Judith L. Ross

Characteristic features of Turner syndrome include short stature and ovarian failure. There is considerable evidence from nonrandomized studies that treatment with recombinant human growth hormone increases adult stature in patients with Turner syndrome. It is commonly used in such patients despite the lack of objective data from randomized, double-blind, placebo-controlled studies. Ovarian failure associated with Turner syndrome is treated with estrogen-replacement therapy. It has been proposed that very low-dose physiologic estrogen replacement during childhood combined with growth hormone therapy could provide an additional benefit on adult height than that achieved with growth hormone therapy alone. The aim of this double-blind, placebo-controlled trial was to investigate the independent effect of growth hormone therapy alone and a regimen of growth hormone combined with early ultra–low-dose estrogen on adult height in girls with Turner syndrome. A total of 149 girls (5.0–12.5 years of age) were randomized to receive 1 of 4 regimens: (1) placebo injection plus childhood oral placebo (n = 39), (2) placebo injection plus childhood oral low-dose estrogen (n = 40), (3) growth hormone injection plus childhood oral placebo (n = 35), and (4) growth hormone injection plus childhood oral low-dose estrogen (n = 35). Doses of growth hormone (0.1 mg per kg of body weight) were injected 3 times per week. Ethinyl estradiol or placebo was administered in oral doses, with adjustment for chronologic age and pubertal status. From the first visit after the 12th birthday, escalating doses of ethinyl estradiol were administered to patients in all groups, according to an escalating dosage regimen. Patients were assessed at 6-month intervals. Growth hormone therapy was continued until patients reached their protocol-specified adult height (defined as the last height measured once the height velocity was less than 1.5 cm per year). For adult height attained at 17.0 ± 1.0 years after a mean study period of 7.2 ± 2.5 years, the mean standard deviation scores for the 4 groups were as follows: −2.81 ± 0.85 for the double-placebo group, −3.39 ± 0.74 for the estrogen-alone group, −2.29 ± 1.10 for the growth hormone-alone group, and −2.10 ± 1.02 for the combined growth hormone-estrogen group (P < 0.001 among the 4 groups). Patients treated with growth hormone attained greater adult height compared with placebo (mean difference in standard deviation score, 0.78 ± 0.13, equivalent to about 5.0 cm; P < 0.001). There was a trend toward a modest synergistic growth benefit in the combined growth hormone-estrogen group compared with the estrogen-alone group; the adult height gain with combined therapy was 0.32 ± 0.17 standard deviation score; P = 0.059. These findings provide objective evidence from a placebo-controlled trial that growth hormone treatment initiated in mid-childhood increases adult height in girls with Turner syndrome. The data also suggest that the combination of ultra–low-dose childhood estrogen replacement and growth hormone therapy may improve the height gain achieved with growth hormone alone.

Insulin-like peptide 3 (INSL3) is a peptide hormone belonging to the relaxin family, produced in mammals by the testis and ovary. In male fetuses it plays an important role in testis descent through its effect on gubernaculum differentiation and some cases of cryptorchidism have been related to a mutation either in the INSL3 gene or the receptor gene. Its secretion markedly increases during pubertal development, but its function after birth is not fully understood. Since low serum levels of INSL3 have been reported in postpubertal males with Klinefelter (KS) syndrome, we compared INSL3 levels during minipuberty in 50 normal infants and in 50 infants with prenatally identified XXY karyotype. In addition to gonadotropins, testosterone, and the Sertoli cell markers inhibin B (INHB) and anti-Mullerian hormone (AMH) were also measured in the same infants. In normal infants aged 16-152 days (n=32) INSL3 levels ranged from indetectable level (<11 pg/ml) to 180 pg/ml (median 88), and in infants aged 153 - 750 days (n=18) from indetectable level to 80 pg/ml (median 32). In age-matched infants with XXY karyotype, INSL3 levels were 26-222 (median 92) at 16-152 days of age (n=32) and <11-110 pg/ml (median 39) at 153-750 days of age (n=18). There was no significant difference between control and KS infants. During minipuberty (first five months of life) INSL3 levels were significantly higher (p<0.01) than in older infants. INHB and AMH levels were similar in control and KS infants. Testosterone levels in KS were within normal range although the majority of values were below the median of controls. In control and KS infants, INSL3 levels were positively correlated with LH levels (Spearman r=0.73 and 0.67, respectively, p<0.01) and with testosterone levels (r=0.72 and 0.57, respectively, p<0.01). On the other hand, INHB levels were highly correlated with FSH levels both in controls and infants with XXY karyotype, while there was no correlation (r=0) between the other Sertoli cell peptide hormone AMH and FSH. Similarly there was no correlation of AMH with testosterone levels, by contrast with the negative correlation reported in pubertal males. These data give evidence that INSL3 production is sensitive to the stimulating action of LH during minipuberty and is therefore a reliable marker of Leydig cell activity. It is expected that INSL3 measurements within the first year of life will provide useful information on testis function in pituitary gonadal axis disorders. Sources of Research Support: IREM grant 2010. Nothing to Disclose: SC, IF, JLR, CB, M-CL, MR, NL

Background/Aims: Untreated girls with Turner syndrome (TS) have growth failure, and adult height is, on average, 20 cm less than predicted height. Treatment with growth hormone (GH) is now standard of care. The objective of this study was to investigate the benefit of adding oxandrolone (Ox) to GH in a long-term, randomized, placebo (Pl)-controlled prospective trial to near adult height in TS. Methods: Prospective, randomized, Pl-controlled study: 76 girls with TS (ages 10–14.9 years) were randomized to receive Ox (0.06 mg/kg/day) or Pl in combination with GH (0.35 mg/kg/week, daily) over 2 years. Auxologic data, breast and pubic hair Tanner stages, and hormone and lipid levels were measured. Subjects who chose to continue were followed in a 2-year double-blind extension, also received estrogen therapy (years 3, 4), and had dual-energy X-ray absorptiometry evaluation of bone density (years 3, 4). Results: At year 4, the change in absolute height and height SDS was greater in the GH/Ox versus GH/Pl group [26.2 ± 6.7 vs. 22.2 ± 5.1 cm, analysis of covariance (ANCOVA) p < 0.001; 1.8 ± 0.9 vs. 1.2 ± 0.7 standard deviation scores, ANCOVA p < 0.001]. Bone mineral density (BMD) of the wrist (0.51 ± 0.17 vs. 0.54 ± 0.05 g/cm2) and spine (0.91 ± 0.34 vs. 0.96 ± 0.13 g/cm2) in the GH/Ox versus GH/Pl groups was similar after 4 years. Breast development was slower in the GH/Ox versus GH/Pl group [year 4: Tanner stage 2.9 ±1.3 (Ox) vs. 4.1 ± 1.3 (Pl), p = 0.003], and menarche was approximately 1 year later. Conclusions: The addition of Ox to GH at mean age 12.0 ± 1.7 year augmented height gain after 4 years of treatment, slowed breast development and did not affect BMD in girls with TS. Whether initiation of Ox prior to initiation of pubertal development would optimize height gain without impeding breast development will require further study.

Objective: The goal of this study was to contrast the cognitive phenotypes in boys with 47,XYY (XYY) karyotype and boys with 47,XXY karyotype [Klinefelter syndrome, (KS)], who share an extra copy of the X‐Y pseudoautosomal region but differ in their dosage of strictly sex‐linked genes.Methods: Neuropsychological evaluation of general cognitive ability, language, memory, attention, visual‐spatial abilities, visual‐motor skills, and motor function.Results: Study cohort: 21 boys with 47,XYY and 93 boys with 47,XXY (KS), age 4–17 years, and 36 age‐matched control boys. Both the XYY and KS groups performed less well, on average, than the controls on tests of general cognitive ability, achievement, language, verbal memory, some aspects of attention, and executive function, and motor function. The boys with XYY on average had more severe and pervasive language impairment, at both simple and complex levels, and the boys with KS on average had greater motor impairment in gross motor function and coordination, especially in running speed and agility.Conclusions: The results from these large XYY and KS cohorts have important neurocognitive and educational implications. From the neurocognitive standpoint, the presenting findings afford an opportunity to gain insights into brain development in boys with XYY and those with KS. From the educational standpoint, it is critical that boys with XYY or KS receive appropriate educational interventions that target their specific learning challenges. These findings also provide important information for counseling clinicians and families about these disorders. © 2009 Wiley‐Liss, Inc. Dev Disabil Res Rev 2009;15:309–317.

The goal of this study was to expand the description of the cognitive development phenotype in boys with Klinefelter syndrome (47,XXY). We tested neuropsychological measures of memory, attention, visual‐spatial abilities, visual‐motor skills, and language. We examined the influence of age, handedness, genetic aspects (parental origin of the extra X chromosome, CAG_n repeat length, and pattern of X inactivation), and previous testosterone treatment on cognition. We studied 50 boys with KS (4.1–17.8 years). There was a significant increase in left‐handedness (P = 0.002). Specific language, academic, attentional, and motor abilities tended to be impaired. In the language domain, there was relative sparing of vocabulary and meaningful language understanding abilities but impairment of higher level linguistic competence. KS boys demonstrated an array of motor difficulties, especially in strength and running speed. Deficits in the ability to sustain attention without impulsivity were present in the younger boys. Neither genetic factors examined nor previous testosterone treatment accounted for variation in the cognitive phenotype in KS. The cognitive results from this large KS cohort may be related to atypical brain lateralization and have important diagnostic and psychoeducational implications. The difficulty in complex language processing, impaired attention and motor function in boys with KS may be missed. It is critical that boys with KS are provided with appropriate educational support that targets their learning challenges in school in addition to modifications that address their particular learning style. These findings would also be an important component of counseling clinicians and families about this disorder.

Turner 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.

Turner syndrome (TS) is a human genetic disorder involving females who lack all or part of one X chromosome. The complex phenotype includes ovarian failure, a characteristic neurocognitive profile and typical physical features. TS features are associated not only with complete monosomy X but also with partial deletions of either the short (Xp) or long (Xq) arm (partial monosomy X). Impaired visual-spatial/perceptual abilities are characteristic of TS children and adults of varying races and socioeconomic status, but global developmental delay is uncommon. The cognitive phenotype generally includes normal verbal function with relatively impaired visual-spatial ability, attention, working memory, and spatially dependent executive function. The constellation of neurocognitive deficits observed in TS is most likely multifactorial and related to a complex interaction between genetic abnormalities and hormonal deficiencies. Furthermore, other determinants, including an additional genetic mechanism, imprinting, may also contribute to cognitive deficits associated with monosomy X. As a relatively common genetic disorder with well-defined manifestations, TS presents an opportunity to investigate genetic and hormonal factors that influence female cognitive development. TS is an excellent model for such studies because of its prevalence, the well-characterized phenotype, and the wealth of molecular resources available for the X chromosome. In the current review, we summarize the hormonal and genetic factors that may contribute to the TS neurocognitive phenotype. The hormonal determinants of cognition in TS are related to estrogen and androgen deficiency. Our genetic hypothesis is that haploinsufficiency for gene/genes on the short arm of the X chromosome (Xp) is responsible for the hallmark features of the TS cognitive phenotype. Careful clinical and molecular characterization of adult subjects missing part of Xp links the TS phenotype of impaired visual spatial/perceptual ability to specific distal Xp chromosome regions. We demonstrate that small, nonmosaic deletion of the distal short arm of the X chromosome in adult women is associated with the same hallmark cognitive profile seen in adult women with TS. Future studies will elucidate the cognitive deficits and the underlying etiology. These results should allow us to begin to design cognitive interventions that might lessen those deficits in the TS population.