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The fetal alcohol syndrome in Japan
The Fetal Alcohol Syndrome in Japan Harumi Tanaka, MD, Masataka Arima, MD and Nobuyuki Suzuki, MD In this retrospective study, the clinical findings of 26 cases borne by alcoholic mothers in Japan are summarized. The information on maternal alcohol drinking and abnormal offspring wqs gathered by a questionnaire survey. Twenty cases, mostly in institutions for mental retardation, were checked from all areas of Japan. Six children from another group were followed during health examinations of children in a selected area with many heavy drinkers. Growth deficiency was found in half of these cases with an increased rate of low birth weight babies (42% of cases) including small-for-date babies (23% of cases). More than 90% of these cases were in the retarded range of intelligence, 50% of which had IQ scores of 51-75. Gross motor development was also delayed. In all of the 6 follow-up cases, craniofacial anomalies such as hypoplastic nose and philtrum, narrow lip vermilion and short palpebral fissures were observed, although these facial features were mild. An aberrant palmar crease was seen with high frequency. CT of 3 cases did not show constant findings. The mothers were said to have drunk about 0.41 or more of 'sake' or whisky daily (average 110 ml of absolute alcohol) throughout. pregnancy. Although typical cases of the fetal alcohol syndrome are less than one-third, this report provides evidence for the presence of mentally retarded children borne by alcoholic mothers in Japan and should alert many medical professionals to this problem. Tanaka H, A rima M, Suzuki N. The fetal alcohol syndrome in Japan. Brain Dev 1981;3:305-11
From the Division of Child Neurology, National Center for Nervous, Mental and Muscular Disorders, Kodaira, Tokyo.
400 case reports have been published in the medical literature [3,4], we do not know the reports from Asian countries. In Japan, only two patients with F AS from one family were reported before this study [5]. The purpose of this report is to'show evidence for the presence of abnormal children borne by alcoholic mothers in Japan and to elucidate the diagnostic features including those of CT scans. This report also should alert many medical doctors and other health professionals to the relationship between unknown mental retardation and maternal alcoholism in Japan, where alcohol consumption is increasing year by year.
Received for pUblication: December 28, 1980. Accepted for pUblication: May 25, 1981.
Subjects and Methods
The fetal alcohol syndrome (F AS) has been recognized in the offspring of alcoholic women, and was first noted by Lemoine et al from France [1] and Jones et al from the United States [2]. The abnormalities can be grouped into four categories, central nervous system dysfunctions, growth deficiencies, characteristic facial anomalies and variable major and minor malformations. Although in America, Canada, and African and European countries, more than
Key words: Mental retardation, growth deficiency, craniofacial anomalies, dermatoglyphics, maternal alcoholism, embryopathy, [etopathy. Correspondence address: Dr. Harumi Tanaka, Division of Child Neurology, National Center for Nervous, Mental and Muscular Disorders, 2620 Ogawa-HigashiMachi, Kodaira, Tokyo 187, Japan.
Information on children with this syndrome was collected in two ways. One retrospective information on maternal alcohol drinking and abnormal offspring was obtained with questionnaires from all areas of Japan from September 1978 to March 1979 [6]. The first question-
naires were sent to 2,573 hospitals with more than 300 beds and institutions such as those for mentally retarded or double handicapped children. According to the second questionnaires, 20 cases borne by alcoholic mothers from 13 hospitals and institutions were checked including the two cases described by Takashima et al [5] . Twenty cases were diagnosed by detecting 2 or more of 3 abnormalities such as growth retardation, central nervous system involvement and minor and major anomalies including cranifacial dysmorphology. Other cases borne by alcoholic mothers who are still being followed by us were obtained from a retrospective study in a selected area with many heavy drinkers and were examined clinically by us from January 1979 to December 1980. Six cases with fetal alcohol effects were detected in this study. Data on 20 cases and their mothers were sent to us by doctors, other professionals and social workers from all areas of Japan. Data on mothers of the 6 children examined by us were reported by social workers and public health nurses as well as the mothers themselves.
Results The abnormalities observed in 20 children borne by alcoholic women from all areas of Japan are presented in Table 1. The cases ranged in age from 1 to 19 years. Craniofacial anomalies
include midface hypoplasia, small upturned nose, narrow lip vermilion and short palpebral fissures. Other abnormalities observed in these children are cardiac defects, cleft palate, abnormal dermatoglyphics, phalangeal hypoplasias, limited extension of elbow, convulsion, hyperactivity, hypotonicity and hemiparesis. Ninetyfive-percent of the cases were in the retarded range of intelligence. Pre- and postnatal growth Table I Abnormalities observed in 20 patients borne by alcoholic women from all areas of Japan (age range 1-19 years) No of affected cases (%) Sex Male Female
13 (65) 7 (35)
Abnormality Growth deficiency* Prenatal Postnatal Microcephaly * Mental retardation ** Craniofacial anomalies Others
9 (45) 10 (50) 6 (30) 19 (95) 7 (35) 13 (65)
* 2 SD or more below the normal for age. ** Mental retardation was estimated by IQ scores below 75.
Table 2 Abnormalities in our 6 follow-up cases Case no Sex
21
24
25
28
31
32
M
F
F
M
M
M
4
1
6
4
4
+ +
+ + +
Age (yrs) Growth deficiency* Prenatal Postnatal Microcephaly * Mental retardation** Craniofacial anomalies Otherst
+ + + + + +
+ +
?
+ +
* 2 SD or more below the normal for age. ** Mental retardation was estimated by IQ scores below 75.
+ + +
+ + +
No of affected cases (%)
+ + +
t Others include aberrant palmar crease, hyperactivity and trllmor in fmgers in case 21, aberrant palmar crease, high-arched palate and depigmented macula in case 25, aberrant palmar crease, narrow palate, short frenulum of tongue, thin ear lobe, asymmetrical cranium and thorax, hypoplastic nipples, retentio testis, no proximal flexion crease of the 5th finger, hyperactivity and clumsiness in case 28, aberrant palmar crease, notching of uvula, asymmetrical cranium and ptosis, and strabismus in case 31, and aberrant palmar crease and strabismus in case 32.
306 Brain & Development, Vol 3, No 3,1981
3 3 2 5 6 5
( 50) ( 50) ( 33) ( 83) (100) ( 83)
••• ....
d
Fig 1 Faces of children borne by alcoholic mothers. a: case 21 , b: case 28, c: case 31, and d: case 32. Note a short and upturned nose with small nostrils and alae and low nasal bridge, short palpebral fissures in a, hypoplastic philtrum and nose in b, c, and d, strabismus in c and d, an asymmetrical ptosis in c, and thinned upper-lip vermilion in d.
I Q scores
Fig 2 IQ scores and motor development in 24 mentally retarded children borne by alcoholic women. IQ scores divided into four groups except for unknown. .. represents very low IQ score which could not be estimated.
Table 3 Birth weight in 26 children borne by alcoholic women No of cases (%)
Low birth weight «2,500g)
+
(~~
Unknown Unknown
1
6 (23) ] 3 (12) 47% 3 (12)
12 (46) 2 ( 8)
SFD: small-for-date infants, AFD: appropriate-fordate infants.
deficiencies were found in half of these cases. Microcephaly and craniofacial anomalies were found in only one-third. The most frequent clinical findings in our 6 follow-up cases are also presented in Table 2. In these follow-up cases, as expected, the frequency of minor craniofacial anomalies increased to 100%. Five of the 6 cases have other abnormalities which include minor and major anomalies except for characteristic craniofacial anomalies, and all 5 cases showed an aberrant palmar crease_ Half of the 6 cases did not show growth deficiency in either the pre- or the postnatal period. In our 6 cases, only case 21 was diagnosed with full external criteria as the typical fetal alcohol syndrome. Case 21 is summarized briefly below_ Case 21; a boy, aged 22 months old now, was borne by a 39-year-old chronic alcoholic mother, who died of alcoholism two years later. The birth weight was 1,900 g after 32 weeks gestation. He walked at 12 months but he was unable to say a word at 22 months of age. He had a short and upturned nose with small nostrils and alae, low nasal bridge, and short palpebral fissures as typical mild craniofacial anomalies (Fig la). There. were also an aberrant palmar crease, hyperactivity and mild fine tremor in the fingers. His gait was awkward with walking on toes and bending trunk forward. Characteristic facial features shared by 4 follow-up children are illustrated in Fig 1. A hypoplastic nose in all cases, hypoplastic philtrum in 3 cases, short palpebral fissures in I case and upper lip with narrow vermilion border in 1 case were noted. As an indicator of prenatal growth deficiency, the birth weight of 26 children borne by alcohol-drinking women is summarized (Table 3). Low birth weights of less than 2,500 g were seen in 47% of the cases and small-for-date infants in 23 %. As central nervous system dysfunctions, IQ scores and motor development in 24 mentally retarded children from our 26 cases are illustrated in Fig 2. Fifty percent of the mentally retarded children borne by alcoholic mothers fall in the IQ range of 51 to 75. The mean month of age for walking alone was also delayed, and the more the motor development was delayed, the lower the IQ scores; 45 months for a very low IQ, 34 months for an IQ range of Tanaka et al: The fetal alcohol syndrome 307
a to 20, 23 months for 21 to 50, and 19 months
for 51 to 75. In our follow-up cases, delayed speech, clumsiness and hyperactivity were commonly noted as neurological symptoms. Cranial computed tomography (CT) was performed for cases 21, 28 and 31 (Fig 3). Greater structural alteration was not observed in the brain. There was slight cortical atrophy by the
enlarged interhemispheric fissure. Slight enlargement of the right lateral ventricle was also demonstrated in case 31, although no neurological findings were seen. Dermatoglyphic abnormalities in 3 male follow-up cases are illustrated in Fig 4. Ulnar loop/whorl in the patterns of fingertips was 6/4 in case 21,,3/6 in case 28, and 8/2 in case
a
b
c
Fig 3 CTscans of children borne by alcoholic mothers. a: case 21. b: case 28. and c: case 31. An
asymmetrical cranium is present in band c. The slightly enlarged frontal interhemispheric fissure in b and the slightly dilated right lateral ventricle in c are demonstrated.
308 Brain & Development. Vol 3, No 3,1981
31. Increased proportions of whorls and radial loop on the right 5th finger were observed as well as both t" and an absent proximal flexion crease on the 5th finger in case 28. An abnormal palmar crease was also found; a simian crease in case 21, a Sydney crease in case 28, and a distal palmar crease formed unusually deep furrows between the second and third fingers in 4 hands of the 3 cases. In the hallucal areas, a distal loop was observed in all 6 feet of the 3 cases. Maternal alcoholic history as well as general background information on our 6 follow-up cases are outlined in Table 4. They drank about 0.4 L of whisky or 'sake' (average 110 mL of absolute alcohol) or more daily throughout pregnancy. About half of these mothers were reported to be chronically alcoholic. Five of the 6 mothers had been drinking for longer than 3 years before pregnancy. The mean maternal age at birth was 35 years. Four of the 6 mothers had abnormal histories of other pregnancies such as prematurity, stillbirth and malformed children. Only 2 mothers were smokers. We concluded that most cases listed in this report in Japan were atypical FAS because of the absence of the full abnormalities such as growth retardation, central nervous system involvement and characteristic facial dysmorphology. Discussion Principal and associated clinical features of F AS observed in 245 affected persons were summarized by Clarren et al [4]. There is a wide
spectrum of effects of alcohol on the fetus and they described that at the most severe end of the spectrum are patients with the unique constellation of anomalies initially termed "fetal alcohol syndrome." Based on this concept, our Japanese cases tended to show mild effects of maternal ethanol consumption. The two cases reported by Takashima et al [5] are also atypical cases as they had no pre- or postnatal
Fig 4 Dermatoglyphic representation in 3 children borne by alcoholic mothers. a: case 21, b: case 28, and c: case 31. Note the simian crease in a, the left Sydney crease, both t", radial loop of the right 5th finger and no proximal flexion crease of the left 5th finger in b, and thf! unusually deep furrow of the distal transverse crease between the 2nd the 3rd fingers in a, band c.
Table 4 Maternal history in our 6 cases Case no
21 History of alcoholism Duration before pregnancy (yrs) Alcohol consumption during pregnancy (ml of absolute alcohol/day or week) Maternal age at birth (yrs) Abnormal history of other pregnancies Tobacco use
24
25
28
CA CA ? >5 >3 >3 Sake, beer Sake Whisky Sake 240 ml/d >155 ml/d >45 ml/w >75 ml/d 38 31 30 39 + + Smoker Smoker
31
32
CA OA >5 >5 Sake Sake, beer >75 ml/d >45 ml/d 40 32 +
CA: chronic alcoholics, OA: occupational alcoholics. Abnormal history of other pregnancies include stillbirth in case 21, abortion and a child with malformation in case 25 and a child with Down syndrome in case 32. Cases 28 and 31 are sibs.
Tanaka et al: The fetal alcohol syndrome 309
growth deficiency. These mild signs and symptoms and that the affected children usually are in homes for mentally retarded children might be the reasons why we could not recognize the adverse effects of maternal alcohol consumption on the fetus until quite recently in Japan. Most infants with F AS are deficient at birth in both height and weight. Early reports described that the degree of linear growth deficiency was more severe than the deficiency of weight at birth, and that none of the patients showed catch-up growth [2]. But it has been recognized that both findings are not always true [4]. Some affected children have shown normal prenatal growth although a typical facial appearance and microscopic brain malformations were observed [4, 7]. The affected children borne by chronic alcoholic mothers show typical and complete features of F AS, but it is also true that there are some timing discrepancies between growth and mental deficiency in these children as shown by Little [8]. He reported that ingestion of an average of 1 ounce of absolute alcohol daily, before pregnancy and in early and late pregnancy was associated with an average decrease in birth weight of 91 g, 95 g and 160 g, respectively. On the other hand, Streissguth et al [9] demonstrated that mental and motor development at 8 months of age was Significantly related to maternal alcohol use during early pregnancy. And also Hanson et al [10] indicated that both moderate and high levels of alcohol intake during early pregnancy may result in alteration of growth and morphogenesis of the fetus. The incidence of low birth weight in our cases was 47% and this was significantly higher than that for other mental deficiencies of prenatal origin in Japanese, 10 to 15%. Mental retardation is one of the most common and serious problems associated with ethanol teratogenicity. Smith et al stressed that F AS has become the third ranking recognized disorder in which mental deficiency is a feature [11]. It was also mentioned that offspring of chronically alcoholic women may have impaired intellectual functions without structural manifestations of F AS and that the grade of mental retardation in F AS ranged from mild to moderate [12, 13]. They also had delayed growth and fine motor development [2, 12]. The mild to moderate retardation of intelligence and delayed mean month of age for walk310 Brain & Development, Vol 3, No 3,1981
ing alone in the children borne by alcoholic mothers observed in our study agreed with the above reports. In our study it was remarkable that the more the motor development was delayed, the lower the IQ scores. The distinctive face in F AS characterized by short palpebral fissures, a hypoplastic upper lip with thin vermilion, a hypoplastic nose and diminished to absent philtrum was slight to mild in alteration in our cases. On the other hand, dermatoglyphic abnormalities and other minor anomalies were more frequently observed in our cases than control patients. In this report we illustrated only male dermatoglyphics as an example because male and female children differed in several dermatoglyphic characteristics [14]. Dermatoglyphic abnormalities in our cases almost agreed with other reports [2, 14-16], although the proximal transverse crease was not clearly hypoplastic. Abnormal dermatoglyphics and increased minor anomalies in our cases may suggest the presence of a toxic effect of alcohol drinking during the period of' active morphogenesis. The more phenotypically involved patients have lower IQ scores [4], and the structural alterations have been demonstrated in the brain of fetuses and infants exposed to alcohol in utero [7, 17]. Demonstrated abnormalities in these cases were neurological heterotopias in the leptomeninges, a disorganized arrangement of the neuronal elements, and an obstructive hydrocephalus internus [7], and a wide spectrum of disorders ranging from severe dysraphic state, arhinencephaly, porencephaly, agenesis of the corpus callosum, and from hydranencephaly to microdysplasias [17, 18]. In our CT findings which were the first reported in cases with F AS, only mild alterations were seen. The asymmetrical cranium and ventricular system or asymmetrical minor anomalies which were observed in our cases may also be one of the features of the effect of the toxic agent in utero. To elucidate the central nervous system dysfunctions in F AS, several animal models were used [19, 20]. In rat models decreased 14 C-Ieucine incorporation into cerebral ribosomes and impaired formation of transfer RNA in brain [21] and decreased total RNA levels in brain, heart, liver and kidney [22] were reported. Chernoff reported recently that prenatal death, malformations and fetal weight in mouse were directly related to maternal blood
alcohol levels [23]. Recently we observed hypoglycemia in fetal rats born to ethanolexposed dams, Which may be a cause of central nervous system dysfunctions in F AS [in press] . Although typical cases of F AS in our report are a few and the mechanisms of mental retardation induced by maternal ethanol consumption remain unclear, we demonstrated at least evidence for the presence of mentally retarded children borne by alcoholic mothers in Japan. It is believed that the number of chronically alcoholic women in Japan is smaller than that in Western countries. The recent trend of increasing alcohol consumption by young Japanese women necessitates serious consideration for the prevention of F AS. Acknowledgments We thank the many doctors and other health professionals whose efforts and understanding of the problems of alcohol-drinking mothers made possible the accumulation of much of these data. This study was supported by Grant No. 80-07-07 from the National Center for Nervous, Mental and Muscular Disorders (NCNMMD) of the Ministry of Health and Welfare, Japan. References 1. Lemoine P, Harousseau H, Borteyru J-P, Menuet J-C. Les enfants de parents alcooliques. Anomalies observees. A propos de 127 cas. Quest Med 1968;25:476-82. 2. Jones KL, Smith DW, Ulleland CN, Streissguth AP. Pattern of malformation in offspring of chronic alcoholic mothers. Lancet 1973;1:126771. 3. Majewski F, Fischbach H, Peiffer J, Bierich JR. Zur Frage der Interruptio bei alkoholkranken Frauen. Dtsch Med Wochenschr 1978; 103:8958. 4. Clarren SK, Smith DW. The fetal alcohol syndrome. N Engl J Med 1978;298:1063-7. 5. Takashima H, Baba K, Kunugida F. One family of the fetal alcohol syndrome in Japan (in Japanese). Alcohol Res (Tokyo) 1978;13:102-3. 6. Tanaka H, Arima M, Ishizuka H, Suzuki N, Takashima H. The fetal alcohol syndrome in Japan (in Japanese). Jpn Med J (Tokyo) 1979; 2897:27-30. 7. Clarren SK, Alvord EC, Sumi SM, Streissguth AP, Smith DW. Brain malformations related to prenatal exposure to ethanol. J Pediatr 1978;92: 64-7.
8. Little RE. Moderate alcohol use during pregnancy and decreased infant birth weight. Am J Public Health 1977;67:1154-6. 9. Streissguth AP, Barr HM, Martin DC, Herman CS. Effects of maternal alcohol, nicotine, and caffeine use during pregnancy on infant mental and motor development at eight months. Alcoholism: Clin Exp Res 1980;4:152-64. 10. Hanson JW, Streissguth AP, Smith DW. The effects of moderate alcohol consumption during pregnancy on fetal growth and morphogenesis. J Pediatr 1978;92:457-60. 11. Smith DW, Jones KL, Hanson JW. Perspectives on the cause and frequency of the fetal alcohol syndrome. Ann NY A cad Sci 1976;273:138-9. 12. Streissguth AP. Psychologic handicaps in children with the fetal alcohol syndrome. Ann NY Acad Sci 1976;273:140-5. 13. Streissguth AP, Landesman-Dwyer S, Martin JC, Smith DW. Teratogenic effects of alcohol in humans and laboratory animals. Science 1980;209: 353-61. 14. Qazi QH, Masakawa A, McGann B, Woods J. Dermatoglyphic abnormalities in the fetal alcohol syndrome. Teratology 1980;21:157-60. 15. Palmer RH, Ouellette EM, Warner L, Leichtman SR. Congenital malformations in offspring of a chronic alcoholic mother. Pediatrics 1974;53: 490-4. 16. Tillner I, Majewski F. Furrows and dermal ridges of the hand in patients with alcohol embryopathy. Hum Genet 1978;42:307-14. 17. Peiffer J, Majewski F, Fischbach H, Bierich JR, Volk B. Alcohol embryo- and fetopathy. Neuropathology of 3 children and 3 fetuses. J Neurol Sci 1979;41:125-37. 18. Jones KL, Smith DW. Recognition of the fetal alcohol syndrome in early infancy. Lancet 1973; 2:999-1001. 19. Tze WJ, Lee M. Adverse effects of maternal alcohol consumption on pregnancy and foetal growth in rats. Nature 1975;257:479-80. 20. Chernoff G.F. The fetal alcohol syndrome in mice. An animal model. Teratology 1977;15: 223-30. 21. Rawat AK. Ribosomal protein synthesis in the fetal and neonatal rat brain as influenced by maternal ethanol consumption. Res Commun Chem Pathol Pharmacol1975; 12:723-32. 22. Henderson GI, Schenker S. The effect of maternal alcohol consumption on the viability and visceral development of the newborn rat. Res Commun Chem Pathol Pharmacol 1977;16:1532. 23. Chernoff GF. The fetal alcohol syndrome in mice: maternal variables. Teratology 1980;22: 71-5.
Tanaka et al: The fetal alcohol syndrome 311
From the Division of Child Neurology, National Center for Nervous, Mental and Muscular Disorders, Kodaira, Tokyo.
400 case reports have been published in the medical literature [3,4], we do not know the reports from Asian countries. In Japan, only two patients with F AS from one family were reported before this study [5]. The purpose of this report is to'show evidence for the presence of abnormal children borne by alcoholic mothers in Japan and to elucidate the diagnostic features including those of CT scans. This report also should alert many medical doctors and other health professionals to the relationship between unknown mental retardation and maternal alcoholism in Japan, where alcohol consumption is increasing year by year.
Received for pUblication: December 28, 1980. Accepted for pUblication: May 25, 1981.
Subjects and Methods
The fetal alcohol syndrome (F AS) has been recognized in the offspring of alcoholic women, and was first noted by Lemoine et al from France [1] and Jones et al from the United States [2]. The abnormalities can be grouped into four categories, central nervous system dysfunctions, growth deficiencies, characteristic facial anomalies and variable major and minor malformations. Although in America, Canada, and African and European countries, more than
Key words: Mental retardation, growth deficiency, craniofacial anomalies, dermatoglyphics, maternal alcoholism, embryopathy, [etopathy. Correspondence address: Dr. Harumi Tanaka, Division of Child Neurology, National Center for Nervous, Mental and Muscular Disorders, 2620 Ogawa-HigashiMachi, Kodaira, Tokyo 187, Japan.
Information on children with this syndrome was collected in two ways. One retrospective information on maternal alcohol drinking and abnormal offspring was obtained with questionnaires from all areas of Japan from September 1978 to March 1979 [6]. The first question-
naires were sent to 2,573 hospitals with more than 300 beds and institutions such as those for mentally retarded or double handicapped children. According to the second questionnaires, 20 cases borne by alcoholic mothers from 13 hospitals and institutions were checked including the two cases described by Takashima et al [5] . Twenty cases were diagnosed by detecting 2 or more of 3 abnormalities such as growth retardation, central nervous system involvement and minor and major anomalies including cranifacial dysmorphology. Other cases borne by alcoholic mothers who are still being followed by us were obtained from a retrospective study in a selected area with many heavy drinkers and were examined clinically by us from January 1979 to December 1980. Six cases with fetal alcohol effects were detected in this study. Data on 20 cases and their mothers were sent to us by doctors, other professionals and social workers from all areas of Japan. Data on mothers of the 6 children examined by us were reported by social workers and public health nurses as well as the mothers themselves.
Results The abnormalities observed in 20 children borne by alcoholic women from all areas of Japan are presented in Table 1. The cases ranged in age from 1 to 19 years. Craniofacial anomalies
include midface hypoplasia, small upturned nose, narrow lip vermilion and short palpebral fissures. Other abnormalities observed in these children are cardiac defects, cleft palate, abnormal dermatoglyphics, phalangeal hypoplasias, limited extension of elbow, convulsion, hyperactivity, hypotonicity and hemiparesis. Ninetyfive-percent of the cases were in the retarded range of intelligence. Pre- and postnatal growth Table I Abnormalities observed in 20 patients borne by alcoholic women from all areas of Japan (age range 1-19 years) No of affected cases (%) Sex Male Female
13 (65) 7 (35)
Abnormality Growth deficiency* Prenatal Postnatal Microcephaly * Mental retardation ** Craniofacial anomalies Others
9 (45) 10 (50) 6 (30) 19 (95) 7 (35) 13 (65)
* 2 SD or more below the normal for age. ** Mental retardation was estimated by IQ scores below 75.
Table 2 Abnormalities in our 6 follow-up cases Case no Sex
21
24
25
28
31
32
M
F
F
M
M
M
4
1
6
4
4
+ +
+ + +
Age (yrs) Growth deficiency* Prenatal Postnatal Microcephaly * Mental retardation** Craniofacial anomalies Otherst
+ + + + + +
+ +
?
+ +
* 2 SD or more below the normal for age. ** Mental retardation was estimated by IQ scores below 75.
+ + +
+ + +
No of affected cases (%)
+ + +
t Others include aberrant palmar crease, hyperactivity and trllmor in fmgers in case 21, aberrant palmar crease, high-arched palate and depigmented macula in case 25, aberrant palmar crease, narrow palate, short frenulum of tongue, thin ear lobe, asymmetrical cranium and thorax, hypoplastic nipples, retentio testis, no proximal flexion crease of the 5th finger, hyperactivity and clumsiness in case 28, aberrant palmar crease, notching of uvula, asymmetrical cranium and ptosis, and strabismus in case 31, and aberrant palmar crease and strabismus in case 32.
306 Brain & Development, Vol 3, No 3,1981
3 3 2 5 6 5
( 50) ( 50) ( 33) ( 83) (100) ( 83)
••• ....
d
Fig 1 Faces of children borne by alcoholic mothers. a: case 21 , b: case 28, c: case 31, and d: case 32. Note a short and upturned nose with small nostrils and alae and low nasal bridge, short palpebral fissures in a, hypoplastic philtrum and nose in b, c, and d, strabismus in c and d, an asymmetrical ptosis in c, and thinned upper-lip vermilion in d.
I Q scores
Fig 2 IQ scores and motor development in 24 mentally retarded children borne by alcoholic women. IQ scores divided into four groups except for unknown. .. represents very low IQ score which could not be estimated.
Table 3 Birth weight in 26 children borne by alcoholic women No of cases (%)
Low birth weight «2,500g)
+
(~~
Unknown Unknown
1
6 (23) ] 3 (12) 47% 3 (12)
12 (46) 2 ( 8)
SFD: small-for-date infants, AFD: appropriate-fordate infants.
deficiencies were found in half of these cases. Microcephaly and craniofacial anomalies were found in only one-third. The most frequent clinical findings in our 6 follow-up cases are also presented in Table 2. In these follow-up cases, as expected, the frequency of minor craniofacial anomalies increased to 100%. Five of the 6 cases have other abnormalities which include minor and major anomalies except for characteristic craniofacial anomalies, and all 5 cases showed an aberrant palmar crease_ Half of the 6 cases did not show growth deficiency in either the pre- or the postnatal period. In our 6 cases, only case 21 was diagnosed with full external criteria as the typical fetal alcohol syndrome. Case 21 is summarized briefly below_ Case 21; a boy, aged 22 months old now, was borne by a 39-year-old chronic alcoholic mother, who died of alcoholism two years later. The birth weight was 1,900 g after 32 weeks gestation. He walked at 12 months but he was unable to say a word at 22 months of age. He had a short and upturned nose with small nostrils and alae, low nasal bridge, and short palpebral fissures as typical mild craniofacial anomalies (Fig la). There. were also an aberrant palmar crease, hyperactivity and mild fine tremor in the fingers. His gait was awkward with walking on toes and bending trunk forward. Characteristic facial features shared by 4 follow-up children are illustrated in Fig 1. A hypoplastic nose in all cases, hypoplastic philtrum in 3 cases, short palpebral fissures in I case and upper lip with narrow vermilion border in 1 case were noted. As an indicator of prenatal growth deficiency, the birth weight of 26 children borne by alcohol-drinking women is summarized (Table 3). Low birth weights of less than 2,500 g were seen in 47% of the cases and small-for-date infants in 23 %. As central nervous system dysfunctions, IQ scores and motor development in 24 mentally retarded children from our 26 cases are illustrated in Fig 2. Fifty percent of the mentally retarded children borne by alcoholic mothers fall in the IQ range of 51 to 75. The mean month of age for walking alone was also delayed, and the more the motor development was delayed, the lower the IQ scores; 45 months for a very low IQ, 34 months for an IQ range of Tanaka et al: The fetal alcohol syndrome 307
a to 20, 23 months for 21 to 50, and 19 months
for 51 to 75. In our follow-up cases, delayed speech, clumsiness and hyperactivity were commonly noted as neurological symptoms. Cranial computed tomography (CT) was performed for cases 21, 28 and 31 (Fig 3). Greater structural alteration was not observed in the brain. There was slight cortical atrophy by the
enlarged interhemispheric fissure. Slight enlargement of the right lateral ventricle was also demonstrated in case 31, although no neurological findings were seen. Dermatoglyphic abnormalities in 3 male follow-up cases are illustrated in Fig 4. Ulnar loop/whorl in the patterns of fingertips was 6/4 in case 21,,3/6 in case 28, and 8/2 in case
a
b
c
Fig 3 CTscans of children borne by alcoholic mothers. a: case 21. b: case 28. and c: case 31. An
asymmetrical cranium is present in band c. The slightly enlarged frontal interhemispheric fissure in b and the slightly dilated right lateral ventricle in c are demonstrated.
308 Brain & Development. Vol 3, No 3,1981
31. Increased proportions of whorls and radial loop on the right 5th finger were observed as well as both t" and an absent proximal flexion crease on the 5th finger in case 28. An abnormal palmar crease was also found; a simian crease in case 21, a Sydney crease in case 28, and a distal palmar crease formed unusually deep furrows between the second and third fingers in 4 hands of the 3 cases. In the hallucal areas, a distal loop was observed in all 6 feet of the 3 cases. Maternal alcoholic history as well as general background information on our 6 follow-up cases are outlined in Table 4. They drank about 0.4 L of whisky or 'sake' (average 110 mL of absolute alcohol) or more daily throughout pregnancy. About half of these mothers were reported to be chronically alcoholic. Five of the 6 mothers had been drinking for longer than 3 years before pregnancy. The mean maternal age at birth was 35 years. Four of the 6 mothers had abnormal histories of other pregnancies such as prematurity, stillbirth and malformed children. Only 2 mothers were smokers. We concluded that most cases listed in this report in Japan were atypical FAS because of the absence of the full abnormalities such as growth retardation, central nervous system involvement and characteristic facial dysmorphology. Discussion Principal and associated clinical features of F AS observed in 245 affected persons were summarized by Clarren et al [4]. There is a wide
spectrum of effects of alcohol on the fetus and they described that at the most severe end of the spectrum are patients with the unique constellation of anomalies initially termed "fetal alcohol syndrome." Based on this concept, our Japanese cases tended to show mild effects of maternal ethanol consumption. The two cases reported by Takashima et al [5] are also atypical cases as they had no pre- or postnatal
Fig 4 Dermatoglyphic representation in 3 children borne by alcoholic mothers. a: case 21, b: case 28, and c: case 31. Note the simian crease in a, the left Sydney crease, both t", radial loop of the right 5th finger and no proximal flexion crease of the left 5th finger in b, and thf! unusually deep furrow of the distal transverse crease between the 2nd the 3rd fingers in a, band c.
Table 4 Maternal history in our 6 cases Case no
21 History of alcoholism Duration before pregnancy (yrs) Alcohol consumption during pregnancy (ml of absolute alcohol/day or week) Maternal age at birth (yrs) Abnormal history of other pregnancies Tobacco use
24
25
28
CA CA ? >5 >3 >3 Sake, beer Sake Whisky Sake 240 ml/d >155 ml/d >45 ml/w >75 ml/d 38 31 30 39 + + Smoker Smoker
31
32
CA OA >5 >5 Sake Sake, beer >75 ml/d >45 ml/d 40 32 +
CA: chronic alcoholics, OA: occupational alcoholics. Abnormal history of other pregnancies include stillbirth in case 21, abortion and a child with malformation in case 25 and a child with Down syndrome in case 32. Cases 28 and 31 are sibs.
Tanaka et al: The fetal alcohol syndrome 309
growth deficiency. These mild signs and symptoms and that the affected children usually are in homes for mentally retarded children might be the reasons why we could not recognize the adverse effects of maternal alcohol consumption on the fetus until quite recently in Japan. Most infants with F AS are deficient at birth in both height and weight. Early reports described that the degree of linear growth deficiency was more severe than the deficiency of weight at birth, and that none of the patients showed catch-up growth [2]. But it has been recognized that both findings are not always true [4]. Some affected children have shown normal prenatal growth although a typical facial appearance and microscopic brain malformations were observed [4, 7]. The affected children borne by chronic alcoholic mothers show typical and complete features of F AS, but it is also true that there are some timing discrepancies between growth and mental deficiency in these children as shown by Little [8]. He reported that ingestion of an average of 1 ounce of absolute alcohol daily, before pregnancy and in early and late pregnancy was associated with an average decrease in birth weight of 91 g, 95 g and 160 g, respectively. On the other hand, Streissguth et al [9] demonstrated that mental and motor development at 8 months of age was Significantly related to maternal alcohol use during early pregnancy. And also Hanson et al [10] indicated that both moderate and high levels of alcohol intake during early pregnancy may result in alteration of growth and morphogenesis of the fetus. The incidence of low birth weight in our cases was 47% and this was significantly higher than that for other mental deficiencies of prenatal origin in Japanese, 10 to 15%. Mental retardation is one of the most common and serious problems associated with ethanol teratogenicity. Smith et al stressed that F AS has become the third ranking recognized disorder in which mental deficiency is a feature [11]. It was also mentioned that offspring of chronically alcoholic women may have impaired intellectual functions without structural manifestations of F AS and that the grade of mental retardation in F AS ranged from mild to moderate [12, 13]. They also had delayed growth and fine motor development [2, 12]. The mild to moderate retardation of intelligence and delayed mean month of age for walk310 Brain & Development, Vol 3, No 3,1981
ing alone in the children borne by alcoholic mothers observed in our study agreed with the above reports. In our study it was remarkable that the more the motor development was delayed, the lower the IQ scores. The distinctive face in F AS characterized by short palpebral fissures, a hypoplastic upper lip with thin vermilion, a hypoplastic nose and diminished to absent philtrum was slight to mild in alteration in our cases. On the other hand, dermatoglyphic abnormalities and other minor anomalies were more frequently observed in our cases than control patients. In this report we illustrated only male dermatoglyphics as an example because male and female children differed in several dermatoglyphic characteristics [14]. Dermatoglyphic abnormalities in our cases almost agreed with other reports [2, 14-16], although the proximal transverse crease was not clearly hypoplastic. Abnormal dermatoglyphics and increased minor anomalies in our cases may suggest the presence of a toxic effect of alcohol drinking during the period of' active morphogenesis. The more phenotypically involved patients have lower IQ scores [4], and the structural alterations have been demonstrated in the brain of fetuses and infants exposed to alcohol in utero [7, 17]. Demonstrated abnormalities in these cases were neurological heterotopias in the leptomeninges, a disorganized arrangement of the neuronal elements, and an obstructive hydrocephalus internus [7], and a wide spectrum of disorders ranging from severe dysraphic state, arhinencephaly, porencephaly, agenesis of the corpus callosum, and from hydranencephaly to microdysplasias [17, 18]. In our CT findings which were the first reported in cases with F AS, only mild alterations were seen. The asymmetrical cranium and ventricular system or asymmetrical minor anomalies which were observed in our cases may also be one of the features of the effect of the toxic agent in utero. To elucidate the central nervous system dysfunctions in F AS, several animal models were used [19, 20]. In rat models decreased 14 C-Ieucine incorporation into cerebral ribosomes and impaired formation of transfer RNA in brain [21] and decreased total RNA levels in brain, heart, liver and kidney [22] were reported. Chernoff reported recently that prenatal death, malformations and fetal weight in mouse were directly related to maternal blood
alcohol levels [23]. Recently we observed hypoglycemia in fetal rats born to ethanolexposed dams, Which may be a cause of central nervous system dysfunctions in F AS [in press] . Although typical cases of F AS in our report are a few and the mechanisms of mental retardation induced by maternal ethanol consumption remain unclear, we demonstrated at least evidence for the presence of mentally retarded children borne by alcoholic mothers in Japan. It is believed that the number of chronically alcoholic women in Japan is smaller than that in Western countries. The recent trend of increasing alcohol consumption by young Japanese women necessitates serious consideration for the prevention of F AS. Acknowledgments We thank the many doctors and other health professionals whose efforts and understanding of the problems of alcohol-drinking mothers made possible the accumulation of much of these data. This study was supported by Grant No. 80-07-07 from the National Center for Nervous, Mental and Muscular Disorders (NCNMMD) of the Ministry of Health and Welfare, Japan. References 1. Lemoine P, Harousseau H, Borteyru J-P, Menuet J-C. Les enfants de parents alcooliques. Anomalies observees. A propos de 127 cas. Quest Med 1968;25:476-82. 2. Jones KL, Smith DW, Ulleland CN, Streissguth AP. Pattern of malformation in offspring of chronic alcoholic mothers. Lancet 1973;1:126771. 3. Majewski F, Fischbach H, Peiffer J, Bierich JR. Zur Frage der Interruptio bei alkoholkranken Frauen. Dtsch Med Wochenschr 1978; 103:8958. 4. Clarren SK, Smith DW. The fetal alcohol syndrome. N Engl J Med 1978;298:1063-7. 5. Takashima H, Baba K, Kunugida F. One family of the fetal alcohol syndrome in Japan (in Japanese). Alcohol Res (Tokyo) 1978;13:102-3. 6. Tanaka H, Arima M, Ishizuka H, Suzuki N, Takashima H. The fetal alcohol syndrome in Japan (in Japanese). Jpn Med J (Tokyo) 1979; 2897:27-30. 7. Clarren SK, Alvord EC, Sumi SM, Streissguth AP, Smith DW. Brain malformations related to prenatal exposure to ethanol. J Pediatr 1978;92: 64-7.
8. Little RE. Moderate alcohol use during pregnancy and decreased infant birth weight. Am J Public Health 1977;67:1154-6. 9. Streissguth AP, Barr HM, Martin DC, Herman CS. Effects of maternal alcohol, nicotine, and caffeine use during pregnancy on infant mental and motor development at eight months. Alcoholism: Clin Exp Res 1980;4:152-64. 10. Hanson JW, Streissguth AP, Smith DW. The effects of moderate alcohol consumption during pregnancy on fetal growth and morphogenesis. J Pediatr 1978;92:457-60. 11. Smith DW, Jones KL, Hanson JW. Perspectives on the cause and frequency of the fetal alcohol syndrome. Ann NY A cad Sci 1976;273:138-9. 12. Streissguth AP. Psychologic handicaps in children with the fetal alcohol syndrome. Ann NY Acad Sci 1976;273:140-5. 13. Streissguth AP, Landesman-Dwyer S, Martin JC, Smith DW. Teratogenic effects of alcohol in humans and laboratory animals. Science 1980;209: 353-61. 14. Qazi QH, Masakawa A, McGann B, Woods J. Dermatoglyphic abnormalities in the fetal alcohol syndrome. Teratology 1980;21:157-60. 15. Palmer RH, Ouellette EM, Warner L, Leichtman SR. Congenital malformations in offspring of a chronic alcoholic mother. Pediatrics 1974;53: 490-4. 16. Tillner I, Majewski F. Furrows and dermal ridges of the hand in patients with alcohol embryopathy. Hum Genet 1978;42:307-14. 17. Peiffer J, Majewski F, Fischbach H, Bierich JR, Volk B. Alcohol embryo- and fetopathy. Neuropathology of 3 children and 3 fetuses. J Neurol Sci 1979;41:125-37. 18. Jones KL, Smith DW. Recognition of the fetal alcohol syndrome in early infancy. Lancet 1973; 2:999-1001. 19. Tze WJ, Lee M. Adverse effects of maternal alcohol consumption on pregnancy and foetal growth in rats. Nature 1975;257:479-80. 20. Chernoff G.F. The fetal alcohol syndrome in mice. An animal model. Teratology 1977;15: 223-30. 21. Rawat AK. Ribosomal protein synthesis in the fetal and neonatal rat brain as influenced by maternal ethanol consumption. Res Commun Chem Pathol Pharmacol1975; 12:723-32. 22. Henderson GI, Schenker S. The effect of maternal alcohol consumption on the viability and visceral development of the newborn rat. Res Commun Chem Pathol Pharmacol 1977;16:1532. 23. Chernoff GF. The fetal alcohol syndrome in mice: maternal variables. Teratology 1980;22: 71-5.
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