Children With Idiopathic Short Stature: An Expanding Role for Genetic Investigation in Their Medical Evaluation.

Short stature in children is a common reason for referral to a pediatric endocrinologist. Many genetic, nutritional, psychological, illness-related, and hormonal causes must be excluded before labeling as idiopathic. Idiopathic short stature is not a diagnosis, but rather describes a large, heterogeneous group of children, who are short and often slowly growing. As new testing paradigms become available, the pool of patients labeled as idiopathic will shrink, although most will have a polygenic cause. Given that many of the new diagnoses are involved in growth plate biology, physical examination should assess for subtle dysmorphology or disproportion of the skeleton that may indicate a heterozygous mutation that in its homozygous state would be apparent. When laboratory evaluations are negative, one may consider genetic testing, such as targeted gene or gene panel, comparative genomic hybridization, or whole exome or whole genome sequencing (respectively). With a known genetic diagnosis, targeted therapy may be possible rather than recombinant human growth hormone, where response is generally poorer than that for children with growth hormone deficiency, because the variety of diagnoses may have varying growth hormone sensitivity. A firm diagnosis has heuristic value: to truncate further diagnostic evaluation, alert the clinician to other possible comorbidities, inform the family for genetic counseling, and direct appropriate targeted therapy, if available.

The validity of automatic methods for estimating skeletal age in young athletes: a comparison of the BAUSport ultrasound system and BoneXpert with the radiographic method of Fels.

This study examined the validity of two automated methods (BAUSport, BoneXpert software using Fels, Greulich-Pyle, Tanner-Whithouse III protocols) for estimating skeletal age (SA) in young athletes in comparison to a reference standard (Fels). 85 male and female athletes, nine to seventeen years of age, from multiple sports were assessed for SA as part of an annual medical and health screening programme. Intra-class correlations demonstrated high degrees of association between the automatic methods for estimating SA (BAUSport r = .98; BoneXpert r = .96-.99) and the discrepancy between SA and chronological age (SA-CA) (BAUSport r = .93; BoneXpert r = .88-.97), with the reference standard. Concordance analyses for the categorisation of participants as early, on-time and late maturing also demonstrated substantial levels of agreement for both methods (BAUSport Kappa = .71; BoneXpert Fels Kappa = .63) with the reference standard. Bland-Altman plots comparing the automatic methods with the reference standard identified statistically significant fixed biases, ranging in magnitude from small to large. Collectively, these results suggest that BoneXpert and BAUSport can provide comparable estimates of SA and SA-CA in young athletes relative to the Fels method. Biases in the estimation of SA should, however, be considered and the automatic methods should be implemented as part of a comprehensive growth and maturity screening protocol. The non-invasive nature of the BAUSport method affords particular advantages (no radiation exposure, portability) in contexts where the regular estimation of SA is recommended.

Human sex chromosome aneuploidies: The hypothalamic-pituitary-gonadal axis.

Sex chromosome aneuploidies (SCA) are relatively common as a group, perhaps 1 per 500 births, but much more common at conception. Many syndromes have been noted in those with these conditions, but not so many data are available concerning the hypothalamic-pituitary-gonadal (HPG) axis. The physiology of the HPG axis is first reviewed at four epochs in time: fetal, birth and mini-puberty, childhood, and adolescence (puberty). Those sections are followed by detailed analysis of the functioning of the HPG axis in individuals with specific SCA with chromosomal numbers ranging from 45 to 49. Robust data are available for the chromosomal complements 47,XXY and 47,XXX with fewer data available for many of the others.

A new approach to the diagnosis of short stature.

Growth is the task of children. We review the normal process of linear growth from the fetus through adolescence and note that growth is the result of age- and gender-dependent interactions among key genetic, environmental, dietary, socioeconomic, developmental, behavioral, nutritional, metabolic, biochemical, and hormonal factors. We then define the wide range of normative data at each stage of growth and note that a pattern within this range is generally indicative of good general health and that growth significantly slower than this range may lead to growth faltering and subsequent short stature. Although not often emphasized, we detail how to properly measure infants and children because height velocity is usually determined from two height measurements (both relatively large values) to calculate the actual height velocity (a relatively much smaller number in comparison). Traditionally the physiology of growth has been taught from an endocrine-centric point-of-view. Here we review the hypothalamic-pituitary-end organ axes for the GH/IGF-1 and gonadal steroid hormones (hypothalamic-pituitary-gonadal axis), both during "mini"-puberty as well as at puberty. However, over the past few decades much more emphasis has been placed on the growth plate and its many interactions with the endocrine system but also with its own intrinsic physiology and gene mutations. These latter, whether individually (large effect size) or in combination with many others including endocrine system-based, may account in toto for meaningful differences in adult height. The clinical assessment of children with short stature includes medical, social and family history, physical exam and importantly proper interpretation of the growth curve. This analysis should lead to judicious use of screening laboratory and imaging tests depending on the pre-test probability (Bayesian inference) of a particular diagnosis in that child. In particular for those with no pathological features in the history and physical exam and a low, but normal height velocity, may lead only to a bone age exam and reevaluation (re-measurement), perhaps 6 months later. he next step depends on the comfort level of the primary care physician, the patient, and the parent; that is, whether to continue with the evaluation with more directed, more sophisticated testing, again based on Bayesian inference or to seek consultation with a subspecialist pediatrician based on the data obtained. This is not necessarily an endocrinologist. The newest area and the one most in flux is the role for genetic testing, given that growth is a complex process with large effect size for single genes but smaller effect sizes for multiple other genes which in the aggregate may be relevant to attained adult height. Genetics is a discipline that is rapidly changing, especially as the cost of exome or whole gene sequencing diminishes sharply. Within a decade it is quite likely that a genetic approach to the evaluation of children with short stature will become the standard, truncating the diagnostic odyssey and be cost effective as fewer biochemical and imaging studies are required to make a proper diagnosis.

Meeting Report: The Role of Beliefs and Perception on Body Size. Proceedings of the 26th Aschauer Soiree, Held at Aschauhof, Altenhof, Germany, May 26th, 2018.

Thirty-one scientists met at Aschauhof, Germany to discuss the role of beliefs and self-perception on body size. In view of apparent growth stimulatory effects of dominance within the social group that is observed in social mammals, they discussed various aspects of competitive growth strategies and growth adjustments. Presentations included new data from Indonesia, a cohort-based prospective study from Merida, Yucatan, and evidence from recent meta-analyses and patterns of growth in the socially deprived. The effects of stress experienced during pregnancy and adverse childhood events were discussed, as well as obesity in school children, with emphasis on problems when using z-scores in extremely obese children. Aspects were presented on body image in African-American women, and body perception and the disappointments of menopause in view of feelings of attractiveness in different populations. Secular trends in height were presented, including short views on so called 'racial types' vs bio-plasticity, and historic data on early-life nutritional status and later-life socioeconomic outcomes during the Dutch potato famine. New tools for describing body proportions in patients with variable degrees of phocomelia were presented along with electronic growth charts. Bio-statisticians discussed the influence of randomness, community and network structures, and presented novel tools and methods for analyzing social network data.

rhGH Abuse for Sports Performance.

Doping is at least as old as the ancient Olympics. Substances taken to improve athletic performance ranged from stimulants to hallucinogenic plant substances, but more recently include anabolic agents. Recombinant human growth hormone, rhGH, is one agent with a relatively short history of use, but few data to unequivocally show that it actually improves performance. However, rhGH has therapeutic use for those GH deficient and the concept of a therapeutic use exemption for those with documented deficiency is outlined along with doping control methods. The athlete's biological passport, a document with all of the analytical data from an athlete, helps in doping control because any one individual will vary for any analyte over a more narrow range than that for a "normal" control population.

Biological maturation of youth athletes: assessment and implications.

The search for talent is pervasive in youth sports. Selection/exclusion in many sports follows a maturity-related gradient largely during the interval of puberty and growth spurt. As such, there is emphasis on methods for assessing maturation. Commonly used methods for assessing status (skeletal age, secondary sex characteristics) and estimating timing (ages at peak height velocity (PHV) and menarche) in youth athletes and two relatively recent anthropometric (non-invasive) methods (status-percentage of predicted near adult height attained at observation, timing-predicted maturity offset/age at PHV) are described and evaluated. The latter methods need further validation with athletes. Currently available data on the maturity status and timing of youth athletes are subsequently summarised. Selection for sport and potential maturity-related correlates are then discussed in the context of talent development and associated models. Talent development from novice to elite is superimposed on a constantly changing base-the processes of physical growth, biological maturation and behavioural development, which occur simultaneously and interact with each other. The processes which are highly individualised also interact with the demands of a sport per se and with involved adults (coaches, trainers, administrators, parents/guardians).

Etiologies and early diagnosis of short stature and growth failure in children and adolescents.

Accurate measurement of height and weight using standardized techniques is a fundamental component of pediatric medical visits. Calculation of height velocity over time enables comparison with standardized growth charts to identify potential deviations from normal. Growth deviations may be expressed as SD from the normal population mean for children of comparable age and sex; children with heights >2 SD below the mean are generally classified as short stature. In a child with suspected impaired growth, a detailed evaluation should be conducted to identify the cause. Such an evaluation may include a combination of personal, family, and social history; physical examination; general and perhaps specialized laboratory evaluations; radiologic examinations; genetic testing; and consultation with a pediatric subspecialist, such as a pediatric endocrinologist. Variants of normal growth include familial short stature, constitutional delay of growth and puberty, and small for gestational age with catch-up growth. Pathological causes of abnormal growth include many systemic diseases and their treatments, growth hormone deficiency, and a series of genetic syndromes, including Noonan syndrome and Turner syndrome. Children with short stature in whom no specific cause is identified may be diagnosed with idiopathic short stature. Early identification of abnormal growth patterns and prompt referral to specialist care offer children with growth failure and/or short stature the greatest chance for appropriate diagnosis, treatment, and improved clinical outcomes.

Dose-sparing and safety-enhancing effects of an IGF-I-based dosing regimen in short children treated with growth hormone in a 2-year randomized controlled trial: therapeutic and pharmacoeconomic considerations.

CONTEXT AND OBJECTIVE: Titrating the dosage of growth hormone (GH) to serum levels of insulin-like growth factor-I (IGF-I) is a feasible treatment strategy in children with GH deficiency (GHD) and idiopathic short stature (ISS). The objective was to assess the dose-sparing effect and theoretical safety of IGF-I-based GH therapy. DESIGN, SETTING AND PATIENTS: This was a post hoc analysis of a previously described 2-year, multicenter, open-label, randomized, outpatient, controlled clinical trial in 172 prepubertal short children [age 7·5 ± 2·4 years; height standard deviation score (HSDS) -2·64 ± 0·61] classified by baseline peak GH levels as GHD (<7 ng/ml) or ISS (≥7 ng/ml). INTERVENTION: Conventional weight-based dosing of GH (0·04 mg/kg/day) (n = 34) or GH dosing titrated to an IGF-I target of 0 SDS (IGF0T; n = 70) or an IGF-I target of +2 SDS (IGF2T; n = 68). MAIN OUTCOME MEASURES: Change in HSDS per GH mg/kg/day dose (∆HSDS/GH dose ratio) and proportion of IGF-I levels above +2 SDS at the end of 2 years. RESULTS: GH dosing titrated to an IGF-I target of 0 SDS was the most dose-sparing treatment regimen for GHD or ISS children (mean±SE ∆HSDS/GH dose ratios 48·1 ± 4·4 and 32·5 ± 2·8, respectively) compared with conventional dosing (30·3 ± 6·6 and 21·3 ± 3·5, respectively; P = 0·02, P = 0·005) and IGF2T (32·7 ± 4·8 and 16·3 ± 2·8, respectively; P = 0·02, P < 0·0001). IGF0T also resulted in the fewest IGF-I excursions above +2 SDS (6·8% vs 30·0% for conventional dosing; P < 0·01). CONCLUSIONS: IGF-I-based GH dosing, targeted to age- and gender-adjusted means, may offer a more dose-sparing and potentially safer mode of therapy than traditional weight-based dosing.

Hurdling over sex? Sport, science, and equity.

Between 1968 and 1999, the International Olympic Committee (IOC) required all female athletes to undergo genetic testing as part of its sex verification policy, under the assumption that it needed to prevent men from impersonating women and competing in female-only events. After critics convinced officials that genetic testing was scientifically and ethically flawed for this purpose, the IOC replaced the policy in 1999 with a system allowing for medical evaluations of an athlete's sex only in cases of "reasonable suspicion," but this system also created injustice for athletes and stoked international controversies. In 2011, the IOC adopted a new policy on female hyperandrogenism, which established an upper hormonal limit for athletes eligible to compete in women's sporting events. This new policy, however, still leaves important medical and ethical issues unaddressed. We review the history of sex verification policies and make specific recommendations on ways to improve justice for athletes within the bounds of the current hyperandrogenism policy, including suggestions to clarify the purpose of the policy, to ensure privacy and confidentiality, to gain informed consent, to promote psychological health, and to deploy equitable administration and eligibility standards for male and female athletes.

Efficacy of IGF-based growth hormone (GH) dosing in nonGH-deficient (nonGHD) short stature children with low IGF-I is not related to basal IGF-I levels.

OBJECTIVE: Weight-based GH dosing is the standard for treating children with short stature. The current study validates the usefulness of IGF-based GH dosing for GH therapy in nonGH-deficient (nonGHD) children and its relationship with pretreatment serum IGF-I concentration. DESIGN AND PATIENTS: In this twelve-month, open-label, randomized controlled study, 151 nonGHD (based on GH-stimulation tests), prepubertal children with short stature and IGF-I levels ≤ 33rd percentile [-0.44 standard deviation score (SDS)] were randomly assigned to receive GH (dose based on IGF-I titration algorithm; n = 114) or to observation (n = 37). GH dose (initially 40 µg/kg/d) was adjusted every 3 months to achieve an IGF-I SDS in the upper normal range (66-99 th percentile). MEASUREMENTS AND RESULTS: In treated children, mean height SDS (HSDS) increased from -2.5 at baseline to -1.7 at 12 months and mean IGF-I SDS increased from -1.7 to 0.1. These parameters remained unchanged in untreated children. There was no relationship between change in HSDS (ΔHSDS) and degree of IGF-I deficiency at baseline. No safety problems were observed. Both groups had a similar advance in bone age. At the end of study, ΔHSDS in treated children showed a positive correlation with IGF-I SDS, but not with GH dose [mean 59 µg/kg/d (range 29-92)], basal IGF-I SDS or 1-month IGF parameters. CONCLUSIONS: In nonGHD subjects with short stature and serum IGF-I concentrations within and below the lower third of normal, adjusting GH dose to achieve an IGF-I level in the upper normal range resulted in a significant increase in HSDS, regardless of basal IGF-I levels.

Neuropsychological recovery and quality-of-life in children and adolescents with growth hormone deficiency following TBI: a preliminary study.

OBJECTIVE: To compare neurocognition and quality-of-life (QoL) in a group of children and adolescents with or without growth hormone deficiency (GHD) following moderate-to-severe traumatic brain injury (TBI). STUDY DESIGNS: Thirty-two children and adolescents were recruited from the TBI clinic at a children's hospital. Growth hormone (GH) was measured by both spontaneous overnight testing and following arginine/glucagon stimulation administration. Twenty-nine subjects participated in extensive neuropsychological assessment. RESULTS: GHD as measured on overnight testing was significantly associated with a variety of neurocognitive and QoL measures. Specifically, subjects with GHD had significantly (p < 0.05) lower scores on measures of visual memory and health-related quality-of-life. These scores were not explained by severity of injury or IQ (p > 0.05). GHD noted in response to provocative testing was not associated with any neurocognitive or QoL measures. CONCLUSIONS: GHD following TBI is common in children and adolescents. Deficits in neurocognition and QoL impact recovery after TBI. It is important to assess potential neurocognitive and QoL changes that may occur as a result of GHD. It is also important to consider the potential added benefit of overnight GH testing as compared to stimulation testing in predicting changes in neurocognition or QoL.

Sex chromosome aneuploidies and fertility: 47,XXY, 47,XYY, 47,XXX and 45,X/47,XXX.

The overall incidence of sex chromosome aneuploidies is approximately 1 per 500 live-born infants, but far more common at conception. I shall review the fertility aspects of the sex chromosome trisomies, XXY, XYY, and XXX, with special reference to the karyotype 45,X/47,XXX. Each has a 'specific' (but variable) phenotype but may be modified by mosaicism. Although the alterations in the hypothalamic-pituitary-gonadal axis are important (and discussed), the emphasis here is on potential fertility and if one might predict that at various epochs within an individual's life span: fetal, 'mini'-puberty, childhood, puberty, and adulthood. The reproductive axis is often affected in females with the 47,XXX karyotype with diminished ovarian reserve and accelerated loss of ovarian function. Fewer than 5% of females with Turner syndrome have the 45,X/47,XXX karyotype. They have taller stature and less severe fertility issues compared to females with the 45,X or other forms of Turner syndrome mosaicism. For the 47,XXY karyotype, non-obstructive azoospermia is almost universal with sperm retrieval by micro-testicular sperm extraction possible in slightly fewer than half of the men. Men with the 47,XYY karyotype have normal to large testes and much less testicular dysfunction than those with the 47,XXY karyotype. They do have a slight increase in infertility compared to the reference population but not nearly as severe as those with the 47,XXY karyotype. Assisted reproductive technology, especially micro-testicular sperm extraction, has an important role, especially for those with 47,XXY; however, more recent data show promising techniques for the in vitro maturation of spermatogonial stem cells and 3D organoids in culture. Assisted reproductive technology is more complex for the female, but vitrification of oocytes has shown promising advances.

Functional hypogonadism in adolescence: an overlooked cause of secondary hypogonadism.

Hypogonadism is a clinical syndrome resulting from failure to produce physiological concentrations of sex steroid hormones with accompanying symptoms, such as slowed growth and delayed pubertal maturation. Hypogonadism may arise from gonadal disease (primary hypogonadism), dysfunction of the hypothalamic-pituitary axis (secondary hypogonadism) or functional hypogonadism. Disrupted puberty (delayed or absent) leading to hypogonadism can have a significant impact on both the physical and psychosocial well-being of adolescents with lasting effects. The diagnosis of hypogonadism in teenagers can be challenging as the most common cause of delayed puberty in both sexes is self-limited, also known as constitutional delay of growth and puberty (CDGP). Although an underlying congenital cause should always be considered in a teenager with hypogonadism, acquired conditions such as obesity, diabetes mellitus, other chronic diseases and medications have all been associated with low sex steroid hormone levels. In this review, we highlight some forms of functional hypogonadism in adolescents and the clinical challenges to differentiate normal variants from pathological states.

Celebration of a century of insulin therapy in children with type 1 diabetes.

Insulin is the key anabolic hormone of metabolism, with clear effects on glycaemia. Near-complete insulin deficiency occurs in type 1 diabetes (T1D), the predominant form affecting children, and uniformly fatal until the discovery of insulin. By the early 20th century, it was known that T1D was caused by the lack of a factor from pancreatic islets, but isolation of this substance proved elusive. In 1921, an unusual team in Toronto comprising a surgeon, a medical student, a physiologist and a biochemist successfully isolated a glucose-lowering pancreatic endocrine secretion. They treated an emaciated 14-year-old boy in 1922, restoring his health and allowing him to live for another 13 years. Thus began an era of remarkable progress and partnership between academia and the pharmaceutical industry to produce drugs that benefit sick people. The Toronto team received the 1923 Nobel Prize, and more Nobel Prizes for work with insulin followed: for elucidation of its amino acid sequence and crystalline structure, and for its role in the development of radioimmunoassays to measure circulating hormone concentrations. Human insulin was the first hormone synthesised by recombinant methods, permitting modifications to enable improved absorption rates and alterations in duration of action. Coupled with delivery via insulin pens, programmable pumps and continuous glucose monitors, metabolic control and quality of life vastly improved and T1D in children was converted from uniformly fatal to a manageable chronic condition. We describe this remarkable ongoing story as insulin remains a paradigm for human ingenuity to heal nature's maladies.

Allometric Scaling of Testosterone Enanthate Pharmacokinetics to Adolescent Hypogonadal Males (IM and SC Administration).

Context: Intramuscular (IM) testosterone enanthate (TE) and testosterone pellets were US Food and Drug Administration approved before 1962 for pediatric use but not studied in controlled trials in adolescents. Objective: An analysis using nonlinear mixed effect (NLME) modeling was designed to evaluate the adult pharmacokinetics (PK) of subcutaneous (SC) and IM TE. This model was used to simulate SC and IM TE administration in adolescents of different weight groups. Methods: Data from adult male patients in a phase 2 trial were used to characterize the PK of TE using population PK modeling for SC and IM administration: Allometry was used to scale PK parameters from the adult model to simulate adolescent (aged 12 to < 18 years) serum testosterone levels at body weights of 30, 40, 50, and 60 kg after weekly, every-other-week (EOW), and monthly SC and IM administration of 12.5, 25, 50, 75, and 100 mg TE regimens. Results: The final data set included 714 samples from 15 patients receiving 100 mg SC TE and 123 samples from 10 patients receiving 200 mg IM TE. In simulated populations, average serum concentration SC:IM ratios were 0.783, 0.776, and 0.757 at steady state for weekly, EOW, and monthly dosing groups, respectively. Simulated regimens of 12.5 mg SC TE monthly produced serum testosterone levels representative of early puberty and simulated pubertal stage progression following multiple subsequent testosterone dose increases. Conclusion: SC TE administration achieved a testosterone exposure-response relationship similar to IM TE in simulated adolescent hypogonadal males, which may reduce size of fluctuations in serum T and related symptoms.

New developments and future trajectories in supernumerary sex chromosome abnormalities: a summary of the 2022 3rd International Workshop on Klinefelter Syndrome, Trisomy X, and XYY.

The 3rd International Workshop on Klinefelter Syndrome, Trisomy X, and 47,XYY syndrome was held in Leiden, the Netherlands, on September 12-14, 2022. Here, we review new data presented at the workshop and discuss scientific and clinical trajectories. We focus on shortcomings in knowledge and therefore point out future areas for research. We focus on the genetics and genomics of supernumerary sex chromosome syndromes with new data being presented. Most knowledge centre specifically on Klinefelter syndrome, where aspects on testosterone deficiency and the relation to bone, muscle and fat were discussed, as was infertility and the treatment thereof. Both trisomy X and 47,XYY syndrome are frequently affected by infertility. Transitioning of males with Klinefelter syndrome was addressed, as this seemingly simple process in practise is often difficult. It is now realized that neurocognitive changes are pervasive in all supernumerary sex chromosome syndromes, which were extensively discussed. New intervention projects were also described, and exciting new data concerning these were presented. Advocacy organizations were present, describing the enormous burden carried by parents when having to explain their child's specific syndrome to most professionals whenever in contact with health care and education systems. It was also pointed out that most countries do not have health care systems that diagnose patients with supernumerary sex chromosome syndromes, thus pinpointing a clear deficiency in the current genetic testing and care models. At the end of the workshop, a roadmap towards the development of new international clinical care guidelines for Klinefelter syndrome was decided.

Diagnosis and testing for growth hormone deficiency across the ages: a global view of the accuracy, caveats, and cut-offs for diagnosis.

Growth hormone deficiency (GHD) is a clinical syndrome that can manifest either as isolated or associated with additional pituitary hormone deficiencies. Although diminished height velocity and short stature are useful and important clinical markers to consider testing for GHD in children, the signs and symptoms of GHD are not always so apparent in adults. Quality of life and metabolic health are often impacted in patients with GHD; thus, making an accurate diagnosis is important so that appropriate growth hormone (GH) replacement therapy can be offered to these patients. Screening and testing for GHD require sound clinical judgment that follows after obtaining a complete medical history of patients with a hypothalamic-pituitary disorder and a thorough physical examination with specific features for each period of life, while targeted biochemical testing and imaging are required to confirm the diagnosis. Random measurements of serum GH levels are not recommended to screen for GHD (except in neonates) as endogenous GH secretion is episodic and pulsatile throughout the lifespan. One or more GH stimulation tests may be required, but existing methods of testing might be inaccurate, difficult to perform, and can be imprecise. Furthermore, there are multiple caveats when interpreting test results including individual patient factors, differences in peak GH cut-offs (by age and test), testing time points, and heterogeneity of GH and insulin-like growth factor 1 assays. In this article, we provide a global overview of the accuracy and cut-offs for diagnosis of GHD in children and adults and discuss the caveats in conducting and interpreting these tests.