Judith L. Ross

Evidence for a Turner Syndrome Locus or Loci at Xp11.2-p22.1

Turner syndrome is the complex human phenotype associated with complete or partial monosomy X. Principle features of Turner syndrome include short stature, ovarian failure, and a variety of other anatomic and physiological abnormalities, such as webbed neck, lymphedema, cardiovascular and renal anomalies, hypertension, and autoimmune thyroid disease. We studied 28 apparently nonmosaic subjects with partial deletions of Xp, in order to map loci responsible for various components of the Turner syndrome phenotype. Subjects were carefully evaluated for the presence or absence of Turner syndrome features, and their deletions were mapped by FISH with a panel of Xp markers. Using a statistical method to examine genotype/phenotype correlations, we mapped one or more Turner syndrome traits to a critical region in Xp11.2-p22.1. These traits included short stature, ovarian failure, high-arched palate, and autoimmune thyroid disease. The results are useful for genetic counseling of individuals with partial monosomy X. Study of additional subjects should refine the localization of Turner syndrome loci and provide a rational basis for exploration of candidate genes.

Turner syndrome and haploinsufficiency

Turner syndrome was one of the first human genetic disorders ascribed to haploinsufficiency but the identification of specific genes responsible for the phenotype has been problematic. Recent data point to several candidate genes, some new and some old, for specific aspects of the phenotype associated with monosomy X in humans.

Use of estrogen in young girls with Turner syndrome Effects on memory

Background: The Turner syndrome (TS) phenotype is characterized by a specific neurocognitive profile of normal verbal skills, impaired visual-spatial and visual-perceptual abilities, and impaired nonverbal more than verbal memory. We compared verbal and nonverbal memory in estrogen- and placebo-treated girls with TS (ages 7 to 9 years) and age-matched female controls. Methods: Children received either estrogen (ethinyl estradiol, 25 ng/kg/d) or placebo for 1 to 3 years (mean, 2.1 ± 0.9 years) in a randomized, double-blind study. Memory and language tasks administered included the Wechsler Intelligence Scale for Children–Revised, Digit Span (forward and backward), the Children’s Word List, the Denman Paragraph, the Peabody Picture Vocabulary Test, Boston Naming, immediate and delayed Recall of the Rey Complex Figure, Nonword Reading, Wide Range Achievement Test–Revised reading subtest, Verbal fluency, and the Token Test. Results: The estrogen-treated TS group performed better than the placebo-treated TS group for the Children’s Word List immediate and delayed recall and the Digit Span backwards test (p < 0.01 to 0.04), although the results were not significant after adjusting for multiple comparisons. The placebo-treated TS group performed less well than the controls for recall of Digit Span backward (p < 0.0001; placebo-treated, 2.8 ± 1.3; estrogen-treated, 3.4 ± 1.2; and controls, 4.2 ± 1.3) and immediate and delayed recall of the Children’s Word List (delayed recall, p < 0.0001; placebo-treated, 6.2 ± 3.1; estrogen-treated, 8.0 ± 2.9; and controls, 9.0 ± 2.9). Performance for these measures was similar for the estrogen-treated TS group and the control group. Conclusions: Estrogen replacement therapy in young girls with Turner Syndrome is associated with improved verbal and nonverbal memory. The optimal patient age, dose, and duration of estrogen replacement require further study.

Persistent cognitive deficits in adult women with Turner syndrome

Background: Turner syndrome (TS) has a characteristic neurocognitive profile. Verbal abilities are, in general, normal; however, women with TS, as a group, have specific deficits in visual-spatial abilities, visual-perceptual abilities, motor function, nonverbal memory, executive function, and attentional abilities. Observed deficits could be caused by genetic or endocrine factors. Objective: To evaluate the specific cognitive deficits that appear to persist in adulthood, are not estrogen-responsive, and may be genetically determined. Methods: The cognitive performance of adult women with TS (n = 71) who were estrogen repleted was compared with verbal IQ– and socioeconomic status–matched female controls (n = 50). Sixty-one women with TS had ovarian failure and received estrogen replacement and 10 had preserved endogenous ovarian function and were not receiving estrogen replacement at the time of evaluation. Results: Similar to children and adolescents with TS, adults with TS have normal verbal IQ but have relative difficulty on measures of spatial/perceptual skills, visual-motor integration, affect recognition, visual memory, attention, and executive function despite estrogen replacement. These deficits are apparent in women with TS despite apparently adequate estrogen effect, either endogenous or by hormone replacement. Conclusion: The cognitive phenotypes of adults with TS, with or without ovarian failure, are similar, indicating that estrogen replacement does not have a major impact on the cognitive deficits of adults with TS.

A turner syndrome neurocognitive phenotype maps to Xp22.3

BackgroundTurner syndrome (TS) is associated with a neurocognitive phenotype that includes selective nonverbal deficits, e.g., impaired visual-spatial abilities. We previously reported evidence that this phenotype results from haploinsufficiency of one or more genes on distal Xp. This inference was based on genotype/phenotype comparisons of individual girls and women with partial Xp deletions, with the neurocognitive phenotype considered a dichotomous trait. We sought to confirm our findings in a large cohort (n = 47) of adult women with partial deletions of Xp or Xq, enriched for subjects with distal Xp deletions.MethodsSubjects were recruited from North American genetics and endocrinology clinics. Phenotype assessment included measures of stature, ovarian function, and detailed neurocognitive testing. The neurocognitive phenotype was measured as a quantitative trait, the Turner Syndrome Cognitive Summary (TSCS) score, derived from discriminant function analysis. Genetic analysis included karyotyping, X inactivation studies, fluorescent in situ hybridization, microsatellite marker genotyping, and array comparative genomic hybridization.ResultsWe report statistical evidence that deletion of Xp22.3, an interval containing 31 annotated genes, is sufficient to cause the neurocognitive phenotype described by the TSCS score. Two other cardinal TS features, ovarian failure and short stature, as well as X chromosome inactivation pattern and subjects age, were unrelated to the TSCS score.ConclusionDetailed mapping suggests that haploinsufficiency of one or more genes in Xp22.3, the distal 8.3 megabases (Mb) of the X chromosome, is responsible for a TS neurocognitive phenotype. This interval includes the 2.6 Mb Xp-Yp pseudoautosomal region (PAR1). Haploinsufficiency of the short stature gene SHOX in PAR1 probably does not cause this TS neurocognitive phenotype. Two genes proximal to PAR1 within the 8.3 Mb critical region, STS and NLGN4X, are attractive candidates for this neurocognitive phenotype.

Executive function in girls with turner's syndrome

Turners syndrome (TS), a genetic disorder affecting girls, has a well‐described neurocognitive profile including difficulty with visuospatial processing and attention skills. The goal of this study was to investigate executive function and attention abilities in girls with TS. Executive skills include the ability to plan, organize, monitor, and execute multistep problem‐solving processes. Measures of attention and executive function were analyzed from 105 girls with TS and from 153 female controls matched for age, IQ, and socioeconomic status. Three age groups were evaluated in order to assess developmental patterns in executive skills. The TS group (all ages) performed significantly less well than did controls on measures of attention, including the Freedom From Distractibility factor of the Wechsler Intelligence Scale for Children‐Revised and the Test of Variables of Attention. In the executive function domain, girls with TS performed at levels comparable to controls on the Wisconsin Card Sort Test and...

Altered brain development in Turner's syndrome An event‐related potential study

We compared event-related brain potentials (ERPs) and reaction time (RT) measures from untreated young (prepubertal and peripubertal; ages 9 to 14) and old (postpubertal; ages 15 to 20) Turners syndrome (TS) subjects with those from normal age-matched controls. Comparisons among groups permitted the assessment of the relative roles of congenital and maturational brain alterations as possible bases of the cognitive deficits in TS. All subjects were presented with series of auditory stimuli, and they either counted one of the two stimuli or made rapid discriminative button presses to both. The results indicated that, whereas the ERPs in young TS females were essentially the same as those in their age-matched controls, the ERPs in old TS females more closely resembled those in both young groups than those in their age-matched controls. Specifically, a late (400 to 900 msec) frontal negative slow wave (Nc) in the old TS subjects failed to show the normal maturational course in which the amplitude and duration of this component steadily decreases with age. Except for slightly greater amounts of N1 amplitude in the young TS group, the latencies, amplitudes, and scalp distributions of the other ERP components (N1, P2, N2, P300) were all the same at all ages in the TS subjects and their controls. Behaviorally, both TS groups had longer RTs than their controls but, consistent with the ERP results, they did not make more errors. The ERP and RT results point to the existence of two kinds of abnormalities in TS females, each from a different mechanism: the ERP results suggest an age-dependent maturational defect while the RT results suggest an age-independent congenital defect.

Phenotype and X inactivation in 45,X/46,X,r(X) cases

We studied a new series of 21 individuals mosaic for a ring X chromosome [r(X)]. Of nine individuals with mental retardation, only one had a r(X) that lacked XIST (X‐inactive‐specific transcript) and was not subject to X inactivation, which would explain the abnormal phenotype; the remaining eight cases had XIST on their r(X). The majority of cases (five of seven) with mental retardation had an apparently early replicating r(X); but the androgen receptor gene (AR) was methylated on one allele in five of six informative cases, including two cases with an early replicating r(X). These conflicting results on two indicators of X inactivation suggest a potential dissociation between late replication and DNA methylation in these r(X) chromosomes, which may fail to become completely silenced. Of the twelve subjects who were not mentally retarded, all had XIST present on their r(X) and most (8/10) showed a late replicating r(X), together with AR methylation in all five informative cases, indicating r(X) inactivation. Thus, the unusual phenotypic features and mental retardation associated with the presence of a r(X) cannot be explained solely on the basis of presence or absence of XIST. The r(X) in cases with mental retardation were consistently smaller than those in individuals with normal intelligence, perhaps indicating inability for small rings to undergo structural changes associated with complete X inactivation or lethality in cases with a large non‐inactivated r(X). Of the Turner syndrome features present in the r(X) cases, only edema was present in a lesser frequency than in 45,X individuals. Our cases generally had a less severe phenotype than those previously reported, suggesting that reported incidences of abnormalities may be influenced by ascertainment bias, with mental retardation potentially unrelated to the presence of the r(X) in some cases.

Developmental changes in neuroendocrine regulation of gonadotropin secretion in gonadal dysgenesis

Patients with gonadal dysgenesis have a marked increase in gonadotropin levels at the age when puberty normally occurs. To determine whether this increase results from a change in the frequency or the amplitude of gonadotropin pulses, we measured the 24-h profile of plasma LH and FSH by RIA in 31 patients with gonadal dysgenesis, aged 2-20 yr. Gonadotropin pulses were defined as a rise from nadir to peak that exceeded 3 times the intraassay coefficient of variation. This criterion, based on an empirical study of RIA noise, reduced the rate of false positive peaks to less than 3-4/24 h. Using this criterion, peak amplitude increased significantly at the time of puberty for both LH and FSH (P less than 0.01). The overall frequency of gonadotropin pulses (the sum of the FSH peaks plus the LH peaks that occurred without a concomitant FSH peak), however, did not differ among prepubertal (12.7 +/- 1.8 peaks/24 h), pubertal aged (14.3 +/- 2.3 peaks/24 h), and adult patients (14.7 +/- 0.9 peaks/24 h). Thus, the increase in gonadotropin concentration in pubertal aged patients with gonadal dysgenesis appears to result primarily from an increase in gonadotropin peak amplitude rather than an increase in peak frequency.