Mary G. Linden

Brain morphology in Klinefelter syndrome: extra X chromosome and testosterone supplementation.

Objective: This study focuses on variation in brain morphology associated with supernumerary X chromosome and Klinefelter syndrome (KS). Using an unselected birth cohort of KS subjects and high-resolution MRI, the authors investigated the neuroanatomic consequences of the 47,XXY karyotype in the presence and absence of exogenous testosterone supplementation. Methods: Regional brain volumes were measured in 10 subjects with KS and 10 age-matched control men. Five of the KS subjects had received testosterone supplementation since puberty (KS+T) and five had not (KS−T). Results: KS subjects showed significant (p < 0.01) reduction in left temporal lobe gray matter volumes compared with normal control subjects. Differences in left temporal gray volumes were also significant between the KS+T and KS−T groups (p < 0.01). Verbal fluency scores were significantly different between the KS+T and KS−T groups as well. Conclusion: Supernumerary X chromosome material in men is associated with a reduction in left temporal lobe gray matter, a finding that is consistent with the verbal and language deficits associated with KS. Also, relative preservation of gray matter in the left temporal region is associated with exposure to exogenous androgen during development. A history of testosterone supplementation also appears to be associated with increased verbal fluency scores in KS patients.

Intrauterine diagnosis of sex chromosome aneuploidy

Objective To provide current information on sex chromosome aneuploidies to obstetricians who encounter such diagnoses and who counsel prospective parents faced with the prenatal diagnosis of a sex chromosome aneuploidy. Data Sources Unbiased information about the natural course of sex chromosome aneuploidy has become available only in the last few years. Current knowledge is based on seven prospective studies on unselected individuals with sex chromosome aneuploidy identified 20–30 years ago. All literature on sex chromosome aneuploidy was reviewed. Karyotypes specifically addressed included the following: 47,XXY, 47,XXX, 47,XYY, 45,X, 45,X/46,XX, 46,XX/47,XXX, and 46,XY/47,XXY. Methods of Study Selection The international studies followed the affected subjects from birth to young adulthood. All published reports, case studies, and articles were reviewed. Tabulation, Integration, and Results All prospective studies were included in the course of determining necessary information for obstetricians and prospective parents. Points addressed for each of the aneuploid karyotypes included expected phenotype, reproductive competence, developmental risks, and intervention therapies. Conclusion Information about sex chromosome aneuploidy can assist obstetricians in providing accurate and comprehensive genetic counseling to parents of affected fetuses, and thereby facilitate the process of making an informed decision about pregnancy management.

Verbal and Spatial Processing Efficiency in 32 Children with Sex Chromosome Abnormalities

ABSTRACT: Spatial and linguistic processing efficiency was evaluated in sixty 8- to 18-yr-old children, including thirteen 47,XXY boys, eleven 47,XXX girls, six girls with 45,X, two girls with 46,X,Xq-, and 28 chromosomally normal controls. Results indicated that the 47,XXX girls performed significantly below controls on all four cognitive tests. Scores of the X monosomy group were reduced on both spatial tests, one requiring rapid information processing and one without time requirements, which is consistent with previous reports of spatial thinking deficits in these propositae. The X monosomy girls also had difficulty completing the high efficiency but not the low efficiency verbal tests. Scores in the 47,XXY group did not differ from controls on either spatial test or on the low efficiency verbal task. When required to rapidly access verbal information from memory, however, the performance of these boys was significantly impaired. This finding confirms earlier reports of impeded verbal fluency in these propositi. Alteration in capacity to rapidly process information appears to distinguish 47,XXY boys and X monosomy girls from their chromosomally normal peers, and suggests that adaptations in their educational setting should be introduced to allow additional time to learn and complete work.

Psychosocial competence of unselected young adults with sex chromosome abnormalities

Very little is known about the adult adaptation of individuals with sex chromosome abnormalities (SCA) except for a few reports based upon biased samples of clinically identified patients. This first report from the Denver SCA study on the adult psychosocial adaptation of 36 unselected propositi, identified at birth, shows a continuation of mild psychological and social problems. Psychiatric interviews and self-reported information revealed that adaptation is quite variable, with many of the nonmosaic propositi not faring as well as their siblings, but in a few instances exceeding the success of brothers and sisters. Within this group of SCA subjects a subset demonstrated more marked pathology and a tendency to over-rate their social adaptation relative to the psychiatric interviewer, suggesting that the exclusive use of self-report questionnaires may not provide accurate assessment of psychological characteristics in this and other special populations. The full adult SCA behavioral phenotype has not yet been established but is emerging through additional reports from this and other studies of unselected SCA adults.

Transition from adolescence to early adulthood: adaptation and psychiatric status of women with 47,XXX.

OBJECTIVE To investigate the adolescent and early adult adaptation of a group of 47,XXX women as compared with their siblings, addressing developmental differences in adaptation and psychiatric status. METHOD Subjects included eleven 47,XXX women and nine female sibling controls. Interviews during adolescence and during early adulthood were semistructured and included a psychiatric evaluation. Four areas of inquiry were (1) relationships with other family members, (2) sense of self-esteem, (3) sexual identity and preference, and (4) responses to life stressors. A DSM-IV psychiatric diagnosis was assigned where appropriate. The Schedule for Affective Disorders and Schizophrenia-Lifetime version was also administered, and assessments of overall functioning and adaptation were completed. RESULTS The 47,XXX women during adolescence and young adulthood were less well adapted; had more stress; had more work, leisure, and relationship problems; had a lower IQ; and showed more psychopathology when contrasted with the comparison group. However, most of the 47,XXX women were self-sufficient and functioning reasonably well, albeit less well than their siblings. CONCLUSIONS This longitudinal study has clarified that previously reported outcomes of severe psychopathology and antisocial behavior in individuals with sex chromosome anomalies are rare and variability in the behavioral phenotype is much larger than originally appreciated.

Environment and Developmental Risk in Children With Sex Chromosome Abnormalities

Abstract Forty-six children with sex chromosome abnormalities (SCA), identified in the chromosome screening of 40,000 consecutive newborns between 1964 and 1974, have been studied longitudinally. Language, motor, psychosocial, and school impairment occurred more frequently in the 38 nonmosaic propositi but not in the 8 mosaic propositi, relative to the group of 32 control siblings. Incidences of motor, school, and psychosocial impairment increased dramatically when the SCA children came from dysfunctional families, as rated by the Family Dysfunction Index, but not in control subjects. Biological factors that influence environmental risk are discussed, and the importance of understanding “protective factors” in unaffected SCA children noted.

Life adaptation in 35 adults with sex chromosome abnormalities

Purpose: This report from the last phase of the 36-year Denver Study provides information about the adult life adaptation of 35 men and women with sex chromosome abnormalities (SCA) followed since their identification at birth.Methods: Sex chromatin screening of 40,000 consecutive newborns between 1964 and 1974 resulted in the cohort of 35 SCA men and women followed to date since birth. Sixteen chromosomally normal siblings served as controls. Data constituting this report was obtained from formal and informal interviews and psychological testing conducted in the final year of this study.Results: The nonmosaic SCA propositi had lower mean intelligence quotients and psychosocial adjustment scores than did siblings. Consistent with these results, propositi also had lower levels of educational achievement and career success, although most have completed school, married, hold full-time employment, and are financially independent.Conclusions: While the SCA adults demonstrated lower levels of cognitive and psychosocial competence, their overall adaptation has been positive, particularly given an early literature suggesting a high rate of psychopathology and severe dysfunction.

Cognitive and Academic Skills in Children with Sex Chromosome Abnormalities

Forty-six unselected children with various sex chromosome abnormalities (14 boys with 47,XXY, 4 boys with 47,XYY, 11 girls with 47,XXX, 9 girls with 45,X, and 8 girls with SCA mosaicism), identified through the consecutive chromosome screening of 40,000 Denver newborns, have been followed developmentally and evaluated in a protocol that included intellectual, language, and achievement testing. Controls consisted of 12 chromosomally normal males and 13 chromosomally normal females who were siblings of various propositi. While most SCA children were not mentally retarded, most of the nonmosaic propositi (31/37) received special education help for learning problems. In general, nonmosaic males were less severely affected than nonmosaic females, who demonstrated significantly reduced mean IQ scores on both Wechsler IQ tests. The inference that learning disorders were genetically mediated in this group was further supported by karyotype-specific findings. 47,XXY boys tended to demonstrate lower verbal skills and a specific reading disability. 47,XXX girls, while more globally impaired, demonstrated evidence of a specific weakness in language skills. 45,X girls tended to be globally impaired, but demonstrated a contrasting specific deficit in spatial thinking skills. Mosaic girls were not significantly different than controls on any measure, an outcome likely occurring because of the low percentage of aneuploid cells in these propositae. Variability was present in each group, and no single profile can characterize all children with any specific SCA. The presence of SCA, therefore, must be viewed as a risk factor creating a tendency towards LD but interacting with a host of other genetic and environmental forces to create a range of phenotypic outcomes.

Compound heterozygous female with fragile X syndrome

We report on a 15-year-old compound heterozygous young woman with fragile X syndrome who has a full mutation of 363 repeats on one X chromosome and a premutation of 103 repeats on the other X chromosome. As predicted, subsequent testing demonstrated that her father carries a premutation (98 repeats) as does her mother (146 repeats). There is only one previous report of a compound heterozygous female with fragile X syndrome. By quantitation of Southern blot signals, the activation ratio for the premutation (the proportion of the premutation on the active X chromosome) was determined to be 0.78. Immunocytochemistry of blood smears showed fragile X mental retardation-1 protein (FMRP) expression in 63.5% of lymphocytes. Cognitively, this woman is functioning in the mid-range of involvement for fragile X females. She attends regular classes and receives supplemental assistance for her learning disabilities. She experiences behavior characteristics typical of females with fragile X syndrome including severe shyness, anxiety, panic episodes, mood swings, and attention deficits. She has responded very well to appropriate treatment including fluoxetine for anxiety, methylphenidate for attentional problems, and educational therapy.

Reply to correspondence from Haverty et al.—“47,XXX associated with major malformations”

We are pleased that our recent articles on genetic counseling and follow-up of prenatally diagnosed children with sex chromosome abnormalities [Linden and Bender, 2002; Linden et al., 2002] have generated a response. Because little unbiased data is available on these conditions, we welcome additional information and dialogue. The review of genito-urinary malformations in femaleswith 47,XXX [Haverty et al., 2003] is of interest, as we continually seek to define the natural history and course of the addition of an X chromosome. The authors present a summary of 16 patients with both 47,XXX and genito-urinary malformations that includes three cases not previously reported. They conclude that the 47,XXX phenotype may include severe genito-urinary malformations and suggest that all 47,XXX infants undergo ultrasound examination of the pelvis and abdomen. Our perspective on this issue is somewhat different. We agree that such an association is possible, but in our opinion the data does not support a clear association at this time. Selection bias must be considered among the 16 reported patients, most of whom were referred for karyotype analysis due to clinical presentation that included presence of malformations. In contrast, when 47,XXX females are ascertained in an unbiased fashion, few physical anomalies are identified. Of the 199,898 infants who participated in consecutive screenings of newborns at seven centers in the 10-year period during the 1960s and 1970s, 49 girls with 47,XXX were identified and enrolled in longitudinal studies. Of these, only onewas identified as having a genito-urinarymalformation [Robinson et al., 1979]. In addition, among the 17 prenatally diagnosed girls followed into adolescence [Linden and Bender, 2002], none had such malformations. Although these numbers are small, they do not suggest a significant association. The incidence of 47,XXX is estimated to be 1 in 1,000 female births, which means that approximately 5–10 girls are born daily in theUnited States alone. The current female population of the United States is estimated to be 141 million [US Census Bureau, 2003], and it would be expected that there are over 100,000 triple X females. Yet, only 16 have been reported to have genito-urinarymalformations.Even if thisnumberwere considerably increased, the incidence would remain statistically low. Because 47,XXX occurs so frequently, the presence of an occasional concurrent condition, such as a genito-urinary malformation, would not be uncommon. If an association between the 47,XXX karyotype and genito-urinary malformation exists, the incidence is likely to be very low. The anxiety associated with a sex chromosome abnormality can be unnecessarily heightened when parents are advised of the risk for a major malformation that is statistically improbable. Because the data is inconclusive, we do not recommend ultrasound of every 47,XXX newborn. However, more studies are needed to investigate this possible association and we welcome further data.