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Dwarfism refers to the phenomenon that children with same gender and age are lower than two standard deviations of normal height in the same living environment. It is of great significance for early diagnosis and early treatment of dwarfism. Dwarfism can be divided into growth hormone deficiency (GHD) and idiopathic short stature (ISS). GHD can be distinguished by growth hormone, while ISS is difficult to distinguish because its hormone features are not obvious. Thus, a computer-aided diagnosis model based on brain image data and clinical features is established for the first time and a dwarfism prediction algorithm is proposed based on multimodal pyradiomics. Firstly, we establish the extraction of pituitary gland based on tensor and binary wavelet model, as the pituitary gland is an important organ that affects the growth hormone. Then, the multi-dimensional fusion model is established to distinguish dwarfism. In the process of distinguishment, the pyradiomics features and clinical features are extracted to distinguish together. Finally, dwarfism computer-aided diagnosis algorithm based on multimodal pyradiomics is realized.

Background Variants in PAPSS2 (3’-PhosphoAdenosine 5’-Phosphosulphate Synthetase 2) present with varying degrees of brachyolmia (short trunk, platyspondyly, mild long bone abnormalities). Our objective is to present the phenotype of male and female siblings with the same novel inactivating variant in PAPSS2. Case report A Jordanian female (case 1), born to consanguineous parents, was referred at 10 years for short stature (SS). She had normal laboratory work up including normal growth hormone (GH) stimulation testing. Spine x-rays done for clinical scoliosis revealed platyspondyly. She attained an adult height of 143.5 cm (-3 SDS). Years later, her brother (case 2) was referred at 21 months of age for SS. His laboratory work up and bone age were normal. His growth velocity declined at 6 years of age, but normal growth factors did not suggest GH deficiency. He returned during puberty and disproportionate body measurements were noted. The skeletal survey revealed platyspondyly, increasing suspicion for growth plate pathology. Exome sequencing in the family revealed a homozygous variant, p.His496Pro (H496P) in PAPSS2 (NM_004670.3:c.1487A>C). Both parents are carriers of the same variant. Discussion PAPSS2 assists with the sulfonation of dehydroepiandrosterone (DHEA) to dehydroepiandrosterone sulphate (DHEA-S) and the sulfonation of proteoglycans in the cartilage, necessary for endochondral bone formation. PAPSS2 inactivating variants present with skeletal dysplasia and elevated DHEA. Conclusion This novel variant in PAPSS2 manifested with mild brachyolmia but disproportionate SS in male and female siblings. Biochemical phenotype with low circulating DHEA-S and high DHEA levels reflect the sulfonation defect.

Sex steroids play an important role in regulating postnatal growth. The interplay between androgens and estrogens is mediated through the activity of aromatase enzyme, which catalyzes the synthesis of estrogens from androgens. Aromatase inhibitors (AIs) are compounds that block the function of the enzyme resulting in depletion of estrogens. In men, estrogens induce pubertal growth spurt and closure of epiphyseal plates, and thus contribute to the attainment of adult height. After loosening of the central restrain of puberty, estrogens in the large part mediate the negative feedback to the hypothalamus and pituitary, and thus control the activity of the hypothalamic–pituitary–gonadal axis. Consequently, AIs have been used in adolescent boys to treat idiopathic short stature and delayed puberty. In this article, we review the published data on the impact of potent 3rd generation AIs on gonadal function and growth in pubertal boys.

One of the most common causes of short stature is a defect of the short stature homeobox-containing (SHOX) gene, which is located in pseudoautosomal region 1 on the distal end of the short arm of chromosomes Xp22.33 and Yp11.32. More than 300 different mutations in the SHOX gene responsible for short stature syndrome have been described. The phenotypic expression of SHOX haploinsufficiency is remarkably varied. The 3 typical clinical presentations, from least to most severe, are idiopathic short stature without skeletal malformations, Leri-Weill dyschondrosteosis (LWD), and Langer mesomelic dysplasia, which is believed to represent the homozygous form of LWD. Despite a higher prevalence in women, suggesting the potentiating action of high estrogen levels on the effects of SHOX deficiency, the syndrome was initially believed to have an autosomal pattern of inheritance. In reality, heterozygous SHOX mutations can be transferred from the Y to the X chromosome and vice versa. This phenomenon is called "the jumping SHOX gene" and corresponds to a pseudoautosomal dominant inheritance. LWD is characterized by mesomelic short stature and Madelung deformity defined by an upward and medial displacement of the radial joint surface, which restricts range of motion. Less specific dysmorphic signs associated with LWD, such as short hands and feet, scoliosis, or muscular hypertrophy, have been described. When reviewing the dental and maxillofacial signs, only limited and summary data (micrognathia and high arched palate) have been published in the literature. This report presents a case of LWD that highlights many other noteworthy dental and maxillofacial signs that are important to clearly identify and appropriately treat.

Short stature remains the most common reason for referral to a pediatric Endocrinologist and its management remains a challenge. One of the main controversies is the diagnosis of idiopathic short stature and the role of new technologies for genetic investigation of children with inadequate growth. Complexities in management of children with short stature includes selection of who should receive interventions such as recombinant human growth hormone, and how should this agent dose be adjusted during treatment. Should anthropometrical data be the primary determinant or should biochemical and genetic data be used to improve growth response and safety? Furthermore, what is considered a suboptimal response to growth hormone therapy and how should this be managed? Treatment of children with short stature remains a "hot" topic and more data is needed in several areas. These issues are reviewed in this paper.

The treatment of constitutional delay of growth and puberty (CDGP) is an underinvestigated area in adolescent medicine. We tested the hypothesis that peroral aromatase inhibition with letrozole is more efficacious than intramuscular injection of low-dose testosterone in inducing puberty in boys with CDGP.We did a randomised, controlled, open-label trial at four paediatric centres in Finland. Boys aged at least 14 years with CDGP who wanted medical intervention and exhibited the first signs of puberty were randomly assigned in blocks of ten to receive either six intramuscular injections of low-dose testosterone (about 1 mg/kg bodyweight) every 4 weeks for 6 months or peroral letrozole 2·5 mg once daily for 6 months. All boys were followed up for 6 months after the end of treatment. The primary outcomes were changes in testicular volume and hormonal markers of puberty at 6 months after treatment initiation, which were assessed in all participants who received the assigned treatment. All patients were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01797718.Between Aug 1, 2013, and Jan 30, 2017, 30 boys were randomly assigned to receive testosterone (n=15) or letrozole (n=15). One boy in the testosterone group was excluded from the primary analyses because of a protocol deviation. During treatment, boys in the letrozole group had higher serum concentrations of luteinising hormone, follicle-stimulating hormone, testosterone, and inhibin B than did boys in the testosterone group. Testicular growth from baseline to 6 months was greater in the letrozole group than in the testosterone group (7·2 mL [95% CI 5·2-9·3] vs 2·2 mL [1·4-2·9]; between-group difference per month 0·9 mL [95% CI 0·6-1·2], p0·0001). Most adverse events were mild. One boy in the testosterone group had aggressive behaviour for 1 week after each injection, and one boy in the letrozole group had increased irritability at 6 months.Letrozole might be a feasible alternative treatment to low-dose testosterone for boys with CDGP who opt for medical intervention. However, the risks and benefits of manipulating the reproductive axis during early puberty should be weighed carefully.Helsinki University Hospital, Academy of Finland, and Finnish Foundation for Pediatric Research.

Background: Idiopathic short stature (ISS) is a common problem in children and causes many economic and social burdens. In Asian countries, East Asian traditional medicine (EATM) therapies are widely used for children with ISS. In this study, we compared and ranked various EATM therapies for the treatment of pediatric ISS using network meta-analysis. Methods: Randomized controlled trials that evaluated various EATMs for pediatric ISS were found through searching 14 electronic databases. The primary outcome was growth velocity (GV). The comparative effectiveness of the treatments was ranked based on the surface under the cumulative ranking curve (SUCRA) and the risk of bias was assessed. The quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations approach. Results: Fourteen studies comprising 1,066 participants were included. HM plus GH showed statistically significant superiority over other EATM therapies including acupuncture (weighted mean difference (WMD) 3.20 cm, 95% confidence interval (CI) 0.40 to 5.99) and HM (WMD 3.70 cm, 95% CI 1.41 to 5.99) for improving GV per year, although there was no difference compared with GH alone (WMD 1.18 cm, 95% CI -0.27 to 2.63). SUCRA indicated that HM plus GH was the most effective therapy for increasing GV, followed by GH, HM plus acupressure, and HM. No serious adverse events were reported. Conclusion: For the treatment of ISS, HM plus GH might have a large beneficial effect and might be a better option than EATM therapies and GH alone. However, more long-term, high-quality trials are warranted to confirm the findings. Protocol registration: PROSPERO (https://www.crd.york.ac.uk/prospero/), CRD42020187160.

This study aims to investigate the efficacy and safety of recombinant human growth hormone (rhGH) in the treatment of idiopathic short stature (ISS).The data of 200 ISS children, who were treated with rhGH from January 2008 to December 2016, were collected and retrospectively analyzed. The data of height, bone age(BA), chronological age(CA), fasting blood glucose, fasting insulin, thyroid function and IGF-1 were collected, and annual growth velocity (GV), height standard deviation score (HtSDS) and related factors that affect GV were statistically analyzed.(1) GV and HtSDS changes: As the time of treatment increased, the GV decreased year by year. The GV in the second year was significantly lower than that in the first year (P .0001), and the GV in the fourth year was significantly lower than that in the third year (P .05). HtSDS gradually increased from the first year to the third year, and became significantly higher than that in the year before the treatment (P .01). The difference in the increase in HtSDS between the fourth year and third year was not statistically significant (P .05). (2) The influence factors of GV included age at initial treatment, IGF-1SDS during treatment and GV in the year before treatment. (3) The most common side effects during treatment included transient hyperglycemia and temporary hyperinsulinemia, and these returned to normal after the treatment was stopped. Some patients presented with accelerated bone age growth after two years of treatment (annual growth of bone age △BA was2 years), compared with children without accelerated bone age growth, and the difference between BA and CA (BA-CA) was significantly reduced at the beginning of the treatment (P .01).rhGH has a good growth promoting effect on ISS children. A variety of factors may affect the GV, and related adverse reactions should be monitored during the treatment.

The effect of heterozygous duplications of SHOX and associated elements on Lėri-Weill dyschondrosteosis (LWD) and idiopathic short stature (ISS) development is less distinct when compared to reciprocal deletions. The aim of our study was to compare frequency and distribution of duplications within SHOX and associated elements between population sample and LWD (ISS) patients. A preliminary analysis conducted on Czech population sample of 250 individuals compared to our previously reported sample of 352 ISS/LWD Czech patients indicated that rather than the difference in frequency of duplications it is the difference in their distribution. Particularly, there was an increased frequency of duplications residing to the CNE-9 enhancer in our LWD/ISS sample. To see whether the obtained data are consistent across published studies we made a literature survey to get published cases with SHOX or associated elements duplication and formed the merged LWD, the merged ISS, and the merged population samples. Relative frequency of particular region duplication in each of those merged samples were calculated. There was a significant difference in the relative frequency of CNE-9 enhancer duplications (11 vs. 3) and complete SHOX (exon1-6b) duplications (4 vs. 24) ( p -value 0.0139 and p -value 0.000014, respectively) between the merged LWD sample and the merged population sample. We thus propose that partial SHOX duplications and small duplications encompassing CNE-9 enhancer could be highly penetrant alleles associated with ISS and LWD development.

As a result of our publication of the first patients with short stature due to a mutation in the gene for PAPP-A2 the question, "Why did you continue to study these patients when they were not more than 2 SDS below normal?" has been proposed surprisingly frequently. We would like to communicate our opinions on why these patients were studied and share the experience on how this process took place. In addition, the choice of treatment is also discussed. We believe that this discovery process is a good example of good clinical practice and international collaboration.

Objective We sought to obtain a better understanding of the burden of short stature using a systematic literature review. Methods Studies of the burden of short stature, of any cause in adults and children, were searched using Embase, MEDLINE and Cochrane databases in April 2020, capturing publications from 2008 onwards. Case series and populations with adult-onset growth hormone deficiency (GHD) were excluded. Results Of 1684 publications identified, 41 studies (33 in children, 8 in adults) were included. All studies assessed human burden. Most study populations in children included short stature due to GHD, idiopathic short stature (ISS) and short stature after being born small for gestational age (SGA). In these populations, four studies showed that quality of life (QoL) in children with short stature was significantly worse than in children with normal stature. A significant association between QoL and short stature was observed in children with chronic kidney disease (CKD) (3 studies), achondroplasia (1 study) and transfusion-dependent β-thalassaemia (1 study), and in samples with mixed causes of short stature (3 studies). Three studies (one in GHD/ISS/SGA and two in CKD) found no significant association between short stature and QoL, and several studies did not report statistical significance. Approximately half of adult studies showed that QoL was reduced with short stature, and the other half showed no association. Two studies, one in adults with Prader–Willi syndrome and one in children with GHD, suggested a potential association between short stature and poorer cognitive outcomes. Three studies demonstrated an increased caregiver burden in parents of children with short stature. Conclusions Evidence suggests that, compared with those with normal stature, children and adults with short stature of any cause may experience poorer QoL. Further research could extend our understanding of the human burden in this field.

Acid-labile subunit (ALS) deficiency (ACLSD) constitutes the first monogenic defect involving a member of the Insulin-like Growth Factor (IGF) binding protein system. The lack of ALS completely disrupts the circulating IGF system. Autocrine/paracrine action of local produced IGF-I could explain the mild effect on growth. In the present work we have revised the more relevant clinical and biochemical consequences of complete ACLSD in 61 reported subjects from 31 families. Low birth weight and/or length, reduced head circumference, height between -2 and -3 SD, pubertal delay and insulin resistance are commonly observed. Partial ACLSD could be present in children initially labeled as idiopathic short stature, presenting low IGF-I levels, suggesting that one functional IGFALS allele is insufficient to stabilize ternary complexes. Dysfunction of the GH-IGF axis observed in ACLSD may eventually result in increased risk for type-2 diabetes and tumor progression. Consequently, long term surveillance is recommended in these patients.

The growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis plays an important role in normal brain development, and GH deficiency inevitably affects the growth of the cerebral cortex. This study was designed to analyze morphological differences in gray matter volume, cortical surface area, and gray matter thickness between children with isolated growth hormone deficiency (IGHD) and children with idiopathic short stature (ISS). Twenty-four children with IGHD (mean age 9.42 years, peak GH 5 μg/l) and 24 controls with ISS (mean age 9.21 years, peak GH 10 μg/l) were included. High-resolution three-dimensional T1-weighted MRIs were acquired at participants' first visit. Measurements of gray matter volume, cortical surface area and gray matter thickness were obtained using FreeSurfer. The total and regional differences between groups were statistically analyzed. Correlations between the FreeSurfer results and GH and IGF-I levels were also obtained. The gray matter volume, cortical surface area and gray matter thickness of the total brain and of the bilateral hemispheres of children with IGHD were significantly smaller than those of children with ISS (all P values 0.05). All the measurements had similar cortical distributions between groups but varied across regions. Cortical regions with significant differences in the mean gray matter volume and surface area were mainly distributed around the bilateral central sulci and the lateral and basal parts of the temporal lobes (all P values 0.05). There were negative correlations between gray matter volume, cortical surface area and GH levels, and the right hemispheric and total cortical surface area correlated significantly with GH levels (all P values 0.05) in children with IGHD. There were significant positive correlations between gray matter volume, cortical surface area and IGF-I levels (all P values 0.05) in both groups, except for in left hemispheric gray matter volume in children with ISS. Children with IGHD have significant morphological changes in the cerebral cortex, which were partially influenced by GH and IGF-I levels. These cortical changes may be related to deficits in their relatively slower development in intelligence, motor performance, and other functions.

ObjectiveTo examine whether attention-deficit/hyperactivity disorder (ADHD) stimulant medication modified the linear growth response to growth hormone (GH) treatment in children enrolled in the American Norditropin Studies: Web-Enabled Research Program.Study designShort, GH treatment-naive children with or without GH deficiency (GHD) received GH therapy. A subset also received ADHD stimulant medication (n = 1190), and others did not (n = 7230). Linear mixed models (adjusted means) examined height SDS (HSDS) and body mass index (BMI) SDS from baseline through year 4. Analyses were repeated with ADHD groups matched for baseline age, height, weight, BMI, and sex. Groups with and without GHD were compared between ADHD groups.ResultsAdjusted change in HSDS for the group receiving ADHD stimulant medication was slightly lower than that for patients not receiving stimulant medication at years 1 to 4 (P −2. Year 4 adjusted change in BMI SDS was greater in the patients receiving ADHD stimulant medication compared with both groups not receiving ADHD stimulant medication (P

The present study aimed to compare the efficacy and safety of recombinant human growth hormone (rhGH) therapy between children with idiopathic short stature (ISS) and growth hormone deficiency (GHD).A total of 150 pediatric patients with ISS and 153 pediatric patients with GHD who received rhGH treatment for more than one year from 2005 to 2016 were enrolled. Growth velocity (GV); height standard deviation (HtSD); insulin-like growth factor-1 standard deviation (IGF-1SD); body mass index (BMI); and the incidence of fasting hyperglycemia, fasting hyperinsulinemia, and hypothyroidism were recorded and compared.At the beginning of treatment, chronological age, bone age, height, and BMI were not statistically significant between the two groups. rhGH dosage in ISS was significantly higher compared with GHD (P = 0). GV from half a year to three years after rhGH therapy was higher in the GHD group compared with the ISS group, but the differences were not statistically significant (P 0 .05). HtSD increased in the two groups after rhGH therapy. HtSD at the beginning and after three years of therapy was not different between groups except for after half a year of therapy. HtSD in patients with ISS was significantly higher compared with GHD (P 0 .05). The incidence of hypothyroidism was significantly higher in the GHD group compared with the ISS group (13.72% vs. 6.0%; P 0.05). Moreover, the incidence of hyperinsulinemia was significantly higher in the ISS group compared with the GHD group (15.33% vs. 7.84%; P 0 .05).rhGH increases growth in children with ISS and GHD. Fasting insulin and thyroid function were closely monitored for long-term follow up.

The short stature homeobox-containing (SHOX) gene, mapped on the pseudoautosomal region of the X and Y chromosomes, strongly affects human height. Therefore, SHOX haploinsufficiency has been reported to cause idiopathic short stature (ISS) and the short stature seen in patients with Turner's syndrome, Leri-Weill dyschondrosteosis, and Langer mesomelic dysplasia. SHOX deletions are responsible for approximately 80% of isolated haploinsufficiency. Aiming to evaluate the prevalence of SHOX gene deletions in the Egyptian patients with unexplained short stature, the present study used FISH analysis to investigate SHOX deletions in 25 patients with ISS. Despite the tiny sample size and the limitations of the used analysis technique, our findings emphasize the importance of including SHOX mutation analysis in the genetic workup of ISS cases. Furthermore, this study could not confirm a correlation of SHOX deletions with any specific clinical feature or an anthropometric measurement.

Recombinant human GH (rhGH) has been available since 1985. This article gives an overview, what has been achieved over the past 30 years in respect to optimization of rhGH treatment for the individual child with GH deficiency and what are the safety issues concerned with this treatment. In the last twenty years significant scientific progress has been made in the diagnosis of GH deficiency, the genetic disorders that are associated with pituitary GH deficiency and the genetics that influence growth in general. On the other hand rhGH is not only used in states of GH deficiency but also various conditions without a proven GH deficiency by classical standards. Clinical studies that investigated both the genetics of growth and the individual responses to rhGH therapy in these patient populations were able to refine our concept about the physiology of normal growth. In most patients under rhGH treatment there is a considerable short-term effect, however the overall gain in growth obtained by a long-term treatment until final height still remains a matter of debate in some of the conditions treated. Also first studies on the long-term safety risks of rhGH treatment have raised the question whether this treatment is similarly safe for all the patient groups eligible for such a treatment. Therefore even in the face of a longstanding safety record of this drug replacement therapy the discussion about the right cost and risk to benefit ratio is continuing. Consequently there is still a need for carefully conducted long-term studies that use modern anthropometric, genetic, and laboratory techniques in order to provide the necessary information for clinicians to select the patients that will benefit best from this valuable treatment without any long term risk.

The growth-promoting effect of starting recombinant human growth hormone (rhGH) at the time of near-ending growth has not been studied in sexually mature boys who will have idiopathic short stature (ISS) as adults because it is believed that such an advanced stage of puberty would preclude favorable results.1) To explore the effects of starting rhGH administration at time of near-ending growth in boys with ISS. 2) To search for predictors of response to rhGH.Fifteen boys aged 15.5 ± 1 years terminating puberty were growing at a rate2 cm/6 months towards a predicted adult height (PAH)-2.5 SDS.Participants received 0.50 ± 0.06 mg/kg · wk of rhGH according to a target-to-treat protocol. When growth became less than 0.5 cm in 3 months or when height has reached 169 cm, rhGH was ceased. Testosterone, growth velocity (GV), height, serum IGF-1, bone age (BA) at hand-wrist and knee score were measured at onset; IGF-1 and height were monitored every 3 months. A formula for PAH was developed. Height increment (HI, adult height-starting height) and height gain (HG, adult height-PAH) were calculated.Following rhGH administration for 11.1 ± 4.8 months, GV-SDS increased from -2.5 ± 1.7 to 3.5 ± 4.3 (P = 2 × 10(-4)), HI = 8.5 ± 3.7 cm, HG = 6.8 ± 4.8 cm and adult height was -1.8 ± 0.9 SDS, compared to a PAH of -2.9 ± 0.6 SDS (P = 4 × 10(-4)). Knee score (P = 2 × 10(-3)), GV at rhGH onset (P = 8 × 10(-3)) and rhGH dose (P = 8 × 10(-3)) were identified as predictors of HI and HG, but BA was not.Our study suggests that 1) a short period of rhGH administration can increase true adult height significantly in boys with ISS at time of near-ending growth; and 2) knee score rather than BA should be used to identify rhGH responders. These preliminary observations await confirmation by larger randomized trials.

Background The possible relationship between the circulating concentrations of T4 and GH sensitivity has not been elucidated. Objective The aim of this study is to evaluate the effect of levothyroxine supplementation on GH sensitivity in prepubertal boys with idiopathic short stature (ISS). Methods We selected 28 prepubertal boys with ISS (mean age 8.2±0.5years) and free T4 (Ft4) concentrations between the 3rd and the 25th percentiles (Ft4: 0.8–1.5ng/dl). They were randomly divided into two groups: Group A received thyroid supplementation (1–3μg/kg/day) for 120days, and Group B received placebo for the same period. To evaluate GH sensitivity, an IGF-I generation test (GH: 33μg/kg/day sc for 3days) was performed in both groups: under basal conditions, and after 120days of levothyroxine supplementation (or placebo). Results After thyroid supplementation, Group A had higher Ft4 concentrations compared with Group B (2.14±0.06 vs 1.48±0.06ng/dl, p =0.01), their growth velocity was significantly higher (2.3±0.1 vs 1.5±0.2cm/4months), and they exhibited a greater increase in IGF-I after GH administration (Group A: 32.5±3.8% vs Group B 17.3±2.6%). Conclusion Supplementation with levothyroxine for 120days promotes an increase in growth velocity, and a greater IGF-I response to short-term GH administration in prepubertal boys with ISS and low-normal thyroid hormone concentrations.

ResumoIntroduçãoO efeito dos fármacos inibidores da aromatase (IA) na estatura de jovens do sexo masculino com baixa estatura idiopática (BEI) tem vindo a ser estudado desde que foi evidenciado o papel dos estrogénios na paragem do crescimento linear. Os ensaios clínicos aleatorizados, duplamente cegos, de caso‐controlo com letrozol indicam impacto positivo na previsão de estatura final em jovens do sexo masculino com BEI, com ou sem atraso constitucional do crescimento e puberdade. Por persistirem aspetos de segurança a requerer melhor estudo, a sua utilização terapêutica continua a ser off‐label.ObjetivosTendo em vista a implementação de um ensaio clínico sobre a terapêutica com IA em jovens do sexo masculino com BEI procedeu‐se a uma revisão sistemática da literatura, na qual se fundamenta a proposta de protocolo apresentada.MétodosPesquisa na base de dados eletrónica Medline de revisões sistemáticas, ensaios clínicos aleatorizados controlados e referências bibliográficas dos artigos selecionados, publicados entre janeiro de 2001 e dezembro de 2012.ConclusõesA terapêutica com um IA de terceira geração (letrozol) poderá ser considerada em jovens do sexo masculino com BEI, altura inferior a pelo menos −2,0 SDS para a idade ou previsão de altura final pelo menos 2,0 SDS abaixo da estatura média parental, desde que já tenha sido iniciada a puberdade e a idade óssea seja inferior a 14 anos. Os principais aspetos de segurança ainda sob discussão na literatura referem‐se a potenciais efeitos a nível ósseo. A utilização de medicamentos off‐label deve obedecer a critérios estritos de prescrição e seguimento das crianças, de forma a minimizar os riscos e obter resultados fiáveis e comparáveis. Apresenta‐se proposta de sistematização de monitorização clínica, imagiológica e laboratorial, bem como critérios de término ou suspensão da mesma.AbstractIntroductionThe effect of aromatase inhibitors in the height of male adolescents with idiopatic short stature has been studied since the role of estrogen in the finishing of the linear growth has been clarified. Randomized controlled double blind clinical trials comparing letrozol with placebo indicate a positive impact on the predicted adult height of male adolescents with idiopatic short stature, either with or without constitutional growth and puberty delay. As there still remain some security aspects requiring better enlightment, their therapeutic use is off‐label.ObjectivesRegarding the development of a clinical trial on the prescription of aromatase inhibitors in male adolescents with idiopathic short stature, a systematic literature review has been performed, which supports the current protocol proposal.MethodsResearch on the electronic database Medline for sistematic reviews, randomized controlled double blind clinical trials and references from the selected articles, published between January 2001 and December 2012.ConclusionsPrescription of a third generation aromatase inhibitor (letrozol) may be considered in male pubertal adolescents with idiopathic short stature with height below −2.0 SDS for their age or predicted adult height 2.0 SDS lower than midparental height, and bone age under 14 years. Potential effects on bone health are the main safety issues under discussion on the published papers. Off‐label therapy should comply to strict prescription and follow‐up criteria, in order to reduce the risks and to obtain valuable and comparable outcomes. A proposal for the clinical, imaging and laboratory follow up of patients under aromatase inhibition is presented, as well as criteria for ending or suspending the treatment.

Objective To investigate the possible association of circulating components of GH-IGFs-IGFBPs system with the GHR-exon 3 genotype in normal and idiopathic short stature (ISS) children. Design Descriptive, cross-sectional study in normal and ISS children. Subjects and methods 192 normal and 81 ISS children (age: 5–17 years) were included. Serum IGF-I, IGFBP3, ALS and GHBP levels were measured. GHR-exon 3 polymorphism (GHRd3) was analyzed by multiplex PCR assay. Normal and ISS children were divided according to GHR-exon 3 genotype: homozygous for the full-length GHR isoform (GHRfl) and carriers of one or two copies of the GHRd3 allele. Results GHRd3 genotype distribution (fl:fl/fl:d3/d3:d3,%) in normal (60:34:6) and ISS (64:32:4) was similar and reached Hardy–Weinberg equilibrium. ISS children had significantly reduced levels of GHBP and GH-dependent factors as compared to controls (p < 0.0001). Within the normal group, homozygous carriers of the GHRfl allele had significantly higher GHBP serum levels than those with one or two copies of the GHRd3 allele (Mean ± SEM; GHRfl: 3.2 ± 0.2 vs GHRd3: 2.7 ± 0.2 nmol/L, p = 0.04). No other significant association with GHR exon 3 polymorphism was found in either the normal or the ISS groups. Conclusions GHR exon 3 polymorphism is distributed similarly in normal and ISS children, however only normal homozygous children for GHRfl allele showed higher GHBP levels. The lack of association between GHBP and GHR polymorphism in ISS children might be related to the heterogeneity of this group, where potential defects in GH receptor action may result in partial GH insensitivity. Fil: Ballerini, María Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; Argentina Fil: Domene, Horacio Mario. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; Argentina Fil: Scaglia, Paula Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; Argentina Fil: Martinez, Alicia Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; Argentina Fil: Keselman, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; Argentina Fil: Jasper, Hector Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; Argentina Fil: Ropelato, María Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas; Argentina

We hypothesized that responses to growth hormone (GH) therapy by idiopathic short stature (ISS) and growth hormone deficiency (GHD) patients were associated with single nucleotide polymorphisms (SNPs) in the leptin ( LEP ) and leptin receptor ( LEPR ) genes. We retrospectively enrolled ISS ( n = 32) and GHD ( n = 38) patients and forty healthy age-and gender-matched children. They were genotyped for the LEP promoter at nt.-2548, and LEPR K109R and LEPR Q223R polymorphisms. Clinical and laboratory variables were determined before and after 2 years of GH treatment. ISS patients with G/A or A/A genotypes of the LEPR Q223R SNP had a significantly higher height velocity (cm/y) than ISS patients with the G/G genotype at 2 years after GH treatment. For GHD patients, G/A or A/A genotype of the LEPR K109R SNP was associated with higher body weight, higher BMI, and higher weight velocity than patients with the G/G genotype before GH treatment, but not after GH treatment. G/A or A/A genotype of the LEPR Q223R SNP was associated with a significantly higher body weight, higher height velocity before treatment, but not after GH treatment. G/A or A/A genotype of the LEPR Q223R SNP was associated with a significantly higher weight velocity before treatment, but a significantly lower weight velocity was found at 2 years after GH treatment. These results suggest LEPR Q223R SNP (rs1137101) is associated with outcomes of GH replacement therapy in ISS and GHD patients.

The availability of recombinant human growth hormone (GH) has broadened its range of clinical applications. Approved indications for GH therapy include treatment of growth hormone deficiency (in children and in adults), Turner syndrome, Prader-Willi syndrome, chronic renal insufficiency and more recently, idiopathic short stature in children, AIDS-related wasting and fat accumulation associated with lipodystrophy in adults. Therapy with GH usually begins at a low dose and is gradually titrated to obtain optimal efficacy while minimizing side effects. It is usually administered on a daily basis by subcutaneous injection, since this was considered to impact upon patient compliance, extended-release GH preparations were developed and new delivery platforms - e.g., auto-injectors and needle-free devices - were introduced in order to improve not only compliance and convenience but also dosing accuracy. In addition, alternative less invasive modes of administration such as the nasal, pulmonary and transdermal routes have also been investigated. Here, we provide an overview of the different technologies and routes of GH administration and discuss the principles, limitations and pharmacological profiles for each approach.

The approach to the child with growth retardation who is in puberty remains an important clinical challenge. The use of high-dose growth hormone (GH), suppression of puberty with GnRH analogs in combination with GH, and the use of selective inhibitors of the aromatase enzyme with aromatase inhibitors (also in combination with GH) are all therapeutic choices that have been studied. Aromatase blockade effectively blocks estrogen production in males with a reciprocal increase in testosterone, and a new generation of aromatase inhibitors, including anastrozole, letrozole and exemestane, is under investigation in adolescent subjects with severe growth retardation. This class of drugs, if judiciously used for a window of time, offers promise as an adjunct treatment of growth delay in pubertal patients with GH deficiency, idiopathic short stature, testotoxicosis, and other disorders of growth. These evolving uses of aromatase inhibitors, however, represent off-label use of the product, and definitive data on their efficacy are not available for each of the conditions mentioned. Safety issues regarding bone health also require further study.

Idiopathic short stature is a condition in which the height of the individual is more than 2 SD below the corresponding mean height for a given age, sex and population, in whom no identifiable disorder is present. It can be subcategorized into familial and non-familial ISS, and according to pubertal delay. It should be differentiated from dysmorphic syndromes, skeletal dysplasias, short stature secondary to a small birth size (small for gestational age, SGA), and systemic and endocrine diseases. ISS is the diagnostic group that remains after excluding known conditions in short children.

In the management of ISS auxological, biochemical, psychosocial and ethical elements have to be considered. In boys with constitutional delay of growth and puberty androgens are effective in increasing height and sexual characteristics, but adult height is unchanged. GH therapy is efficacious in increasing height velocity and adult height, but the inter-individual variation is considerable. The effect on psychosocial status is uncertain. Factors affecting final height gain include GH dose, height deficit in comparison to midparental height, age and first year height velocity. In case of a low predicted adult height at the onset of puberty, addition of a GnRH analogue can be considered. Although GH therapy appears safe, long-term monitoring is recommended.

Objective Adult females receiving GH may be less sensitive to the metabolic effects of GH than males, however these differences are less well studied in adolescence. We aimed to investigate if metabolic effects of GH vary by gender during puberty. Design Sixteen adolescents (8 M/8 F, mean age (SE): 13.1 ± 0.2 yr) with significant short stature due to either GH insufficiency or idiopathic short stature were studied before and after 8 w of daily GH therapy. Differences in rates of protein and glycerol turnover (13C leucine and d5-glycerol infusions), substrate oxidation rates (indirect calorimetry), hormones, growth factors, lipid concentrations, body composition (DEXA) and 1 yr growth velocity were measured. Results Protein synthesis rates per kg FFM were similar in boys and girls before and after GH and increased similarly on treatment in both genders. Rates of whole body lipolysis were similar at baseline and increased after GH in both genders comparably. Plasma lipids were similar between boys and girls before and after GH, and triglycerides increased post-GH in both. Insulin increased after GH comparably in both genders, yet no significant difference in glucose or adiponectin concentrations during treatment or between genders was observed. IGF-I concentrations were similar between boys and girls at baseline, but with a more robust increase in males after 8 w of GH (boys: +629 ± 65 ng/ml, girls: +331 ± 67, p = 0.007). Body composition changes and bone mineral density were similar between genders after GH. HT SDS increased comparably after 1 yr (boys −2.2 ± 0.09 to −1.77 ± 0.11, p = 0.0002; girls −2.49 ± 0.24 to −2.02 ± 0.25, p = 0.04). There were no gender differences on the linear growth responses after 12 mo. Conclusions As compared to girls, boys had: (1) similar sensitivity to GH for protein synthesis, lipolysis, lipid concentrations and body composition changes as well as comparable glucose and adiponectin concentrations; (2) higher IGF-I responses to 8 w of GH. Differences in IGF-I during GH treatment may account in part for the gender differences in physique and strength that develop during human puberty; however, using conventional doses of GH, these differences do not translate into differences in linear growth after 12 mo. Contrary to adults, these data do not support the need for different GH dosing depending on gender during puberty.

Objective Genetic factors play an expanding role in understanding growth hormone (GH) disorders, therefore the German KIMS Pharmacogenetics Study was initiated with the aim of genotyping various GH-/IGF-I-axis-related genes of GH-deficient adult patients to investigate genotype:phenotype relationships and response to GH therapy. Patients and methods 129 consecutively enrolled GH-deficient adult patients were genotyped for variant 1 (V1) of the alternatively spliced noncoding exons in the 5′-untranslated region and for the nine coding exons of the GH receptor (GHR) gene, which obviously play a striking role in the function of the GH-IGF-I-axis. After detection of a heterozygous, non-synonymous mutation R179C in exon 6 in one single patient with acquired GH-deficiency (GHD) in late adulthood, analysis of her clinical data followed, leading to the diagnosis of mild short stature (−1.5 SD). For further endocrine evaluation, five pituitary stimulation tests (arginine) of this patient were statistically compared to stimulation tests (arginine) of ten GH-deficient control patients, retrospectively. Results The formerly in patients with Laron syndrome and idiopathic short stature reported mutation R179C leads to an amino acid change from an arginine residue (codon CGC) to a cysteine residue (codon TGC) in position 179 of the extracellular domain of the GHR. Statistical analysis revealed significant decreased IGF-I/GH 0 ratio ( p = 0.004) and IGF-I/GH max ratio ( p = 0.001) of the index patient compared to the control patients, implying growth hormone resistance of the index patient at the level of the GHR, according to the detected R179C mutation. Conclusions This study reports on the unusual case of a patient with mild short stature, who acquired GHD in late adulthood due to a non-secreting pituitary adenoma and get additionally diagnosed for pre-existing growth hormone insensitivity due to a formerly in two short statured patients described, single, heterozygous, non-synonymous mutation in the GHR. Our findings support the theory that heterozygous mutations in the GHR gene can have mild phenotypical consequences.

There is no way to predict early the growth response to growth hormone (GH) treatment in short children with intrauterine growth retardation (IUGR) or idiopathic short stature (ISS).To evaluate the capacity of the procollagen type 1 amino-terminal propeptide (P1NP), a new marker of bone formation, to help in this prediction.Longitudinal study of 30 patients treated at 7.7 (range: 2.2-12.5) years for IUGR (n=16) or ISS (n=14) with GH (0.47 and 0.33 or 0.4mg/kg/week respectively). P1NP and insulin-like growth factor I (IGF I) were measured before and after 3-6 months of GH treatment.Before treatment, IUGR patients were younger and shorter than ISS patients, but their other characteristics were similar. IGF I Z-score (ZS) and P1NP concentrations were positively correlated in the whole population (Rho=0.48; P=0.01). After 3-6 months of treatment, both concentrations increased in IUGR and ISS (P0.01). They remained correlated only in ISS (Rho=0.54; P0.05). P1NP before treatment was negatively correlated (Rho=-0.67, P=0.015) with the growth rate (SD) during the first year of treatment in ISS but not in IUGR; IGF I ZS was not. The changes in P1NP for the whole population over 3-6 months, but not the changes in IGF I ZS, were positively correlated with the growth rate (Rho=0.41, P=0.03).Lower basal plasma P1NP concentrations predict better growth response to GH treatment during the first year in ISS children. Greater increases in its concentrations after 3-6 months of GH treatment may also predict a better growth response in both ISS and IUGR.

SHOX is a homeobox-containing gene, highly conserved among species as diverse as fish, chicken and humans. SHOX gene mutations have been shown to cause idiopathic short stature and skeletal malformations frequently observed in human patients with Turner, Leri–Weill and Langer syndromes. We cloned the chicken orthologue of SHOX, studied its expression pattern and compared this with expression of the highly related Shox2. Shox is expressed in central regions of early chick limb buds and proximal two thirds of later limbs, whereas Shox2 is expressed more posteriorly in the proximal third of the limb bud. Shox expression is inhibited distally by signals from the apical ectodermal ridge, both Fgfs and Bmps, and proximally by retinoic acid signaling. We tested Shox functions by overexpression in embryos and micromass cultures. Shox-infected chick limbs had normal proximo-distal patterning but the length of skeletal elements was consistently increased. Primary chick limb bud cell cultures infected with Shox showed an initial increase in cartilage nodules but these did not enlarge. These results fit well with the proposed role of Shox in cartilage and bone differentiation and suggest chick embryos as a useful model to study further the role of Shox in limb development.

Recombinant human insulin-like growth factor-I (rhIGF-I) has been used during the past decade for the treatment of severe IGF-I defi ciency resulting from growth-hormone receptor defi ciency (Laron syndrome), and for growth-hormone gene deletion in which inactivating antibodies to exogenous recombinant human growth hormone have developed. In total, about 150 patients have been treated with rhIGF-I for these conditions. Data for 61 of these patients were used for US Food and Drug Administration approval of rhIGF-I (mecasermin; Increlex, Tercica, Brisbane, CA, USA) and data for another 25 patients in approval of the binary protein complex of rhIGF-I and IGF-I binding protein-3 (mecasermin rinfabate; iPlex, Insmed, Glen Allen, VA, USA), as orphan drugs. The manufacturers refer to these conditions, in which severe IGF-I defi ciency is secondary to growth-hormone insensitivity, as severe primary IGF-I defi ciency (IGFD), an imprecise and inaccurate designation that permits inclusion of a large group of children with idiopathic short stature. The singularity of this terminology is shown by a Medline search for “primary IGF-I defi ciency” or “primary IGFD”, which yielded only fi ve items—three review articles by a company offi cer and consultants for each of the manufacturers, a review by Laron, and another paper from his group that refers to Laron syndrome both as primary growth-hormone resistance and as primary IGF-I defi ciency. A review in 2004 of emerging medical ventures suggested possible reasons for promoting such imprecise and relatively obscure terminology

Objective We analyzed postnatal growth in children with familial short stature (FSS) with regard to small (SGA) or appropriate (AGA) for gestational age status at birth. Study design We studied 96 otherwise healthy short-statured children (58 males; SGA: n = 41, AGA: n = 55). At least one of the parents was short-statured. Cross-sectional data for length/height and weight for the first 4 years of age were collected retrospectively. Results AGA children had a mean length of 0.09 ± 1.02 standard deviation score (SDS) at birth, −1.57 ± 1.16 SDS after 1 year of age, and −2.36 ± 0.72 SDS after 4 years. SGA children had a mean length of −2.04 ± 1.06 SDS at birth, −2.70 ± 1.12 SDS at 1 year of age, and −3.05±0.86 SDS at 4 years. The loss of length SDS within the first 2 years of life was greater in AGA than in SGA children. SGA children were significantly shorter than AGA children at all of the study points (p Conclusions Children with an FSS background born AGA show catch-down growth to their lower familial range during the first 2 years of life. SGA children did not catch up to their AGA peers at any time.

La talla baja es el motivo de consulta más frecuente en las consultas de endocrinología pediátrica. Diferentes entidades nosológicas se caracterizan por una disminución de la velocidad de crecimiento y una talla anormalmente baja. Unas están bien caracterizadas; otras corresponden a la denominada talla baja idiopática (TBI). Ésta abarca a los niños que presentan un crecimiento por debajo de –2 DE de los valores de la talla media correspondiente a los niños de su población de similar edad y sexo, en los que se han descartado las causas conocidas de talla baja. No incluye a aquellos niños que presentan únicamente un retraso constitucional del crecimiento y el desarrollo. Diferentes ensayos clínicos demuestran la eficacia del tratamiento con hormona de crecimiento (rhGH) para que estos niños consigan un crecimiento recuperador. Por ello, la TBI debe considerarse como una entidad que se debe tener en cuenta en el diagnóstico de un paciente con talla baja y patrón de crecimiento anómalo que puede beneficiarse del tratamiento con rhGH. : Short stature is the leading cause of consultation in Pediatric Endocrinology. Decreased growth velocity and abnormally short height are characteristic of several different nosologic entities. Some are well characterized, while others correspond to what is known as idiopathic short stature (ISS). ISS includes children who grow less than 2 SD of the mean height values corresponding to their peers of similar age and the same sex, in whom the known causes of short stature have been ruled out. The diagnosis of ISS does not include children who only present a constitutional delay in growth and development. Several clinical trials have demonstrated the efficacy of growth hormone (rhGH) treatment in achieving catch-up growth in these children. Therefore, ISS should be kept in mind in the diagnosis of patients with short stature and abnormal growth patterns, who may benefit from rhGH treatment.

The state of bone health and the effect of growth hormone (GH) therapy on bone and body composition in children with idiopathic short stature (ISS) are largely unknown. A direct role of GH deficiency (GHD) on bone density is controversial. Using dual-energy X-ray absorptiometry, this study measured total body bone mineral content (TB BMC), body composition, and volumetric bone mineral density (vBMD) at the lumbar spine (LS) and femoral neck (FN) in 77 children (aged 3-17 years) with ISS (n = 57) and GHD (n = 20). Fifty-five children (GHD = 13) receiving GH were followed over 24 months including measurement of bone turnover. At diagnosis, size-corrected TB BMC SDS was greater (P

Leri-Weill dyschondrosteosis (LWD) is a pseudoautosomal dominant disorder characterized by disproportionate short stature and a characteristic curving of the radius, known as the "Madelung deformity." SHOX mutations resulting in SHOX haploinsufficiency have been found in LWD and in a variable proportion of patients with idiopathic short stature (ISS), whereas homozygous loss of SHOX results in the more severe Langer mesomelic dysplasia (LMD). Defects in SHOX have been identified in approximately 60% of LWD cases, whereas, in the remaining approximately 40%, the molecular basis is unknown. This suggests either genetic heterogeneity or the presence of mutations in unanalyzed regions of SHOX, such as the upstream, intragenic, or downstream regulatory sequences. Therefore, the pseudoautosomal region 1 (PAR1) of 80 patients with LWD, in whom SHOX deletions and mutations had been excluded, was screened for deletions by use of a new panel of microsatellite markers. We identified 12 patients with LWD who presented with a novel class of PAR1 deletions that did not include SHOX. The deletions were of variable size and mapped at least approximately 30-530 kb downstream of SHOX. In our cohort, this type of deletion accounted for 15% of cases. In all cases, the deletions cosegregated with the phenotype. No apparent phenotypic differences were observed between patients with SHOX deletions and those with this new class of PAR1 deletions. Thus, we present here the identification of a second PAR1 region implicated in the etiopathogenesis of LWD. Our findings suggest the presence of distal regulatory elements of SHOX transcription in PAR1 or, alternatively, the existence of an additional locus apparently involved in the control of skeletal development. Deletion analysis of this newly identified region should be included in the mutation screening of patients with LWD, LMD, and ISS.

Growth hormone (GH) therapy has evolved rapidly over the past decade. Ongoing research has demonstrated a clear role for therapeutic GH in a wide spectrum of pediatric disorders involving both poor growth and abnormal body composition. Although guidelines for GH dosing are not fully established, a series of key studies has delineated the range of dosages that are useful in the treatment of children with growth disorders. The recent approval of idiopathic short stature (ISS) as an indication for GH therapy presents further challenges in optimizing the care of GH-treated patients. ISS is now recognized as a diverse collection of environmental and molecular abnormalities, some of which involve the GH-IGF axis. Emerging data indicate that serum IGF-I measurements are not only useful in the diagnosis of growth abnormalities but, in conjunction with auxological measurements, are also a powerful tool for assessing GH efficacy. While it is clear that many ISS patients respond to GH, some individuals will not show a satisfactory response. Monitoring IGF-I levels and change in height SDS during treatment can assist the physician in distinguishing those patients in whom GH successfully and safely induces statural growth from those with partial or complete GH insensitivity who might benefit from modified GH treatment protocols or alternate therapies. In addition, serum IGF-I measurements are increasingly used as part of a rational monitoring strategy to ensure safety of GH dosing in light of cumulative data associating high IGF-I levels with potential malignancy risk, and low IGF-I levels with cardiovascular disease risk.

The aim of the study was to investigate the effect of standard insulin tolerance test on plasma leptin levels in children with idiopathic short stature (ISS) and in children with growth hormone deficiency (GHD). Furthermore, plasma leptin levels were analyzed with regard to age, body mass index (BMI), and plasma levels of human growth hormone and of insulin-like growth factor-1 (IGF-1). Sixty-three patients with a height below the third percentile, an age of 10.24 ± 0.40 years and a BMI standard deviation score (SDS) of −0.78 ± 0.13 (weight SDS −0.07 ± 0.12; height SDS −2.39 ± 0.10) were investigated (mean ± SD). Based on responses to insulin tolerance test, the patients were classified as ISS (n = 49) or GHD (n = 14). Plasma leptin levels were significantly lower in all patients 60 minutes (P < .001) and 120 minutes (P < .001) after insulin administration. This effect was independent of GHD, and no difference in leptin decrease was found when comparing patients with ISS to those with GHD. A correlation was found when comparing plasma leptin levels of all patients to BMI SDS (r = 0.43; P < .001) and plasma IGF-1 levels (r = 0.31; P < .01). Furthermore, positive correlation was found when BMI SDS was compared to IGF-1 (r = 0.25; P < .05). In summary, we found that insulin administration in children with short stature decreases plasma leptin levels, equally in those with and without GHD.

When the only source of therapeutic human growth hormone (hGH) was pituitary-derived GH, rationing of this precious resource was a necessity. Recombinant DNA technology made hGH abundant, but this abundance also brought uncertainty, controversy, and discomfort to practitioners trying to practice ethically responsible medicine. Early debates focused on two central questions: (1) If hGHwere proven effective at increasing the height of children without GH deficiency (GHD), would the diagnosis of GHD be morally relevant in determining entitlement to hGH treatment? (2) Regardless of underlying cause, should the treatment of short stature be considered a medical problem justifying medical treatment, and, if so, to what degree? We argued that hGH effectiveness and serious disability rather than the designation of GHD should guide access. Others countered that patients with GHD had a disease deserving treatment, whereas children short from other causes did not have a disease (at least not that of GHD) and that to treat them would constitute enhancement and not therapy. The intervening years have in some ways clarified and in some ways complicated this debate. hGH has been approved by the Food and Drug Administration (FDA) for treatment of non–GH-deficient children with Turner syndrome, chronic renal insufficiency, short stature caused by intrauterine growth retardation, and, most recently, children with severe familial or idiopathic short stature (ISS). Thus, there is now consensus that the cause of short stature is not morally relevant in deciding who is entitled to treatment. The utility of GHD as a necessary or sufficient criterion for eligibility for treatment is a priori problematic, since the definition and ascertainment of GHD is still controversial and elusive. Isolated GHD (as conventionally diagnosed) is usually neither complete nor permanent. A continuum of GH secretion spans the clinical presentations of ‘‘partial’’ versus ‘‘severe’’ isolated GHD versus ‘‘complete’’ (ie, multiple pituitary hormone deficiency state) GHD. Children with isolated GHD (IGHD) without identifiable central nervous system abnormalities or metabolic evidence indicative of severe GHD (eg, hypoglycemia or abnormal body composition) comprise the majority of and most controversial hGH-treated patients. In the discussion below, ‘‘GHD’’ refers to these patients, not to severe, permanent GHD associated with hypoglycemia, identifiable central nervous system malformations, or multiple pituitary hormone deficiencies. In addition to proving the irrelevance of underlying cause, this transformation in practice has unmasked the limited relevance of the treatment/enhancement distinction in determining who is entitled to treatment. Defenders of this distinction argued that the non-GHD child did not have a disease and that the use of hGH in such a situation constituted enhancement, implicitly an inappropriate goal of the practice of medicine. Today, it is acknowledged that the non–GH-deficient child’s central concern is identical to that of the child with GHD; namely, ‘‘I am short and I would like to be taller.’’ To the child and the parent, it is irrelevant whether the condition being treated is a well-characterized ‘‘disease’’ caused by GHD or a less well-understood process, as is the case in Turner syndrome and ISS. If ‘‘enhancement’’ refers to a desire for a child to be taller than he would be if left alone, then all children involved in this debate are seeking enhancement. The object of concern is not GH deficiency but short stature, and the only relevant question is whether there is safe, effective, affordable treatment. From the Department of Pediatrics, University of Wisconsin Medical School, Madison, Wisconsin. Dr Allen serves as a grant reviewer for the Genentech Center for Research and receives research grant support from Genentech, Inc, and Eli Lilly, Inc. Submitted for publication Sept 15, 2003; last revision received Jan 15, 2004; accepted Feb 18, 2004. Reprint requests: David B. Allen, MD, Professor of Pediatrics, H4/448 CSC– Pediatrics, 600 Highland Ave, Madison, WI 53792-4108. E-mail: dballen@wisc.edu. J Pediatr 2004;144:648–52. 0022-3476/$ see front matter Copyrighta 2004 Elsevier Inc. All rights reserved.

Since 1958 growth hormone (GH) has been used as substitution treatment for children with GH deficiency. At present, it is clear that a dose of 0.23 mg/kg/week can lead to a final height close to target height, but in view of the wide inter-individual variation, alternative regimens based on invidualizing the dosage with the help of prediction models are being investigated. The best strategy during puberty (increase the dosage, delay puberty) is still uncertain. The value of GH in idiopathic short stature is still heavily debated, although the average final height gain on 0.33 mg/kg/week is 5-7 cm. GH is efficacious in short stature due to chronic renal failure and Prader-Willi syndrome. In other conditions insufficient data are available. There are few side-effects.

Objective: Changes in health-related quality of life (HRQOL) and self-esteem were studied in children with idiopathic short stature (ISS) participating in a study on the effect of growth hormone treatment. Study design: Prepubertal children (n = 36) with ISS were randomly assigned to a treatment or control group. Children with ISS, their parents, and the pediatrician completed HRQOL and self-esteem questionnaires 3 times in 2 years. Results: At the start, children with ISS did not have lower scores than the norm population, except for social functioning HRQOL. The pediatrician reported an improvement of HRQOL in the treatment group, the parents reported no change, and the children in the treatment group reported the same, or sometimes even worse, HRQOL or self-esteem than the control group. Changes related to the child's satisfaction with height and hardly to growth itself. Conclusion: The assumption that growth hormone treatment improves HRQOL in children with ISS could not be supported in this study. Chemicals/CAS: Growth Hormone, 9002-72-6

To determine the 1-year effectiveness and safety of nutritional supplementation with the study formula on linear growth and weight gain in short and lean prepubertal children and to validate the previously reported findings in those initially treated with placebo.Two-phase 1-year intervention (double-blind placebo-controlled [0-6 months] and open-labeled extension [6-12 months]) in which all participants were offered to continue the study using the study formula. Anthropometric measures and 3-day food diary were assessed at baseline and after 6 and 12 months of intervention.A total of 129 out of 150 children (86%) completed the open-labeled extension-phase. In "good" consumers of the formula (intake ≥50% of recommended dose) throughout the entire year height-SDS continued to improve in the extension phase, with a total gain of 0.19 ± 0.14 SD. In "good" consumers of the formula initially randomized to the placebo-group, the gain in height-SDS significantly improved (from 0.04 ± 0.13 to 0.12 ± 0.11; P = .001), replicating the results of the "good" consumers of the formula during the blinded-phase (0.12 ± 0.12). "Poor" consumers (intake 50% of recommended dose) did not improve their height-SDS. No significant changes in body mass index SDS were observed with the consumption of the formula. A dose-response was found between the amount of formula consumed/kg and the increment in height-SDS and weight-SDS (r = 0.36; P .001 and r = 0.18; P = .041, respectively). No serious adverse events were reported.One year of a nutritional supplement was effective in promoting the linear growth of short and lean prepubertal children, with no change in body mass index status.ClinicalTrials.gov:NCT01158352.

Linear growth is a multifactorial trait involving environmental, hormonal and genetic factors. The multitude of growth-affecting genetic factors has recently been supplemented by the discovery of the homeobox gene SHOX. Although originally described as causing idiopathic short stature, SHOX mutations are also responsible for mesomelic growth retardation and Madelung deformity in Léri-Weill dyschondrosteosis and Langer mesomelic dysplasia. Furthermore, recent studies implicate SHOX haploinsufficiency in the etiology of additional somatic stigmata frequently observed in Turner syndrome. Therefore, SHOX has a broad functional scope and leads to a variety of different phenotypes upon mutation.

El mosaicismo 45,X/46,XY tiene una amplia expresividad clínica. El 90 % de los casos de diagnóstico prenatal son varones fenotípicamente normales, mientras que los casos de diagnóstico posnatal engloban un amplio espectro clínico que incluye síndrome de Turner, disgenesia gonadal mixta, seudohermafroditismo masculino y varones aparentemente normales. Se indican los hallazgos clínicos, endocrinológicos, citogenéticos e histológicos de 3 pacientes con fenotipo masculino normal y mosaicismo 45,X/46,XY de diagnóstico posnatal durante su estudio por talla baja. Sólo uno de los pacientes presentaba rasgos turnerianos. No se ha encontrado correlación entre la proporción de líneas celulares 45,X y 46,XY en sangre, gónadas y fenotipo. La posibilidad de desarrollar complicaciones como disgenesia del tejido gonadal con riesgo de malignización e infertilidad y talla baja susceptible de beneficiarse del tratamiento con hormona de crecimiento implica la necesidad de un seguimiento estrecho sobre todo en aquellos pacientes de diagnóstico prenatal y posnatal con fenotipo normal. : There is wide variation in the clinical expression of 45,X/46,XY mosaicism. Ninety percent of prenatally diagnosed boys have normal male phenotype at birth, while those diagnosed postnatally show a wide spectrum of phenotypes, ranging from Turner syndrome, mixed gonadal dysgenesis, and male pseudohermaphroditism to apparent normality.We report the clinical, cytogenetic, endocrinologic and histologic findings in three boys with an apparently normal male phenotype and 45,X/46,XY mosaicism who were diagnosed postnatally because of their short stature. With the exception of one patient with Turner stigmata, no other abnormal features were found.No correlation between the proportion of 45,X/46,XY cell lines in blood, gonads and phenotype was found. Both prenatally and postnatally diagnosed boys with normal male phenotype must be followed-up because they can develop late-onset abnormalities, such as dysgenetic testes leading to infertility or neoplastic transformation, and short stature, which could be improved with growth hormone therapy.

Recent studies of the growth hormone insulinlike growth factor I (IGF I) axis suggest that these hormones are involved in several physiologic processes, in addition to growth. Thus, several lines of evidence indicate an increasingly important role for recombinant human growth hormone as a part of the modern therapeutic armamentarium. In addition to the treatment of children with growth hormone deficiency, administration of growth hormone appears to be of considerable benefit to girls with Turner syndrome, children with chronic renal failure, and adults with growth hormone deficiency or human immunodeficiency virus (HIV) wasting syndrome. Moreover, its therapeutic use is being investigated in other conditions, such as children with idiopathic short stature, the healthy elderly, and the critically ill. However, long-term surveillance among growth hormone recipients is needed to fully evaluate its risk-benefit profile.

To investigate how growth hormone (GH)-releasing peptide (GHRP) and GH-releasing hormone (GHRH) interact in patients with short stature, we examined the acute effects of GHRH1-29NH 2 , GHRP-2, and the combination of GHRH1-29NH 2 and GHRP-2 on GH release in children with GH insufficiency ([GHI] group A) and idiopathic short stature ([ISS] group B). Ten children with GHI (aged 11.8 ± 1.1 years; height, −4.2 ± 0.5 SDS) and five children with ISS (aged 11.1 ± 1.2 years; height, −3.2 ± 0.1 SDS) were studied. Intravenous bolus infusions of GHRH1-29NH 2 (1 μg/kg), GHRP-2 (1 μg/kg), and GHRH plus GHRP-2 (each 1 μg/kg), were administered in a randomized order. Because of the variability of GH responses, results were analyzed by a nonparametric statistical method. Patients in group A showed low GH responses to both GHRH1-29NH 2 and GHRP-2 stimulation: in only three of 10 and one of nine cases, respectively, were the peak GH levels above 5.0 μg/L. GH area under the curve (AUC) 90 minutes after GHRP-2 administration was slightly less than for GHRH1-29NH 2 (179 ± 150 v 214 ± 68 μg/L · min, P = .06). In group B, GH responses to GHRH1-29NH 2 and GHRP-2 were approximately of the same magnitude (1,943 ± 819 v 1,981 ± 887 μg/L · min, P = .9). After a combined challenge with GHRH1-29NH 2 and GHRP-2, five of eight children in group A had peak GH concentrations greater than 5 μg/L. GH AUC of the GHRH1-29NH 2 plus GHRP-2 test in group A (1,136 ± 764 μg/L · min) was significantly greater than GH AUC of the GHRP-2 bolus ( P = .02) but was not different from GH AUC of GHRH1-29NH 2 ( P = .09). A dramatic response to combined GHRH1-29NH 2 and GHRP-2 administration was observed in group B, with peak GH levels above 100 μg/L in four of five children. GH AUC of the GHRH1-29NH 2 and GHRP-2 combined study (7,035 ± 1,513 μg/L · min) was significantly greater than the AUC obtained after administration of GHRH1-29NH 2 (1,943 ± 819 μg/ L · min, P = .015) or GHRP-2 (1,982 ± 887, P = .014) alone. Thus, although intravenous bolus GHRP-2 was shown to release GH in children with various forms of short stature, the response is likely to be dependent on the presence of endogenous or exogenous GHRH.

Objective: To determine whether some patients with idiopathic short stature have partial resistance to growth hormone (GH). Patients with idiopathic short stature have decreased serum levels of the GH receptor-related GH-binding protein (GHBP), and low GHBP levels are associated with complete GH insensitivity (Laron) syndrome. We hypothesized that patients with idiopathic short stature and low GHBP levels may also have a degree of GH insensitivity. Design: Retrospective analysis of patients in a multicenter study. Setting: Ninety-six National Cooperative Growth Study centers in the United States and Canada. Subjects: Five hundred eleven patients with idiopathic short stature who were treated with GH. All patients had a baseline height standard deviation score of less than -2 and a maximum stimulated GH level greater than 10 μg/L. Of these, 101 (20) had a baseline GHBP standard deviation score of -2 or less. Results: The patients with low GHBP levels, in comparison with those with normal GHBP levels, had a lower mean extracted standard deviation score for insulin-like growth factor I (-3.3 ± 1.1 vs -2.5 ± 1.4; p p p = 0.74, 0.61 respectively) with comparable doses of GH. Conclusions: Patients with idiopathic short stature and low GHBP levels, compared with those with normal GHBP levels, had significantly lower standardized levels of insulin-like growth factor I, and higher mean 12-hour GH levels, which suggest partial GH insensitivity. There was no significant correlation of GHBP levels with the growth response to exogenous GH. (J PEDIATR 1995;127:244-50)

In adults patients, administration of human growth hormone and growth hormone synthesized by recombinant DNA technology (rGH) results in sodium and fluid retention and weight gain. This study was performed to determine whether rGH administration in children with idiopathic short stature (ISS) caused any clinical evidence of sodium retention. The parameters assessed included blood pressure, height, weight, plasma renin activity (PRA), aldosterone, and atrial natriuretic peptide (ANP). These were measured in nine treated children after 0, 3, 6, 9, and 12 months of growth hormone therapy; seven untreated children served as controls. After 12 months, the treated children had no significant increases in measurements of blood pressure, PRA, aldosterone, and ANP. Although treated children gained more weight than control patients, they also grew faster. Therefore, there was no significant difference in weight for height percentile for treated children when compared with normal controls. After 1 year of therapy, the administration of rGH to children with ISS does not result in any clinically significant evidence of sodium retention.