Marsha L. Davenport

Approach to the Patient with Turner Syndrome

Turner syndrome (TS) occurs in about 1:4000 live births and describes females with a broad constellation of problems associated with loss of an entire sex chromosome or a portion of the X chromosome containing the tip of its short arm. TS is associated with an astounding array of potential abnormalities, most of them thought to be caused by haploinsufficiency of genes that are normally expressed by both X chromosomes. A health care checklist is provided that suggests screening tests at specific ages and intervals for problems such as strabismus, hearing loss, and autoimmune thyroid disease. Four areas of major concern in TS are discussed: growth failure, cardiovascular disease, gonadal failure, and learning disabilities. GH therapy should generally begin as soon as growth failure occurs, allowing for rapid normalization of height. Cardiac imaging, preferably magnetic resonance imaging, should be performed at diagnosis and repeated at 5- to 10-yr intervals to assess for congenital heart abnormalities and the emergence of aortic dilatation, a precursor to aortic dissection. Hypertension should be aggressively treated. For those with gonadal dysgenesis, hormonal replacement therapy should begin at a normal pubertal age and be continued until the age of 50 yr. Transdermal estradiol provides the most physiological replacement. Finally, nonverbal learning disabilities marked by deficits in visual-spatial-organizational skills, complex psychomotor skills, and social skills are common in TS. Neuropsychological testing should be routine and families given support in obtaining appropriate therapy, including special accommodations at school.

Consensus Development for the Supplementation of Vitamin D in Childhood and Adolescence

aMeyer Children Hospital, Haifa, Israel; bMarmara University, Istanbul, Turkey; cUniversity of North Carolina, Chapel Hill, N.C., USA; dVrije Universiteit, Amsterdam, The Netherlands; eAcademic Hospital V.V.B., Brussels, Belgium; fJohns Hopkins University, Baltimore, Md., USA; gBirmingham Children’s Hospital, Birmingham, UK; hUniversitatskinderklinik, Cologne, Germany; iDana Children’s Hospital, Tel Aviv, Israel; jKaplan Hospital Rehovot, Israel

Growth failure in early life: An important manifestation of Turner syndrome

The goals of this study were to test the hypothesis that girls with Turner syndrome (TS) experience growth failure early in life and to establish model-based normative growth charts for 0- to 8-year-old American girls with TS. Full-term girls with TS who had 5 or more measurements of height obtained during their first 10 years of life prior to initiation of growth hormone, estrogen and/or androgen therapy were eligible for this study. A nonlinear mixed-effects model comprising the first two components of the infancy-childhood-puberty (ICP) model of growth was fitted to the longitudinal height measurements and compared with those of healthy American girls. Height measurements (n = 1,146) from 112 girls with TS (45,X: 57.1%; 45,X/46,XX: 12.5%; 46,X, iso(X): 4.5%, and other: 25.9%) were analyzed. Mean height SDS fell from –0.68 at birth to –1.60 at 1 year, –1.80 at 2 years and –1.95 at 3 years. When compared to controls (676 girls, 4,537 measurements), girls with TS grew more slowly due to three principal factors: a slow growth rate of the infancy component, a slow growth rate at the onset of the childhood component, and delayed onset of the childhood component. Traditional concepts of growth failure in TS should be revised. Physicians should consider the diagnosis of TS in any girl with unexplained failure to thrive or short stature, even in the first 3 years of life.

Continuous subcutaneous glucose monitoring in children with type 1 diabetes mellitus: a single-blind, randomized, controlled trial.

Background:  Tight glycemic control delays the long‐term complications of type 1 diabetes mellitus (T1DM) but increases the risk for hypoglycemia. The continuous glucose‐monitoring system (CGMS) provides blood glucose (BG) readings every 5 min, and its accuracy and reliability has been established in adults. However, there are limited data on its efficacy and safety in children. The purpose of this study was to determine if CGMS use improves metabolic control in children with T1DM.

Visuospatial executive function in Turner syndrome: functional MRI and neurocognitive findings

Abstract Turner syndrome is a genetic disorder that results from an abnormal or missing X chromosome in females and is typically associated with impairments in visuospatial, but not verbal, information processing. These visuospatial processing impairments may be exacerbated with increased task demands, such as those engaged during working memory (WM). While previous studies have examined spatial WM function in Turner syndrome, none have directly compared the neural correlates of spatial and verbal WM processes across the encoding, maintenance and retrieval phases. We employed both neurocognitive assessments and functional MRI (fMRI) to examine the neural circuitry underlying both verbal and visuospatial WM functions in individuals with Turner syndrome and normal controls. We furthermore examined the vulnerability of task-related fMRI activation to distracters presented during WM maintenance. Fifteen healthy female volunteers and eight individuals with Turner syndrome performed a delayed-response WM task during fMRI scanning. Neurocognitive tests revealed impaired performance across both verbal and spatial domains in Turner syndrome, with greater impairment on tasks with WM demands. Frontoparietal regions in controls showed significantly sustained levels of activation during visuospatial WM. This sustained activation was significantly reduced in the group with Turner syndrome. Domain-specific activation of temporal regions, in contrast, did not differ between the two groups. Sensory distraction during the WM maintenance phase did not differentially alter frontoparietal activation between the two groups. The results reveal impaired frontoparietal circuitry recruitment during visuospatial executive processing in Turner syndrome, suggesting a significant role for the X chromosome in the development of these pathways.

Ascertainment Bias in Turner Syndrome: New Insights From Girls Who Were Diagnosed Incidentally in Prenatal Life

Objective. To evaluate differences in phenotype and other clinical features between patients who have Turner syndrome diagnosed incidentally (on the basis of a prenatal karyotype performed for reasons unrelated to suspicion of Turner syndrome, eg, advanced maternal age) or traditionally (on the basis of either a prenatal karyotype performed for abnormal ultrasound findings or a postnatal karyotype performed for clinical findings suggesting Turner syndrome). Methods. Analysis was performed on baseline data from 88 girls, aged 9 months to 4 years, who were randomized into a multicenter growth hormone intervention trial. Baseline information included a detailed medical history (especially of cardiac and renal anomalies), examination for presence of phenotypic features characteristic of Turner syndrome, length or height (depending on age) expressed as a standard deviation score, and weight standard deviation score. Patients were classified to either the “incidental” (N = 16) or the “traditional” (N = 72) diagnosis group as described above. Results. The incidental group had significantly fewer total phenotypic features of Turner syndrome than the traditional group (3.6 ± 2.9 vs 6.7 ± 2.9). When subgrouped by karyotype, the proportion of patients who manifested phenotypic features was greatest in patients with a 45,X nonmosaic karyotype, lowest in the patients with 45,X/46,XX mosaicism, and intermediate in those with “other” karyotypes. Fewer congenital cardiac defects were observed in the incidental group (31%) compared with the traditional group (64%), but there was no difference between the groups in the prevalence of renal defects. Karyotype distribution differed significantly between the traditional and incidental groups: 74% versus 19% had the nonmosaic 45,X karyotype in the traditional group and 7% versus 56% had the mosaic 45,X/46,XX karyotype. Conclusions. Patients whose Turner syndrome was diagnosed incidentally had significantly fewer phenotypic features and cardiac defects, as well as a greater proportion of mosaic karyotypes, compared with patients whose Turner syndrome was diagnosed clinically. These results support the theory that significant ascertainment bias exists in our understanding Turner syndrome, with important implications for prenatal counseling.

Turner syndrome: A pattern of early growth failure

The purpose of this study was to determine the pattern of early growth in girls with Turner syndrome. Analysis was performed on a total of 464 longitudinal measurements of height, obtained from birth to 8 years of age from 37 girls with Turner syndrome who did not have significant cardiac disease or autosomal abnormalities. All data were obtained prior to the initiation of any hormonal therapy. Mean height SDS fell from ‐0.5 at birth to ‐1.5 at age 1 year and ‐1.8 at age 1.5 years. Growth curves fitted using the first two components of the infancy‐childhood‐puberty model of growth revealed that growth failure was due to (a) mild growth retardation in utero, (b) slow growth during infancy, (c) delayed onset of the childhood component of growth and (d) slow growth during childhood. Physicians should consider the diagnosis of Turner syndrome in any girl with an unexplained failure to thrive or with short stature, even during the first 2 years of life.

X chromosome inactivation and micronuclei in normal and Turner individuals

Abstract Studies on aneuploidy have shown that the X is the most frequently lost chromosome in females, and that the number of X chromosome-positive micronuclei increases with age in women. Recently, we showed that the inactive X chromosome is incorporated preferentially in micronuclei. The objectives of the current study were, firstly, to determine the incidence of X chromosome incorporation into micronuclei in males and, secondly, to determine the incidence of X chromosome incorporation into micronuclei of females with Turner syndrome. Blood samples were obtained from 18 male newborns and 35 normal adult males ranging in age from 22 to 79 years and from seven women with non-mosaic Turner syndrome aged 11–39 years. Isolated lymphocytes were cultured in the presence of cytochalasin B and 2000 binucleated cells per subject were scored for micronuclei. Cells were then hybridized with the biotinylated X centromere-specific probe, pBamX7, and visualized with fluorescein-conjugated avidin. All micronucleated cells were relocated and evaluated for the presence or absence of the X chromosome. Of the 335 micronuclei observed, 6.6% (22/335) contained an X chromosome. Analysis of variance shows a statistically significant increase, for both males and Turner females, in the number of X chromosome-positive micronuclei with age (P < 0.001). These data also show that the X chromosome is included in micronuclei from males more often than would be expected by chance (P < 0.005; χ2 analysis, 15 df). Here we show that there is a tenfold difference in the frequency of X chromosome-positive micronuclei in 46,XX females compared to 46,XY males and 45,X females, providing further support to our previous finding that the X chromosome in micronuclei is the inactive chromosome.

The Effect of Growth Hormone on Craniofacial Growth and Dental Maturation in Turner Syndrome

Serial cephalometric and panoramic radiographs from a mixed longitudinal group of 28 subjects with Turner syndrome (TS), age 4.4-19.0 years, were evaluated for annualized growth increments of the craniofacial complex and dental development and were compared with a longitudinal control group from the Burlington growth study. The short and retrognathic face characteristic of the syndrome was due largely to the increased cranial base angle, decreased posterior face height, and decreased mandibular length, all of which were significantly different from the controls. Although increases in statural height occurred in the TS children who were treated with human growth hormone (GH), there was little or no effect on growth of the jaws, particularly in the older subjects, and the characteristic facies of the syndrome persisted. Dental development was advanced in all TS subjects, and GH administration had no effect on the rate of dental development.

Effect of Intravenous Insulin-like Growth Factor I in Two Patients with Leprechaunism

ABSTRACT: Leprechaunism (Donohue syndrome) is an autosomal recessive disorder characterized by hyperglycemia, extreme insulin resistance, dysmorphic features, failure to thrive, and early death. In this study, recombinant IGF-I, which has both insulin-like and anabolic effects, was administered to two infants with leprechaunism in an attempt to reduce hyperglycemia and improve nutritional status. IGF-I was infused for 66 h in patient FL-1 and 62 h in patient NC-2, with maximal infusion rates of 110 and 40 μg/kg/h, respectively. Although supraphysiologic concentrations of IGF-I were achieved (459 and 1583 μg/L in FL-1 and NC-2, respectively), there were no apparent glucoselowering or nitrogen-sparing effects. Insulin concentrations decreased from extremely high values (16804 and 10224 μmol/L) but remained elevated (611 pmol/L in FL-1 and 5869 pmol/L in NC-2). No changes in serum and urinary urea nitrogen or electrolytes occurred. IGF binding protein-2, which was the predominant IGF binding protein in serum by ligand blot and immunoblot, did not change with IGF-I infusion. IGF binding protein-3 levels were low at baseline and increased slightly during the infusion. We hypothesize that the lack of significant glucose-lowering and anabolic responses to IGF-I could be secondary to a postreceptor defect in IGF-I signaling resulting from the absence of functional insulin receptors.