 10 years) of the Divisions of Child Neurology and Neurology of the Institute of Neurological Science, and the Departments of Pediatrics, Psychiatry, Dermatology, and Urology; from 10 hospitals in Shimane and Tottori Prefectures by asking pediatricians, psychiatrists, neurologists and dermatologists; and from 20 institutions for retarded children and adults in this area by examining all institutionalized patients. Diagnosis of tuberous sclerosis was made on the basis of either (a) angiofibroma of the face, (b) circumscribed hypomelanosis (naevi or hair) and nodular calcific density on skull X-ray or computer assisted tomography, or (c) cerebral biopsy specimens. This revealed 44 propositi. All propositi were classified into familial cases (familials) or sporadic cases (sporadics) depending on the presence or absence of the conditions in their parents. The relatives of familials and the children of the propositi who had married were examined as far as possible. In every case information including present address, birth place, parental age, sibships, prenatal history, and birth weight from census registers, hospital records, and/or questionnaires was obtained. The prevalence in the general population of the San-in district was evaluated by ascertaining the patients living in this area in October 1979. The frequency in live-births was calculated by ascertaining the patients born in this area. The birth order effect was studied by HaldaneSmith's method. The information on prenatal history and birth weight of affected cases was compared with that of their normal sibs and that of the general population. Result
All of the propositi, except case No 5 whose diagnosis was made on a biopsied specimen of a cerebral tumor, had clinical manifestations corresponding to the diagnostic criteria. Among the 44 propositi, there were 23 males and 21 females with a sex ratio of 1.10, and 37 patients (84%) were classified as sporadics (Table 1) and the other 7 (16%) as familials. In one family (No 38), it was very probable that the father, now dead, had angiofibroma of the face and we classified this family as a familial. In another family (No 40) the father was an epileptic and demented man with depigmented naevi on the back. Although he did not have angiofibroma 58 Brain & Development, Vol 3, No 1, 1981
of the face, retinal phacoma or calcification on skull X-rays, we considered him as a "forme fruste" and classified this family as a familial. By surveying the offspring of 4 sporadics who had children and the relatives of 6 familials, 8 patients including an affected parent were diagnosed to have tuberous sclerosis (Fig 1). A total of 52 affected individuals were ascertained in the San-in district. Age of the ascertained 49 living cases ranged between 2 years and 65 years and one or more patients were found in each five-year age group between 0 and 55 years old (Table 2). This shows the patients in this series were almost equally collected from all age groups. Mental retardation was present in 34 (65%) of the total 52 cases and 31 (70%) of the 44 propositi. Forty-two patients (81 %) of the total 52 cases and 38 (86%) of the 44 propositi presented convulsions. According to published reports [2-6] , in which the patients were collected not only from institutions for the mental defective or epileptic but also derrnatologic and ophthalmologic clinics, the frequency of mental retardation among the patients with tuberous sclerosis ranged between 61% and 73%, and that of epilepsy between 83% and 93%. The frequencies of mental retardation and epilepsy in our series are in good comparison with those of previous reports. This shows that the patients in this survey were reasonably collected also from the non-epileptic or normal intelligence population. These findings show that the results of this survey represent the general population reasonably.
Clinical Features These are summarized in Table 1 and Fig 1. Skin and hair manifestations of 26 personally examined cases and computer assisted tomographic findings of 7 affected children in this series have already been reported in detail [7, 8]. Prevalence of Living Cases in a Population Of the 52 patients 44 were living in the San-in district, which has a population of 1,380,000 (October 1979). The prevalence in the general population was 3.2 x 10-5 • Thirty-two patients out of the 44 living cases were sporadic cases (Table 2), so that the prevalence of sporadics was 2.3 x 10-5 • Taking into consideration the presence of patients who were not ascertained
by this survey and the presence of "forme fruste" cases who had been overlooked in hospitals, these values are regarded as a minimal estimation of the prevalence.
1945 (after World War II) coincided with the present address except for one case (No 25, born in Tottori and living in Shimane) and the 10 institutionalized children who moved in the district. The number of live-births in this area between 1945 and 1946 was not known because of World War II, and between 1947 and 1978 there were about 840,000 live-births in this area.
Frequency of Tuberous Sclerosis in a Series of Births The birth place of each sporadic born after Table 1 Summary of clinical data in sporadics Case No 1 (T) No 2 (0) No 3 (T) No 4 (S) No 5 (T) No 6 (T) No 7 (S) No 8 (T) No 9 (0) No 10 (S) No 11 (S) No 12 (T) No 13 (T) No 14 (T) No 15 (S) No 16 (S) No 17 (S) No 18 (T) No 19 (T) No 20 (S) No 21 (0) No 22 (T) No 23 (T) No 24 (T) No 25 (S) No 26 (S) No 27 (T) No 28 (T) No 29 (T) No30(T) No 31 (T) No 32 (T) No 33 (T) No 34 (T) No 35 (T) No 36 (T) No 37 (S)
Sex Birth M 1977 F 1977 M 1977 M 1977 F 1977 F 1976 M 1974 M 1974 F 1971 M 1971 M 1968 F 1966 M 1966 M 1965 F 1963 F 1962 M 1960 F 1959 F 1958 M 1957 M 1957 F 1957 M 1955 F 1952 F 1952 M 1952 F 1951 F 1949 M 1949 F 1948 M 1943 F 1942 F 1941 F 1936 M 1936 M 1930 M 1927
Parental age M F 27 32 21 43 26 36 29 22 40 31 31 30 26 35 31 27 28 40 27 30 19 25 23 31 31 25 33
24 26 22 26 24 29 28 21 36 30 30 30 31 34 28 30 23 34 28 28 23 29 22 26 27 21 31
37 23 34
38 23 32
22
19
Sibships P NP P NPN SPN NAAP PN P NAP P NPA NPN PNN ANP NPAAN PN PAN NNP NP ANP PN NP PN NPN P NPN NNP NP NAAAPN P NNP P NPNN PNNNN NP PNNNN NPNNNNN
AF ND MR EP CA + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +
+ + + + + + + + + + + + + + + + + + + + + + NR NR NR
+
+ + + + + + + + + + + + +
+ + + + + + + + + + + + + + + + +
+
+ + + + + + + + + + + + +
+
+
+ + + + + + + + +
-
+ + NR NR
-
+ + + + + + + + + + + + + + NE + + NE NE + NE + NE + + + NE NE NE NE NE NE NE NE NE
Others
Giant ,?ell astro. (brain, 1978) Paresis Giant cell astro. (brain, 1978)
Giant cell astro. (eye, 1973) Dwarfism
Urinary stone
Cystoadenoma (mamma, 1977) Paresis Paresis Dwarfism, Death 1970 (pneumonia) Death 1969 (accident)
Dwarfism Fibrolipoma (Kidney, 1972) Angiolipoma (Kidney, 1977)
(T) = living in Tottori, (S) = living in Shimane, (0) = living in other places, M = male, F = female, N = normal sib, P = patients, S = stillbirth, A = abortion, AF = angiofibroma of face, ND = naevus depigmentosum, MR = mental retardation, EP = epilepsy, CA = calcifications on skull X-ray or computed tomography, Giant cell astro. (brain, 1978) = operation of brain tumor in 1978 and histology revealed giant cell astrocytoma. Cystoadenoma (mamma, 1977) = operation of mammary tumor in 1977 and histology revealed cystoadenoma. NR = not recorded, NE = not examined.
Ohno et al: Frequency of tuberous sclerosis 59
No. 38 (S)
CiIq0 0 060000
[!!
I
1984-1931 (beri-beri)t
Oil!
t
J L
1954
@@@O
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. l
1927 1929
o e 0
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~ 1944 (accident in
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e
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'" 1965 ,1967 1968 (dwarfism) No. 34 (T)
9T
O
1961-'62 (pneumonia)t
delivery)t
.,
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1974
No. 36 (T)
roooo
'" 1936
~Io ~ ~
1967 1970 1973
01 0
(diphtheria)t
1953",19541958
No. 33 (T)
No. 44 (0)
No. 42, 43 (S)
No. 41 (S)
'" 1941
~
",.1947
1971 1974 1974 1978
1963
O(!!
0000
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19431946",1948
(ileus)t
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No. 40 (S)
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No. 39 (S)
OrO ~ 0000
h
'" 1930
1956-'72 1959 (renal insufficiency)t
o [)
00000
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I
[] 0 fil 0
1938 1940 1944 1947
Fig 1 Pedigrees of familial cases and sporadic cases who had children, (8), (T), (0) =living in 8himane (8),
Tottori (T), or others (0). 0 = male, 0 = female, .,.0 = propositus, Dt =deceased, ~ =angiofibroma of face, ~ = naevus depigmentosum, ~ = epilepsy, Iil = febrile convulsion during childhood, I!J =severe mental retardation, EJ = mild mental retardation,
Except for the 7 sporadic cases born before 1946, there were 27 births of sporadics between 1947 and 1978. In addition, 2 children borne by a mother with tuberous sclerosis (No 33) had angiofibroma and 5 propositi of familials (Nos 39 to 43) were born in this area during this period. Then a total of 34 births occurred between 1947 and 1948, and the frequency of tuberous sclerosis in the series of live-births was 4.0 x 10-5 and that of sporadics was 3.2 x 10- 5 (Table 3). This is also considered to be minimal.
Table 2 Age distribution of ascertained living cases Age (years)
0- 5 6-10 11-15 16-20 21-25 26-30 31-35 36-40 41-45 46-50 51-55 56Total
60 Brain & Development, Vol 3, No 1,1981
No of case (sporadics) Living in 8himane and Tottori 7
2
7
4 5 5 3 3 2 1 3
2 44
(7)
(1) (4) (4) (4) (5)
Living in others
1 2
(1)
1
(1)
5
(3)
(1)
(1)
(2) (2) (1) (1) (32)
Table 3 Frequency of tuberous sclerosis in live-births (1947-1978, Shimane and Tottori) Year of birth
No of cases (sporadics)
Total live· births (Shimane and Tottori)
1947-50 1951-60 1961-70 1971-78
5 (3) 11 (10) 9 (6) 9 (8)
192,378 293,411 198,525 156,679
34 (27)
1947-78
Frequency (sporadics) 2.6 3.7 4.5 5.7 4.0
840,993
x x x x x
10-5 10-5 10-5 10-5
(1.6 (3.4 (3.0 (5.1
x
x
10-5 ) 10-5 ) 10-5 ) 10-5 )
5
(3.2
x
10-5 )
10-
x x
Table 4 Maternal age of sporadics Maternal age -19 Sporadics
= 31) (N = 31)
(N
Controls (517816)
0.31 (5153)
40-
20-24
25-29
30-34
35-39
9
10
9
2
0
8.86 (147954)
14.40 (240521)
5.80 (96965)
1.45 (24183)
0.18 (3040)
Mutation Rate The sporadics who are indistinguishable clinically from the familials are regarded as a fresh mutation that arose in the germ cell of a parent. A direct estimation of mutation rate results in % x 3.2 X 10-5 = l.6 X 10-5 per gene per gene· ration. This is also minimal. Birth Order and Parental Age Contrary to the findings for other dominant diseases such as neurofibromatosis (9), the role of increased parental age in the occurrence of tuberous sclerosis mutants had not been demonstrated [2, 10]. Maternal ages at birth of 31 sporadics were compared with those of the general population in the San-in district between 1954 and 1976 (Table 4). The maternal age for children born before 1953 was not registered in this area and the ratios of the five-year age groups were almost the same in the period from 1954 to 1976, so we used the maternal age between 1954 and 1976 as a control. The frequency of the sporadics borne by mothers over 30 years of age was slightly higher than that of the controls, but not signifi· cantly (X2 = 2.256, P < 0.1). The mean mater· nal age at birth of the sporadics (N = 29: Nos 1-28 and No 30) was 27 .65 and that of their
Table 5 Prenatal history and birth weight Affected Normal sibs (N = 32) (N = 32) Poor fetal movement* Threatened abortion . Early rupture of amnion Asphyxia Low birth weight <2,500 g Mean birth weight
4 3 4 3 8 2,834 g
o 1 1 1
2,985 g
*A1though fetal mpvements are subjective feeling, in questionnaires three types of answer were indicated: 1) felt movements with or without kicking of fetus; 2) did not feel any movements of fetus; 3) stopped movements during course of pregnancy. We defined the latter two answers as poor.
normal sibs (N = 30) was 27.23 with a difference of + 0.42. The mean birth paternal age of sporadics was 29.62 and that of the normal sibs was 30.10 with a difference of -0.48. These results were considered to be inSignificant. Birth order was obtained for all sporadics and the birth order effect was examined by HaldaneSmith's test [11], which indicated no significant deviation from the theoretical expectation, i.e. observed 6A =420 and theoretical 6A = Ohno et al: Frequency of tuberous sclerosis 61
+1. 5
3500g
...........•.
3000g
2500g
.......
...............
2000g
1500g
..a:a . .... ~
",-
. .....
..
.~
... ,.
.... ,
sn*
1.-· """:1:';' SD'"
•....
--.- .....
........... 34
35
36
37
38
39
40
41
42
43
44
45
weeks
term of pregnancy
*
by Funakawa 1964
(22)
Fig 2 Birth weigh t and length of gestation
426 ± 31.89. Prenatal History and Birth Weight To determine the prenatal effects of the tuberous sclerosis gene on the fetus, exact information on prenatal history and birth weight was obtained for 32 patients and 32 normal sibs including 3 familials. Histories of threatened abortion, poor fetal movements, early rupture of the amnion and neonatal asphyxia were high in children with tuberous sclerosis (Table 5). The mean birth weight for the tuberous sclerosis group was 2,834 g, which is slightly less than the mean birth weight for normal sibs; 2,985 g (Table 5). The incidence of low birth weight, less than 2,500 g, was 25% (8/32) (Fig 2). The incidence of low birth weight for the general population of Tottori between 1956 and 1977, which had not been registered before 1955, was 7.5% (about 15,000/198,000 live-births). Except for the patients born before 1955, the frequency of low birth weight in patients with tuberous sclerosis was 30% (7/23), which was 4 times greater than that of the general popUlation (X2 = 22.98, p < 0.005). These results appeared to indicate that the intrauterine growth and activity were affected in a considerable number of the patients, which may explain the high frequency of dwarfism among the children with tuberous sclerosis, Le. 9% (4/44 propositi).
Discussion The problem in the genetic study of tuberous sclerosis is the variable expression of this con62 Brain & Development, Vol 3, No 1, 1981
dition, especially the presence of a milder form, "forme fruste." Detection of the milder form or diagnosis in early childhood are necessary to allow precise genetic study. Hypomelanotic macules have been recognized as an important early sign of tuberous sclerosis [12-14]. This lesion has occasionally a characteristic shape, oval or leaf-shaped, and histology reveals distinctive features; number of melanocyte normal, decrease in size of melanosome, decrease in melanization of melanosome and so on [14, 15]. This is of considerable diagnostic value, however, without histology, the usefulness in the diagnosis of isolated cases who have no other signs of tuberous sclerosis remains uncertain. Intracranial calcification has been reported to be another characteristic finding of tuberous sclerosis. The calcifications at the walls of the ventricular system seen on computer assisted tomography have been reported to be useful for early diagnosis of patients and for the detection of milder forms [8, 16]. Similar calcifications may be found in other diseases which cause epilepsy and mental retardation such as congenital toxoplasmosis. The diagnosis of an isolated case who has intracranial calcification without any other signs of tuberous sclerosis also remains uncertain. However, we considered a case with periventricular calcification and circumscribed hypomelanosis during childhood was most probably tuberous sclerosis, and we used this combination of features as a diagnostic criterion for ascertaining affected children before the appearance of angiofibroma of the face. As another possibility for early diagnosis or detection of milder forms, Rundle [17] reported that serum alpha-2-macroglobulin is significantly high in affected cases and suggested it to be useful for genetic counceling. We have preliminarily measured serum alpha-2macroglobulin of 17 affected children under 15 years old. There is no significant difference between patients and age-matched controls (data unpublished). Serum alpha-2-macroglobulin is considered to be of no use for the early diagnosis or the detection of milder forms during childhood. There have been several popUlation studies of tuberous sclerosis in the past. Population surveys in certain geographical areas were conducted by Stevenson and Fisher [1] , Nevin and Pearce [2] and Singer [3]. Their estimates of prevalence were one in 150,000 of the general
population of Northern Ireland, one in 100,000 of that of the Oxford Regional Hospital area, and one in 170,000 of the Chinese population of Hong Kong, respectively. The prevalence in the general population of the San-in district was about one in 31,000 (3.2 x 10-5 ), which was the highest value among the surveys in certain geographical areas. However, all these rates represent minimal estimates of true prevalence since many cases with mild or no clinical manifestations were undoubtedly overlooked in these surveys and, due to this, the prevalence rates for comparative purposes may not always be meaningful. Indeed, the prevalence rates indirectly estimated by the incidence of tuberous sclerosis among mental deficients were higher than these prevalence rates observed by actual population surveys; one in 30,000 of the general population of England [18], one in 20,000 to 40,000 in North Carolina [19] and one in 23,000 in Poland [10]. The prevalence rate in this study on the Japanese population is rather comparable to these indirectly estimated prevalence rates of Caucasians. Although the first sign of tuberous sclerosis usually appears during childhood, affected cases have been found among stillbirths and newborns. All cases detected within the first week after birth were pathologically diagnosed by the typical tubers on the brain [20, 21]. Periventricular tubers can occasionally be detected by computer assisted tomography even in infancy. These facts ·suggest that the brain lesion of tuberous sclerosis is formed in the embryonic life or in the early stage of life. Because of this we are interested in the condition of affected cases during the prenatal and perinatal periods. The present data revealed that the frequency of low birth weight, less than 2,500 g, was significantly high among patients with tuberous sclerosis and the frequency of prenatal and perinatal troubles of affected cases was higher than that of normal sibs. These facts may suggest that the tuberous sclerosis gene tends to interfere with fetal growth and activity. Acknowledgments We are grateful to the many doctors and teachers who provided us with the facilities for surveying and examining the patients under their care. Index patients were collected from many sources as follows: Division of Neurology (Nos 24, 25, 30, 39), Department of Psychiatry (Nos 23, 26, 29, 31, 38, 41), Pediatrics
(Nos 18, 24, 26), Dermatology (Nos 12, 15, 19, 26, 29, 31, 33, 34), Urology (Nos 36, 37), Division of Child Neurology (Nos 1-15,17,21,44), Tottori Univ. Hosp.; Izumo Prefectural Central Hosp. (Nos 4, 20, 40); Koryo Hosp. (No 43); Matsue Red Cross Hosp. (No 26); Hamada National Hosp. (No 10); Tottori Prefectural Central Hosp. (No 14); Kurayoshi Kousei Hosp. (No 3); Yonago National Hosp., Kurayoshi Hosp. (Nos 18, 32, 35); Tottori Red Cross Hosp., San-in Rosai Hosp., National Sanatorium Matsue Hosp. (Nos 15, 28); National Sanatorium Tottori Hosp. (Nos 12, 27, 28); Sazanami-Gakuen (Nos 16, 17,42); Matsue-Gakuen, Yasugi-Gakuen, Suginoko-Gakuen, Kurumi-Gakuen, Hamada-Gakuen, Kokubu-Gakuen, Kaisei-Gakuen, 1st and 2nd Shikano-Kachimien (No 22); Matsuno-Seibo-Gakuen (No 14); Mominokien, Kezin-Kaikan (No 35); Kibohno-Ie, Kohfuen, Kuwanokien, Ryokufuen, and Oh-hiraen (No 32). And we are also grateful to the many patients and their parents for answering our questions and questionnaires, and for giving their permission for examination. This investigation was aided by a grant from the Ministry of Health and Welfare of Japan for the Handicapped Children.
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Ohno et al: Frequency of tuberous sclerosis 63
13. 14.
15.
16.
Fukuyama Y. Clinical observation of phacomatosis in infancy and childhood. Pediatr Univ Tokyo 1964;10:3541. Gold AP, Freeman JM. Depigmented naevi: the earliest sign of tuberous sclerosis. Pediatrics 1965 ;35: 1003-5. Fitzpatrick TB, Szabo G, Hori Y, Shimone AA, Reed WB, Greenberg MH. White leaf-shaped macules. Earliest visible sign of tuberous sclerosis. Arch DermatoI1968;98:1-6. Jimbow K, Fitzpatrick TB, Szabo G, Hori Y. Congenital circumscribed hypomelanosis: a characterization based on electron microscopic study of tuberous sclerosis, naevus depigmentosum, and piebaldism. J Invest Dermatoll975;64:50-62. Gomez MR, Mellinger JF, Reese DF. The use of computerized transaxial tomography in the diagnosis of tuberous sclerosis. Mayo Clin Proc 1975; 50:553-6.
64 Brain & Development, Voll, No 1, 1981
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