Pubertal and Gonadal Outcomes in 46,XY Individuals with Partial Androgen Insensitivity Syndrome Raised as Girls.

INTRODUCTION: Although it was common in the 1970s-1990s to assign female gender of rearing to 46,XY infants with limited virilization of varying etiologies, including those with partial androgen insensitivity syndrome (PAIS), long-term data on outcomes for these individuals are sparse. Therefore, our goal was to use the power of an international registry to evaluate clinical features, surgical management, and pubertal data in patients with a molecularly confirmed diagnosis of PAIS who were born before 2008 and were raised as girls. METHODS: The current study interrogated the International Disorders of Sex Development Registry for available data on management and pubertal outcomes in individuals with genetically confirmed PAIS who were raised as girls. RESULTS: Among the 11 individuals who fulfilled the key criteria for inclusion, the external masculinization score (EMS) at presentation ranged from 2 to 6 (median 5); 7 girls underwent gonadectomy before the age of 9 years, whereas 4 underwent gonadectomy in the teenage years (≥ age 13). Clitoral enlargement at puberty was reported for 3 girls (27%) who presented initially at the time of puberty with intact gonads. In the 9 individuals (82%) for whom gonadal pathology data were provided, there was no evidence of germ cell tumor at median age of 8.1 years. All girls received estrogen replacement, and 8/11 had attained Tanner stage 4-5 breast development at the last assessment. CONCLUSION: In general, although it appears that female assignment in PAIS is becoming uncommon, our data provide no evidence to support the practice of prophylactic prepubertal gonadectomy with respect to the risk of a germ cell tumor.

Prevention of Growth Failure in Turner Syndrome: Long-Term Results of Early Growth Hormone Treatment in the "Toddler Turner" Cohort.

INTRODUCTION: In the randomized "Toddler Turner" study, girls who received growth hormone (GH) starting at ages 9 months to 4 years (early-treated [ET] group) had marked catch-up growth and were 1.6 ± 0.6 SD taller than untreated (early-untreated [EUT]) control girls after 2 years. However, whether the early catch-up growth would result in greater near-adult height (NAH) was unknown. Therefore, this extension study examined the long-term effects of toddler-age GH treatment on height, pubertal development, and safety parameters. METHODS: Toddler Turner study participants were invited to enroll in a 10-year observational extension study for annual assessments of growth, pubertal status, and safety during long-term GH treatment to NAH for both ET and EUT groups. RESULTS: The ET group was taller than the EUT group at all time points from preschool to maturity and was significantly taller at the onset of puberty (p = 0.016), however, the difference was not significant at NAH. For the full cohort (ET + EUT combined, n = 50) mean (± SD) NAH was 151.2 ± 7.1 cm at age 15.0 ± 1.3 years. NAH standard deviation score (SDS) was within the normal range (>-2.0) for 76% of ET and 60% of EUT subjects (68% overall) and correlated strongly with height SDS at GH start (r = 0.78; p < 0.01), which in turn had a modest inverse correlation with age at GH start (i.e., height SDS declined with increasing age in untreated girls [r = -0.30; p = 0.016]). No new safety concerns arose. CONCLUSION: Although the ET group was taller throughout, height SDS at NAH was not significantly different between groups due to catch-down growth of ET girls during lapses in GH treatment after the Toddler study and similar long-term GH exposure overall. Early initiation of GH by age 6 years, followed by uninterrupted treatment during childhood, can prevent ongoing growth failure and enable attainment of height within the normal range during childhood, adolescence, and adulthood.

Height Gain and Safety Outcomes in Growth Hormone-Treated Children with Idiopathic Short Stature: Experience from a Prospective Observational Study.

BACKGROUND/OBJECTIVES: Growth hormone (GH) treatment of idiopathic short stature (ISS) received US Food and Drug Administration approval in 2003. We assessed height gain and safety in 2,450 children with ISS treated with GH in US clinical practice. METHODS: Short-term height gain, near-adult height (NAH), and safety outcomes were investigated using Genetics and Neuroendocrinology of Short Stature International Study data. RESULTS: Compared to children with isolated idiopathic GH deficiency (IGHD), those with ISS were shorter at baseline but had similar age and GH dose. Mean ± SD height SD score (SDS) increase was similar for ISS and IGHD, with 0.6 ± 0.3 (first), 0.4 ± 0.3 (second), 0.3 ± 0.3 (third), and 0.1 ± 0.3 (fourth year) for ISS. Girls with ISS (27% of subjects) were younger and shorter than boys but had similar height gain over time. At NAH in the ISS group (n = 467), mean ± SD age, GH duration, and height SDS were 17.3 ± 2.3 years, 4.6 ± 2.7 years, and -1.2 ± 0.9, respectively. Height gain from baseline was 1.1 ± 1.0 SDS and was greater for boys than girls (1.2 ± 1.0 vs. 0.9 ± 0.9), but boys were treated longer (5.1 ± 2.8 vs. 3.6 ± 2.5 years). Adverse events were reported for 24% with ISS versus 20% with IGHD - most were common childhood conditions or previously reported in GH-treated patients. CONCLUSIONS: GH-treated children with ISS achieved substantial height gain, similar to patients with IGHD. Fewer GH-treated girls were enrolled than boys, but with similar height SDS gain over time. No ISS-specific safety issues were identified. Thus, GH treatment of ISS appears to have a safety/effectiveness profile similar to that of IGHD.

Genetic Polymorphisms Associated with Idiopathic Short Stature and First-Year Response to Growth Hormone Treatment.

BACKGROUND/AIMS: The term idiopathic short stature (ISS) describes short stature of unknown, but likely polygenic, etiology. This study aimed to identify genetic polymorphisms associated with the ISS phenotype, and with growth response to supplemental GH. METHODS: Using a case-control analysis we compared the prevalence of "tall" versus "short" alleles at 52 polymorphic loci (17 in growth-related candidate genes, 35 identified in prior genome-wide association studies of adult height) in 94 children with ISS followed in the Genetics and Neuroendocrinology of Short Stature International Study, versus 143 controls from the Fels Longitudinal Study. RESULTS: Four variants were nominally associated with ISS using a genotypic model, confirmed by a simultaneous confident inference approach: compared with controls children with ISS had lower odds of "tall" alleles (odds ratio, 95% CI) for GHR (0.52, 0.29-0.96); rs2234693/ESR1 (0.50, 0.25-0.98); rs967417/BMP2 (0.39, 0.17-0.93), and rs4743034/ZNF462 (0.40, 0.18-0.89). Children with ISS also had lower odds of the "tall" allele (A) at the IGFBP3 -202 promoter polymorphism (rs2855744; 0.40, 0.20-0.80) in the simultaneous confident inference analysis. A significant association with 1st-year height SD score increase during GH treatment was observed with rs11205277, located near 4 known genes: MTMR11, SV2A, HIST2H2AA3, and SF3B4; the latter, in which heterozygous mutations occur in Nager acrofacial dysostosis, appears the most relevant gene. CONCLUSIONS: In children with ISS we identified associations with "short" alleles at a number of height-related loci. In addition, a polymorphic variant located near SF3B4 was associated with the GH treatment response in our cohort. The findings in our small study warrant further investigation.

Surgery of Anomalies of Gonadal and Genital Development in the "Post-Truth Era".

This article aims to examine the current issues of debate concerning the management of atypical gonadal and genital development (AGD). Understanding this complex subject begins with defining the distinct AGD conditions, the aims and nature of surgical treatments, and the perceptions of affected individuals and their families. The evolving societal and medical contexts in this field are confronting facts and opinions, leading to a significant change in attitudes and approaches.

Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting.

Turner syndrome affects 25-50 per 100,000 females and can involve multiple organs through all stages of life, necessitating multidisciplinary approach to care. Previous guidelines have highlighted this, but numerous important advances have been noted recently. These advances cover all specialty fields involved in the care of girls and women with TS. This paper is based on an international effort that started with exploratory meetings in 2014 in both Europe and the USA, and culminated with a Consensus Meeting held in Cincinnati, Ohio, USA in July 2016. Prior to this meeting, five groups each addressed important areas in TS care: 1) diagnostic and genetic issues, 2) growth and development during childhood and adolescence, 3) congenital and acquired cardiovascular disease, 4) transition and adult care, and 5) other comorbidities and neurocognitive issues. These groups produced proposals for the present guidelines. Additionally, four pertinent questions were submitted for formal GRADE (Grading of Recommendations, Assessment, Development and Evaluation) evaluation with a separate systematic review of the literature. These four questions related to the efficacy and most optimal treatment of short stature, infertility, hypertension, and hormonal replacement therapy. The guidelines project was initiated by the European Society for Endocrinology and the Pediatric Endocrine Society, in collaboration with The European Society for Pediatric Endocrinology, The Endocrine Society, European Society of Human Reproduction and Embryology, The American Heart Association, The Society for Endocrinology, and the European Society of Cardiology. The guideline has been formally endorsed by the European Society for Endocrinology, the Pediatric Endocrine Society, the European Society for Pediatric Endocrinology, the European Society of Human Reproduction and Embryology and the Endocrine Society. Advocacy groups appointed representatives who participated in pre-meeting discussions and in the consensus meeting.

Mortality in Children Receiving Growth Hormone Treatment of Growth Disorders: Data From the Genetics and Neuroendocrinology of Short Stature International Study.

Context: Although pediatric growth hormone (GH) treatment is generally considered safe for approved indications, concerns have been raised regarding potential for increased risk of mortality in adults treated with GH during childhood. Objective: To assess mortality in children receiving GH. Design: Prospective, multinational, observational study. Setting: Eight hundred twenty-seven study sites in 30 countries. Patients: Children with growth disorders. Interventions: GH treatment during childhood. Main Outcome Measure: Standardized mortality ratios (SMRs) and 95% confidence intervals (CIs) using age- and sex-specific rates from the general population. Results: Among 9504 GH-treated patients followed for ≥4 years (67,163 person-years of follow-up), 42 deaths were reported (SMR, 0.77; 95% CI, 0.56 to 1.05). SMR was significantly elevated in patients with history of malignant neoplasia (6.97; 95% CI, 3.81 to 11.69) and borderline elevated for those with other serious non-GH-deficient conditions (2.47; 95% CI, 0.99-5.09). SMRs were not elevated for children with history of benign neoplasia (1.44; 95% CI, 0.17 to 5.20), idiopathic GHD (0.11; 95% CI, 0.02 to 0.33), idiopathic short stature (0.20; 95% CI, 0.01 to 1.10), short stature associated with small for gestational age (SGA) birth (0.66; 95% CI, 0.08 to 2.37), Turner syndrome (0.51; 95% CI, 0.06 to 1.83), or short stature homeobox-containing (SHOX) gene deficiency (0.83; 95% CI, 0.02 to 4.65). Conclusions: No significant increases in mortality were observed for GH-treated children with idiopathic GHD, idiopathic short stature, born SGA, Turner syndrome, SHOX deficiency, or history of benign neoplasia. Mortality was elevated for children with prior malignancy and those with underlying serious non-GH-deficient medical conditions.

Safety Outcomes and Near-Adult Height Gain of Growth Hormone-Treated Children with SHOX Deficiency: Data from an Observational Study and a Clinical Trial.

BACKGROUND/AIMS: To assess auxological and safety data for growth hormone (GH)-treated children with SHOX deficiency. METHODS: Data were examined for GH-treated SHOX-deficient children (n = 521) from the observational Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS). For patients with near-adult height information, GeNeSIS results (n = 90) were compared with a clinical trial (n = 28) of SHOX-deficient patients. Near-adult height was expressed as standard deviation score (SDS) for chronological age, potentially increasing the observed effect of treatment. RESULTS: Most SHOX-deficient patients in GeNeSIS had diagnoses of Leri-Weill syndrome (n = 292) or non-syndromic short stature (n = 228). For GeNeSIS patients with near-adult height data, mean age at GH treatment start was 11.0 years, treatment duration 4.4 years, and height SDS gain 0.83 (95% confidence interval 0.49-1.17). Respective ages, GH treatment durations and height SDS gains for GeNeSIS patients prepubertal at baseline (n = 42) were 9.2 years, 6.0 years and 1.19 (0.76-1.62), and for the clinical trial cohort they were 9.2 years, 6.0 years and 1.25 (0.92-1.58). No new GH-related safety concerns were identified. CONCLUSION: Patients with SHOX deficiency who had started GH treatment before puberty in routine clinical practice had a similar height gain to that of patients in the clinical trial on which approval for the indication was based, with no new safety concerns.

Development of additional pituitary hormone deficiencies in pediatric patients originally diagnosed with isolated growth hormone deficiency due to organic causes.

OBJECTIVE: To determine characteristics of children initially diagnosed with isolated growth hormone deficiency (IGHD) of organic aetiology, who later developed multiple pituitary hormone deficiencies (MPHD). DESIGN: Data were analysed for 716 growth hormone-treated children with organic IGHD, who were growth hormone-naïve at baseline in the multinational, observational Genetics and Neuroendocrinology of Short Stature International Study. METHODS: Development of MPHD was ascertained from investigator-provided diagnoses, adverse events and concomitant medications. Analyses were performed for all patients and separately for those who developed MPHD within 4.5 years or had >3.5 years follow-up and continued to have IGHD (4-year cohort). RESULTS: MPHD developed in 71/716 (9.9%) children overall, and in 60/290 (20.7%) in the 4-year cohort. The most frequent additional deficiencies were thyroid-stimulating hormone (47 patients) and gonadotropins (23 patients). Compared with those who remained with IGHD, children who developed MPHD had more severe GHD at study entry, significantly lower baseline insulin-like growth factor1, peak stimulated growth hormone, and more frequent diagnosis of intracranial tumour or mutation of gene(s) controlling hypothalamic-pituitary development and/or function. Multivariate logistic regression analyses identified female gender, longer follow-up, higher baseline age and lower peak stimulated growth hormone as predictors of MPHD development. CONCLUSIONS: MPHD is more likely to develop in patients with severe organic IGHD, especially those with history of intracranial tumour or mutation of gene(s) controlling hypothalamic-pituitary development and/or function. Older baseline age, female gender and longer follow-up duration were also associated with higher incidence of MPHD. Long-term monitoring of pituitary function is recommended, irrespective of the aetiology of GHD.

Global Disorders of Sex Development Update since 2006: Perceptions, Approach and Care.

The goal of this update regarding the diagnosis and care of persons with disorders of sex development (DSDs) is to address changes in the clinical approach since the 2005 Consensus Conference, since knowledge and viewpoints change. An effort was made to include representatives from a broad perspective including support and advocacy groups. The goal of patient care is focused upon the best possible quality of life (QoL). The field of DSD is continuously developing. An update on the clinical evaluation of infants and older individuals with ambiguous genitalia including perceptions regarding male or female assignment is discussed. Topics include biochemical and genetic assessment, the risk of germ cell tumor development, approaches to psychosocial and psychosexual well-being and an update on support groups. Open and on-going communication with patients and parents must involve full disclosure, with the recognition that, while DSD conditions are life-long, enhancement of the best possible outcome improves QoL. The evolution of diagnosis and care continues, while it is still impossible to predict gender development in an individual case with certainty. Such decisions and decisions regarding surgery during infancy that alters external genital anatomy or removes germ cells continue to carry risk.

Radiological Features in Patients with Short Stature Homeobox-Containing (SHOX) Gene Deficiency and Turner Syndrome before and after 2 Years of GH Treatment.

BACKGROUND/AIMS: The short stature homeobox-containing (SHOX) gene is one of many genes that regulate longitudinal growth. The SHOX deficiency (SHOX-D) phenotype, caused by intragenic or regulatory region defects, ranges from normal stature to mesomelic skeletal dysplasia. We investigated differences in radiological anomalies between patients with SHOX-D and Turner syndrome (TS) and the effect of 2 years of growth hormone (GH) treatment on these anomalies. METHODS: Left hand/wrist, forearm and lower leg radiographs were assessed at baseline and after 2 years in children with genetically confirmed SHOX-D (GH-treated and untreated groups) and TS (GH-treated) in a randomised, controlled, multinational study. RESULTS: Radiological anomalies of hand, wrist and forearm were common in SHOX-D and TS. Radial bowing appeared more prevalent in SHOX-D, while lower leg anomalies were more common in TS. There were no significant differences in radiological findings between GH-treated and untreated patients with SHOX-D after 2 years. CONCLUSION: GH treatment had no systematic effect on skeletal findings in SHOX-D, based on limited radiological differences between the GH-treated and untreated groups at 2 years. Bone age radiographs allow assessment of radiological signs indicating a potential diagnosis of SHOX-D and may lead to earlier genetic confirmation and initiation of GH therapy.

Proceedings from the Turner Resource Network symposium: the crossroads of health care research and health care delivery.

Turner syndrome, a congenital condition that affects ∼1/2,500 births, results from absence or structural alteration of the second sex chromosome. There has been substantial effort by numerous clinical and genetic research groups to delineate the clinical, pathophysiological, cytogenetic, and molecular features of this multisystem condition. Questions about the molecular-genetic and biological basis of many of the clinical features remain unanswered, and health care providers and families seek improved care for affected individuals. The inaugural "Turner Resource Network (TRN) Symposium" brought together individuals with Turner syndrome and their families, advocacy group leaders, clinicians, basic scientists, physician-scientists, trainees and other stakeholders with interest in the well-being of individuals and families living with the condition. The goal of this symposium was to establish a structure for a TRN that will be a patient-powered organization involving those living with Turner syndrome, their families, clinicians, and scientists. The TRN will identify basic and clinical questions that might be answered with registries, clinical trials, or through bench research to promote and advocate for best practices and improved care for individuals with Turner syndrome. The symposium concluded with the consensus that two rationales justify the creation of a TRN: inadequate attention has been paid to the health and psychosocial issues facing girls and women who live with Turner syndrome; investigations into the susceptibility to common disorders such as cardiovascular or autoimmune diseases caused by sex chromosome deficiencies will increase understanding of disease susceptibilities in the general population.

Brain responses to sexual images in 46,XY women with complete androgen insensitivity syndrome are female-typical.

Androgens, estrogens, and sex chromosomes are the major influences guiding sex differences in brain development, yet their relative roles and importance remain unclear. Individuals with complete androgen insensitivity syndrome (CAIS) offer a unique opportunity to address these issues. Although women with CAIS have a Y chromosome, testes, and produce male-typical levels of androgens, they lack functional androgen receptors preventing responding to their androgens. Thus, they develop a female physical phenotype, are reared as girls, and develop into women. Because sexually differentiated brain development in primates is determined primarily by androgens, but may be affected by sex chromosome complement, it is currently unknown whether brain structure and function in women with CAIS is more like that of women or men. In the first functional neuroimaging study of (46,XY) women with CAIS, typical (46,XX) women, and typical (46, XY) men, we found that men showed greater amygdala activation to sexual images than did either typical women or women with CAIS. Typical women and women with CAIS had highly similar patterns of brain activation, indicating that a Y chromosome is insufficient for male-typical human brain responses. Because women with CAIS produce male-typical or elevated levels of testosterone which is aromatized to estradiol these results rule out aromatization of testosterone to estradiol as a determinate of sex differences in patterns of brain activation to sexual images. We cannot, however, rule out an effect of social experience on the brain responses of women with CAIS as all were raised as girls.

Effects of low-dose estrogen replacement during childhood on pubertal development and gonadotropin concentrations in patients with Turner syndrome: results of a randomized, double-blind, placebo-controlled clinical trial.

CONTEXT: The optimal approach to estrogen replacement in girls with Turner syndrome has not been determined. OBJECTIVE: The aim of the study was to assess the effects of an individualized regimen of low-dose ethinyl estradiol (EE2) during childhood from as early as age 5, followed by a pubertal induction regimen starting after age 12 and escalating to full replacement over 4 years. DESIGN: This study was a prospective, randomized, double-blind, placebo-controlled clinical trial. SETTING: The study was conducted at two US pediatric endocrine centers. SUBJECTS: Girls with Turner syndrome (n = 149), aged 5.0-12.5 years, were enrolled; data from 123 girls were analyzable for pubertal onset. INTERVENTION(S): Interventions comprised placebo or recombinant GH injections three times a week, with daily oral placebo or oral EE2 during childhood (25 ng/kg/d, ages 5-8 y; 50 ng/kg/d, ages >8-12 y); after age 12, all patients received escalating EE2 starting at a nominal dosage of 100 ng/kg/d. Placebo/EE2 dosages were reduced by 50% for breast development before age 12 years, vaginal bleeding before age 14 years, or undue advance in bone age. MAIN OUTCOME MEASURES: The main outcome measures for this report were median ages at Tanner breast stage ≥2, median age at menarche, and tempo of puberty (Tanner 2 to menarche). Patterns of gonadotropin secretion and impact of childhood EE2 on gonadotropins also were assessed. RESULTS: Compared with recipients of oral placebo (n = 62), girls who received childhood low-dose EE2 (n = 61) had significantly earlier thelarche (median, 11.6 vs 12.6 y, P < 0.001) and slower tempo of puberty (median, 3.3 vs 2.2 y, P = 0.003); both groups had delayed menarche (median, 15.0 y). Among childhood placebo recipients, girls who had spontaneous breast development before estrogen exposure had significantly lower median FSH values than girls who did not. CONCLUSIONS: In addition to previously reported effects on cognitive measures and GH-mediated height gain, childhood estrogen replacement significantly normalized the onset and tempo of puberty. Childhood low-dose estrogen replacement should be considered for girls with Turner syndrome.

Development of additional pituitary hormone deficiencies in pediatric patients originally diagnosed with idiopathic isolated GH deficiency.

OBJECTIVE: We assessed the characteristics of children initially diagnosed with idiopathic isolated GH deficiency (IGHD) who later developed additional (multiple) pituitary hormone deficiencies (MPHD). DESIGN: Data were analyzed for 5805 pediatric patients with idiopathic IGHD, who were GH-naïve at baseline and GH-treated in the multinational, observational Genetics and Neuroendocrinology of Short Stature International Study. METHODS: Development of MPHD was assessed from investigator diagnoses, adverse events, and concomitant medications. Analyses were performed for all patients and for those who developed MPHD within 4.5 years or had ≥3.5 years, follow-up and continued to have IGHD (4-year cohort). RESULTS: MPHD developed in 118/5805 (2.0%) children overall, and in 96/1757 (5.5%) in the 4-year cohort. Patients who developed MPHD had more profound GHD, with decreased height SDS, IGF1 SDS and peak stimulated GH, and greater height decrement vs target, compared with children who continued to have IGHD (P<0.001 for each variable). Delivery complications, congenital anomalies, and perinatal/neonatal adverse events occurred more frequently in patients who developed MPHD. The most frequent additional deficiency was TSH (82 patients overall); four patients developed two pituitary hormone deficiencies and one developed three deficiencies. Multivariable logistic regression indicated that years of follow-up (odds ratio 1.55), baseline age (1.17), baseline height SDS (0.69), and peak stimulated GH (0.64) were associated with the development of MPHD. CONCLUSIONS: MPHD is more likely to develop in patients with more severe idiopathic IGHD. Older baseline age, lower baseline height SDS, and longer follow-up duration are associated with increased risk of development of MPHD.

GH treatment to final height produces similar height gains in patients with SHOX deficiency and Turner syndrome: results of a multicenter trial.

CONTEXT: Growth impairment in short stature homeobox-containing gene (SHOX) deficiency and Turner syndrome share a similar etiology. Because of the established effect of GH treatment on height in patients with Turner syndrome, we hypothesized that GH therapy would also stimulate growth in patients with SHOX deficiency. OBJECTIVE: Our objectives were to evaluate long-term efficacy of GH treatment in short patients with SHOX deficiency and to compare the effect on final (adult) height (FH) in patients with SHOX deficiency and Turner syndrome. DESIGN AND SETTING: A prospective, multinational, open-label, randomized 3-arm study consisting of a 2-year control period and a subsequent extension period to FH. The treatment groups were 1) SHOX-D-C/GH (untreated during the control period, GH-treated during the extension), 2) SHOX-D-GH/GH, and 3) Turner-GH/GH (GH-treated during both study periods). PATIENTS: Short-statured prepubertal patients with genetically confirmed SHOX deficiency (n = 49) or Turner syndrome (n = 24) who participated in the extension. INTERVENTION: Depending on the study arm, patients received a daily sc injection of 0.05 mg/kg recombinant human GH from start of the study or start of the extension until attainment of FH or study closure. RESULTS: Height SD score gain from start of GH treatment to FH was similar between the combined SHOX-deficient groups (n = 28, 1.34 ± 0.18 [least-squares mean ± SE]) and the Turner group (n = 19, 1.32 ± 0.22). In this FH population, 57% of the patients with SHOX deficiency and 32% of the patients with Turner syndrome achieved a FH greater than -2 SD score. CONCLUSIONS: GH treatment in short children with SHOX deficiency showed similar long-term efficacy as seen in girls with Turner syndrome.

Associations between pituitary imaging abnormalities and clinical and biochemical phenotypes in children with congenital growth hormone deficiency: data from an international observational study.

BACKGROUND/AIMS: Magnetic resonance imaging (MRI) is used to investigate the etiology of growth hormone deficiency (GHD). This study examined relationships between MRI findings and clinical/hormonal phenotypes in children with GHD in the observational Genetics and Neuroendocrinology of Short Stature International Study, GeNeSIS. METHODS: Clinical presentation, hormonal status and first-year GH response were compared between patients with pituitary imaging abnormalities (n = 1,071), patients with mutations in genes involved in pituitary development/GH secretion (n = 120) and patients with idiopathic GHD (n = 7,039). RESULTS: Patients with hypothalamic-pituitary abnormalities had more severe phenotypes than patients with idiopathic GHD. Additional hormonal deficiencies were found in 35% of patients with structural abnormalities (thyroid-stimulating hormone > adrenocorticotropic hormone > luteinizing hormone/follicle-stimulating hormone > antidiuretic hormone), most frequently in patients with septo-optic dysplasia (SOD). Patients with the triad [ectopic posterior pituitary (EPP), pituitary aplasia/hypoplasia and stalk defects] had a more severe phenotype and better response to GH treatment than patients with isolated abnormalities. The sex ratio was approximately equal for patients with SOD, but there was a significantly higher proportion of males (approximately 70%) in the EPP, pituitary hypoplasia, stalk defects, and triad categories. CONCLUSION: This large, international database demonstrates the value of classification of GH-deficient patients by the presence and type of hypothalamic-pituitary imaging abnormalities. This information may assist family counseling and patient management.

United States multicenter study of factors predicting the persistence of GH deficiency during the transition period between childhood and adulthood.

BACKGROUND: Many patients with childhood-onset growth hormone (GH) deficiency do not fulfill diagnostic criteria for GH deficiency (GHD) after attainment of adult height and may not require long-term GH treatment. Patients with history of idiopathic GHD (IGHD) pose the greatest management dilemma, as data regarding factors predictive of persistent GHD in this group are lacking. OBJECTIVES: The objective of this study was to assess potential predictors of persistent GHD in a US patient cohort during transition from childhood to adulthood, particularly in patients with history of IGHD. METHODS: We studied 73 US patients with history of childhood-onset GHD screened at 21 US pediatric endocrine centers for a randomized clinical trial of GH replacement after attainment of adult height. The cohort comprised 42 boys/men and 31 girls/women aged14-22 years, who had received ≥1 year of GH treatment and had completed linear growth. The main outcome measures were sensitivity, specificity, positive and negative predictive values (PPV, NPV) of clinical and hormonal factors for persistent GHD (defined a priori in this study as peak GH < 5 µg/L). RESULTS: For the cohort as a whole, the best predictors of persistent GHD (100% PPV) were history of organic hypothalamic-pituitary disorder or ≥2 additional pituitary hormone deficiencies (PHD). Best predictors of persistent GHD in patients with childhood history of IGHD were standard deviation scores (SDS) for serum insulin-like growth factor binding protein-3 (IGFBP-3) below -2.0, and for insulin-like growth factor-I (IGF-I) below -5.3 (measured ≥6 weeks after completion of GH treatment; PPV 100% for both), and age <4 years at original diagnosis (PPV 89%). IGF-I above -1.6 SDS had 100% NPV. CONCLUSIONS: US patients with an organic cause of childhood-onset GHD or ≥2 additional PHDs may not require GH stimulation testing to reconfirm GHD after completion of childhood treatment. In contrast, patients with idiopathic childhood-onset GHD almost invariably require retesting, as GHD persists in only a minority (those who were very young at initial diagnosis and those who have subnormal IGFBP-3 or extremely low IGF-I after completion of childhood treatment). Subnormal posttreatment IGF-I (<-2.0 SDS) lacked predictive power for persistent GHD, whereas IGF-I > -1.6 SDS was 100% predictive of GH sufficiency.

Determinant factors of gender identity: a commentary.

Paediatric specialists involved in the care of children with disorders of sex development may be expected to provide straightforward answers to questions concerning the "true sex" of a child, reflecting common perceptions of sex/gender as an immutable binary biological reality. This article highlights how much more broad and complex the topic of gender identity and its development is. Many theories have been put forward to advance knowledge of gender identity. Against the breadth and depth of this vast topic, the current overview is inevitably incomplete. It begins by arguing for a more consistent use of 'sex' and 'gender'. It considers in turn three influential theoretical frameworks that lend themselves to empirical research. These are: 1) the role of the brain; 2) the role of socialisation; and 3) multi-dimensional gender development. The article ends by suggesting potentially fruitful questions and areas for future research.