Adult Height in 299 Patients with Turner Syndrome with or without Growth Hormone Therapy: Results and Literature Review.

CONTEXT: Treatment with growth hormone (GH) is considered effective in improving adult height (AH) in Turner syndrome (TS). However, there are few studies comparing AH between treated patients and a concurrent untreated group. OBJECTIVE: To assess the efficacy of GH treatment in improving AH in TS and to review previous published studies with treated and untreated groups. PARTICIPANTS AND METHODS: We retrospectively analyzed clinical data and AH of a large cohort of GH-treated (n = 168) and untreated (n = 131) patients with TS. Data are shown as median and interquartile range (IQR). We assessed pretreatment variables related with AH and compared our results with 16 studies that also included an untreated group. RESULTS: The GH-treated group was 6.2 cm taller than the untreated group (AH = 149 cm [IQR 144.5-152.5 cm] vs. 142.8 cm [IQR 139-148 cm], p < 0.001) after 4.9 years of GH treatment with a dose of 0.35 mg/kg/week. AH SDS corrected for target height (TH) was 7.2 cm higher in GH-treated patients. AH SDS ≥-2 was more frequent in GH-treated patients (43%) than in untreated patients (16%, p < 0.001). AH SDS was also more frequently within the TH range in the GH-treated group (52%) than in the untreated group (15%, p < 0.001). Height SDS at start of GH therapy and TH SDS were positively correlated with AH (p < 0.001; R2 = 0.375). Considering the current result together with previous similar publications, a mean AH gain of 5.7 cm was observed in GH-treated (n = 696) versus untreated (n = 633) patients. CONCLUSIONS: Our study strengthens the evidence for efficacy of GH therapy in patients with TS from different populations.

Insulin Sensitivity and Pancreatic ß-Cell Function in Ecuadorian Women With Turner Syndrome.

Objective: To assess insulin sensitivity and pancreatic ß-cell function in an adult population of Ecuadorian individuals with Turner syndrome (TS). Design and Methods: This was a cross-sectional correlational study conducted in TS subjects (>20 years old; n = 38). A standard 2-h oral glucose tolerance test was performed in both women with TS and the reference group. Glucose, lipids, insulin, and C-peptide concentrations were measured. Homeostasis Model Assessment (HOMA) of Insulin Resistance, Quantitative Insulin Sensitivity Check Index, McAuley, Matsuda, and Belfiore indices were calculated to evaluate the degree of insulin resistance (IR). The pancreatic ß-cell function was assessed using HOMA-ß, basal C-Peptide Index (CPI), and CPII at 120'. Results: A higher prevalence of impaired glucose tolerance was found in TS subjects compared with the reference group. Although significant differences were found for glucose concentrations at 60' and 120' (but not at 0'), only the baseline insulin concentrations differed significantly between the two groups. The values of the IR indices were statistically different between study and reference groups. A significant number of TS subjects diagnosed with IR were differently classified according to the index applied. The concentrations of C-peptide at 0' and 120' of TS subjects were similar to those of the control group. In contrast, the CPI and CPII values in the study group were significantly lower than those in the control group. Conclusion: It is impossible to select the best surrogate method for the assessment of IR in women with TS. The CPI and CPII values could be preferable to other indices to assess the pancreatic ß-cell function in TS subjects. Our findings suggest that IR and pancreatic ß-cell dysfunction could be independent events in women with TS, and both conditions seem to be caused by the disease per se. Our results imply that early screening and intervention for TS would be therapeutic for TS women.

Near Adult Height in Girls with Turner Syndrome Treated with Growth Hormone Following Either Induced or Spontaneous Puberty.

OBJECTIVE: To understand whether spontaneous vs induced puberty and the type and route of estrogen influence the height of girls with Turner syndrome on growth hormone (GH). STUDY DESIGN: Search of an international database of children treated with GH revealed 772 girls with Turner syndrome followed from GH initiation to near adult height. Data from girls with sustained spontaneous puberty (n = 145) were compared with those requiring estrogens for induction or maintenance of puberty (n = 627). RESULTS: At GH start, mean age (7.5 vs 7.9 years), weight (-1.7 vs -1.7 SDS), and body mass index (0.2 SDS vs 0.1 SDS) were similar for girls with spontaneous puberty and with induced puberty. Although those girls with spontaneous puberty were shorter than those with induced puberty, when midparental height was taken into consideration, starting heights in both groups averaged -2.8 SDS. Both groups received approximately 0.3 mg/kg/week of GH. Girls with spontaneous puberty initiated puberty and reached near adult height earlier than girls with induced puberty (12.6 ± 1.8 years vs 13.4 ± 1.4 years and 16.0 ± 1.3 years vs 16.9 ± 1.4 years, respectively). Although girls with spontaneous puberty grew more in the first year of GH therapy and between the onset of puberty and near adult height (11.0 cm vs 9.3 cm), height SDS at near adult height and the length of time in puberty before reaching near adult height were comparable. A 45,X karyotype was detected in 22.1% of girls with spontaneous puberty and in 58.4% of girls with induced puberty. Patients receiving transdermal estrogens did not grow better than those on oral estrogens. Adverse event reporting was comparable between groups. CONCLUSIONS: Girls with Turner syndrome with spontaneous puberty tended to grow better in response to GH than girls with induced puberty, but not enough to produce a difference in height SDS at near adult height.

Clinical and cytogenetic features of 516 patients with suspected Turner syndrome - a single-center experience.

BACKGROUND: Clinical suspicion of Turner syndrome (TS) may be challenging. Short stature and absent puberty are not mandatory and the dysmorphic picture is widely variable. The aim of the study was to describe a representative sample of patients with suspected TS in a single center and to verify which set of features may help discriminate those with TS. METHODS: This was a retrospective study of patients with suspected TS evaluated between 1989 and 2012 with the same clinical and cytogenetic protocols. Data regarding reason for referral, age and height at diagnosis, birth data, pubertal features and dysmorphisms were analyzed. RESULTS: TS was diagnosed in 36% of 516 patients; structural chromosome anomalies predominated (42%). Short stature was the main reason for referral of patients with and without TS. The mean age of patients at first visit, with TS or without TS was similar (11.89 and 11.35 years, respectively), however, infants and adolescents predominated in the TS group. The mean full-term birth weight was lower in patients with TS as well as height at diagnosis, but normal height z-score was found in 17% of patients. Spontaneous puberty occurred in 30% of TS patients aged 13 years or more, but most had pubertal delay. Residual lymphedema, webbed neck, cubitus valgus, hyperconvex nails, shield chest, abnormal nipples, pigmented nevi, short fourth metacarpal and shorter height were the best discriminators for girls with TS. CONCLUSIONS: Though short stature, pubertal delay and typical stigmata should prompt investigation of TS, lack of one of these features should not exclude this hypothesis. Dysmorphisms other than those considered "typical" should be sought on physical examination.

Efectividad y seguridad de la somatropina para el tratamiento de la restricción del crecimiento en niñas con síndrome de Turner / Effectiveness and safety of somatropin for the treatment of growth restriction in girls with Turner syndrome

Introducción: la somatropina es una opción para el tratamiento de la restricción del crecimiento en niñas con síndrome de Turner. Esta evaluación tecnológica se desarrolló en el marco de la actualización integral del Plan Obligatorio de Salud para el año 2015. Objetivo: evaluar la efectividad y seguridad de la somatropina comparada con placebo o no tratamiento para la restricción del crecimiento en niñas con síndrome de Turner. Metodología: la evaluación fue realizada de acuerdo con un protocolo definido a priori por el grupo desarrollador. Se realizó una búsqueda sistemática en MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects y LILACS, sin restricciones de idioma y limitada a revisiones sistemáticas publicadas en los últimos cinco años. Las búsquedas en bases de datos fueron hechas entre octubre y diciembre de 2014 y se complementaron mediante búsqueda manual en bola de nieve y una consulta con expertos temáticos. La tamización de referencias se realizó por dos revisores de forma independiente y los desacuerdos fueron resueltos por consenso. La selección de estudios fue realizada mediante la revisión en texto completo de las referencias preseleccionadas, verificando los criterios de elegibilidad. Se seleccionaron revisiones sistemáticas de ensayos clínicos, su calidad fue valorada con la herramienta AMSTAR. Las características de las revisiones fueron extraídas a partir de las publicaciones originales. Se realizó una síntesis narrativa de las estimaciones del efecto para las comparaciones y desenlaces de interés a partir de los estudios de mejor calidad con AMSTAR. Resultados: se seleccionó una revisión sistemática que incluyó 28 ensayos clínicos (1830 pacientes), cinco de estos ensayos (496 pacientes) fueron relevantes para la pregunta abordada por la presente evaluación. La somatropina comparada con placebo se asoció con un aumento estadísticamente significativo de la velocidad de crecimiento y no presentó una diferencia estadísticamente significativa sobre el contenido mineral óseo total. En comparación con no tratamiento, la somatropina se asoció con un aumento estadísticamente significativo de la velocidad de crecimiento, desviación estándar de la velocidad de crecimiento, talla, desviación estándar de la talla, desviación estándar de la talla para adulto con Turner y desviación estándar de la talla ajustada por edad específica para síndrome de Turner. La velocidad de crecimiento fue significativamente más alta con bajas y altas dosis de somatropina en comparación con placebo. Se presentó una diferencia estadísticamente significativa en contra de la somatropina versus placebo sobre la frecuencia de otitis media (ocurrencia/empeoramiento). En comparación con no tratamiento, la somatropina se asoció con una disminución estadísticamente significativa en la aparición de bocio, y un aumento estadísticamente significativo en la ocurrencia de procedimientos quirúrgicos, otitis media, trastornos del oído, trastornos de la articulación, trastornos respiratorios y sinusitis. Conclusiones: el desempeño global de la somatropina para el tratamiento de la restricción del crecimiento en niñas con síndrome de Turner, muestra que la mayoría de los desenlaces de efectividad favorecen a la somatropina, mientras que la mayoría de los eventos adversos están en contra de esta tecnología. Estas conclusiones se basan en los hallazgos de una revisión sistemática de alta calidad.(AU)

Y chromosome in Turner syndrome: detection of hidden mosaicism and the report of a rare X;Y translocation case.

Turner syndrome (TS) is a common genetic disorder in females associated with the absence of complete or parts of a second sex chromosome. In 5-12% of patients, mosaicism for a cell line with a normal or structurally abnormal Y chromosome is identified. The presence of Y-chromosome material is of medical importance because it results in an increased risk of developing gonadal tumours and virilisation. Molecular study and fluorescence in situ hybridisation approaches were used to study 74 Brazilian TS patients in order to determine the frequency of hidden Y-chromosome mosaicism, and to infer the potential risk of developing malignancies. Additionally, we describe one TS girl with a very uncommon karyotype 46,X,der(X)t(X;Y)(p22.3?2;q11.23) comprising a partial monosomy of Xp22.3?2 together with a partial monosomy of Yq11.23. The presence of cryptic Y-chromosome-specific sequences was detected in 2.7% of the cases. All patients with Y-chromosome-positive sequences showed normal female genitalia with no signs of virilisation. Indeed, the clinical data from Y-chromosome-positive patients was very similar to those with Y-negative results. Therefore, we recommend that the search for hidden Y-chromosome mosaicism should be carried out in all TS cases and not be limited to virilised patients or carriers of a specific karyotype.

Growth curves for girls with Turner syndrome.

The objective of this study was to review the growth curves for Turner syndrome, evaluate the methodological and statistical quality, and suggest potential growth curves for clinical practice guidelines. The search was carried out in the databases Medline and Embase. Of 1006 references identified, 15 were included. Studies constructed curves for weight, height, weight/height, body mass index, head circumference, height velocity, leg length, and sitting height. The sample ranged between 47 and 1,565 (total = 6,273) girls aged 0 to 24 y, born between 1950 and 2006. The number of measures ranged from 580 to 9,011 (total = 28,915). Most studies showed strengths such as sample size, exclusion of the use of growth hormone and androgen, and analysis of confounding variables. However, the growth curves were restricted to height, lack of information about selection bias, limited distributional properties, and smoothing aspects. In conclusion, we observe the need to construct an international growth reference for girls with Turner syndrome, in order to provide support for clinical practice guidelines.

Turner syndrome patients' ultrasound profile.

OBJECTIVE: Evaluate the uterus and ovary by ultrasonography, considering the genotype, pubertal development and hormonal levels. MATERIALS AND METHODS: Cross-sectional study of 53 (7-53 years old) patients with Turner syndrome considering pubertal development by Tanner stage, puberty induced or not and the ultrasound examination. RESULTS: The patients were 10 prepubertal and 43 with pubertal signs. Uterus was found adequate in 12 (57.1%) patients and all had spontaneous puberty. Hypoplasic uterus was found in all prepubertal patients and in 28 (52.8%) patients pubescent. The ovaries were visualized bilaterally in 32 (60%) patients and unilaterally in 15 (27.7%). Ovaries were appropriate bilaterally in eight (15.1%). In pubertal patients, the average volume being significantly higher in those with spontaneous puberty (p = 0.04 and 0.03, respectively). We found no significant difference in uterine volume, when considered estrogen route and karyotype. CONCLUSION: The ultrasonographic pattern in patients with spontaneous puberty without secondary failure was appropriate. The karyotype and the route estrogen therapy were not related to the standard of ultrasound study of the uterus and ovary.

Spontaneous puberty in girls with early diagnosis of Turner syndrome / Puberdade espontânea em meninas com diagnóstico precoce de síndrome de Turner

OBJECTIVE: To verify if the frequency of spontaneous pubertal development among girls with Turner syndrome (TS) diagnosed in infancy and childhood is greater than that of patients diagnosed later. SUBJECTS AND METHODS: Thirty three girls aged < 10 years at the time of diagnosis were evaluated regarding pubertal development. The frequency of spontaneous puberty was compared with that of girls aged > 13 years diagnosed at the same service. RESULTS: Sixteen of 32 informative patients had signs of spontaneous puberty, a frequency greater than that of patients diagnosed later. In six patients, there was no progression of puberty; menarche occurred in six, and one became pregnant, but the fetus was a stillborn. Spontaneous puberty was absent in all cases with 45,X karyotype. CONCLUSIONS: The greater prevalence of spontaneous puberty in girls whose diagnosis was not based on pubertal delay suggests that, among those diagnosed later, there is a bias towards patients with hypogonadism. Arq Bras Endocrinol Metab. 2012;56(9):653-7.

OBJETIVO: Verificar se a frequência de puberdade espontânea em meninas com síndrome de Turner (ST) diagnosticadas na infância é superior a de pacientes diagnosticadas posteriormente. SUJEITOS E MÉTODOS: Foram avaliadas 33 meninas < 10 anos ao diagnóstico quanto ao desenvolvimento puberal. A frequência de puberdade espontânea foi comparada com a de pacientes com mais de 13 anos diagnosticadas no mesmo serviço. RESULTADOS: Dezesseis das 32 pacientes informativas tiveram sinais puberais espontâneos, frequência superior a daquelas diagnosticadas posteriormente. Em seis delas, não houve progressão da puberdade; a menarca ocorreu em seis casos e uma paciente ficou grávida, porém o feto foi natimorto. Em todos os casos com cariótipo 45,X não ocorreu puberdade espontânea. CONCLUSÕES: A maior prevalência de puberdade espontânea em meninas cujo diagnóstico não se baseou em atraso puberal sugere que naquelas detectadas posteriormente haja distorção em favor de pacientes com hipogonadismo. Arq Bras Endocrinol Metab. 2012;56(9):653-7.

Association of vitamin D receptor gene Cdx2 polymorphism with bone markers in Turner syndrome patients.

BACKGROUND: Turner syndrome (TS) patients usually have low bone mineral density (BMD) and increased risk of osteoporotic fractures. We have previously demonstrated an association of bb (BsmI polymorphic site) and ff (FokI polymorphic site) vitamin D receptor (VDR) genotypes with reduced BMD in TS patients. AIM: To analyze the relationship between VDR-Cdx2 polymorphism and BMD as well as bone metabolic variables in TS patients. METHODS: Fifty-five TS patients and 59 control women were studied. VDR-Cdx2 genotypes were determined using TaqMan probes in a real time thermocycler. Lumbar and femoral BMD were determined by dual-energy X-ray absorptiometry (DEXA) and serum intact parathyroid hormone, osteocalcin and beta3-CrossLaps were determined by electrochemiluminescence. RESULTS: Patients with genotype GG had higher levels of both osteocalcin and beta-CrossLaps as compared to patients with genotype GA (p < 0.01 and p < 0.05, respectively). CONCLUSION: Patients carrying genotype GG have higher levels of bone formation and resorption markers. This indicates a more active bone turnover that could impact on their future bone mineral density.

Spontaneous puberty in girls with early diagnosis of Turner syndrome.

OBJECTIVE: To verify if the frequency of spontaneous pubertal development among girls with Turner syndrome (TS) diagnosed in infancy and childhood is greater than that of patients diagnosed later. SUBJECTS AND METHODS: Thirty three girls aged < 10 years at the time of diagnosis were evaluated regarding pubertal development. The frequency of spontaneous puberty was compared with that of girls aged > 13 years diagnosed at the same service. RESULTS: Sixteen of 32 informative patients had signs of spontaneous puberty, a frequency greater than that of patients diagnosed later. In six patients, there was no progression of puberty; menarche occurred in six, and one became pregnant, but the fetus was a stillborn. Spontaneous puberty was absent in all cases with 45,X karyotype. CONCLUSIONS: The greater prevalence of spontaneous puberty in girls whose diagnosis was not based on pubertal delay suggests that, among those diagnosed later, there is a bias towards patients with hypogonadism.

The role of the SHOX gene in the pathophysiology of Turner syndrome.

Turner syndrome (TS) affects 1:2500 live females. It is caused by partial or complete absence of a sex chromosome. Patients with deletions of the distal segment of the short arm of X chromosome (Xp-) including haploinsufficiency of the SHOX (short stature homeobox) have, more often, short stature, skeletal abnormalities and hearing impairments. This article evaluates the current knowledge of the SHOX gene role in TS pathophysiology. Articles were searched from MEDLINE and LILACS databases, in the past 10 years, using the following keywords: Turner syndrome, SHOX gene, haploinsufficiency, short stature and hearing loss. As the inheritance of only one copy of the SHOX gene does not explain most of TS anomalies, more studies are needed to explain them. These studies will also improve understanding how SHOX participates in cartilage and bone growth and will help develop novel therapeutic strategies focused on SHOX-related disorders.

Effects of growth hormone on body proportions in Turner syndrome compared with non-treated patients and normal women.

BACKGROUND: The majority of anthropometric assessments in Turner syndrome (TS) patients has focused on height. AIM: To analyze body proportions in young adult TS patients either treated or not treated with rhGH, and to compare them with a group of age-matched healthy women. SUBJECTS AND METHODS: Standing height, sitting height, weight, foot and leg lengths, arm span, head circumference, biliac and biacromial diameters were measured in 52 non-treated TS patients, 30 treated with rhGH and 133 healthy women. RESULTS: Age at the start of rhGH therapy varied from 7.8 to 15.1 yr (10.0±1.3 yr), the duration of treatment from 2.8 to 8.2 yr (3.7±1.5 yr) and the mean recombinant human GH (rhGH) dose was 0.42 mg/kg/week (from 0.32 to 0.50 mg/kg/week). Nontreated patients did not show any difference in anthropometric variables when compared with the treated ones, except for hand length (p=0.02) and height (p=0.05), which were increased in the treated group. All anthropometric variables, except head circumference, were different when comparing TS patients (either treated or not) with age-matched healthy women. CONCLUSION: Brazilian TS patients either treated or not with rhGH showed almost no differences in terms of their body proportions. This result is probably due to the late age at the start of treatment, and/or the short period of rhGH administration. Hand length was different between the groups, showing the importance of including the extremities in body proportion assessment during rhGH treatment of TS patients.

Turner's syndrome and subclinical autoimmune thyroid disease: a two-year follow-up study.

Although autoimmune thyroid disease (AITD) is frequent in Turner's syndrome (TS), followup studies are scant, and there are none regarding subclinical thyroiditis. We investigated thyroid function and morphology in 17 patients with TS (mean age 14.6 years) with transient and asymptomatic variations of TSH and/or thyroid hormones. Our 2-year follow-up included measurements of TSH, free T4, T3 and TPO and Tg antibodies, ultrasound (US) (first and last evaluations) and scintigraphy (first evaluation). Thyroid volume was evaluated relative to the patients' stature. Fourteen had abnormal hormones, including four with hypothyroidism and one with hyperthyroidism, ten had positive antibodies, and all had abnormalities on US; uptake was normal in 14/16. Abnormal hormones were independent of antibodies, number of US findings, age, time of disease and volume. At the end of the follow-up, antibodies were associated with a high number of abnormal US features, particularly heterogeneous texture. Our results indicate that recurring thyroid hormone variations in TS are due to chronic AITD.

[Evidences for subclinic chronic autoimmune thyroid disease in girls with Turner Syndrome]. / Evidências de doença tireóidea auto-imune crônica subclínica em portadoras da Síndrome de Turner.

Patients with Turner syndrome (TS) frequently exhibit transient, recurrent and asymptomatic variations of TSH and/or thyroid hormones (TH). This work was carried out to evaluate thyroid function and structure in patients with TS who had had such variations in hormone concentrations. Our sample comprised 24 patients, 17 less than 20-years old. Evaluation included serum levels of TSH, free T4, total T3, TPO and Tg autoantibodies, thyroid ultrasound (US) and scintigraphy with 99mTc-pertechnetate. Thirteen patients had abnormal TSH and/or TH levels; 23 exhibited US features compatible with chronic thyroid disorder, particularly thyromegaly (established according to volume expected for stature) and heterogeneous echogenicity. Uptake was normal in 21 cases and tracer distribution was homogeneous in 22. The finding of abnormal hormone concentrations was independent of age, length of time since the first similar finding, thyroid autoantibodies, number of abnormalities at US and abnormal scintigraphic findings. Patients aged more than 20 years had higher frequency of thyroid antibodies and heterogeneous echogenicity, and thyroid volume was significantly correlated to length of time since detection of the first hormone variation, indicating progressive thyroid disease. These results suggest that subclinical thyroid dysfunction in TS is due to chronic autoimmune thyroid disease.

Growth hormone treatment and left ventricular dimensions in Turner syndrome.

OBJECTIVE: To determine whether cardiac dimensions were different in girls with Turner syndrome (TS) who received growth hormone (GH) compared with those who did not receive GH. STUDY DESIGN: This retrospective, cross-sectional study analyzed echocardiograms in 86 females with TS divided into GH-treated (n = 67) and untreated (n = 19) groups. The subjects all participated in the National Institutes of Health protocol between 2001 and 2006. RESULTS: The average age was 16.2 years (range, 10 to 25 years), and average duration of GH treatment was 4.4 years (range, 1 to 14 years). The GH-treated group was taller by approximately 7 cm (P = .004), but cardiac dimensions normalized to body surface area (BSA), including septal and posterior wall thickness and left ventricular (LV) mass and internal diameters, did not differ significantly between the 2 groups. The fractional shortening index was similar in the 2 groups. Multiple regression analyses indicated that BSA, but not duration of GH treatment, predicted LV dimensions in girls with TS. CONCLUSIONS: GH treatment of girls with TS increases stature but does not disproportionately affect cardiac dimensions.