Aims: To evaluate three guidelines for selecting short children for diagnostic workup in a general pediatric clinic. Methods: All patients (n = 131) aged 3.00-9.99 years who were referred for growth failure to a general pediatric clinic were evaluated for their medical history and growth and examined. All of them underwent the same standardized diagnostic workup. Retrospectively, the criteria for the diagnostic workup from three guidelines (proposed in the Netherlands, Finland and the UK) were applied, and their sensitivity was assessed. A Dutch reference sample (n = 958) was used for calculating population specificity. Results: In 23 patients (17.6%), a pathological cause of their growth failure was found. The sensitivity of the original Dutch, Finnish and British guidelines was 73.9, 78.3 and 56.5% and their specificity 98.5, 83.7 and 95.8%, respectively. When adding recent growth deflection to the Dutch guideline, sensitivity increased to 87%, but specificity decreased markedly (to 87%). Conclusion: The proposed cutoff values for height standard deviation score and distance to target height/mid-parental height, as used in the Netherlands and Finland, are effective for population growth monitoring, and superior to the monitoring algorithm in the UK. Growth deflection irrespective of height is an important sign of acquired growth disorders, but its specificity is too low for population screening.

In adolescents, pathological causes for growth failure and pubertal delay are common, and we recommend a combination of height SDS, distance to THSDS and growth deflection for deciding on further diagnostic testing.

Bone geometry can be described in terms of periosteal and endocortical growth and is partly determined by sex steroids. Periosteal and endocortical apposition are thought to be regulated by testosterone and estrogen, respectively. Gender‐affirming hormone (GAH) treatment with sex steroids in transgender people might affect bone geometry. However, in adult transgender people, no change in bone geometry during GAH was observed. In this study, we investigated changes in bone geometry among transgender adolescents using a gonadotropin‐releasing hormone agonist (GnRHa) and GAH before achieving peak bone mass. Transgender adolescents treated with GnRHa and subsequent GAH before the age of 18 years were eligible for inclusion. Participants were grouped based on their Tanner stage at the start of GnRHa treatment and divided into early, mid, and late puberty groups. Hip structure analysis software calculating subperiosteal width (SPW) and endocortical diameter (ED) was applied to dual‐energy X‐ray absorptiometry scans performed at the start of GnRHa and GAH treatments, and after ≥2 years of GAH treatment. Mixed‐model analyses were performed to study differences over time. Data were visually compared with reference values of the general population. A total of 322 participants were included, of whom 106 were trans women and 216 trans men. In both trans women and trans men, participants resembled the reference curve for SPW and ED of the experienced gender but only when GnRHa was started during early puberty. Those who started during mid and late puberty remained within the reference curve of the gender assigned at birth. A possible explanation might be sought in the phenomenon of programming, which conceptualizes that stimuli during critical windows of development can have major consequences throughout one's life span. Therefore, this study adds insights into sex‐specific bone geometry development during puberty of transgender adolescents treated with GnRHa, as well as the general population. © 2021 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Context Transgender adolescents can receive GnRH analogues (GnRHa) and gender affirming hormone therapy (GAHT), but little is known about effects on growth and adult height. This is of interest since height differs between sexes and some trans girls wish to limit their growth. Objective Investigate effects of GnRHa and GAHT on growth, and the efficacy of growth-reductive treatment. Design Retrospective cohort study. Setting Specialised tertiary gender clinic. Participants 161 trans girls treated with GnRHa and estradiol at a regular dose (2 mg) or high growth-reductive doses of estradiol (6 mg) or ethinylestradiol (EE, 100-200 µg). Main outcome measures Growth, adult height and difference from predicted adult height (PAH) and target height. Results Growth velocity and bone maturation decreased during GnRHa, but increased during GAHT. Adult height after regular dose treatment was 180.8 ± 5.4 cm which was 2.2 cm below PAH at start GnRHa (95%CI 0.8 to 3.6), and close to target height (-0.2 cm, 95%CI -1.5 to 1.1). Compared to regular dose treatment, high dose estradiol and EE reduced adult height by 1.8 cm (95%CI -0.6 to 4.1) and 4.1 cm (95%CI 0.6 to 7.6), respectively. Conclusion Growth decelerated during GnRHa and accelerated during GAHT. After regular dose treatment, adult height was slightly lower than predicted at start of GnRHa, likely due to systematic overestimation of PAH as described in boys from the general population, but not significantly different from target height. High dose EE resulted in greater reduction of adult height than high dose estradiol, but this needs to be weighed against possible adverse effects.

<b><i>Introduction:</i></b> Neonatal screening programs for congenital hypothyroidism (CH) have been implemented worldwide to facilitate early diagnosis and treatment. The Dutch neonatal CH screening is primarily based on the measurement of thyroxine (T4). When T4 is low, an additional thyroxine-binding globulin (TBG) measurement is performed to reduce the number of false-positive screening results due to harmless TBG deficiency. Here, we present a case of a rare functional TBG deficiency leading to a false suspicion of CH. <b><i>Case Presentation:</i></b> Neonatal screening in this patient revealed a decreased T4, normal TSH, and normal TBG concentration, suggesting central CH. However, free T4 was normal. DNA sequencing analysis revealed a novel, hemizygous mutation (c.139G&#x3e;A) in <i>SERPINA7</i>, the gene encoding TBG, resulting in the substitution of the conserved amino acid alanine to threonine at position 27. Crystal structure analyses showed that this substitution has a detrimental effect on binding of T4 to TBG. <b><i>Conclusions:</i></b> The novel <i>SERPINA7</i> variant in this patient led to a false suspicion of central hypothyroidism in the Dutch T4-based neonatal screening program. It is important to recognize patients with such TBG defects to prevent unnecessary additional testing and treatment.

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Bone geometry can be described in terms of periosteal and endocortical growth and is partly determined by sex steroids. Periosteal and endocortical apposition are thought to be regulated by testosterone and estrogen, respectively. Gender-affirming hormone (GAH) treatment with sex steroids in transgender people might affect bone geometry. However, in adult transgender people no change in bone geometry during GAH was observed. In this study, we investigated changes in bone geometry among transgender adolescents using a gonadotropin-releasing hormone agonist (GnRHa) and GAH prior to achieving peak bone mass. Transgender adolescents treated with GnRHa and subsequent GAH at our center before the age of 18 years were eligible for inclusion. Participants were grouped based on their Tanner stage at the start of GnRHa treatment and divided into early, mid, and late puberty groups. Hip Strength Analysis software calculating subperiosteal width (SPW) and endocortical diameter (ED) was applied to dual-energy X-ray absorptiometry scans performed at start of GnRHa and GAH treatments, and after ≥ 2 years of GAH treatment. Mixed model analyses were performed to study differences over time. Data were visually compared with reference values of the general population retrieved from the literature. A total of 322 participants were included, of whom 106 trans women and 216 trans men. In both trans women and trans men participants resembled the reference curve for SPW and ED of the experienced gender, but only when GnRHa was started during early puberty. Those who started during mid- and late puberty remained within the reference curve of the gender assigned at birth. A possible explanation might be sought in the phenomenon of programming, which conceptualizes that stimuli during critical windows of development can have major consequences throughout one’s lifespan. Therefore, this study adds insights into sex-specific bone geometry development during puberty of transgender adolescents treated with GnRHa, as well as the general population.