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Sex chromosome abnormalities occur in at least 1 in 400 births and include the well-described 47,XXX, 47,XXY, 47,XYY, and 45,X karyotypes. The addition of more than one extra X or Y chromosome occurs rarely, and little information is available in the medical literature. Individual case reports make up most of this body of knowledge, and all are based on subjects who identified themselves postnatally. Many were ascertained through screenings of institutions and hospitals; thus, there is no unbiased information on the natural history of poly X and Y karyotypes. A direct relationship between the number of additional sex chromosomes and the severity of the phenotype is generally assumed. The purpose of this article is to summarize what is known about these conditions and to present 10 additional cases. The karyotypes include, 48,XXXX, 49,XXXXX, 48,XXYY, 48,XXXY, 49,XXXXY, 49,XXXYY, 48,XYYY, 49,XYYYY, and 49,XXYYY. Pediatrics 1995;96:672-682; sex chromosome abnormalities, tetrasomy, pentasomy, 48,XXXX, 49,XXXXX, 48,XXYY, 48,XXXY, 49,XXXXY, 49,XXXYY, 48,XYYY, 49,XYYYY, 49,XXYYY.
SUMMARIES AND CASE REPORTS^
48,XXXX^
Approximately 40 cases of 48,XXXX or tetrasomy X have been described [5] since the first two reports by Carr et al in 1961. [6] Like 47,XXX, this multiple X chromosome disorder can be diagnosed only by karyotyping, because there are no consistent clinical features or specific abnormalities. Stature is variable, but among adult 48,XXXX women, tall stature is common, with an average height of 169 cm. Facial abnormalities are usually minor and have included epicanthic folds, hypertelorism, and nystagmus. Skeletal anomalies generally consist of clinodactyly and radioulnar synostosis. Genitalia are usually normal, but development of secondary sex characteristics can be incomplete. Almost one third of the reports of 48,XXXX consist of adult women, and of these, approximately half had normal menarche and menopause, whereas the other half had menstrual dysfunction. Three 48,XXXX women have reproduced: a 33 year old gave birth to a healthy child and another child with trisomy 21; [7] a 20 year old had a stillbirth with an omphalocele; [8] and a third woman, age 27, had a healthy daughter with a 46,XX karyotype. [9].
Mental retardation is characteristic of 48,XXXX, with an average IQ of 60 (range reported from less than 30 to 75). There has been one report of a 48,XXXX female with a normal IQ; at age 5 her IQ was 101, and at 27 years of age her intelligence was low average. [9] Speech and language disorders occur frequently and may include articulation defects and a delay in both expressive and receptive language. Language is often reported to be appropriate for mental ability.
There is no consistent behavioral phenotype. Individuals with 48,XXXX have been described in various reports as pleasant, friendly, and cooperative as well as socially inappropriate, aggressive, and emotionally labile. Approximately half of the adult women have had periodic bouts of unstable behavior generally described as angry, disruptive, and inappropriate.
A.D. Figure 1 is a 4-year-old girl who was born after a 36-week gestation to a gravida 2, para 1, 18-year-old Hispanic woman and a 21-year-old Hispanic man, both healthy with unremarkable family histories. Neither parent completed high school. Two other daughters, ages 5 years and 1 year, are healthy. A genetic work-up was performed at age 20 months because of developmental delay, hypotonia, strabismus, congenital torticollis, and congenital hip dysplasia. Cytogenetic analysis of 100 cells indicated a fragile X-negative, 48,XXXX karyotype. A.D. was conceived while her mother was taking birth control pills, which were discontinued at 5 weeks' gestation. The pregnancy was complicated by intermittent spotting and placenta abruptio. At birth A.D. weighed 5 lb 1 oz (less than the fifth percentile) and was small for gestational age. No neonatal complications or dysmorphology were observed. At 6 months she was noted to have right congenital hip dysplasia and congenital torticollis. During her first year several respiratory infections developed; these included otitis media, bronchitis, and pneumonia. She also had episodes of occasional choking and severe constipation. Ischemic necrosis of the femoral head began to develop by 2 years of age. An electroencephalogram, subsequent to a concussion, was normal.
A.D.'s development has been markedly delayed. She walked at 18 months. At 20 months on the Bayley Scales of Infant Development she scored 66 on the mental scale and 68 on the motor scale. The results of the Peabody Motor Scales at age 42 months were 24 months for gross motor skills and 31 months for fine motor skills. Currently, her large motor coordination is poor, and she is clumsy. Language development has been severely delayed. Her first words were at approximately 24 months. By 30 months she had developed a 20-word vocabulary but could not combine 2 words. At age 4 years her score on the Peabody Picture Vocabulary Scale was 78, equivalent to the seventh percentile, and she was still using only single words.
Behavior has not been a concern. A.D. is generally appropriate with both peers and adults but occasionally demonstrates her temper as a result of frustration over her lack of ability to communicate. She attends a special education preschool and receives physical therapy, occupational therapy, and speech therapy.
A.R. Figure 2 is a 5-year 10-month-old girl who was born at term to a gravida 4, para 3, 23-year-old woman and a 28-year-old man, both high school graduates. The parents are Hispanic and may share a common ancestor. The mother has a maternal uncle with severe mental retardation, cause unknown, and all other family history is unremarkable. Two siblings of A.R. are healthy, but another brother has learning disabilities. Severe developmental delays during the toddler and preschool years prompted a chromosomal investigation at age 5 years, which indicated 20 of 20 cells to be 48,XXXX. The pregnancy was complicated by oligohydramnios and intrauterine growth retardation. Bradycardia was prolonged during the 4-hour labor. Birth weight was 5 lb 6 oz (less than the fifth percentile), and she was small for gestational age. No birth abnormalities or neonatal complications were noted. At 4 months of age, A.R. was hypotonic and had strabismus. By 9 months of age, she was found to have gross motor delay. A.R. has a history of recurrent otitis media, Staphylococcus aureus infection, and anemia. She had a diagnosis of asthma at age 5 years.
Her development has been significantly delayed. Results of the Peabody Picture Vocabulary Test at age 5.5 years indicated an age equivalent of 3 years 3 months and placed A.R. at the first percentile. Administration of the Wechsler Preschool and Primary Scale of Intelligence (five subtests) resulted in an extrapolated score of 57, below the first percentile, indicating mild mental retardation.
A.R. is a friendly child who generally engages in solitary or parallel play. She can become frustrated with peers, because her social skills are poorly developed, and this often results in hitting other children. She is unable to remember simple school routines, and a teacher has noted that "every day is like her first day with everything new." Her distractibility suggests that she may have attention deficit hyperactivity disorder. A.R. attends a school for learning-disabled children and receives physical, occupational, and speech therapy.
49,XXXXX^
The manifestations of penta X are more severe than those of tetra X, and 49,XXXXX has been reported less frequently. Since the first case report in 1963 of a 2-year-old girl with three extra X chromosomes, [10] less than 25 additional cases have been documented in the literature, [11] and none of these describes a girl older than 16 years. The characteristic penta X phenotype includes mental retardation, short stature, coarse facial features, and skeletal and limb anomalies. Intrauterine and postnatal growth retardation are common features. Craniofacial anomalies often include microcephaly, hypertelorism, epicanthic folds, upward-slanting palpebral fissures, a depressed and/or broad nasal bridge, and a short, broad neck. Congenital heart defects usually consist of patent ductus arteriosis or a ventricular septal defect. Both osseous and articular anomalies are usually present and can include bilateral clinodactyly of the hands and feet, radioulnar synostosis, generalized joint laxity with multiple dislocations, and talipes equinovarus. Bilateral transverse palmar creases are common. External genitalia are normally female in appearance. On further examination, several girls have been noted to have small uteri. Puberty has been delayed in two adolescent girls, and fertility is assumed to be reduced but is undocumented. There is no report of pregnancy in a 49,XXXXX woman.
These girls are mentally retarded, with an average IQ of 50 (range, 20 to 75). Speech is delayed, and communication is difficult. Behavioral characteristics are frequently not described, and no distinct behavioral profile has emerged. Most 49,XXXXX girls are said to be shy and cooperative.
L.J. Figure 3 is 15 years old and is the second oldest penta X girl to be reported. She was the first child of parents who were in their early 20s at her birth and are high school graduates. They have a healthy younger daughter. A genetic evaluation for multiple congenital anomalies at age 8 years revealed the 49,XXXXX karyotype. L.J. is small, with height (140 cm) and weight (30 kg) both below the fifth percentile and a head circumference (51 cm) below the second percentile. Facies are coarse and include a broad forehead, a depressed nasal bridge, telecanthus, low-set ears, a prognathic jaw, and a short neck. L.J. has had significant orthopedic problems, including four surgeries for bilateral genu valgus as well as dislocated elbows and radioulnar synostosis. Cardiac structure and function have been normal. Her genitalia are normal female, and at 15 she is still prepubertal.
48,XXYY^
This karyotype is the most common variant of Klinefelter syndrome. The addition of an extra Y chromosome has been generally thought to result in more severe cognitive and behavioral problems in addition to the physical features of 47,XXY. However, a bias of ascertainment exists, because at least one third of the more than 120 worldwide reported cases were obtained from mental and behavioral hospital screenings in the 1960s and 1970s. The first case was that of a 15-year-old boy in an institution for the mentally retarded reported by Muldal and Ockey in 1960. [12] The incidence is estimated to be 1 in 50 000 male births [13] and is not associated with advanced parental age. Propositi as old as 70 have been described.
Men with 48,XXYY are usually tall with an adult height greater than 6 ft (> 171 cm), and they are thus taller than 47,XXY men. The upper segment-to-lower segment ratio is decreased (< 1), with long, thin legs and a eunuchoid habitus being characteristic. Facial characteristics are variable, and skeletal findings are generally minor. Hypertrophic hypogonadism is similar to that of 47,XXY men: increased follicle-stimulating hormone and luteinizing hormone, decreased testosterone, small testes, and sparse body hair. About half have been reported to have small penises. Testicular histology is similar to 47,XXY and includes hyalinization of the seminiferous tubules, hyperplasia and fibrosis of interstitial (Leydig) cells, and lack of spermatogenesis. Testosterone therapy is similar to that prescribed for Klinefelter syndrome. The presence of gynecomastia has been reported frequently and is not prevented by testosterone supplementation. Peripheral vascular disease consisting of leg ulcers and varicose veins has been observed occasionally.
In published case reports, mild mental retardation has been a characteristic finding. Most IQs have ranged from 60 to 80 but at least 10% were above 80, and IQs up to 111 have been reported. [13] Speech delay is often noted, with receptive skills better than expressive skills. Motor delay and decreased coordination are similar to that observed in 47,XXY boys.
Behavior is often shy and reserved, but reports of impulsive and aggressive tendencies are more typical. Because karyotypes were performed in many instances because of behavioral problems, a bias of ascertainment needs to be considered. It is generally assumed that psychosocial development and behavior are more disturbed than in 47,XXY.
The following two cases are noteworthy in that neither boy has significant behavior problems, and both boys have IQs in the low normal range.
M.B. Figure 4 is a 13-year-old boy and the third of four children born to a 31-year-old mother and 32-year-old father, both college graduates. The other children are healthy. Because of speech and language delays and mild dysmorphism, a karyotype analysis was performed on M.B. at age 8, which indicated all cells to be 48,XXYY. He is now a tall (90%) adolescent with slightly coarse facies: bilateral epicanthic folds, simplified ears with prominent antihelices, a prominent nasal bridge, and prognathism. His teeth are large with long roots, and extensive orthodontia is being undertaken. Skeletal findings and genitalia are normal prepubertal. He has mild asthma.
Moderate behavioral concerns have abated recently. Temper tantrums were common for M.B. since age 3 years and were attributed to his frustration as a result of inability to communicate and to keep pace with peers or with his siblings. He has always been a sensitive, anxious, and immature child, preferring friends younger than himself. His decreased self-esteem is similar to that often seen in 47,XXY adolescents. Since placement in a school for children with learning disabilities, he has begun to gain confidence and has a more positive attitude. His parents have exposed their son to a variety of activities and interests, as well as provided consistent intervention and support when needed.
R.I. Figure 5 is a 12-year-old boy who was was born to a healthy couple in their early 20s who are both college graduates. The family history includes multiple sclerosis in the maternal grandmother and learning disabilities in two half-cousins. The parents of R.I. have a healthy daughter. At 6 years of age, R.I. was determined to be 48,XXYY when he was evaluated for motor delay and learning disabilities. R.I. is currently below the 10th percentile for height and weight, which is in contrast to the usual tall phenotype. His parents' heights are at the 40th and 60th percentiles. He has slightly coarse features, including a narrow face, epicanthic folds, telecanthus, and a slight overbite. Skeletal abnormalities consist of radioulnar synostosis and clinodactyly of the fifth digits of the hands and feet. His penis is of normal size, but his testes are small (3 cm). He has had bilateral inguinal hernias, one of which has been repaired.
48,XXXY^
The addition of an X chromosome to the Klinefelter syndrome karyotype results in 48,XXXY. Only 50 cases have been reported since Barr et al described the first case in 1959, [14] and only two cases have been cited in the literature in the last decade. [15,16] The reason for this recent lack of reports is not known but may be attributable to a phenotype relatively similar to the 47,XXY phenotype. Individuals ranging in age from infancy to 60 years have been described. Two sets of identical twins with the 48,XXXY karyotype have been reported. [17,18] Most cases were ascertained more than 20 years ago, many through inpatient screenings of hospitals for the mentally retarded or psychologically disturbed, and thus much of the information known about 48,XXXY male patients may be particularly biased.
The 48,XXXY karyotype is considered a variant of Klinefelter syndrome, with features generally more pronounced than 47,XXY but less severe than 49,XXXXY. Stature is normal to tall, with a decreased upper segment-to-lower segment ratio. Hypertelorism and epicanthic folds are common. Simplified ears and mild prognathism have been reported. Skeletal anomalies include clinodactyly, abnormalities of the elbows, and radioulnar synostosis. Males with 48,XXXY have hypergonadotrophic hypogonadism and testicular histology similar to 47,XXY and 48,XXYY. At least one fourth of the patients have had hypoplastic penises. These males are infertile and may benefit from testosterone therapy, usually beginning in adolescence. Gynecomastia is frequently reported. An occasionally reported finding is an abnormal glucose tolerance test, but no data on the incidence of diabetes are available.
Mild mental retardation usually has been observed, with an IQ range of 20 to 76 reported; most fall in the 40- to 60-point range. Speech delay is common, as are slow motor development and subsequent poor coordination.
Behavior is often immature for chronologic age but consistent with the level of intelligence. Most reports have described these males as being passive, placid, pleasant, and cooperative. The aggressive behavior described in 48,XXYY is seldom observed in this group.
J.K. Figure 6 is now 19 years old and in his final year of high school. He was the first pregnancy of 26-year-old college-educated parents, both with advanced degrees. Two younger siblings are healthy. J.K. has been followed since 3 years of age, when he was referred for hypospadius, penile chordee, bifid scrotum, and cryptorchidism; a karyotype analysis indicated all cells to contain two additional X chromosomes. J.K. is tall (70%) without gross dysmorphism. He has a prominent brow, epicanthic folds, a broad nasal bridge, and prominent ears. Aside from mild clinodactyly, there are no skeletal abnormalities. He does not have gynecomastia. His penis and testes are small, and he has been receiving testosterone injections for 2 years.
Immaturity and passivity have been troublesome for J.K. for many years. His social skills are poor, and he is essentially without companions except for a younger brother and sister. Emancipation from his family and independence will be difficult for him to achieve.
49,XXXXY^
The most severe variant of Klinefelter syndrome is 49,XXXXY. This karyotype has been reported more than 100 times [19] since the first case in 1960, [20] and its incidence is estimated to be 1 in 85 000 to 1 in 100 000 male births. [21] It seems to be somewhat common in the literature compared with other poly X syndromes, possibly because of the severe clinical phenotype. Characteristic features include coarse facies, skeletal anomalies, hypogenitalism, and mental retardation.
The list of possible physical features is numerous. The skull is usually microcephalic and may be brachycephalic or dolichocephalic. A combination of several anomalies contributes to a coarse facial appearance and can include hypertelorism, epicanthic folds, upslanting palpebral fissures, a broad nasal bridge, a broad nose, low-set and malformed ears, and mandibular prognathism. A cleft palate and/or bifid uvula are often observed. The neck is generally short and broad, whereas the thorax is narrow. Cardiac defects, most frequently patent ductus arteriosus, are present in 15% to 20% of cases. There is generally skeletal involvement consisting of radioulnar synostosis, genu valgum, pes cavus, and clinodactyly of the fifth digits of hand and feet. Most have short stature. Such findings are accompanied by hypotonia and hyperextensible joints. Genitalia are hypoplastic, and cryptorchidism is frequent in these males with hypergonadotrophic hypogonadism. The life span does not seem to be decreased.
Mental retardation is characteristic of 49,XXXXY, with the mean IQ estimated by Borghgraef et al to be 35. [22] The range is usually 20 to 60, but there have been isolated reports of a few boys in the 67 to 72 span; [19,23,24] the final adult IQ is unknown. Lomelino and Reiss [25] described a 5-year-old 49,XXXXY boy with an IQ of 78, but it is not known whether this cognitive level will decrease over time, as has been reported. [22,26] There is generally severe retardation of language development characterized by poor speech fluency, and nonverbal skills are greater than verbal skills.
Behavior is described as timid and shy to friendly with a generally pleasant demeanor. However, periods of irritability are not uncommon, and episodic temper tantrums may occur. These males may have a low frustration tolerance and can react strongly to minimal changes. Although many were ascertained through institutional surveys, others have been able to live and work in semisupervised settings.
J.F. Figure 7 is a 21-year-old man who has been living in residential placement for 10 years. He was born to a gravida 2, para 1 24-year-old mother and 29-year-old father, both high school graduates with nonsignificant medical histories. A maternal great aunt had a 46,XX/47,XXX karyotype. An older half-brother is healthy. J.F. was diagnosed with the 49,XXXXY karyotype at birth, subsequent to a genetic evaluation for low Apgar scores and respiratory distress. He has characteristic physical anomalies, including coarse facies, radioulnar synostosis, and hypogonadism. In contrast to most 49,XXXXY men with short stature, he is 185 cm tall (90%) and weighs 65 kg (35%); his mother's height is at the 60th percentile, and paternal height is at the 25th percentile. Severe joint instability has been present, and his ability to walk unaided has been decreasing. J.F. has a history of congenital heart disease previously reported as patent ductus arteriosis and pulmonary hypertension. [27] He has a seizure disorder and mild hydrocephalus; a computed tomographic (CT) scan at 12 years of age revealed diffuse atrophy of the cerebrum and cerebellum.
J.H. Figure 8 is 27 years old and was born to healthy college-educated parents in their mid-20s with a healthy daughter. His chromosomes were examined at 3 years of age, subsequent to developmental delay and a facial appearance suggesting Down syndrome. Currently, he is 172 cm in height (25%) and weighs 53.5 kg (< 5%). He is microcephalic, and a CT scan at age 19 years revealed mild enlargement of the ventricles. J.H. has a narrow forehead and unusual facies caused by left facial hypoplasia and right facial palsy. Other features include ptosis, a broad nasal bridge, low-set ears with prominent auricles, a cleft palate, mild prognathism, mild webbing of the neck, and a narrow thorax with sloping shoulders. He was diagnosed in infancy as having an atrial septal defect, patent ductus arteriosus, and an anomalous coronary artery; these were corrected surgically and previously reported in 1975. [27] Skeletal malformations consist of bilateral radioulnar synostosis, scoliosis, and hyperextensible joints. His balance is diminished, and he has a mild tremor of the hands. Genitalia are small, and cryptorchidism of the right testis was noted at birth. At age 27 he is Tanner stage 1.
At age 13, low-dose testosterone replacement therapy (25 mg depotestosterone cypionate every 3 weeks) was begun in full support of the propositus and his parents because of hypertrophic hypogonadism, failure to develop secondary sexual characteristics, low energy level, and the parents' wish to have him identify more comfortably with adolescent boys. Physical changes occurred slowly, and he became more energetic and social; however, he began occasional public masturbation. When the dose was increased to 50 mg, inappropriate sexual behavior increased, and therapy was discontinued at age 16. As a young adult, J.H. has continued to be sexually active, often with developmentally delayed women.
Until his mid-20s, the behavior of J.H. was usually socially appropriate. A series of family events, which concurred with his move out of the home to a sheltered environment and a job, were thought to precipitate periods of alcohol abuse, major depression, and problems with the law. The combination of counseling and psychotropic medication has helped modify his behavior. He continues to live in a supervised apartment with a roommate and generally has adapted well. Much of his success is attributable to a very protective and supportive family.
B.T. Figure 9 is a 15-year-old boy who was the first pregnancy of healthy, college-educated parents in their 20s. They have a younger healthy son. After 5 years of chronic upper respiratory illness, developmental delays, and observed mild dysmorphic features, a karyotype analysis revealed the presence of three extra X chromosomes. He was also diagnosed as having asthma. B.T. is 160 cm tall (20%), weighs 54 kg (35%), and his head circumference is 53.5 cm (25%). Facial features include a dolichocephalic skull, a low hairline, a prominent brow, a broad nasal bridge, telecanthus, a marked overbite, and a short, broad neck. B.T. has a bifid uvula and an elevated palate. A CT scan of the skull was normal, as was an echocardiogram. He has an abnormal craniocervical junction, a rotated pelvis, contractures of the digits, bilateral clinodactyly, radioulnar synostosis, and hyperextensible joints. His testes and penis are small, and he has a shawl scrotum. Bilateral hernia repair occurred at 6 years of age.
B.T.'s behavior is generally appropriate, and he gets along well with his brother. He is usually passive but has a low frustration tolerance that is compounded by his inability to communicate and is expressed through temper tantrums and inappropriate gestures. B.T. has attention deficits without hyperactivity, although he occasionally acts impulsively. He attends a school for handicapped children.
49,XXXYY^
This poly X and Y karyotype has been reported only five times and includes a case of a prenatally diagnosed fetus, which was terminated. [28] The other four males, ages 3 to 42 years, were all moderately to severely mentally retarded. [29-32] Physical features included normal to tall stature, facial dysmorphology, gynecomastia, and hypogonadism. Behavior was described as generally passive with occasional outbursts and aggression. We report the fifth instance of a live-born 49,XXXYY male.
S.P. Figure 10 is a 6-year-old boy, the second child born to healthy, college-educated parents, ages 30 and 32 years. Their older son is healthy. As an infant, S.P. was severely hypotonic and had developmental delays, which prompted karyotype studies at age 12 months. He was also diagnosed at this time as having asthma. S.P. is a large boy (height, 113 cm, 75th percentile; weight, 19.1 kg, 50th percentile; and head circumference, 54 cm, 98th percentile) with a prominent forehead, a broad nasal bridge, epicanthic folds, posteriorly rotated ears, and micrognathia. An electroencephalogram at age four was normal, but magnetic resonance imaging indicated ventricular enlargement and deficient white matter in the frontal lobes. His chest is narrow with thin sloping shoulders that are readily approximated. He has bilateral clinodactyly of the hands and toes. Genitalia are small.
48,XYYY^
This is the most benign of the polysomy Y conditions. Eight cases have been reported since Townes et al [33] described the first case in 1965, a 5-year-old boy ascertained because of mild psychomotor retardation. The other seven cases have included a 9-year-old boy and six adults, ages 20 to 52 years. [34-40] The 48,XYYY karyotype does not present with a consistent phenotype. Most adults have tall stature. Minor malformations such as transverse palmar creases, clinodactyly, and abnormal teeth have been reported, but no conspicuous physical anomalies are common. Both children had frequent upper respiratory infections. The genitalia in the boys were normal in appearance, but hypogonadism with azoospermia was present in five of the six adult men.
Psychomotor retardation in the boys consisted of delayed age of walking and delayed speech. The IQs among the propositi were generally in the low normal range with a span of 65 to 86, and performance IQs were greater than verbal IQs. Behavior has been reportedly troublesome, characterized by impulsivity and a low frustration tolerance. Occasional aggressive outbursts and poor emotional stability seem to be fairly consistent in 48,XYYY males. There has been one report of occasionally severe behavioral disturbances in an adolescent; he was the product of parental neglect and had a brother with behavior problems. [36].
49,XYYYY^
Three cases of 49,XYYYY have been reported and consist of boys 1, 2, and 7 years old who were ascertained at birth because of the presence of dysmorphic features. [41-43] Facial anomalies have included hypertelorism, low-set ears, and micrognathia. Radioulnar synostosis, scoliosis, and clinodactyly were consistent skeletal findings, but stature has varied from the 10th to 90th percentiles. Genitalia were normal at birth in all cases, but a follow-up study on one propositus at age 3 years indicated elevated basal levels of plasma gonadotropins and an increased response to luteinizing hormone releasing hormone; it was assumed that testicular insufficiency, similar to that seen in 47,XXY males, would be likely. [44] Mental retardation, motor retardation with hypotonia, and speech delay are features. Behavior characteristics were reported in two patients at age 7 years; a boy followed since 1 year of age was said to be impulsive with a low frustration threshold, [45] and the other was aggressive and temperamental. [43].
49,XXYYY^
A single report of the 49,XXYYY karyotype described a 7-year-old boy with facial dysmorphism and mental retardation. [46] Physical features included microcephaly, hypertelorism, upslanting palpebral fissures, a broad nose and philtrum, and micrognathia. A CT scan of the skull was normal. Consistent with other poly Y karyotypes, recurrent upper respiratory infections were present. Stature was at the 80th percentile, and radioulnar synostosis as well as delayed bone age were noted. Genitalia were normal. He had mental retardation with an IQ of 46. No information was reported regarding behavior.
DISCUSSION^
Effect of Supernumerary X and Y Chromosomes^
The addition of more than one extra X and/or Y chromosome to a normal female or male karyotype results in physical and mental abnormalities. It is generally assumed that there is a direct relationship between the number of supernumerary X chromosomes and phenotypic abnormalities and mental retardation, with each additional chromosome increasing the severity. This was acknowledged as early as 1962 in the initial reports of 49,XXXXY males. [47].
Somatic development is most significantly affected in several areas. Skeletal and cardiovascular abnormalities can become increasingly severe with each addition of an X chromosome. Gonadal development in males is particularly susceptible to extra genetic material. The addition of a single X chromosome to a 46,XY karyotype results in seminiferous tubal dysgenesis, rendering infertile such males with Klinefelter syndrome. Additional extra X chromosomes in polysomy X males (48,XXXY and 49,XXXXY) can result in not only infertility but hypoplastic and malformed genitalia. Among females the effect on fertility is less definitive. 47,XXX women are generally fertile, but 48,XXXX women have reduced fertility, with a few experiencing normal menses but most reporting abnormal or absent cycles. No penta X women have been described; both 49,XXXXX teenagers have remained prepubertal at midadolescence.
The increasing number of X chromosomes also affects cognitive development. Mental capacity diminishes directly with the number of extra X chromosomes. Studies of children with SCA (47,XXY, 47,XXX, 45,X, and 47,XYY) have indicated an approximate 10- to 15-point reduction in IQ points compared with their chromosomally normal siblings. [48] The addition of a second extra X chromosome reduces the IQ further, with the average IQ of individuals with 48,XXXY and 48,XXXX karyotypes reported to be approximately 60. The further addition of a third extra X chromosome in the 49,XXXXX and 49,XXXXY karyotypes results in even more severe mental retardation. Because there is great variability within each karyotype group, conclusions must be drawn cautiously, but the approximate 15- to 16-point IQ reduction for each supernumerary X chromosome first suggested by Polani in 1977 [49] is generally a reliable estimate of intelligence. Language is also directly affected by the number of X chromosomes. Individuals with SCA are at risk for language disabilities and delays, but such risks are significantly increased among those with polysomy X karyotypes. Delays in both expressive and receptive language are common, with expressive language being more severely affected. This is most apparent among those with the 49,XXXXX and 49,XXXXY karyotypes in which there are many reports of limited vocabularies and the inability to articulate. Such expressive difficulties contribute to behavior problems in many of the polysomy X karyotypes in which this disability can lead to frustration, which then is expressed in impulsive outbursts, anger, and temper tantrums. In a like manner, motor coordination is also affected by the addition of chromosome material. Poor coordination is a feature of all karyotypes, with diminishing abilities demonstrated as more Xs are added. Thus, all major areas of development are affected by the addition of extra X chromosome material.
Because few cases of polysomy Y karyotypes have been reported, such generalities regarding supernumerary Y chromosomes are not as reliable. The addition of more than two Y chromosomes usually results in physical and mental impairment, but the effects and abnormalities seem to be more limited. The resultant phenotype of a polysomy Y karyotype (48,XYYY and 49,XYYYY) usually consists of minor malformations in facial appearance and skeletal features. Genitalia reportedly appear normal in boys, but hypogonadism can be present in adults. Developmental problems are similar to, but to a lesser degree of severity than, those in individuals with polysomy X karyotypes. Based on the reported cases of polysomy Y karyotypes, Das et al [46] have concluded that the severity of clinical features is not related to the number of supernumerary Y chromosomes. Because additional Y chromosomes are often accompanied by additional X chromosomes (48,XXYY, 49,XXXYY, and 49,XXYYY) it is difficult in these cases to ascribe specific characteristics in the phenotype to either the X or Y chromosome. More data are needed to determine the effect of extra Y chromosomes on growth, development, and behavior.
Ascertainment Bias^
When the technique for screening individuals for X and Y chromosome abnormalities was developed in the 1960s and 1970s, several research groups used the new methods to study unique populations. Most often the subjects consisted of prison inmates or institutionalized patients with behavior problems and/or mental deficiencies. These early studies formed the body of information available for many years on individuals with extra X and Y chromosomes. Much of that data and its conclusions subsequently have been refuted by the prospective studies of propositi ascertained at birth and followed into adulthood in several centers. [1-4] We now know that the prognosis for individuals with SCA is not as poor as formerly stated, and that great variability exists for each karyotype. Unfortunately, because of the rarity of the polysomy X and Y karyotypes, no such prospective studies have been possible that would present an unbiased body of knowledge about such individuals. Thus, any conclusions about polysomy X and Y karyotypes are based on affected individuals who have identified themselves clinically, usually with significant problems. Furthermore, to our knowledge, there are no instances of prenatally diagnosed polysomic X and/or Y children who are being followed. The literature includes several reports of such cases in which the family chose to terminate the pregnancy, and the fetal phenotypes have been inconsistent. The physical findings of a 20-week-old 49,XXXXY fetus reported by Rehder et al [50] included facial features suggesting Down syndrome, skeletal abnormalities, and hypogonadism. In four other instances of terminations in the second trimester of 49,XXXXY, 49,XXXYY, and 48,XXYY fetuses, no gross malformations were observed; [51-53] the gonadal histology was abnormal in one 49,XXXXY specimen. [51] Whether more benign phenotypes of sex chromosome polysomy and tetrasomy karyotypes are possible has not been established. It is of interest that both of the 48,XXYY boys reported in this paper have IQs greater than the majority of reports, and neither exhibits any of the behavior problems associated with this karyotype. Our 48,XXXY adolescent (J.K.) has an IQ greater than that in any previous report. Sheridan et al [19,23] and Hersh et al [24] describe three 49,XXXXY boys whose delays are significantly less than those generally reported. It is most likely that other instances exist that are at odds with the information that has been based mainly on institutionalized individuals. In the meantime, conclusions are dependent on previously reported cases, which exist only in small numbers. It would be in the interest of all clinicians and geneticists to publish case studies of any polysomy X and Y karyotypes to appreciate the potential for individuals with these syndromes.
Environment^
For individuals with X and Y chromosome abnormalities, the importance of a supportive family and a healthy environment cannot be overemphasized. Previous studies of children with the single loss or addition of an X or Y chromosome have concluded that such affected individuals are more sensitive to a stressful environment than are their chromosomally normal siblings. [54] In a like manner, those with several extra sex chromosomes also function better in the presence of intact families committed to their well-being. [23,24,45].
In the previous 10 cases in this article, several individuals are achieving at higher levels than those generally reported. In each case, the parents have been involved in all aspects of their child's development and education. They have initiated early intervention by pursuing professional help for their child at the first sign of a delay. The parents have been actively involved in their child's education through interaction with school personnel and agencies. The children have been exposed to many varied activities and experiences and are praised for their progress and their strengths, while their limitations and delays are minimized. Goals have been realistic and have included appropriate expectations for learning, behavior, and self-care. In short, these parents have acted as advocates for their children in every setting.
Parental Origin of Multiple X and/or Y Chromosomes^
The recent advances in molecular genetic techniques have been used to determine the parental origin of extra sex chromosomes in more than 20 instances of tetrasomy and polysomy. Using restriction fragment length polymorphisms and hypervariable dinucleotide repeat sequences, the origin of the extra X and Y chromosomes has been studied in the following karyotypes: 48,XXXX, 49,XXXXX, 48,XXYY, 48,XXXY, and 49,XXXXY. In all but one instance, a single parent contributed all of the additional sex chromosomes, with the other parent contributing a single X or Y chromosome. [55-57] The single exception was a case of uniparental maternal tetrasomy in a 48,XXXX karyotype, in which no paternal sex chromosome material was detected. [58] Among all other females with 48,XXXX or 49,XXXXX karyotypes, one X chromosome was contributed by the father and the remaining three or four X chromosomes by the mother. This is similar for all males studied with a 49,XXXXY karyotype--the Y chromosome is the sole paternal contribution, and the four X chromosomes are all of maternal origin. For the 48,XXYY karyotype, all four cases have indicated the additional X and Y chromosome to be of paternal origin. Two additional X chromosomes in the 48,XXXY karyotype can be contributed by either parent.
We have studied the parental origin of sex chromosomes in five of our polysomy X and/or Y subjects. The results include the following: case 3, 49,XXXXX, maternal; cases 4 and 5, 48,XXYY, paternal; case 6, 48,XXXY, paternal; and case 8, 49,XXXXY, maternal. [55].
CONCLUSION^
The presence of more than one extra sex chromosome in an individual has a detrimental effect on growth and development. Most often affected are the skeletal, cardiac, and gonadal systems accompanied by varying degrees of facial dysmorphism. Mental retardation and speech delays or impairments are often present. Behavioral characteristics have been inconsistently reported and are difficult to ascribe to a specific karyotype. Within each polysomy X and/or Y group, substantial variability exists, such that a generalized prognosis is not possible. Factors that seem to assist these individuals in maximizing their potential include a stable family and a strong and supportive environment. Because a majority of the information is based on a bias of ascertainment, there is a dire need for more case reports to appreciate the variability of each karyotype. It is probable that less severely affected individuals with polysomy X and/or Y karyotypes exist.
ACKNOWLEDGMENTS^
This study was supported in part by grant 5R01-HD10032 from the US Public Health Service, National Institute of Child Health and Human Development, and grant M01 RR00069 from the General Clinical Research Centers Program, National Center for Research Resources, National Institutes of Health.
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