Case Study Pervasive Developmental Disorder in Monozygotic Twins JELENA VUKICEVIC, M.D.,
AND
BRYNA SIEGEL, PH.D .
Monozygotic twin brothers were diagnosed as having pervasive developmental disorder , not Abstract. otherwise specified (DSM-llI-R) . They show different levels of cognitive and behavioral impairment , consistent with a greater number of suboptimal pre-, peri-, and postnatal factors present in one of the twins. Th is case study lends support to the hypothesis that genetic factors are of importance in the expression of a pervasive developmental disorder, but that degree of developmental delay, its severity, and certain clinical features may be determined by nongenetic suboptimal pre-, peri-, and postnatal events. J. Am . Acad. Child Adolesc. Psychiatry, 1990, 29,6:897900. Key Words: autism, pervasive developmental disorder , twins, obstetrics suboptimality.
Pervasive developmental disorder (PDD) is a broad category covering children primarily with impairment in the development of reciprocal social interaction and verbal communication skills. The most widely recognized and severe form of this disorder is autistic disorder (AD). A milder form is pervasive developmental disorder, not otherwise specified (PDDNOS). Incidence for AD is four to five per 10,000 and for all PDD 10 to 15 per 10,000 (Zahner and Pauls, 1987). The disorder is 4 to 5 times more common in males. The etiology for PDD is still unknown although there is now strong support for a genetic factor from twin and sibling studies (Folstein and Rutter , 1977; Ritvo et aI., 1985; Bryson et aI. , 1988; Steffenburg et aI., 1989). Folstein and Rutter (1988), in reviewing empirical data on the genetics of autism, conclude that the causes of autism are probably heterogeneous, involving multiple gene loci, and also, probably, involving interaction with other postconception developmental factors. They suggest that the genotype may be responsible for abnormality in language or social development but could be compounded by these other factors, producing autism (and mental retardation in up to 90% of those affected). This has been supported by recent findings by Steffenberg et aI. (1989) where there was more perinatal risk in the histories of the autistic twin from DZ pairs, discordant for autism but concordant for cognitive disorder in 30% of pairs. Thus , multiple etiologies can be seen as possibly responsible for a common pathology or pathophysiology resulting in autism. Studies of risk recurrence, multiplex families, and suboptimal pre-, peri-, and postnatal risk factors shed light on
Accepted June 19 , 1990 . Dr. Yukicevic is Resident in Pediatrics, Department of Pediatrics, Stanford University School of Medicine, Stanford, California. Dr. Siegel is Assistant Adjun ct Professor of Psychiatry, Department of Psychiatry, Langley Porter Psychiatric Institute, University of California , San Francisco, California. This research was supported by the John Merck Fund and by NIMH Grant No. MH-39437. Reprint requests to Dr. Siegel, Langley Porter Psychiatric Institute, Box CAS, 401 Parnassus Ave., San Francisco, CA 94143 . 0890-8567/90/2906-0897$02.00/0© 1990by the American Academy of Child and Adolescent Psychiatry.
alternative hypotheses about how a multifactorial etiology for autism might work. Smalley et aI. (1988) pooled data from genetic studies of autism that together had included 886 siblings, 45 MZ and 36 DZ twin pairs. They concluded that 2.7% of siblings of AD children were also AD, and that concordance in MZ twins were 64%; in DZ twins, 9%. These risk recurrence data empirically support the role of a nongenetic interactive factor, and possibly a specific additive risk from twinning. Pre-, peri- , and postnatal risks associated with autism are more sensitive predictors of the diagnosis of AD than they are specific to it-there is a higher rate of these risks in autistic children than in nondevelopmentally disabled controls, but not higher than the prevalence among other children with the same amount of developmental disability (Bryson et aI., 1988). One study has shown that there are more of these suboptimal factors in the histories of "sporadic" cases of autism than in cases from families multiplex for autism (Mason-Brothers et al., 1987), suggesting that sometimes the genetic liability for autism may be so strong that autism will occur, even in the absence of a " trigger. " Taken together , findings to date support three possible hypotheses: (1) suboptimal obstetric factors alone may cause autism; (2) the genetic liability for autism in combination with suboptimal obstetric factors acting as a trigger may cause autism (the multifactorial model); or (3) the genotype alone causes autism, at least, in some cases, and that in those cases, suboptimal obstetric events actually are observed occurring at random. Given these three possible ways in which autism might develop, the purpose of this case study was to develop hypotheses as to which clinical signs of PDD may be a function of genotype, which may be a function of postconception suboptimality , and which might result from an interaction of the two. This issue is addressed because, while studies now strongly support a multifactorial model for etiology, at least for some cases, specific symptoms that might result from the putative genotype alone rather than from genotype plus triggering risk factors together are less well understood.
Case Study Twin brothers, age 4Y2, were evaluated for a possible diagnosis of AD. The parents were concerned with delayed
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language and atypical play and social relatedness compared to other children their age. Parental and family history. The twins' parents were 36 years old (mother) and 32 years old (father) at the time of conception. Family history is unremarkable on both parents' sides, except for Mrs. P., who had started to walk at 18 months of age and had delayed puberty. She is now taller than average as is Mr. P. There is no family history of AD, PDDNOS, or mental retardation (MR). Pre- and perinatal history. This was the first pregnancy for Mrs. P. During pregnancy, the mother experienced spotting at 13 weeks of gestation, followed by ultrasound that revealed twins. Her weight gain during pregnancy was 10 kg, and she noted little fetal movement. At 27 weeks of gestation, she began to experience preterm labor and was put on bed rest for 11 weeks. Mrs. P. took ritodrine, terbutaline and progesterone for the last 6 weeks of pregnancy. The twins were born at 38 weeks by a planned C-section delivery due to breech presentation. The first-born twin ("A") had a birth weight of 1,928 gm and obtained an Apgar score of 3 and 7 at 1 and 5 minutes, respectively. It was felt that he possibly aspirated meconium. He had a slow heart rate (less than 100 b/min), difficulty breathing, hypoglycemia (20 mg/ml), and his hematocrit was 80. A monochorionic placenta was present, and the possibility of a twin transfusion syndrome was considered. He did not require intubation, and hypoglycemia responded to 10% dextrose. Sepsis was ruled out. The second-born twin ("B ") was 2,226 gm at birth. He did much better than his brother and obtained an Apgar score of 8 and 9 at 1 and 5 minutes, respectively, and went home at 5 days with his mother. "A" remained in the hospital five days longer than "B", and a partial exchange transfusion was carried out. He was in an incubator and did well, and he joined his family at 10 days of age. Early development. Both twins were breast-fed and grew well during the first 3 months. At about 4 to 5 months, the rate of growth reached a plateau for both boys. Growth did not pick up. Delays in early motor milestones were also in evidence. Both boys first sat up at 11 months and walked at 18 months, but the parents were reassured by their pediatrician that this was normal for twins. Overall health for both boys was good except for an allergy to cow's milk in "A" . However, height and weight remained below the third percentile for both boys. At the age of 1 year, it became apparent that "A" and "B" were somehow socially unresponsive and not interested in attending to or learning language. By age 15 to 18 months, this concern began to focus specifically on receptive language, particularly failures to respond to simple commands. Language and social development. The parents described the twins as very different in behavior, although very alike in appearance: "A" was a pleaser, ready to do something for you in a certain particular way; on the other hand, "B" was more concerned with pleasing himself. "B" was usually dominant, always getting things first, had better language (expressive and comprehensive), and insisted more on following routines. "A" had more sparse language, and was more echolalic, but was more socially responsive. "B" 898
used some language for commenting, but most language produced was instrumental in function. "B" showed little eye contact or social smiling in the context of either verbal or nonverbal interaction. "A" had less intelligible language, and although 60% of his language was reported to be spontaneous, often commenting on objects in his environment, it had a holistic, concrete quality. "A" would, for example, say "Unplug it" as a general "Help me" request. "A" would gaze, obtain eye contact, and smile appropriately during verbal or nonverbal interaction while "B" would not. (Both twins have problems with articulation, but it is more pronounced in "A" than in "B." They usually do not verbalize to one another, nor play together.) The parents reported that' 'B" has been very distressed over changes in the environment and has shown catastrophic reactions to everyday events. For example, he insists on keeping his plate on the table even when he is finished eating, and he has gone on to doing something else. "A" has shown a range of hyper- and hyposensitivity to perceptual stimuli. These include an attraction to vestibular stimulation, such as escalators, and some auditory hypersensitivities, including covering his ears in school when the sound level in the classroom goes up and orienting to low noises, such as the sound of the heating system. Behavioral observations. The boys were seen on three occasions over a year, 2 times at the clinic and once in their home. They appeared to be very cute boys without any dysmorphisms, looking younger than their chronological age. On the first visit, "B" was more silent than" A" who was ready to leave from the beginning, waving bye-bye. They were much less anxious on the second visit and were more ready to explore the environment. On both occasions very little interaction was observed between them. In an unfamiliar environment, "B'" s isolative behavior increased. His attention span was good and his play was mental age appropriate. He enjoyed doing puzzles and liked to draw pictures with many details. He also showed some odd interests in toys such as spinning and flicking objects. "B" tended to dominate toys and activities, ignoring and excluding his brother. "A" was more social (to unfamiliar people) and used his father as a base for exploratory play in the clinic, although in a somewhat perseverative and stereotyped fashion. Although notably more socially attached to their parents than "B", "A'" s social approaches to his mother and father were less frequent than that of a typical 4-year-old, or a child of comparable mental age. Intelligence testing and adaptive functioning. "A" obtained a mental age of 46 months on the Merrill Palmer Scales of Mental Tests, which would place him in the mild mentally retarded range. "B" obtained a mental age of 61 months which represents a normal intelligence. On the Vineland Adaptive Behavior Scales, "A" and "B" achieved the following age-equivalent (years, months) scores, respectively: Communication, 1 year, 8 months and 1 year, 3 months (receptive, 1 year, 5 months and 1 year, 6 months; expressive, 3 years, 7 months and 1 year, 1 month); Daily Living, 2 years, 5 months and 1 year, 11 months (personal, 2 years, 5 months and 2 years, 0 months; domestic, 3 years, 3 months and 2 years, 0 months; community, 2 years, 5 l.Am.Acad. ChildAdolesc.Psychiatry, 29:6, November1990
PDD IN MZ TWINS TABLE
1. DSM-Ill-R Criteria for Autistic Disorder Met by Twins A and B (with clinical examples)
Criteria Are Rated According to Each Twin's Mental Twin
Ap. Qualitative impairment in reciprocal social interaction Marked lack of awareness of others (B ignores parents most of time) Abnormal comfort seeking Impaired imitation Abnormal social play (twins don 't engage in spontaneous, reciprocal games) Abnormal peer friendships (twins ignore presence of other except to grab toys) Qualitative impairment in communication and imagination No mode of communicat ion Abnormal nonverbal communication (B has very little eye contact) Absence of imaginati ve activity Abnormal speech production Abnormal speech content (B says "unplug it" to ask for help) Abnormal conversation al skill (little spontaneous, expressive, or contingent talk) Markedly restricted range of activities and interests Stereotyped body movements (A flicks at toys) Preoccupation with parts of objects (A covers ears in response to certain sounds) Marked distress in change in environment (B does not want to see plate removed after eating) Insistence on following routines Restricted range of interests (odd interests-toy vacuum (A & B), ironing board (B»
Twin
A
B
+
with sufficiently lessened severity to disqualify him from being rated as symptomatic in that area. Examination of chromosomes and zygosity. No fragile-X chromosomes or other abnormalities were seen on cytogenetic testing. The boys were remarkably alike in appearance. Parents reported that they had sometimes confused them when they were younger . Presence of a monochorionic placenta was recorded at birth, thus no additional tests to prove zygosity were conducted. Discussion
+
+
+
+
+
+
+
+
+
+ +
+
+
months and 2 years, 2 months); Socialization, 1 year, 0 months and 1 year, 1 month (interpersonal, 1 year, 9 months and 0 years, 10 months; play, 0 years, 9 months and 0 years, 11 months; coping , 1 year, 5 months and 1 year , 5 months); motor, 2 years, 11 months and 3 years , 7 months (gross, 2 years, 5 months and 2 years , 9 months; fine, 3 years , 11 months and 4 years, 5 months); and an Adaptive Behavior Composite of 23 and 24 months. Thus, although "A" was cognitively less able than " B", he showed better overall communication and daily living skills , better interpersonal skill, but worse motor skills. Diagnostic assessm ent. The twins were evaluated using the DSM-III-R criteria for AD. Both of them met seven out of 16 criteria from the DSM-III-R symptom checklist , given their respective mental ages (Table 1). If a child is positive on eight of 16 criteria, including at least two from A, the social domain; one from B, the communication domain; and one from C, activities and interests ; the diagnosis of AD is assigned. Using the DSM-III-R scoring criteria, the PDDNOS diagnosis is assigned if the child has at least one symptom from first and one symptom from second domain . Thus , PDDNOS constitute s a less severe or full-blown disorder than autism but has the same symptoms. It should be noted that for each positive symptom that at least one twin showed, the same symptom would be present in the other twin but l.Am .Acad . Child Adolesc.Psychiatry, 29:6, November 1990
Genetic factors . In the case of these twins, it is reasonable to suggest that shared symptoms may stem from an expression of the genotype because of monozygosity, even though there is no positive family history for other cases of POD. An examination of their shared clinical features showed they had some similar social impairments-abnormal social play and an inability to engage in peer friendships. Both were unable to engage in simple turn-taking conversation , even given the sizes of their vocabularies . In addition , both exhibited a restricted range of interests ; they fought over a toy vacuum until their mother bought a second one . Later, each developed other odd interests, such as drawing the bathroom in detail and spotting Union 76 logos. Suboptimality. The boys shared a number of suboptimal factors during pregnancy: monozygotic twinning , midtrimester spotting , low maternal weight gain during pregnancy, and diminished fetal movement. In addition to this , twin " A" had lower birth weight , difficulty breathing , low heart rate, hypoglycemia, and high hematocrit. Using a multifactorial model that would consider the interactive effects of a genetic liability and suboptimality , the additional insults suffered by " A" could be seen as possibly related to additional symptoms he exhibited. These included idiosyncratic language, stereotyped body movements, and preoccupation with parts of objects. In an earlier study, it was found that each of these particular symptoms was positively correlated with magnitude of developmental delay (Siegel et aI., 1989). Thus , these findings appear consistent with the fact that "A" had more cogniti ve impairment, possibly secondary to his greater suboptimality. Conversely, the symptoms experienced by "B, " and not by " A," could result from the fact that more cognitive impairment may "blunt" the ability to manifest symptoms that may require some basal level of mental development before they can be expressed (e.g. , "B" showed resistance to changes in the . environment, while "A" did not). Twinning. Twin pregnancies are typically treated as risk pregnancies because of intrauterine crowding and limitations in nourishment for the fetuses (Parson , 1988). Even with improved pre- and perinatal care, the incidence of mortality and morbidity for twin births is still higher than for singletons . Monozygotic twins have an additional disadvantage because genetic material should be divided. Monozygotic twinning is thought to be due to chance, unrelated to heredity , resulting from a delay in implantation associated with nutritional status, hypoxia, or other stressors (Parson, 1988). This delay leads to monozygotic twins, generally with a monochorionic placenta (Newton, 1986; McCulloch, 1988).
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Twinning itself has not been shown to be a significant risk factor for development of PDD. In this case study, the fact that the mother gained just 10 kg during pregnancy and twin "B'''s birth weight was appropriate for gestational age is suggestive of intrauterine deprivation for twin" A " , possibly due to even earlier problems experienced by that twin . Generally, intrauterine growth of twins is similar to singletons up to 30 weeks of gestation (Blecker et al., 1979). Placental insufficiency in twin pregnancies is usually manifested by 38 weeks of gestation. However, maternal weight gain during pregnancy does not differ significantly among mothers of PDD children, children compared to those with idiopathic MR, or normal children (Torrey and Hersh, 1975) . However, diminished fetal movement during pregnancy has been recorded occasionally in the histories of PDD children but has not been shown to be significantly different from normals or those with idiopathic MR (Mason-Brothers et al. , 1987). Additional risks . None of the additional suboptimal factors present in twin "A" are specific for PDD children, but all of them can cause general , nonspecific central nervous system impairment (McCulloch , 1988; O'Brien and Hay , 1987). Clinically, these factors appear to be associated with an IQ in the range of mild MR and more difficulty with language use and articulation, both of which were more pronounced in twin "A". Overall difference in IQ between monozygotic twins correlates with birth weight difference (Segal , 1985; O'Brien and Hay , 1987). Failure-to-thrive and motor milestone delays are not specific for, nor commonly seen in , children with PDD (Paul , 1987). Here again, given the maternal developmental history, the growth failure of these twins may have had a genetic basis, though independent of the genotype for PDD. It seems that these twins had the potential for developing PDD and they did so, but twin "A" had more suboptimal factors present, and thus experienced generalized nonspecific CNS impairment, in addition to PDD. "A" showed more cognitive delay and, in particular, more language delay. Overall, he seemed more social, but more retarded in his development than his twin brother. " B " appeared less impaired cognitively but more impaired socially , consistent with his diagnosis of PDDNOS and his exposure to fewer suboptimal factors. Thus, this case study suggests that suboptimal pre- and perinatal factors may be related to delayed development and may, in fact, blunt the effect of PDD . The
900
form of PDD seen in these twins possibly may be viewed as aberrant, rather than delayed development, resulting from the genotype for autism. References Blecker, O. P., Breuer, W. & Huidecoper, B. L. (1979), A study of birth weight, placenta, weight and mortality of twins as compared to singletons. Br. J . Obstet, Gynecol., 86:111-118 . Bryson, S ., Smith, 1. & Eastwood, D. (1988), Obstetrical suboptimality in autisticchildren. J . Am . Acad. Child Adolesc. Psychiatry, 27:418-422.
Folstein, S. & Rutter, M. (1977), Infantile autism: a genetic study of 21 twin pairs. J. Child Psychol. Psychiatry, 18:297-321. - - - - (1988), Autism: familial aggregation and genetic implications. J Autism Dev, Disord ., 18:3-30. Mason-Brothers, A., Ritvo, E., Guze, B. & Freeman, B. J. (1987) , Pre-, peri- and postnatal factors in 181 autistic patientsfrom single and multiple incidence families. J. Am. Acad . Child Adolesc. Psychiatry, 26:39-42 .
McCulloch, K. (1988), Neonatal problems in twins. Clin. Perinatol., 15:141-158.
Newton, E. R. (1986), Antepartum care in multiple gestation. Semin. Perinatol., 10:19-29.
O'Brien, P. J. & Hay, D. A. (1987), Birthweight difference, the transfusion syndrome and the cognitive development of monozygotic twins. Acta Genet. Med. Gemellol., 36:191-196 . Paul, R. (1987), Natural history. In: Handbook for Autism and Pervasive Developmental Disorders, eds. D. J. Cohen & M. A. Donellan. New York: J. Wiley & Sons, Inc. Parson , M. (1988), Effects of twins: maternal, fetal, and labor. Clin. Perinatol., 15:41-53.
Ritvo, E. R., Freeman, B. J., Mason-Brothers , A., Mo, A. & Ritvo, A. M. (1985 ), Concordance for the syndrome of autism in 40 pairs of afflicted twins. Am. J . Psychiatry, 142:74-77 . Segal, N. L. (1985), Monozygotic and dizygotic twins: a comparative analysis of mental ability profiles. Child Dev ., 56:1051-1058. Siegel, B., Vukicevic, J., Elliott, G. R. & Kraemer, H. C. (1989 ), The use of signal detection theory to assess DSM-III-R criteria for autistic disorder. J . Am. Acad . Child Adolesc . Psychiatry , 28:542548.
Smalley, S. L., Asarnow, R. F. , and Spence, M. A. (1988), Autism and genetics: a decadeof research. Arch. Gen. Psychiatry, 45:953961.
Steffenberg, S., Gillberg, C., Hellgren, L., Andersson, L., Gillberg , I. C., Jakobsson, O. & Bohman, M. (1989), A twin studyof autism in Denmark, Finland, Iceland, Norway, and Sweden. J. Child Psychol. Psychiatry, 30:405-416 .
Torrey, F. & Hersh, S. (1975), Earlychildhood psychosis andbleeding during pregnancy. Journal of Autism and Childhood Schizophrenia, 15:287-297.
Zahner, G. & Pauls, L. D. (1987), Epidemiological surveys on infantile autism. In: Handbook of Autism and Pervasive Developmental Disorders. eds. D. J. Cohen & M. A. Donellan. New York: J. Wiley & Sons Inc.
J.Am.Acad. Child Adolesc . Psychiatry, 29:6, November 1990
AND
BRYNA SIEGEL, PH.D .
Monozygotic twin brothers were diagnosed as having pervasive developmental disorder , not Abstract. otherwise specified (DSM-llI-R) . They show different levels of cognitive and behavioral impairment , consistent with a greater number of suboptimal pre-, peri-, and postnatal factors present in one of the twins. Th is case study lends support to the hypothesis that genetic factors are of importance in the expression of a pervasive developmental disorder, but that degree of developmental delay, its severity, and certain clinical features may be determined by nongenetic suboptimal pre-, peri-, and postnatal events. J. Am . Acad. Child Adolesc. Psychiatry, 1990, 29,6:897900. Key Words: autism, pervasive developmental disorder , twins, obstetrics suboptimality.
Pervasive developmental disorder (PDD) is a broad category covering children primarily with impairment in the development of reciprocal social interaction and verbal communication skills. The most widely recognized and severe form of this disorder is autistic disorder (AD). A milder form is pervasive developmental disorder, not otherwise specified (PDDNOS). Incidence for AD is four to five per 10,000 and for all PDD 10 to 15 per 10,000 (Zahner and Pauls, 1987). The disorder is 4 to 5 times more common in males. The etiology for PDD is still unknown although there is now strong support for a genetic factor from twin and sibling studies (Folstein and Rutter , 1977; Ritvo et aI., 1985; Bryson et aI. , 1988; Steffenburg et aI., 1989). Folstein and Rutter (1988), in reviewing empirical data on the genetics of autism, conclude that the causes of autism are probably heterogeneous, involving multiple gene loci, and also, probably, involving interaction with other postconception developmental factors. They suggest that the genotype may be responsible for abnormality in language or social development but could be compounded by these other factors, producing autism (and mental retardation in up to 90% of those affected). This has been supported by recent findings by Steffenberg et aI. (1989) where there was more perinatal risk in the histories of the autistic twin from DZ pairs, discordant for autism but concordant for cognitive disorder in 30% of pairs. Thus , multiple etiologies can be seen as possibly responsible for a common pathology or pathophysiology resulting in autism. Studies of risk recurrence, multiplex families, and suboptimal pre-, peri-, and postnatal risk factors shed light on
Accepted June 19 , 1990 . Dr. Yukicevic is Resident in Pediatrics, Department of Pediatrics, Stanford University School of Medicine, Stanford, California. Dr. Siegel is Assistant Adjun ct Professor of Psychiatry, Department of Psychiatry, Langley Porter Psychiatric Institute, University of California , San Francisco, California. This research was supported by the John Merck Fund and by NIMH Grant No. MH-39437. Reprint requests to Dr. Siegel, Langley Porter Psychiatric Institute, Box CAS, 401 Parnassus Ave., San Francisco, CA 94143 . 0890-8567/90/2906-0897$02.00/0© 1990by the American Academy of Child and Adolescent Psychiatry.
alternative hypotheses about how a multifactorial etiology for autism might work. Smalley et aI. (1988) pooled data from genetic studies of autism that together had included 886 siblings, 45 MZ and 36 DZ twin pairs. They concluded that 2.7% of siblings of AD children were also AD, and that concordance in MZ twins were 64%; in DZ twins, 9%. These risk recurrence data empirically support the role of a nongenetic interactive factor, and possibly a specific additive risk from twinning. Pre-, peri- , and postnatal risks associated with autism are more sensitive predictors of the diagnosis of AD than they are specific to it-there is a higher rate of these risks in autistic children than in nondevelopmentally disabled controls, but not higher than the prevalence among other children with the same amount of developmental disability (Bryson et aI., 1988). One study has shown that there are more of these suboptimal factors in the histories of "sporadic" cases of autism than in cases from families multiplex for autism (Mason-Brothers et al., 1987), suggesting that sometimes the genetic liability for autism may be so strong that autism will occur, even in the absence of a " trigger. " Taken together , findings to date support three possible hypotheses: (1) suboptimal obstetric factors alone may cause autism; (2) the genetic liability for autism in combination with suboptimal obstetric factors acting as a trigger may cause autism (the multifactorial model); or (3) the genotype alone causes autism, at least, in some cases, and that in those cases, suboptimal obstetric events actually are observed occurring at random. Given these three possible ways in which autism might develop, the purpose of this case study was to develop hypotheses as to which clinical signs of PDD may be a function of genotype, which may be a function of postconception suboptimality , and which might result from an interaction of the two. This issue is addressed because, while studies now strongly support a multifactorial model for etiology, at least for some cases, specific symptoms that might result from the putative genotype alone rather than from genotype plus triggering risk factors together are less well understood.
Case Study Twin brothers, age 4Y2, were evaluated for a possible diagnosis of AD. The parents were concerned with delayed
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language and atypical play and social relatedness compared to other children their age. Parental and family history. The twins' parents were 36 years old (mother) and 32 years old (father) at the time of conception. Family history is unremarkable on both parents' sides, except for Mrs. P., who had started to walk at 18 months of age and had delayed puberty. She is now taller than average as is Mr. P. There is no family history of AD, PDDNOS, or mental retardation (MR). Pre- and perinatal history. This was the first pregnancy for Mrs. P. During pregnancy, the mother experienced spotting at 13 weeks of gestation, followed by ultrasound that revealed twins. Her weight gain during pregnancy was 10 kg, and she noted little fetal movement. At 27 weeks of gestation, she began to experience preterm labor and was put on bed rest for 11 weeks. Mrs. P. took ritodrine, terbutaline and progesterone for the last 6 weeks of pregnancy. The twins were born at 38 weeks by a planned C-section delivery due to breech presentation. The first-born twin ("A") had a birth weight of 1,928 gm and obtained an Apgar score of 3 and 7 at 1 and 5 minutes, respectively. It was felt that he possibly aspirated meconium. He had a slow heart rate (less than 100 b/min), difficulty breathing, hypoglycemia (20 mg/ml), and his hematocrit was 80. A monochorionic placenta was present, and the possibility of a twin transfusion syndrome was considered. He did not require intubation, and hypoglycemia responded to 10% dextrose. Sepsis was ruled out. The second-born twin ("B ") was 2,226 gm at birth. He did much better than his brother and obtained an Apgar score of 8 and 9 at 1 and 5 minutes, respectively, and went home at 5 days with his mother. "A" remained in the hospital five days longer than "B", and a partial exchange transfusion was carried out. He was in an incubator and did well, and he joined his family at 10 days of age. Early development. Both twins were breast-fed and grew well during the first 3 months. At about 4 to 5 months, the rate of growth reached a plateau for both boys. Growth did not pick up. Delays in early motor milestones were also in evidence. Both boys first sat up at 11 months and walked at 18 months, but the parents were reassured by their pediatrician that this was normal for twins. Overall health for both boys was good except for an allergy to cow's milk in "A" . However, height and weight remained below the third percentile for both boys. At the age of 1 year, it became apparent that "A" and "B" were somehow socially unresponsive and not interested in attending to or learning language. By age 15 to 18 months, this concern began to focus specifically on receptive language, particularly failures to respond to simple commands. Language and social development. The parents described the twins as very different in behavior, although very alike in appearance: "A" was a pleaser, ready to do something for you in a certain particular way; on the other hand, "B" was more concerned with pleasing himself. "B" was usually dominant, always getting things first, had better language (expressive and comprehensive), and insisted more on following routines. "A" had more sparse language, and was more echolalic, but was more socially responsive. "B" 898
used some language for commenting, but most language produced was instrumental in function. "B" showed little eye contact or social smiling in the context of either verbal or nonverbal interaction. "A" had less intelligible language, and although 60% of his language was reported to be spontaneous, often commenting on objects in his environment, it had a holistic, concrete quality. "A" would, for example, say "Unplug it" as a general "Help me" request. "A" would gaze, obtain eye contact, and smile appropriately during verbal or nonverbal interaction while "B" would not. (Both twins have problems with articulation, but it is more pronounced in "A" than in "B." They usually do not verbalize to one another, nor play together.) The parents reported that' 'B" has been very distressed over changes in the environment and has shown catastrophic reactions to everyday events. For example, he insists on keeping his plate on the table even when he is finished eating, and he has gone on to doing something else. "A" has shown a range of hyper- and hyposensitivity to perceptual stimuli. These include an attraction to vestibular stimulation, such as escalators, and some auditory hypersensitivities, including covering his ears in school when the sound level in the classroom goes up and orienting to low noises, such as the sound of the heating system. Behavioral observations. The boys were seen on three occasions over a year, 2 times at the clinic and once in their home. They appeared to be very cute boys without any dysmorphisms, looking younger than their chronological age. On the first visit, "B" was more silent than" A" who was ready to leave from the beginning, waving bye-bye. They were much less anxious on the second visit and were more ready to explore the environment. On both occasions very little interaction was observed between them. In an unfamiliar environment, "B'" s isolative behavior increased. His attention span was good and his play was mental age appropriate. He enjoyed doing puzzles and liked to draw pictures with many details. He also showed some odd interests in toys such as spinning and flicking objects. "B" tended to dominate toys and activities, ignoring and excluding his brother. "A" was more social (to unfamiliar people) and used his father as a base for exploratory play in the clinic, although in a somewhat perseverative and stereotyped fashion. Although notably more socially attached to their parents than "B", "A'" s social approaches to his mother and father were less frequent than that of a typical 4-year-old, or a child of comparable mental age. Intelligence testing and adaptive functioning. "A" obtained a mental age of 46 months on the Merrill Palmer Scales of Mental Tests, which would place him in the mild mentally retarded range. "B" obtained a mental age of 61 months which represents a normal intelligence. On the Vineland Adaptive Behavior Scales, "A" and "B" achieved the following age-equivalent (years, months) scores, respectively: Communication, 1 year, 8 months and 1 year, 3 months (receptive, 1 year, 5 months and 1 year, 6 months; expressive, 3 years, 7 months and 1 year, 1 month); Daily Living, 2 years, 5 months and 1 year, 11 months (personal, 2 years, 5 months and 2 years, 0 months; domestic, 3 years, 3 months and 2 years, 0 months; community, 2 years, 5 l.Am.Acad. ChildAdolesc.Psychiatry, 29:6, November1990
PDD IN MZ TWINS TABLE
1. DSM-Ill-R Criteria for Autistic Disorder Met by Twins A and B (with clinical examples)
Criteria Are Rated According to Each Twin's Mental Twin
Ap. Qualitative impairment in reciprocal social interaction Marked lack of awareness of others (B ignores parents most of time) Abnormal comfort seeking Impaired imitation Abnormal social play (twins don 't engage in spontaneous, reciprocal games) Abnormal peer friendships (twins ignore presence of other except to grab toys) Qualitative impairment in communication and imagination No mode of communicat ion Abnormal nonverbal communication (B has very little eye contact) Absence of imaginati ve activity Abnormal speech production Abnormal speech content (B says "unplug it" to ask for help) Abnormal conversation al skill (little spontaneous, expressive, or contingent talk) Markedly restricted range of activities and interests Stereotyped body movements (A flicks at toys) Preoccupation with parts of objects (A covers ears in response to certain sounds) Marked distress in change in environment (B does not want to see plate removed after eating) Insistence on following routines Restricted range of interests (odd interests-toy vacuum (A & B), ironing board (B»
Twin
A
B
+
with sufficiently lessened severity to disqualify him from being rated as symptomatic in that area. Examination of chromosomes and zygosity. No fragile-X chromosomes or other abnormalities were seen on cytogenetic testing. The boys were remarkably alike in appearance. Parents reported that they had sometimes confused them when they were younger . Presence of a monochorionic placenta was recorded at birth, thus no additional tests to prove zygosity were conducted. Discussion
+
+
+
+
+
+
+
+
+
+ +
+
+
months and 2 years, 2 months); Socialization, 1 year, 0 months and 1 year, 1 month (interpersonal, 1 year, 9 months and 0 years, 10 months; play, 0 years, 9 months and 0 years, 11 months; coping , 1 year, 5 months and 1 year , 5 months); motor, 2 years, 11 months and 3 years , 7 months (gross, 2 years, 5 months and 2 years , 9 months; fine, 3 years , 11 months and 4 years, 5 months); and an Adaptive Behavior Composite of 23 and 24 months. Thus, although "A" was cognitively less able than " B", he showed better overall communication and daily living skills , better interpersonal skill, but worse motor skills. Diagnostic assessm ent. The twins were evaluated using the DSM-III-R criteria for AD. Both of them met seven out of 16 criteria from the DSM-III-R symptom checklist , given their respective mental ages (Table 1). If a child is positive on eight of 16 criteria, including at least two from A, the social domain; one from B, the communication domain; and one from C, activities and interests ; the diagnosis of AD is assigned. Using the DSM-III-R scoring criteria, the PDDNOS diagnosis is assigned if the child has at least one symptom from first and one symptom from second domain . Thus , PDDNOS constitute s a less severe or full-blown disorder than autism but has the same symptoms. It should be noted that for each positive symptom that at least one twin showed, the same symptom would be present in the other twin but l.Am .Acad . Child Adolesc.Psychiatry, 29:6, November 1990
Genetic factors . In the case of these twins, it is reasonable to suggest that shared symptoms may stem from an expression of the genotype because of monozygosity, even though there is no positive family history for other cases of POD. An examination of their shared clinical features showed they had some similar social impairments-abnormal social play and an inability to engage in peer friendships. Both were unable to engage in simple turn-taking conversation , even given the sizes of their vocabularies . In addition , both exhibited a restricted range of interests ; they fought over a toy vacuum until their mother bought a second one . Later, each developed other odd interests, such as drawing the bathroom in detail and spotting Union 76 logos. Suboptimality. The boys shared a number of suboptimal factors during pregnancy: monozygotic twinning , midtrimester spotting , low maternal weight gain during pregnancy, and diminished fetal movement. In addition to this , twin " A" had lower birth weight , difficulty breathing , low heart rate, hypoglycemia, and high hematocrit. Using a multifactorial model that would consider the interactive effects of a genetic liability and suboptimality , the additional insults suffered by " A" could be seen as possibly related to additional symptoms he exhibited. These included idiosyncratic language, stereotyped body movements, and preoccupation with parts of objects. In an earlier study, it was found that each of these particular symptoms was positively correlated with magnitude of developmental delay (Siegel et aI., 1989). Thus , these findings appear consistent with the fact that "A" had more cogniti ve impairment, possibly secondary to his greater suboptimality. Conversely, the symptoms experienced by "B, " and not by " A," could result from the fact that more cognitive impairment may "blunt" the ability to manifest symptoms that may require some basal level of mental development before they can be expressed (e.g. , "B" showed resistance to changes in the . environment, while "A" did not). Twinning. Twin pregnancies are typically treated as risk pregnancies because of intrauterine crowding and limitations in nourishment for the fetuses (Parson , 1988). Even with improved pre- and perinatal care, the incidence of mortality and morbidity for twin births is still higher than for singletons . Monozygotic twins have an additional disadvantage because genetic material should be divided. Monozygotic twinning is thought to be due to chance, unrelated to heredity , resulting from a delay in implantation associated with nutritional status, hypoxia, or other stressors (Parson, 1988). This delay leads to monozygotic twins, generally with a monochorionic placenta (Newton, 1986; McCulloch, 1988).
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VUKICEVIC AND SIEGEL
Twinning itself has not been shown to be a significant risk factor for development of PDD. In this case study, the fact that the mother gained just 10 kg during pregnancy and twin "B'''s birth weight was appropriate for gestational age is suggestive of intrauterine deprivation for twin" A " , possibly due to even earlier problems experienced by that twin . Generally, intrauterine growth of twins is similar to singletons up to 30 weeks of gestation (Blecker et al., 1979). Placental insufficiency in twin pregnancies is usually manifested by 38 weeks of gestation. However, maternal weight gain during pregnancy does not differ significantly among mothers of PDD children, children compared to those with idiopathic MR, or normal children (Torrey and Hersh, 1975) . However, diminished fetal movement during pregnancy has been recorded occasionally in the histories of PDD children but has not been shown to be significantly different from normals or those with idiopathic MR (Mason-Brothers et al. , 1987). Additional risks . None of the additional suboptimal factors present in twin "A" are specific for PDD children, but all of them can cause general , nonspecific central nervous system impairment (McCulloch , 1988; O'Brien and Hay , 1987). Clinically, these factors appear to be associated with an IQ in the range of mild MR and more difficulty with language use and articulation, both of which were more pronounced in twin "A". Overall difference in IQ between monozygotic twins correlates with birth weight difference (Segal , 1985; O'Brien and Hay , 1987). Failure-to-thrive and motor milestone delays are not specific for, nor commonly seen in , children with PDD (Paul , 1987). Here again, given the maternal developmental history, the growth failure of these twins may have had a genetic basis, though independent of the genotype for PDD. It seems that these twins had the potential for developing PDD and they did so, but twin "A" had more suboptimal factors present, and thus experienced generalized nonspecific CNS impairment, in addition to PDD. "A" showed more cognitive delay and, in particular, more language delay. Overall, he seemed more social, but more retarded in his development than his twin brother. " B " appeared less impaired cognitively but more impaired socially , consistent with his diagnosis of PDDNOS and his exposure to fewer suboptimal factors. Thus, this case study suggests that suboptimal pre- and perinatal factors may be related to delayed development and may, in fact, blunt the effect of PDD . The
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form of PDD seen in these twins possibly may be viewed as aberrant, rather than delayed development, resulting from the genotype for autism. References Blecker, O. P., Breuer, W. & Huidecoper, B. L. (1979), A study of birth weight, placenta, weight and mortality of twins as compared to singletons. Br. J . Obstet, Gynecol., 86:111-118 . Bryson, S ., Smith, 1. & Eastwood, D. (1988), Obstetrical suboptimality in autisticchildren. J . Am . Acad. Child Adolesc. Psychiatry, 27:418-422.
Folstein, S. & Rutter, M. (1977), Infantile autism: a genetic study of 21 twin pairs. J. Child Psychol. Psychiatry, 18:297-321. - - - - (1988), Autism: familial aggregation and genetic implications. J Autism Dev, Disord ., 18:3-30. Mason-Brothers, A., Ritvo, E., Guze, B. & Freeman, B. J. (1987) , Pre-, peri- and postnatal factors in 181 autistic patientsfrom single and multiple incidence families. J. Am. Acad . Child Adolesc. Psychiatry, 26:39-42 .
McCulloch, K. (1988), Neonatal problems in twins. Clin. Perinatol., 15:141-158.
Newton, E. R. (1986), Antepartum care in multiple gestation. Semin. Perinatol., 10:19-29.
O'Brien, P. J. & Hay, D. A. (1987), Birthweight difference, the transfusion syndrome and the cognitive development of monozygotic twins. Acta Genet. Med. Gemellol., 36:191-196 . Paul, R. (1987), Natural history. In: Handbook for Autism and Pervasive Developmental Disorders, eds. D. J. Cohen & M. A. Donellan. New York: J. Wiley & Sons, Inc. Parson , M. (1988), Effects of twins: maternal, fetal, and labor. Clin. Perinatol., 15:41-53.
Ritvo, E. R., Freeman, B. J., Mason-Brothers , A., Mo, A. & Ritvo, A. M. (1985 ), Concordance for the syndrome of autism in 40 pairs of afflicted twins. Am. J . Psychiatry, 142:74-77 . Segal, N. L. (1985), Monozygotic and dizygotic twins: a comparative analysis of mental ability profiles. Child Dev ., 56:1051-1058. Siegel, B., Vukicevic, J., Elliott, G. R. & Kraemer, H. C. (1989 ), The use of signal detection theory to assess DSM-III-R criteria for autistic disorder. J . Am. Acad . Child Adolesc . Psychiatry , 28:542548.
Smalley, S. L., Asarnow, R. F. , and Spence, M. A. (1988), Autism and genetics: a decadeof research. Arch. Gen. Psychiatry, 45:953961.
Steffenberg, S., Gillberg, C., Hellgren, L., Andersson, L., Gillberg , I. C., Jakobsson, O. & Bohman, M. (1989), A twin studyof autism in Denmark, Finland, Iceland, Norway, and Sweden. J. Child Psychol. Psychiatry, 30:405-416 .
Torrey, F. & Hersh, S. (1975), Earlychildhood psychosis andbleeding during pregnancy. Journal of Autism and Childhood Schizophrenia, 15:287-297.
Zahner, G. & Pauls, L. D. (1987), Epidemiological surveys on infantile autism. In: Handbook of Autism and Pervasive Developmental Disorders. eds. D. J. Cohen & M. A. Donellan. New York: J. Wiley & Sons Inc.
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