Coming Up Short: Risks of Bias in Assessing Psychological Outcomes in Growth Hormone Therapy for Short Stature.

CONTEXT: Two often cited assumptions for treating children with GH are that short stature (SS), as an isolated physical characteristic, is associated with psychosocial morbidity and that GH treatment may increase height and improve psychological adjustment. Findings across studies regarding the psychological consequences associated with GH management of children with SS are variable and frequently contradictory. The purpose of this systematic review is to evaluate the degree to which any conclusions about the relative risks or benefits of GH treatment on psychological outcomes can be made based on the published literature. EVIDENCE ACQUISITION: Electronic databases were searched for randomized clinical trials and nonrandomized studies, published between 1958-2014, in which GH was administered for management of children with SS and psychosocial, cognitive, academic, or health-related quality of life outcomes were assessed. Methodological quality of each study was assessed using the Cochrane Collaboration's tool for assessing risk of bias. EVIDENCE SYNTHESIS: Eighty studies were evaluated. No studies were rated as having a low risk of bias, the risk of bias was unclear in seven study outcome areas, and the remaining studies were judged as having a high risk of bias. CONCLUSIONS: The high risk of bias present in the majority of the literature on GH treatment effects on psychological outcomes (in particular, lack of blinding) substantially weakens confidence in their results. This may serve to explain the variability of findings for these outcomes across studies.

Disorders of Sex Development (DSD): Networking and Standardization Considerations.

Syndromes resulting in Disorders of Sex Development (DSD) are individually rare. Historically, this fact has hindered both clinical research and the delivery of evidence-based care. Recognizing the need for advancement, members of European and North American medical societies produced policy statements, notably the Consensus Statement on Management of Intersex Disorders, which recognize that optimal healthcare in DSD requires multidisciplinary teams in conjunction with networking of treatment centers and continued development of patient registries. This paper summarizes efforts in Europe and the U.S. toward creating networks focused on expanding discovery and improving healthcare and quality of life outcomes in DSD. The objectives and function of registry-based networks (EuroDSD/I-DSD), learning collaboratives (DSD-net), clinical outcomes research (DSD-Life), and networking hybrids (DSD-TRN) are reviewed. Opportunities for, and barriers to standardization in research and care are highlighted in light of practical considerations, for example, limitations in reliably classifying anatomic phenotypes and gaps in behavioral health staffing resources. The role of patient-reported outcomes is considered, with emphasis on integrating patient perspectives, given findings of limited agreement in outcome ratings by healthcare providers and patients. Finally, the characteristics of clinical centers likely to deliver the highest quality outcomes are discussed.

Promoting Shared Decision Making in Disorders of Sex Development (DSD): Decision Aids and Support Tools.

Specific complaints and grievances from adult patients with disorders of sex development (DSD), and their advocates center around the lack of information or misinformation they were given about their condition and feeling stigmatized and shamed by the secrecy surrounding their condition and its management. Many also attribute poor sexual function to damaging genital surgery and/or repeated, insensitive genital examinations. These reports suggest the need to reconsider the decision-making process for the treatment of children born with DSD. This paper proposes that shared decision making, an important concept in adult health care, be operationalized for the major decisions commonly encountered in DSD care and facilitated through the utilization of decision aids and support tools. This approach may help patients and their families make informed decisions that are better aligned with their personal values and goals. It may also lead to greater confidence in decision making with greater satisfaction and less regret. A brief review of the past and current approach to DSD decision making is provided, along with a review of shared decision making and decision aids and support tools. A case study explores the need and potential utility of this suggested new approach.

Parenting Children with Disorders of Sex Development (DSD): A Developmental Perspective Beyond Gender.

Advances in therapeutics for specific conditions have contributed to a categorical psychological approach to chronic diseases that affect children. Consensus statements and clinical guidelines recognize stress associated with disorders of sex development (DSD) for patients and their caregivers - yet much remains to be learned concerning the social adjustment, mental health, and quality of life of affected children and their families. We present preliminary data on the psychosocial comorbidities of caregivers of children with DSD, including stigma, isolation, stress, anxiety, and depressive symptomatology. Evidence is offered in support of individualized psychological approaches for families according to such variables as: 1) gender of the caregiver, 2) gender of the affected child and 3) presence of genital ambiguity at birth. Development of feasible, targeted interventions to ameliorate psychosocial comorbidities among caregivers is needed to optimize social adjustment, mental health, and health-related quality of life (HRQoL) for children with DSD.

Targeted massively parallel sequencing provides comprehensive genetic diagnosis for patients with disorders of sex development.

Disorders of sex development (DSD) are rare disorders in which there is discordance between chromosomal, gonadal, and phenotypic sex. Only a minority of patients clinically diagnosed with DSD obtains a molecular diagnosis, leaving a large gap in our understanding of the prevalence, management, and outcomes in affected patients. We created a novel DSD-genetic diagnostic tool, in which sex development genes are captured using RNA probes and undergo massively parallel sequencing. In the pilot group of 14 patients, we determined sex chromosome dosage, copy number variation, and gene mutations. In the patients with a known genetic diagnosis (obtained either on a clinical or research basis), this test identified the molecular cause in 100% (7/7) of patients. In patients in whom no molecular diagnosis had been made, this tool identified a genetic diagnosis in two of seven patients. Targeted sequencing of genes representing a specific spectrum of disorders can result in a higher rate of genetic diagnoses than current diagnostic approaches. Our DSD diagnostic tool provides for first time, in a single blood test, a comprehensive genetic diagnosis in patients presenting with a wide range of urogenital anomalies.

Psychosocial adaptation of middle childhood boys with hypospadias after genital surgery.

OBJECTIVE: To compare the psychosocial adaptation of boys with hypospadias after genital surgery to a community sample. METHODS: Boys (6 to 10 years) with a history of hypospadias repair (n = 175) were compared with a community sample (n = 333) in a postal questionnaire survey using the Child Behavior Checklist. RESULTS: Few significant differences between cases and controls emerged. Boys with hypospadias were (slightly) lower in social involvement but did not perform more poorly in school. Boys with hypospadias displayed fewer externalizing behavior problems than controls, but a significant difference in nocturnal enuresis was not detected. Level of behavior problems did not differentiate hypospadias severity subgroups, but greater surgical and hospitalization experiences were associated with increased internalizing problems. Poorer cosmetic appearance of the genitals was associated with worse school performance. CONCLUSIONS: Surgically corrected hypospadias should not be considered a risk factor for poor psychosocial adaptation in childhood, but emotional problems increase with the number of hospital-related experiences.

Perceived versus measured height. Which is the stronger predictor of psychosocial functioning?

The relationship between perceptions versus measured height and children's psychosocial adaptation in a sample of medically referred youth with short stature was investigated. All children referred for a growth evaluation to one regional pediatric endocrinology clinic received a psychosocial screening assessment as a routine component of their initial visit. Data were collected for patients ages 4-18 years (n = 620) with heights ranging from -4.0 to -1.1 SD for age- and gender-adjusted population norms. Patients (8 years and older) and in all cases a parent/guardian served as informant through paper-and-pencil questionnaires. Both children and parents overestimated the child's height. Overestimations of height were associated with greater patient and parent satisfaction with stature. Perceived height was more strongly associated with psychosocial adaptation than was measured height. Clinical management decisions designed to enhance patient quality of life by increasing projected adult height through hormonal interventions should take into account both measured and perceived patient height.

Growth hormone therapy in childhood-onset growth hormone deficiency: adult anthropometric and psychological outcomes.

The current adult heights of hypopituitary children treated with recombinant human growth hormone (rGH) now range between -1.5 and -0.7 height standard deviations (Ht SDS) of control populations. These height outcomes are markedly better than the ones observed following treatment with pituitary-derived human growth hormone (pGH) (between -4.7 and -2.0 Ht SDS). Although treatment with rGH has not yielded adult heights that are equal to genetic target heights, the discrepancy is much less now than in previous decades. Higher rGH dose, longer duration of treatment, early age at diagnosis, correction of height deficit prior to onset of puberty, and daily rGH injections have had beneficial effects on final adult heights. The current dosing regimens (0.3-0.18 mg/kg/wk) have not had an adverse effect on bone maturation and have not stimulated an earlier onset of puberty. Although height gains in puberty are less than controls, a majority of treated subjects reach heights within the normal range for adults. Higher doses of rGH during puberty have been studied in limited numbers of adolescents with positive effects; however, standard dosing will likely continue to be used because of financial considerations and safety concerns. Further improvements in adult heights are likely to be reported when the youngest children who began rGH in 1985 complete their growth. Several studies have investigated the quality of life (QOL) of GH-deficient (GHD) patients who, as children, had been treated with GH predominantly during the pGH era. Domains of functioning assessed include educational attainment, employment, and marital status. Although some studies have reported a generally positive adaptation, others have shown this group to exhibit marked deficits. Limited adult height outcomes in the pGH era of GH therapy has sometimes been used to account for poor outcomes. Variable behavioral findings are likely related to sample heterogeneity and disparate research methodologies and designs, most particularly the choice of control or comparison groups. In addition to summarizing this older literature, we report on a recently completed investigation in which the QOL adjustment of GHD patients is compared to that of same-sex siblings. Comparisons between GHD cases and norms for standardized questionnaires indicated both better and worse functioning in several domains. In contrast, very limited differences were detected between GHD cases and same-sex siblings. IGHD (isolated growth hormone deficiency) patients were functioning better than those with MPHD (multiple pituitary hormone deficiencies), but the effect sizes of these differences in most areas were relatively small. Adult height and degree of growth over the course of GH therapy were generally unrelated to QOL outcomes. Findings from the present study underscore the importance of selecting unbiased control/comparison groups in evaluating psychological outcomes among GHD adults.

Current dosing of growth hormone in children with growth hormone deficiency: how physiologic?

The current doses of recombinant growth hormone (rGH) are two to three times those used in the pituitary growth hormone era. These rGH doses (0.025 to 0.043 mg/kg/d) are similar to or moderately greater than the physiologic requirements. Growth velocity and height gains have been shown to be greater with 0.05 mg/kg/d of rGH than with 0.025 mg/kg/d. Larger doses of GH and early initiation of treatment result in greater heights at the onset of puberty and greater adult heights. Earlier onset of puberty and more rapid maturation, as indicated by bone age, were not observed in children who were given 0.18 to 0.3 mg/kg/wk of rGH. The frequency of adverse events is very low, but diligent surveillance of all children who are treated with rGH is essential.

Quality of life among formerly treated childhood-onset growth hormone-deficient adults: a comparison with unaffected siblings.

Several studies have investigated the quality of life (QOL) of GH-deficient (GHD) adults who, as children, had been treated with GH. Variable findings are probably related to sample heterogeneity and disparate research methodologies and designs, particularly the choice of control or comparison groups. In addition to comparing a relatively large sample to questionnaire norms, the present study is the first to compare the QOL adjustment of GHD patients to that of same sex siblings. A total of 140 former patients (76% of those eligible; mean age, 26 yr; n = 95 isolated GHD, n = 45 multiple pituitary hormone deficiencies; 117 males and 23 females) and 53 same sex siblings (84% participation), 18 yr and older, participated in the telephone questionnaire survey. The majority of interviews with GHD patients (78%) and siblings (87%) were conducted blind to the subject's clinical status. Comparisons between GHD patients and norms for standardized questionnaires indicated both better and worse functioning in several domains. In contrast, very limited differences were detected between GHD cases and same sex siblings. Isolated GHD patients were functioning better than those with multiple pituitary hormone deficiencies, but the effect sizes of these differences in most areas were relatively small. Adult height and degree of growth over the course of GH therapy were generally unrelated to QOL outcomes. Findings from the present study underscore the importance of selecting unbiased control/comparison groups in evaluating psychological outcomes among GHD adults.

Outcome of lower L-thyroxine dose for treatment of congenital hypothyroidism.

The appropriateness of the recommended L-thyroxine dose (10-15 micrograms/kg/day) for the treatment of congenital hypothyroidism has been questioned because of the risk of iatrogenic hyperthyroidism. We report the outcome of 23 newborns with congenital primary hypothyroidism treated with 25 micrograms L-thyroxine per day (5.3-9.2 micrograms/kg/day) and followed for an average of 59 months. Serum thyroxine (T4) values increased (X = 11.4 +/- 2.7 micrograms/dL) within 4 weeks posttherapy; eight infants had T4 levels > or = 13 micrograms/dL on only half the currently recommended dose. Thyroid-stimulating hormone (TSH) values remained elevated in 18 of 21 patients for 2-21 months despite a high-normal T4. Psychometric tests were performed in 19 of the 23 patients. The mean Full Scale IQ for the congenital hypothyroid group (n = 16) was 101.4 +/- 13.2 with comparable Verbal and Performance IQ scores. Patients with a bone age (BA) of < or = 32 weeks or T4 < 2 micrograms/dL at initial evaluation had significantly Lower Verbal IQ scores. A standardized parent-report assessment of behavioral and emotional functioning revealed subgroup scale scores that were indistinguishable from nonclinical norms. We conclude that (1) average range IQ scores and positive behavioral adaptation are observed in congenitally hypothyroid children treated with L-thyroxine doses lower than currently recommended; (2) the L-thyroxine dose should be individualized to prevent iatrogenic hyperthyroidism; (3) TSH normalization should not be a primary objective of treatment, and (4) a prospective study comparing the advantages and risks of different doses of L-thyroxine is needed.

Gender development in boys born with hypospadias.

Fetal testicular androgens in several mammalian species are responsible for the sexual differentiation of both the genitalia and the brain, the latter effect being related to behavioral sex-dimorphisms. Because prenatal endocrine abnormalities can be inferred from genital defects, studies of individuals born with anomalies potentially elucidate the contribution of androgens to the development of gender-related variation in human behavior. This study concerns the gender-role behavior of middle childhood boys (ages 6-10 years; n = 175) born with hypospadias, an androgen-related genital anomaly. Parents completed standardized gender behavior questionnaires in a postal survey. Hypospadias subjects did not show consistent differences from a community control group (n = 333) in feminine behavior, but significant, small, increases in masculine behavior were found. Severity of the hypospadias was unrelated to gender-role behavior. A number of surgery-related hospitalizations, however, were correlated with increased gender-atypical behavior. It is concluded that the hypoandrogenization associated with hypospadias does not interfere with the development of gender-typical masculine behavior.

Short stature: a psychosocial burden requiring growth hormone therapy?

BACKGROUND: Changes in the diagnosis of endocrine-based growth disorders and the advent of biosynthetic growth hormone have altered the long-standing policy of treating only those individuals with "classic" growth hormone deficiency. One justification for treating short children is to improve their psychosocial adaptation. The present investigation assessed the positive and negative behavioral adaptation, self-perceptions of domain-specific competencies, and global self-worth of a large, diagnostically heterogeneous sample of children and adolescents referred to pediatric endocrinologists for a growth evaluation. METHODS: All patients seen in a pediatric endocrine clinic (180 boys and 78 girls; 4 to 18 years) with a height at the fifth percentile or lower were included. Parents of all participating children completed the Child Behavior Checklist. Patients 8 years and older completed the Self-Perception Profile and those 11 years and older, in addition, completed the Youth Self Report. Short-stature (SS) subjects were compared with normative and psychiatric samples. RESULTS: The SS boys were described by parents as being significantly less socially competent and showing more behavioral and emotional problems than a normative sample selected for mental health. However, they were significantly more socially competent and showed fewer psychopathologic symptoms than a psychiatric referred sample of comparable age. The SS boys described themselves as less socially active but did not report more behavior disturbance than the normative sample. The SS boys' self-perceptions of domain-specific competencies and global self-worth were comparable to a normative comparison group with the exception that older subjects (13 years or older) described their athletic abilities more positively and their work competence more negatively. The SS girls were, with few exceptions, indistinguishable from the normal comparison groups on both parent- and self-report measures of social competency and behavior disturbance. Younger SS girls (ages 8 to 12 years) described their athletic competence and behavioral conduct more positively than the comparison group on the self-esteem questionnaire. Patient height deficit was unrelated to scores on the three questionnaires. Finally, no statistically significant differences in psychosocial functioning were detected between children with "normal-variant" SS and those with pathologic growth disorders. SS and those with pathologic growth disorders. CONCLUSIONS: Short-stature girls show more adaptive psychosocial functioning than SS boys. In either sex, SS does not appear to be associated with clinically significant psychosocial morbidity. Severity of the height deficit does not correlate with the level of behavioral adaptation. These observations challenge the justification of providing growth hormone therapy for all short children to improve their psychosocial functioning.

Gender-related assessment of childhood play.

Parent-report based scales for the assessment of sex-dimorphic behavior are an important tool in research on psychosexual differentiation and its disorders. This paper presents the factor analysis and corresponding scale development for the slightly expanded Child Game Participation Questionnaire (Bates & Bentler, 1973), based on the parents of a demographically diverse school sample of 355 girls and 333 boys aged 6 to 10 years. Evidence supporting each of three theoretical positions in gender assessment--unidimensional bipolar, two-dimensional unipolar, and multidimensional--was provided. Effect sizes were unusually large for gender, but small for age, socioeconomic level, and race/ethnicity.

Variability in middle childhood play behavior: effects of gender, age, and family background.

Parent-report questionnaires for the assessment of gender-normative and gender-atypical behavior in childhood offers researchers the opportunity to conduct large-scale screenings of community samples of boys and girls. One important aspect of childhood gender role behavior includes play. Although play behavior inventories have been used clinically for the identification of gender disturbed boys, recent community-based surveys of play behavior in both genders are lacking. The present postal questionnaire survey of parents of 688, 6- to 10-year-old children (boys = 333, girls = 355) attending one public school district (74% of the eligible sample), clarifies how subject's age, family race/ethnicity, and socioeconomic status influence gender differences in play. Significant gender differences were detected for 63 of the 69 games. With but few exceptions, the magnitude of the gender differences in play remained relatively constant across middle childhood. Older boys and girls decreased their participation in activities numerically dominated by girls whereas the reverse was true for male-dominated activities. Parents' educational level influenced play for only a minority of items. Finally, whereas race/ethnicity significantly predicted game/activity participation in approximately one half of the items, a consistent influence of this variable on gender-related play did not emerge. In spite of dramatic changes in women's roles in the U.S. society over the past three decades, gender differences in middle childhood play have remained strong.

Seasonal patterns in eating disorder subgroups.

Patients with bulimia nervosa (BN) often have seasonal patterns of mood and appetite that compare with patterns seen in seasonal affective disorder (SAD). Seasonal patterns in other eating disorder (ED) subgroups have not been adequately described. We report on seasonal patterns in mood, weight, appetite, sleep, social activity, and energy in 154 consecutive admissions to an outpatient ED program: 60 patients with anorexia nervosa (AN), 31 with BN, 34 with a history of both AN and BN (AN/BN), and 29 with an ED not otherwise specified (ED-NOS). AN patients had significantly less seasonal variation overall than either bulimic subgroup, as measured by the global seasonality score (GSS) on the Seasonal Patterns Assessment Questionnaire (SPAQ). AN patients also showed less seasonal change in mood, weight, and energy than BN patients, and less variation in mood and appetite than AN/BN patients.