Heightism, growth hormone treatment, and social functioning: a holistic approach to a persistent clinical challenge.

PURPOSE OF REVIEW: Use of recombinant human growth hormone (rhGH) treatment to increase height in children with non-growth hormone deficient short stature is becoming more common. Yet, the evidence to support the notion that augmenting height directly leads to increased well being, specifically psychosocial well being, is inconsistent, with high-quality evidence lacking. RECENT FINDINGS: Review of recent studies demonstrates that the association between height augmentation and psychosocial well being is complex. The direct contribution of height to well being may be less than the current model of clinical care of short stature assumes. Rather, the new studies provide evidence to support a role for psychosocial factors, including height-related beliefs, social support, and coping skills, in promoting psychosocial well being, specifically quality of life and self-esteem. SUMMARY: Clinical care of short stature would benefit from incorporating a holistic model of care that considers psychosocial interventions in addition to, or instead of, rhGH treatment.

Youth and Parent Perceptions of Youth Decision-Making Roles Regarding Evaluation for Short Stature.

Youth decision-making involvement (DMI) in medical treatment associates with greater adherence and feelings of self-efficacy. However, little is known about youth DMI regarding medical evaluation and diagnostic procedures. Using thematic analysis of semi-structured interviews, we explored parent (n=24) and youth (n=24) perceptions of youth roles in the decision to undergo evaluation for short stature. Five themes emerged about evaluation decisions including: parents/providers were gatekeepers, some parents sought youth agreement, conversations focused on logistics, some parents gave limited information, and youth expressed anxiety. Results suggest that including youth in discussions about evaluation may alleviate anxiety and uncertainty about upcoming procedures.

Diagnosis and treatment of growth hormone deficiency in children on the ketogenic diet: A case series.

The ketogenic diet (KD) can have a negative impact on the linear growth and body composition of children. The aims of this study were to review two centers' experience with children who developed height deceleration on the KD and determine if the height deceleration was secondary to growth hormone deficiency (GHD), and if growth hormone therapy (GHT) would be effective and safe (not altering ketosis or seizure frequency). Retrospective chart reviews were performed on patients with KD referred to Endocrinology between 2013 and 2018. Seventeen children were identified. Data reviewed included: demographics, growth velocity, KD ratio, protein/calorie intake, lab results, GH dosage, Tanner stage, and seizure frequency, and endocrine recommendations. Descriptive statistics were performed. Of the 17 children referred to the Endocrine Division, seven children were growth hormone deficient and began GHT. Data were provided for six patients (2 males, 4 females; age 2-7 years at the start of KD) on the KD for >6 years and on GHT for >4 years. Growth for all patients stabilized or increased. IGF-1 z-scores normalized. GHT did not affect seizure frequency or ketosis. GHT in those with GHD can be an appropriate option allowing better growth while still maintaining ketogenic therapy and seizure control. PLAIN LANGUAGE SUMMARY: The KD can be an effective treatment for difficult-to-control epilepsy and some disorders of carbohydrate metabolism. The KD can adversely affect the linear growth (height) of children. This case series reviewed six patients who had slow linear growth. It was found that all six children had growth hormone deficiency, grew better with growth hormone treatments, and that their seizures and ketone levels were not affected.

Growth Hormone Treatment for Non-GHD Disorders: Excitement Tempered by Biology.

The success of growth hormone (GH) replacement in children with classical GH deficiency has led to excitement that other causes of short stature may benefit similarly. However, clinical experience has shown less consistent and generally less dramatic effects on adult height, perhaps not surprising in light of increased understanding of GH and growth plate biology. Nonetheless, clinical demand for GH treatment continues to grow. Upon the 20th anniversary of the US Food and Drug Administration's approval of GH treatment for idiopathic short stature, this review will consider the factors underlying the expansion of GH treatment, the biological mechanisms of GH action, the non-GH-deficient uses of GH as a height-promoting agent, biological constraints to GH action, and future directions.

Endocrine Health and Health Care Disparities in the Pediatric and Sexual and Gender Minority Populations: An Endocrine Society Scientific Statement.

Endocrine care of pediatric and adult patients continues to be plagued by health and health care disparities that are perpetuated by the basic structures of our health systems and research modalities, as well as policies that impact access to care and social determinants of health. This scientific statement expands the Society's 2012 statement by focusing on endocrine disease disparities in the pediatric population and sexual and gender minority populations. These include pediatric and adult lesbian, gay, bisexual, transgender, queer, intersex, and asexual (LGBTQIA) persons. The writing group focused on highly prevalent conditions-growth disorders, puberty, metabolic bone disease, type 1 (T1D) and type 2 (T2D) diabetes mellitus, prediabetes, and obesity. Several important findings emerged. Compared with females and non-White children, non-Hispanic White males are more likely to come to medical attention for short stature. Racially and ethnically diverse populations and males are underrepresented in studies of pubertal development and attainment of peak bone mass, with current norms based on European populations. Like adults, racial and ethnic minority youth suffer a higher burden of disease from obesity, T1D and T2D, and have less access to diabetes treatment technologies and bariatric surgery. LGBTQIA youth and adults also face discrimination and multiple barriers to endocrine care due to pathologizing sexual orientation and gender identity, lack of culturally competent care providers, and policies. Multilevel interventions to address these disparities are required. Inclusion of racial, ethnic, and LGBTQIA populations in longitudinal life course studies is needed to assess growth, puberty, and attainment of peak bone mass. Growth and development charts may need to be adapted to non-European populations. In addition, extension of these studies will be required to understand the clinical and physiologic consequences of interventions to address abnormal development in these populations. Health policies should be recrafted to remove barriers in care for children with obesity and/or diabetes and for LGBTQIA children and adults to facilitate comprehensive access to care, therapeutics, and technological advances. Public health interventions encompassing collection of accurate demographic and social needs data, including the intersection of social determinants of health with health outcomes, and enactment of population health level interventions will be essential tools.

Patient and Parent Characteristics Related to Quality of Life and Self-Esteem in Healthy Youth Undergoing Provocative Growth Hormone Testing.

OBJECTIVE: To examine how height and youth as well as parenting characteristics associate with quality of life (QoL) and self-esteem among healthy youth undergoing growth evaluation with growth hormone (GH) testing. STUDY DESIGN: Healthy youth, aged 8-14 years, undergoing provocative GH testing, and a parent completed surveys at or around the time of testing. Surveys collected demographic data; youth and parent reports of youth health-related QoL; youth reports of self-esteem, coping skills, social support, and parental autonomy support; and parent reports of perceived environmental threats and achievement goals for their child. Clinical data were extracted from electronic health records. Univariate models and multivariable linear regressions were used to identify factors associated with QoL and self-esteem. RESULTS: Sixty youth (mean height z score -2.18 ± 0.61) and their parents participated. On multivariable modeling, youth perceptions of their physical QoL associated with higher grade in school, greater friend and classmate support, and older parent age; youth psychosocial QoL with greater friend and classmate support, and with less disengaged coping; and youth height-related QoL and parental perceptions of youth psychosocial QoL with greater classmate support. Youth self-esteem associated with greater classmate support and taller mid-parental height. Youth height was not associated with QoL or self-esteem outcomes in multivariable regression. CONCLUSIONS: Perceived social support and coping skills, rather than height, were related to QoL and self-esteem in healthy short youth and may serve as an important potential area for clinical intervention.

Views on Short Stature of Female vs Male Endocrine Pediatric Patients Undergoing Provocative Growth Hormone Testing and Their Parents.

OBJECTIVE: Boys outnumber girls in short stature evaluations and growth hormone treatment despite absence of gender differences in short stature prevalence. Family views on short stature influence medical management, but gender-based analysis of these views is lacking. This study explored endocrine patients' and their parents' perceptions of short stature and its impact on quality of life by patient gender. METHODS: Patients aged 8 to 14 years undergoing provocative growth hormone testing and 1 parent each completed semistructured interviews. Clinical data were extracted by chart review. RESULTS: Twenty-four patient-parent dyads (6 female patients, 22 mothers; predominantly non-Hispanic White) participated. Six major themes emerged: (1) patients' perceptions of their short stature were similar by gender, (2) physical experiences of short stature were similar by gender, (3) social experiences of short stature were both similar and different by gender, (4) parental perceptions of short stature as a factor limiting their child's functionality were similar by gender, (5) concern about societal stigma related to short stature arose for both genders, and (6) patients' perceptions of parental messaging about the import of their short stature were similar by gender. CONCLUSION: Our data reveal more similarities than differences between genders in patient perceptions and patient and parent-reported experiences of short stature. Worry about stature-related stigma was noted for patients of both genders. Parental messaging about short stature emerged as an important area to explore further by patient gender. Our findings suggest that clinicians should be wary of making gender or stigma-based assumptions when evaluating children with short stature.

Menstrual Cycle Patterns After Concussion in Adolescent Patients.

OBJECTIVE: To describe menstrual cycle patterns in adolescents with concussion and investigate whether menstrual cycle phase at injury influenced postconcussion cycle pattern changes or concussion symptoms. STUDY DESIGN: Data were collected prospectively from patients aged 13-18 years presenting to a specialty care concussion clinic for an initial visit (≤28 days postconcussion) and, if clinically indicated, at a follow-up visit 3-4 months postinjury. Primary outcomes included menstrual cycle pattern change since injury (change/no change), menstrual cycle phase at time of injury (calculated using date of last period before injury), and symptom endorsement and severity, measured by Post-Concussion Symptom Inventory (PCSI). Fisher exact tests were used to determine the association between menstrual phase at injury and change in cycle pattern. Multiple linear regression was used to determine whether menstrual phase at injury was associated with PCSI endorsement and symptom severity, adjusting for age. RESULTS: Five hundred twelve postmenarchal adolescents were enrolled (age 15.2 ± 1.4 years), with 111 (21.7%) returning for follow-up at 3-4 months. Menstrual pattern change was reported by 4% of patients at initial visit and 10.8% of patients at follow-up. At 3-4 months, menstrual phase at injury was not associated with menstrual cycle changes (P = .40) but was associated with endorsement of concussion symptoms on the PCSI (P = .01). CONCLUSIONS: At 3-4 months' postconcussion, 1 in 10 adolescents experienced a change in menses. Menstrual cycle phase at injury was associated with postconcussion symptom endorsement. Leveraging a large sample of postconcussion menstrual patterns, this study represents foundational data regarding potential menstrual cycle effects of concussion in female adolescents.

Autocrine IGF-II-Associated Cancers: From a Rare Paraneoplastic Event to a Hallmark in Malignancy.

The paraneoplastic syndrome referred in the literature as non-islet-cell tumor hypoglycemia (NICTH) and extra-pancreatic tumor hypoglycemia (EPTH) was first reported almost a century ago, and the role of cancer-secreted IGF-II in causing this blood glucose-lowering condition has been widely established. The landscape emerging in the last few decades, based on molecular and cellular findings, supports a broader role for IGF-II in cancer biology beyond its involvement in the paraneoplastic syndrome. In particular, a few key findings are constantly observed during tumorigenesis, (a) a relative and absolute increase in fetal insulin receptor isoform (IRA) content, with (b) an increase in IGF-II high-molecular weight cancer-variants (big-IGF-II), and (c) a stage-progressive increase in the IGF-II autocrine signal in the cancer cell, mostly during the transition from benign to malignant growth. An increasing and still under-exploited combinatorial pattern of the IGF-II signal in cancer is shaping up in the literature with respect to its transducing receptorial system and effector intracellular network. Interestingly, while surgical and clinical reports have traditionally restricted IGF-II secretion to a small number of solid malignancies displaying paraneoplastic hypoglycemia, a retrospective literature analysis, along with publicly available expression data from patient-derived cancer cell lines conveyed in the present perspective, clearly suggests that IGF-II expression in cancer is a much more common event, especially in overt malignancy. These findings strengthen the view that (1) IGF-II expression/secretion in solid tumor-derived cancer cell lines and tissues is a broader and more common event compared to the reported IGF-II association to paraneoplastic hypoglycemia, and (2) IGF-II associates to the commonly observed autocrine loops in cancer cells while IGF-I cancer-promoting effects may be linked to its paracrine effects in the tumor microenvironment. Based on these evidence-centered considerations, making the autocrine IGF-II loop a hallmark for malignant cancer growth, we here propose the functional name of IGF-II secreting tumors (IGF-IIsT) to overcome the view that IGF-II secretion and pro-tumorigenic actions affect only a clinical sub-group of rare tumors with associated hypoglycemic symptoms. The proposed scenario provides an updated logical frame towards biologically sound therapeutic strategies and personalized therapeutic interventions for currently unaccounted IGF-II-producing cancers.

Safety and Efficacy of Pediatric Growth Hormone Therapy: Results From the Full KIGS Cohort.

CONTEXT: The Kabi/Pfizer International Growth Database (KIGS) is a large, international database (1987-2012) of children treated with recombinant human growth hormone (rhGH) in real-world settings. OBJECTIVE: This work aimed to evaluate the safety and efficacy of rhGH from the full KIGS cohort. METHODS: Data were collected by investigators from children with growth disorders treated with rhGH (Genotropin [somatropin]; Pfizer). Safety was evaluated in all treated patients, and efficacy in those treated for 1 year or more. A subgroup included patients treated for 5 years or more (≥ 2 years prepubertal) who had reached near-adult height (NAH). Main outcomes included adverse events (AEs), serious AEs (SAEs), and height growth. RESULTS: The full KIGS cohort (N = 83 803 [58% male]) was treated for idiopathic GH deficiency (IGHD; 46.9%), organic GHD (10.0%), small for gestational age (SGA; 9.5%), Turner syndrome (TS; 9.2%), idiopathic short stature (ISS; 8.2%), and others (16.2%). Median rhGH treatment duration was 2.7 years and observation 3.1 years. SAEs occurred in 3.7% of patients and death in 0.4%. The most common SAEs were recurrence of craniopharyngioma (n = 151), neoplasm (n = 99), and cancer (n = 91); and scoliosis (n = 91). Median first-year delta height-SD score (SDS) (Prader) in prepubertal patients was 0.66 (IGHD), 0.55 (ISS), 0.58 (TS), and 0.71 (SGA). Median gains in NAH-SDS were 1.79 (IGHD), 1.37 (ISS), and 1.34 (SGA) for boys, and 2.07 (IGHD), 1.62 (ISS), 1.07 (TS), and 1.57 (SGA) for girls. CONCLUSION: Data from KIGS, the largest and longest running international database of rhGH-treated children, show that rhGH is safe and increases short-term height gain and adult height across GHD and non-GHD conditions.

Clinical Indications for Growth Hormone Therapy.

Growth hormone (GH) is an injectable medication originally used to replace the deficiency of the hormone, but has expanded to treating conditions that may reduce growth and adult height even when the body maintains endogenous GH production. In the United States, there are 8 Food and Drug Administration (FDA)-approved indications for pediatric GH therapy: GH deficiency, Prader-Willi Syndrome, small for gestational age (SGA) without catch-up growth, idiopathic short stature, Turner syndrome, SHOX gene haploinsufficiency, Noonan Syndrome, and chronic renal insufficiency. We characterize the growth patterns and effects of GH treatment in each of these indications. We also review patterns of growth that warrant referral to a pediatric endocrinologist, as well as safety updates. This review is intended to guide practitioners on the initial evaluation and management of patients with short stature, and the indications for GH therapy.

Safety of growth hormone replacement in survivors of cancer and intracranial and pituitary tumours: a consensus statement.

Growth hormone (GH) has been used for over 35 years, and its safety and efficacy has been studied extensively. Experimental studies showing the permissive role of GH/insulin-like growth factor 1 (IGF-I) in carcinogenesis have raised concerns regarding the safety of GH replacement in children and adults who have received treatment for cancer and those with intracranial and pituitary tumours. A consensus statement was produced to guide decision-making on GH replacement in children and adult survivors of cancer, in those treated for intracranial and pituitary tumours and in patients with increased cancer risk. With the support of the European Society of Endocrinology, the Growth Hormone Research Society convened a Workshop, where 55 international key opinion leaders representing 10 professional societies were invited to participate. This consensus statement utilized: (1) a critical review paper produced before the Workshop, (2) five plenary talks, (3) evidence-based comments from four breakout groups, and (4) discussions during report-back sessions. Current evidence reviewed from the proceedings from the Workshop does not support an association between GH replacement and primary tumour or cancer recurrence. The effect of GH replacement on secondary neoplasia risk is minor compared to host- and tumour treatment-related factors. There is no evidence for an association between GH replacement and increased mortality from cancer amongst GH-deficient childhood cancer survivors. Patients with pituitary tumour or craniopharyngioma remnants receiving GH replacement do not need to be treated or monitored differently than those not receiving GH. GH replacement might be considered in GH-deficient adult cancer survivors in remission after careful individual risk/benefit analysis. In children with cancer predisposition syndromes, GH treatment is generally contraindicated but may be considered cautiously in select patients.

Expanded cardiovascular phenotype of Myhre syndrome includes tetralogy of Fallot suggesting a role for SMAD4 in human neural crest defects.

Tetralogy of Fallot (ToF) can be associated with a wide range of extracardiac anomalies, with an underlying etiology identified in approximately 10% of cases. Individuals affected with Myhre syndrome due to recurrent SMAD4 mutations frequently have cardiovascular anomalies, including congenital heart defects. In addition to two patients in the literature with ToF, we describe five additional individuals with Myhre syndrome and classic ToF, ToF with pulmonary atresia and multiple aorto-pulmonary collaterals, and ToF with absent pulmonary valve. Aorta hypoplasia was documented in one patient and suspected in another two. In half of these individuals, postoperative cardiac dysfunction was thought to be more severe than classic postoperative ToF repair. There may be an increase in right ventricular pressure, and right ventricular dysfunction due to free pulmonic regurgitation. Noncardiac developmental abnormalities in our series and the literature, including corectopia, heterochromia iridis, and congenital miosis suggest an underlying defect of neural crest cell migration in Myhre syndrome. We advise clinicians that Myhre syndrome should be considered in the genetic evaluation of a child with ToF, short stature, unusual facial features, and developmental delay, as these children may be at risk for increased postoperative morbidity. Additional research is needed to investigate the hypothesis that postoperative hemodynamics in these patients may be consistent with restrictive myocardial physiology.

Perceptions of Youth and Parent Decision-Making Roles Regarding Recombinant Human Growth Hormone Treatment.

Recombinant human growth hormone (rhGH) is prescribed to youth with growth hormone deficiency (GHD) to support normal growth and ensure healthy physical development, and to youth without GHD to address height concerns. Perceptions of youth involvement in rhGH treatment decisions have not been explored. This study aimed to examine perceptions of youth and parent roles in decisions around rhGH treatment. Youth (n = 22, 11.5 ± 2.0 years) who had undergone evaluation for short stature and their parents (n = 22) participated in semi-structured interviews after stimulation test results had been received. Interviews revealed the following themes: 1) parent provided youth with support; 2) parent facilitated youth's decision-making involvement; 3) youth had no role or did not remember their role; and 4) youth did not remember conversations with their parents or providers. Parents facilitated their children's involvement by sharing information and seeking their opinions. Whereas some participants described youth as having a substantial decision-making role, not all youth felt they were involved, and some youth could not recall conversations about rhGH. Parents can bolster youth involvement by having conversations using developmentally appropriate language, which is critical to youth feeling empowered and developing efficacy over their own care.

Growth Hormone Stimulation Testing Patterns Contribute to Sex Differences in Pediatric Growth Hormone Treatment.

INTRODUCTION: Males are twice as likely as females to receive pediatric growth hormone (GH) treatment in the USA, despite similar distributions of height z (HtZ)-scores in both sexes. Male predominance in evaluation and subspecialty referral for short stature contributes to this observation. This study investigates whether sex differences in GH stimulation testing and subsequent GH prescription further contribute to male predominance in GH treatment. METHODS: Retrospective chart review was conducted of all individuals, aged 2-16 years, evaluated for short stature or poor growth at a single large tertiary referral center between 2012 and 2019. Multiple logistic regression models were constructed to analyze sex differences. RESULTS: Of 10,125 children referred for evaluation, a smaller proportion were female (35%). More males (13.1%) than females (10.6%) underwent GH stimulation testing (p < 0.001) and did so at heights closer to average (median HtZ-score -2.2 [interquartile range, IQR -2.6, -1.8] vs. -2.5 [IQR -3.0, -2.0], respectively; p < 0.001). The proportion of GH prescriptions by sex was similar by stimulated peak GH level. Predictor variables in regression modeling differed by sex: commercial insurance predicted GH stimulation testing and GH prescription for males only, whereas lower HtZ-score predicted GH prescription for females only. CONCLUSIONS: Sex differences in rates of GH stimulation testing but not subsequent GH prescription based on response to GH stimulation testing seem to contribute to male predominance in pediatric GH treatment. That HtZ-score predicted GH prescription in females but not males raises questions about the extent to which sex bias - from children, parents, and/or physicians - as opposed to objective growth data, influence medical decision-making in the evaluation and treatment of short stature.

Racial and Ethnic Disparities in the Investigation and Treatment of Growth Hormone Deficiency.

OBJECTIVE: To determine if the racial/ethnic inequity in growth hormone (GH) use is due to differences in GH stimulation testing and/or prescribing patterns in children referred for endocrine evaluation of short stature. STUDY DESIGN: Retrospective chart review was performed including children aged 2-16 years, height z-score of ≤-1.5, and of non-Hispanic White (NHW), non-Hispanic Black (NHB), or Hispanic race/ethnicity, referred for endocrine growth evaluation between January 2012 and December 2019. RESULTS: This study included 7425 children (5905 NHW, 800 NHB, and 720 Hispanic). GH stimulation testing was performed in 992, and 576 were prescribed GH. NHW children were 1.4 (95% CI, 1.04-1.8) times more likely than NHB children and 1.7 (95% CI, 1.2-2.2) times more likely than Hispanic children to undergo GH stimulation testing. GH-treated NHB children had (1) a lower median peak GH concentration when compared with NHW (P = .02) and Hispanic (P = .08) children (NHB 4.7 ng/mL [95% CI, 1.2-8.3 ng/mL] ng/mL, NHW 7.2 ng/mL [95% CI, 4.9-9.7 ng/mL], Hispanic 7.1 ng/mL [95% CI, 4.3-11.9 ng/mL]); (2) lower median height z-scores than NHW (P = .01) but not Hispanic children (P = .5); and (3) a greater height deficit from midparental height when compared with NHW (P = .01) and Hispanic (P = .002) children. CONCLUSIONS: Racial and ethnic disparities exist in the evaluation and treatment of children with disordered growth. This likely results from both overinvestigation of NHW children as well as underinvestigation and undertreatment of children from minority communities. The evaluation and treatment of children with short stature should be determined by clinical concern alone, but this is not current practice.

Provocative growth hormone testing in children: how did we get here and where do we go now?

OBJECTIVES: Provocative growth hormone (GH) tests are widely used for diagnosing pediatric GH deficiency (GHD). A thorough understanding of the evidence behind commonly used interpretations and the limitations of these tests is important for improving clinical practice. CONTENT: To place current practice into a historical context, the supporting evidence behind the use of provocative GH tests is presented. By reviewing GH measurement techniques and examining the early data supporting the most common tests and later studies that compared provocative agents to establish reference ranges, the low sensitivity and specificity of these tests become readily apparent. Studies that assess the effects of patient factors, such as obesity and sex steroids, on GH testing further bring the appropriateness of commonly used cutoffs for diagnosing GHD into question. SUMMARY AND OUTLOOK: Despite the widely recognized poor performance of provocative GH tests in distinguishing GH sufficiency from deficiency, limited progress has been made in improving them. New diagnostic modalities are needed, but until they become available, clinicians can improve the clinical application of provocative GH tests by taking into account the multiple factors that influence their results.