FETUS, PLACENTA, AND NEWBORN
Fetal alcohol syndrome: Seven new cases JOHN
J.
JOHN
T.
DENNIS
MULVIHILL,
M.D.
KLIMAS, C.
M.D.
STOKES,
HERMAN
M.
Baltimore
and Bethesda,
M.D.
RISEMBERG,
M.D.
Maryland
In one year, the ‘yetal alcohol syndrome” (FAS) was recognized in seven newborn and older infants, bringing the total in the current literature to 26 cases. This recently rediscovered disorder consists of severe prenatal and postnatal growth failure, mental deficiency, and characteristic hypoplasia of the middle face and orbits with minor malformations of the heart and joints. The mothers have chronic alcoholism. By identayying and counseling such women, obstetricians and gynecologists may prevent the occurrence of the syndrome or diagnose it in the neonate
two miscarriages of unknown gestational age. Beginning after her first two pregnancies, the mother’s alcoholism with wine and beer was recognized for at least 10 years by physicians, social workers, family, and herself. Her disease was complicated by mild pancreatitis and slight abnormalities of liver function. During the last 5 months of a 37 weeks’ pregnancy, she was given vitamins and regular prenatal care and, 4 weeks before delivery, had one episode of abdominal pain, called alcoholic gastritis. After normal labor and delivery, the infant developed hyperbilirubinemia, which peaked at 15 mg. per 100 ml. and subsided after 24 hours of phototherapy. Irritability and tremulousness, first noted on the third day, were not explained by sepsis or abnormalities of serum glucose, calcium, or phosphorus, and persisted to discharge on day 21. At age 23 months (Fig. 2, A and B), weight was 8,160 grams, length 78 cm., and head circumference 45.5 cm. (fiftieth Stuart percentiles for 7, 15, and 9 months, respectively). He had occipital flattening and balding, right ocular ptosis, a high-pitched cry, left cryptorchism (inguinal testis), lack of complete extension of both knees, right transitional simian crease, and a small caf&au-lait spot on the left buttock. The left palpebral fissure was 18 mm. long, the right 20 mm. The palate, pinnae, and heart were normal. Other neurologic tests were normal except for mental development: the
AFFECTED infants were ascertained in various medical settings of The Johns Hopkins University School of Medicine, most often for maternal neglect or failure to thrive: however, two newborn patients were diagnosed because alcoholism had been recognized in the mothers before delivery. The first patient, reported in detail, epitomizes the syndrome. Selected aspects of the other cases are noted briefly and clinical details are summarized together with previously reported cases’-’ (Table I, Figs. 1 to 3).
THE
Case reports Patient 1. The mother’s five prior pregnancies by different men produced, in sequence: two term infants (normal on examination at ages 14 and 13 years), one premature infant, unavailable for examination, and From the Department of Pediatrics, The Johns Hopkins Uniuersihr School of Medicine, and the Ebidemiolopv Branch, hation& 6ancer Ins&e. ’ -’ Received for publication Revised
November
.4ccepted December
July
14, 1975.
13, 1975. 8, I975.
Reprint requests: Dr. John J. Mulvihill, Landow Building, Room A-521, Epidemiology Branch, National Cancer Institute, Bethesda, Maryland 20014.
937
938
Mulvihill et al.
MINIMAL
PATlENT
Fig. 1. Minimal frequency parenthesis is the number
Table
I. Characteristics
of mother,
of defects in 19 published cases’-’ of informative cases, if not 26. Key:
gestation,
Age of onset abuse (yr.)
of alcohol
Duration of abuse (yr.) Maternal age at delivery (yr.) Birth order Weight gain during pregnancy (Kg.)
Duration of pregnancy (wk.) Weight Length
at birth at birth
(Kg.) (cm.)
Head circumference birth
at
and the present seven +(present), -(absent).
patients.
In
and birth Patient
Characteristic
% WITH DEFECT
(race and sex)*
1 EM
2 BM
3 BF
1 MuF
5 BM
6 RM
7 BM
22
22
25
?I
23f
23-i:
27
22.1
(18)
10 32
8 30
6 31
IO 3I
2 25
ti 29
3 30
i.3 30.3
(20) (23)
616 10
919 6
717 .i
414 -
516 -
616 7
5/j 43
5.3156 4.0
(22) (15)
37 1.95 44 30%
28 1.17 37 28
34 1.38 37 28
40 1.59 40.5 -
34 2.69 48.5 34
40 2.47 --
2.95 -
37.3 I .84 42.3 36.1
(23) (26) (21) (19)
9
6
1
5
li
B
6.2
(18)
23
1
0
14
50
Mean
(No. ii
(cm.)
Apgar score at one minute Age at diagnosis
(mo.)
*Abbreviations: B, black; tNumber with information &Same mother. $Delivered at home.
13
16
19
(26)
Mu, mulatto; M, male; F, female; -, (26 infants
born
in 25 gestations
Bayley test indicated a mental age of 13 months and a motor age of 14 months; the Vineland social maturity quotient was 51. Laboratory examinations, many carried out before age 4 months, included negative or normal values for routine serum chemistries, protein, IgM, urinalyses, VDRL, electroencephalogram, karyotype, intravenous pyelogram, and assay for abnormal amino acids or other metabolites in urine. By 23 months of age, skull radiographs, normal at age 2 months, showed no
unknown. to 23 different
mothers).‘-’
digital markings, a thickened calvarium, and schlcrotic sutures, suggesting poor brain growth. Skeletal radiographs showed small orbits and delayed mineralization of terminal phalanges of fourth and fifth toes. Bone age was consistent with chronoiogic age. Patient 2. Results of the mother’s prior pregnancies included two abortions and a premature birth. Alcoholism with gin and beer, also present in her husband and siblings, was complicated by liver disease and delirium tremens. When she presented for pre-
Volume
125
Number7
natal care in mid-trimester, she was treated for gonorrhea and positive serology for syphilis. At 28 weeks of gestation, while recovering from emergency laparotomy which revealed hemorrhagic (alcoholic) gastritis, she precipitously delivered without sterile precautions. The baby had respiratory distress and received antibiotics for presumed neonatal sepsis. Fluorescent treponemal antibody was present in cord blood at a titer of 1:60, with IgM-specific antibody of 1: 10. Cerebral spinal fluid serology was repeatedly negative and blood serology was negative at age 5 months. At age 15 months (Fig. 2, C), dysmorphic features beyond those in Fig. 1 included low-set ears with prominent antihelix, a 6 by 6 cm. anterior fontanelle, and a Grade 2/6 systolic murmur, considered to be pulmonary artery stenosis. Psychomotor development was delayed. Patient 3. The pregnancy was complicated by maternal anemia (hematocrit 25 per cent), consistent with a toxic anemia of alcoholism on bone marrow examination. When the mother presented in labor, she appeared to be acutely intoxicated from alcohol. She had postaxial polydactyiy of the hands and a history of partial pneumonectomy for tuberculosis 4 years before the birth of the patient. Her prior pregnancies by different men resulted in three term infants, one early abortus, and two premature infants (one stillborn, one with club feet). The patient’s dysmorphic features included low-set ears, bilateral sixth fingers, cleft soft palate, and bilateral talipes equinovarus. At 5 months of age, her Denver Developmental Evaluation was at 4 weeks’ level. Patient 4. Throughout pregnancy, the mother daily consumed six cans of beer and a quarter of a liter of Scotch, smoked heavily, ate poorly, and, in the first trimester, took decongestants and aspirin for a chronic cold. Besides a spontaneous abortion, prior pregnancies by different men resulted in a term infant weighing 1.9 kilograms and a 7 month premature infant, both said to be normal at ages 7 and 4 years. During these gestations, alcohol was allegedly not used to excess. Patient 4 (Fig. 2, D) spent her first month in a premature nursery because of low birth weight and was hospitalized with bronchiolitis at age 4 months. Skeletal defects included a large anterior fontanelle, bilateral talipes calcaneovalgus and, in the hands, polydactyly and hyperplasia of the second and fifth middle phalanges. At age 20 months, Bayley testing showed a mental age of 16 months and a motor age of 15, and the Vineland social quotient was 103. Patients 5 and 6. When first evaluated at age 6 months, Patient 5 was thought to have delayed development with normal growth, because of presumed hypoxia during birth at home. IQ was 41 by Cattell Infant Intelligence Scale and the Vineland social quotient was 41. When FAS was diagnosed in his younger brother, Patient 5 was re-examined at age 50 months, and the syndrome was recognized because of
Fetal alcohol syndrome
939
Fig. 2. Patients 1 (A and B), 2 (C), 4 (D), and 7 (E and F). bilateral esotropia, decreased supination bilaterally, and short palpebral fissures. Bilateral cervical ribs and persistent rhinorrhea were also noted. After delivery of Patient 6, the mother shot the father and, 3 weeks later, was found dead in her apartment. Autopsy revealed fatty metamorphosis of the liver, atrophic gastritis, and mild glomerulonephritis and pyelonephritis. Patient 6 had mild neonatal respiratory distress, clinodactyly, sacral dimple, and diminished elbow extension and supination accompanying severely delayed growth and development. Patient 7. By age four months, this boy (Fig. 2, E and F) was hospitalized three times because of neglect, with
940
Mulvihill
et al.
l-i_ 7 MONTHS
YEARS AGE
Fig. 3. Growth in length of palpebral fissure (measured as shown in insert). Means rt 2 SD. were calculated from data for white children.’ Squares indicate present cases with patient number on top; open dots are all published cases in which information was available. Number in parentheses beside symbol is actual measurement, if less than 17.5 mm.. the break in the ordinate. the mother often drunk. Remarkable features were a 2 by 2 cm. cutaneous hemangioma of the left forearm and signs of neurologic impairment at age 6 months (tremulousness, occasional cortical thumbs, and slight rigidity of upper limbs). Four older half-siblings, born before severe maternal alcoholism, were said to be normal.
Comment ‘The present series confirms and extends findings in recently published casesr-r and makes a total of 14 females and 12 males in three races (whites, blacks, and American Indians). The patients may first present to a variety of health professionals, including the obstetrician alert to the sometimes subtle manifestations of chronic alcoholism. The mothers are multiparous, with long-standing, severe alcoholism from all types of beverages-wine, beer, and spirits. Despite variations in estimated duration of pregnancy (12 premature, nine term, and two prolonged), birth measurements fall below average for gestational age. The babies are small for dates in an unusual way, with birth length more severely decreased than birth weight and head circumference. In maternal malnutrition, the opposite holds: fetal weight is more retarded than length.* During infancy, however, the FAS patients increase more in length than in weight, while remaining small. Analysis of dysmorphic features in 26 cases (Fig. 1) indicates that no defect is pathognomonic, but ocular
and facial anomalies predominate. Prior reports emphasized a high frequency of short palpebral fissures, although there are three caveats: (1) palpebral fissures are difficult to measure; (2) normal standards are from an old survey of 243 white childrens; (3) when S.b.‘s are calculated from the original data, eight cases of FAS are within two deviations from the mean, although all are below average (Fig. 3). Nonetheless, objective measurement remains important, since primary hypoplasia of the entire globe and orbit in FAS may give the impression of normal palpebral fissures. Other common eye abnormalities include epicanthal folds (11 patients), convergence defects (five), and ptosis (five). In most cases, skeletal defects are mild, such as camptodactyly, clinodactyly, and decreased range of motion at elbow, hip, or knee, but several patients had hip dislocation. The ,joint problem and frequently abnormal palmar creases may reflect neuromuscular dysfunction in utero since normal joint and crease development depends on adequate joint motion during morphogenesis. Cardiac defects are likewise frequent but mild. Of 13 patients with suspect&congenital heart disease, four were considered to have ventricular septal defects that spontaneously closed and only two required surgery or cardiac catheterization. Mental deficiency is common and- may be the most sensitive manifestation of maternal alcohol abuse during pregnancy. For example, Patient 5 would have remained undiagnosed had not the full FAS been
Volume Number
125 7
obvious in a subsequent sib, more heavily exposed to alcohol in utero. Some may doubt the validity of the syndrome. It is not new, but has been rediscovered several times, as suggested by reports from France” and previously cited historical references? The FAS can be readily distinguished from other patterns of multiple malformations which share some features, such as the syndromes of Cornelia de Lange, Smith-Lemli-Opitz, trisomy-18, familial blepharophimosis,” and fetal hydantoin.” The diagnosis is based on a typical maternal and gestational history with signs of prenatal and postnatal growth deficiency, delayed development, short palpebral fissures, and cardiac or joint anomalies which may be minor; these features are, admittedly, nonspecific and quite common. But the syndrome also may be frequent, like alcoholism. Among the offspring of 23 clearly alcoholic women in the Collaborative Perinatal Project, six cases
Fetal
alcohol
syndrome
941
of FAS (26 per cent) were found, as judged by minimal data in the clinical records (vs. none in controls).‘3 Of 76 sibs and half-sibs of 21 probands in the literature, seven (9 per cent) have the syndrome. This must be a low estimate, since some of the pregnancies antedated maternal alcoholism. The occurrence of FAS is likely to reflect the amount and duration of fetal exposure to alcohol; however, it is plausible that genetic polymorphism of enzymes for ethanol metabolism may alter fetal susceptibility,‘” as suggested by a mouse model of the FAS.” In fact, ethanol may not be the only teratogen in alcoholic beverages. The primary teratologic action may be potentiated by other compounds that cross the placenta, such as aldehydes and heavy metals,16 and by the social and medical complications of alcoholism, such as inadequate nutrition, altered intermediary metabolism, and irregular medical care.
REFERENCES
1. Jones, K. L., Smith, D. W., Ulleland, C. N., and Streissguth, A. P.: Pattern of malformation in offspring of chronic alcoholic mothers, Lancet 1: 1267, 1973. 2. Jones, K. L., and Smith, D. W.: Recognition of the fetal alcohol syndrome in early infancy, Lancet 2: 999, 1973. 3. Ferrier, P. E., Nicod, I., and Ferrier, S.: Fetal alcohol syndrome, Lancet 2: 1496, 1973. 4. Hall, B. D., and Orenstein, W. A.: Noonan’s phenotype in an offspring of an alcoholic mother, Lancet 1: 680, 1974. 5. Palmer, R. H., Ouellette, E. M., Warner, L., and Leichtman, S. R.: Congenital malformations in offspring of a chronic alcoholic mother, Pediatrics 53: 490, 1974. 6. Saule, H.: Fetales Alkohol-Syndrom: Ein Fallbericht, Klin. Wdiatr. 186: 452, 1974. 7. Tenbrinck, M. S., and Buchin, S. Y.: Fetal alcohol syndrome: Report of a case, J. A. M. A. 232: 1144, 1975. 8. Chouke, K. S.: The epicanthus or mongolian fold in Caucasian children, Am. J. Phys. Anthropol. 13: 255, 1929.
9. Stein, Z., and Susser, M.: The Dutch famine, 1944-1945, and the reproductive process. I. Effects on six indices at birth, Pediatr. Res. 9: 70, 1975. 10. Lamache, M. A.: Reflexions sur la descendance des alcooliques, Bull. Acad. Natl. Med. 151: 517, 1967. 11. Smith, D. W.: Recognizable Patterns of Human Malformation, Philadelphia, 1970, W. B. Saunders Company. 12. Hanson, J. W., and Smith, D. W.: The fetal hydantoin syndrome, J. Pediatr. 87: 285, 1975. 13. Jones, K. L., Smith, D. W., Streissguth, A. P., and Myrianthopoulos, N. C.: Outcome of offspring of chronic alcoholic women, Lancet 1: 1076, 1974. 14. Smith, M., Hopkinson, D. A., and Harris, H.: Developmental changes and polymorphism in human alcohol dehydrogenase, Ann. Hum. Genet. 34: 251, 1971. 15. Chernoff, G. F.: A mouse model of the fetal alcohol syndrome (abst.), Teratology 11: 14A, 1975. 16. Palmisano, P. A., Sneed, R. C., and Cassady, G.: Untaxed whiskey and fetal lead exposure, J. Pediatr. 75: 869, 1969.
Fetal alcohol syndrome: Seven new cases JOHN
J.
JOHN
T.
DENNIS
MULVIHILL,
M.D.
KLIMAS, C.
M.D.
STOKES,
HERMAN
M.
Baltimore
and Bethesda,
M.D.
RISEMBERG,
M.D.
Maryland
In one year, the ‘yetal alcohol syndrome” (FAS) was recognized in seven newborn and older infants, bringing the total in the current literature to 26 cases. This recently rediscovered disorder consists of severe prenatal and postnatal growth failure, mental deficiency, and characteristic hypoplasia of the middle face and orbits with minor malformations of the heart and joints. The mothers have chronic alcoholism. By identayying and counseling such women, obstetricians and gynecologists may prevent the occurrence of the syndrome or diagnose it in the neonate
two miscarriages of unknown gestational age. Beginning after her first two pregnancies, the mother’s alcoholism with wine and beer was recognized for at least 10 years by physicians, social workers, family, and herself. Her disease was complicated by mild pancreatitis and slight abnormalities of liver function. During the last 5 months of a 37 weeks’ pregnancy, she was given vitamins and regular prenatal care and, 4 weeks before delivery, had one episode of abdominal pain, called alcoholic gastritis. After normal labor and delivery, the infant developed hyperbilirubinemia, which peaked at 15 mg. per 100 ml. and subsided after 24 hours of phototherapy. Irritability and tremulousness, first noted on the third day, were not explained by sepsis or abnormalities of serum glucose, calcium, or phosphorus, and persisted to discharge on day 21. At age 23 months (Fig. 2, A and B), weight was 8,160 grams, length 78 cm., and head circumference 45.5 cm. (fiftieth Stuart percentiles for 7, 15, and 9 months, respectively). He had occipital flattening and balding, right ocular ptosis, a high-pitched cry, left cryptorchism (inguinal testis), lack of complete extension of both knees, right transitional simian crease, and a small caf&au-lait spot on the left buttock. The left palpebral fissure was 18 mm. long, the right 20 mm. The palate, pinnae, and heart were normal. Other neurologic tests were normal except for mental development: the
AFFECTED infants were ascertained in various medical settings of The Johns Hopkins University School of Medicine, most often for maternal neglect or failure to thrive: however, two newborn patients were diagnosed because alcoholism had been recognized in the mothers before delivery. The first patient, reported in detail, epitomizes the syndrome. Selected aspects of the other cases are noted briefly and clinical details are summarized together with previously reported cases’-’ (Table I, Figs. 1 to 3).
THE
Case reports Patient 1. The mother’s five prior pregnancies by different men produced, in sequence: two term infants (normal on examination at ages 14 and 13 years), one premature infant, unavailable for examination, and From the Department of Pediatrics, The Johns Hopkins Uniuersihr School of Medicine, and the Ebidemiolopv Branch, hation& 6ancer Ins&e. ’ -’ Received for publication Revised
November
.4ccepted December
July
14, 1975.
13, 1975. 8, I975.
Reprint requests: Dr. John J. Mulvihill, Landow Building, Room A-521, Epidemiology Branch, National Cancer Institute, Bethesda, Maryland 20014.
937
938
Mulvihill et al.
MINIMAL
PATlENT
Fig. 1. Minimal frequency parenthesis is the number
Table
I. Characteristics
of mother,
of defects in 19 published cases’-’ of informative cases, if not 26. Key:
gestation,
Age of onset abuse (yr.)
of alcohol
Duration of abuse (yr.) Maternal age at delivery (yr.) Birth order Weight gain during pregnancy (Kg.)
Duration of pregnancy (wk.) Weight Length
at birth at birth
(Kg.) (cm.)
Head circumference birth
at
and the present seven +(present), -(absent).
patients.
In
and birth Patient
Characteristic
% WITH DEFECT
(race and sex)*
1 EM
2 BM
3 BF
1 MuF
5 BM
6 RM
7 BM
22
22
25
?I
23f
23-i:
27
22.1
(18)
10 32
8 30
6 31
IO 3I
2 25
ti 29
3 30
i.3 30.3
(20) (23)
616 10
919 6
717 .i
414 -
516 -
616 7
5/j 43
5.3156 4.0
(22) (15)
37 1.95 44 30%
28 1.17 37 28
34 1.38 37 28
40 1.59 40.5 -
34 2.69 48.5 34
40 2.47 --
2.95 -
37.3 I .84 42.3 36.1
(23) (26) (21) (19)
9
6
1
5
li
B
6.2
(18)
23
1
0
14
50
Mean
(No. ii
(cm.)
Apgar score at one minute Age at diagnosis
(mo.)
*Abbreviations: B, black; tNumber with information &Same mother. $Delivered at home.
13
16
19
(26)
Mu, mulatto; M, male; F, female; -, (26 infants
born
in 25 gestations
Bayley test indicated a mental age of 13 months and a motor age of 14 months; the Vineland social maturity quotient was 51. Laboratory examinations, many carried out before age 4 months, included negative or normal values for routine serum chemistries, protein, IgM, urinalyses, VDRL, electroencephalogram, karyotype, intravenous pyelogram, and assay for abnormal amino acids or other metabolites in urine. By 23 months of age, skull radiographs, normal at age 2 months, showed no
unknown. to 23 different
mothers).‘-’
digital markings, a thickened calvarium, and schlcrotic sutures, suggesting poor brain growth. Skeletal radiographs showed small orbits and delayed mineralization of terminal phalanges of fourth and fifth toes. Bone age was consistent with chronoiogic age. Patient 2. Results of the mother’s prior pregnancies included two abortions and a premature birth. Alcoholism with gin and beer, also present in her husband and siblings, was complicated by liver disease and delirium tremens. When she presented for pre-
Volume
125
Number7
natal care in mid-trimester, she was treated for gonorrhea and positive serology for syphilis. At 28 weeks of gestation, while recovering from emergency laparotomy which revealed hemorrhagic (alcoholic) gastritis, she precipitously delivered without sterile precautions. The baby had respiratory distress and received antibiotics for presumed neonatal sepsis. Fluorescent treponemal antibody was present in cord blood at a titer of 1:60, with IgM-specific antibody of 1: 10. Cerebral spinal fluid serology was repeatedly negative and blood serology was negative at age 5 months. At age 15 months (Fig. 2, C), dysmorphic features beyond those in Fig. 1 included low-set ears with prominent antihelix, a 6 by 6 cm. anterior fontanelle, and a Grade 2/6 systolic murmur, considered to be pulmonary artery stenosis. Psychomotor development was delayed. Patient 3. The pregnancy was complicated by maternal anemia (hematocrit 25 per cent), consistent with a toxic anemia of alcoholism on bone marrow examination. When the mother presented in labor, she appeared to be acutely intoxicated from alcohol. She had postaxial polydactyiy of the hands and a history of partial pneumonectomy for tuberculosis 4 years before the birth of the patient. Her prior pregnancies by different men resulted in three term infants, one early abortus, and two premature infants (one stillborn, one with club feet). The patient’s dysmorphic features included low-set ears, bilateral sixth fingers, cleft soft palate, and bilateral talipes equinovarus. At 5 months of age, her Denver Developmental Evaluation was at 4 weeks’ level. Patient 4. Throughout pregnancy, the mother daily consumed six cans of beer and a quarter of a liter of Scotch, smoked heavily, ate poorly, and, in the first trimester, took decongestants and aspirin for a chronic cold. Besides a spontaneous abortion, prior pregnancies by different men resulted in a term infant weighing 1.9 kilograms and a 7 month premature infant, both said to be normal at ages 7 and 4 years. During these gestations, alcohol was allegedly not used to excess. Patient 4 (Fig. 2, D) spent her first month in a premature nursery because of low birth weight and was hospitalized with bronchiolitis at age 4 months. Skeletal defects included a large anterior fontanelle, bilateral talipes calcaneovalgus and, in the hands, polydactyly and hyperplasia of the second and fifth middle phalanges. At age 20 months, Bayley testing showed a mental age of 16 months and a motor age of 15, and the Vineland social quotient was 103. Patients 5 and 6. When first evaluated at age 6 months, Patient 5 was thought to have delayed development with normal growth, because of presumed hypoxia during birth at home. IQ was 41 by Cattell Infant Intelligence Scale and the Vineland social quotient was 41. When FAS was diagnosed in his younger brother, Patient 5 was re-examined at age 50 months, and the syndrome was recognized because of
Fetal alcohol syndrome
939
Fig. 2. Patients 1 (A and B), 2 (C), 4 (D), and 7 (E and F). bilateral esotropia, decreased supination bilaterally, and short palpebral fissures. Bilateral cervical ribs and persistent rhinorrhea were also noted. After delivery of Patient 6, the mother shot the father and, 3 weeks later, was found dead in her apartment. Autopsy revealed fatty metamorphosis of the liver, atrophic gastritis, and mild glomerulonephritis and pyelonephritis. Patient 6 had mild neonatal respiratory distress, clinodactyly, sacral dimple, and diminished elbow extension and supination accompanying severely delayed growth and development. Patient 7. By age four months, this boy (Fig. 2, E and F) was hospitalized three times because of neglect, with
940
Mulvihill
et al.
l-i_ 7 MONTHS
YEARS AGE
Fig. 3. Growth in length of palpebral fissure (measured as shown in insert). Means rt 2 SD. were calculated from data for white children.’ Squares indicate present cases with patient number on top; open dots are all published cases in which information was available. Number in parentheses beside symbol is actual measurement, if less than 17.5 mm.. the break in the ordinate. the mother often drunk. Remarkable features were a 2 by 2 cm. cutaneous hemangioma of the left forearm and signs of neurologic impairment at age 6 months (tremulousness, occasional cortical thumbs, and slight rigidity of upper limbs). Four older half-siblings, born before severe maternal alcoholism, were said to be normal.
Comment ‘The present series confirms and extends findings in recently published casesr-r and makes a total of 14 females and 12 males in three races (whites, blacks, and American Indians). The patients may first present to a variety of health professionals, including the obstetrician alert to the sometimes subtle manifestations of chronic alcoholism. The mothers are multiparous, with long-standing, severe alcoholism from all types of beverages-wine, beer, and spirits. Despite variations in estimated duration of pregnancy (12 premature, nine term, and two prolonged), birth measurements fall below average for gestational age. The babies are small for dates in an unusual way, with birth length more severely decreased than birth weight and head circumference. In maternal malnutrition, the opposite holds: fetal weight is more retarded than length.* During infancy, however, the FAS patients increase more in length than in weight, while remaining small. Analysis of dysmorphic features in 26 cases (Fig. 1) indicates that no defect is pathognomonic, but ocular
and facial anomalies predominate. Prior reports emphasized a high frequency of short palpebral fissures, although there are three caveats: (1) palpebral fissures are difficult to measure; (2) normal standards are from an old survey of 243 white childrens; (3) when S.b.‘s are calculated from the original data, eight cases of FAS are within two deviations from the mean, although all are below average (Fig. 3). Nonetheless, objective measurement remains important, since primary hypoplasia of the entire globe and orbit in FAS may give the impression of normal palpebral fissures. Other common eye abnormalities include epicanthal folds (11 patients), convergence defects (five), and ptosis (five). In most cases, skeletal defects are mild, such as camptodactyly, clinodactyly, and decreased range of motion at elbow, hip, or knee, but several patients had hip dislocation. The ,joint problem and frequently abnormal palmar creases may reflect neuromuscular dysfunction in utero since normal joint and crease development depends on adequate joint motion during morphogenesis. Cardiac defects are likewise frequent but mild. Of 13 patients with suspect&congenital heart disease, four were considered to have ventricular septal defects that spontaneously closed and only two required surgery or cardiac catheterization. Mental deficiency is common and- may be the most sensitive manifestation of maternal alcohol abuse during pregnancy. For example, Patient 5 would have remained undiagnosed had not the full FAS been
Volume Number
125 7
obvious in a subsequent sib, more heavily exposed to alcohol in utero. Some may doubt the validity of the syndrome. It is not new, but has been rediscovered several times, as suggested by reports from France” and previously cited historical references? The FAS can be readily distinguished from other patterns of multiple malformations which share some features, such as the syndromes of Cornelia de Lange, Smith-Lemli-Opitz, trisomy-18, familial blepharophimosis,” and fetal hydantoin.” The diagnosis is based on a typical maternal and gestational history with signs of prenatal and postnatal growth deficiency, delayed development, short palpebral fissures, and cardiac or joint anomalies which may be minor; these features are, admittedly, nonspecific and quite common. But the syndrome also may be frequent, like alcoholism. Among the offspring of 23 clearly alcoholic women in the Collaborative Perinatal Project, six cases
Fetal
alcohol
syndrome
941
of FAS (26 per cent) were found, as judged by minimal data in the clinical records (vs. none in controls).‘3 Of 76 sibs and half-sibs of 21 probands in the literature, seven (9 per cent) have the syndrome. This must be a low estimate, since some of the pregnancies antedated maternal alcoholism. The occurrence of FAS is likely to reflect the amount and duration of fetal exposure to alcohol; however, it is plausible that genetic polymorphism of enzymes for ethanol metabolism may alter fetal susceptibility,‘” as suggested by a mouse model of the FAS.” In fact, ethanol may not be the only teratogen in alcoholic beverages. The primary teratologic action may be potentiated by other compounds that cross the placenta, such as aldehydes and heavy metals,16 and by the social and medical complications of alcoholism, such as inadequate nutrition, altered intermediary metabolism, and irregular medical care.
REFERENCES
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9. Stein, Z., and Susser, M.: The Dutch famine, 1944-1945, and the reproductive process. I. Effects on six indices at birth, Pediatr. Res. 9: 70, 1975. 10. Lamache, M. A.: Reflexions sur la descendance des alcooliques, Bull. Acad. Natl. Med. 151: 517, 1967. 11. Smith, D. W.: Recognizable Patterns of Human Malformation, Philadelphia, 1970, W. B. Saunders Company. 12. Hanson, J. W., and Smith, D. W.: The fetal hydantoin syndrome, J. Pediatr. 87: 285, 1975. 13. Jones, K. L., Smith, D. W., Streissguth, A. P., and Myrianthopoulos, N. C.: Outcome of offspring of chronic alcoholic women, Lancet 1: 1076, 1974. 14. Smith, M., Hopkinson, D. A., and Harris, H.: Developmental changes and polymorphism in human alcohol dehydrogenase, Ann. Hum. Genet. 34: 251, 1971. 15. Chernoff, G. F.: A mouse model of the fetal alcohol syndrome (abst.), Teratology 11: 14A, 1975. 16. Palmisano, P. A., Sneed, R. C., and Cassady, G.: Untaxed whiskey and fetal lead exposure, J. Pediatr. 75: 869, 1969.
