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Novel Insights Into the Genetic Causes of Short Stature in Children

Affiliation.

• 1 Department of Paediatrics, University of Chieti, Chieti, Italy.
• PMID: 35949366
• PMCID: PMC9354945
• DOI: 10.17925/EE.2022.18.1.49

Short stature is a common reason for consulting a growth specialist during childhood. Normal height is a polygenic trait involving a complex interaction between hormonal, nutritional and psychosocial components. Genetic factors are becoming very important in the understanding of short stature. After exclusion of the most frequent causes of growth failure, clinicians need to evaluate whether a genetic cause might be taken into consideration. In fact, genetic causes of short stature are probably misdiagnosed during clinical practice and the underlying cause of short stature frequently remains unknown, thus classifying children as having idiopathic short stature (ISS). However, over the past decade, novel genetic techniques have led to the discovery of novel genes associated with linear growth and thus to the ability to define new possible aetiologies of short stature. In fact, thanks to the newer genetic advances, it is possible to properly re-classify about 25-40% of children previously diagnosed with ISS. The purpose of this article is to describe the main monogenic causes of short stature, which, thanks to advances in molecular genetics, are assuming an increasingly important role in the clinical approach to short children.

Keywords: Short stature; children; genetic cause; growth hormone.

© Touch Medical Media 2022.

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Conflict of interest statement

Disclosures: Concetta Mastromauro and Francesco Chiarelli have no financial or non-financial relationships or activities to declare in relation to this article.

Figure 1:. Genetic defects of growth hormone–insulin-like…

Figure 1:. Genetic defects of growth hormone–insulin-like growth factor-1 axis

Figure 2:. Genetic defects of growth plate…

Figure 2:. Genetic defects of growth plate paracrine factors

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CRAIG BARSTOW, MD, AND CAITLYN RERUCHA, MD

Am Fam Physician. 2015;92(1):43-50

Author disclosure: No relevant financial affiliations.

Short stature is defined as a height more than two standard deviations below the mean for age (less than the 3rd percentile). Tall stature is defined as a height more than two standard deviations above the mean for age (greater than the 97th percentile). The initial evaluation of short and tall stature should include a history and physical examination, accurate serial measurements, and determination of growth velocity, midparental height, and bone age. Common normal variants of short stature are familial short stature, constitutional delay of growth and puberty, and idiopathic short stature. Pathologic causes of short stature include chronic diseases; growth hormone deficiency; and genetic disorders, such as Turner syndrome. Tall stature has the same prevalence as short stature, but it is a much less common reason for referral to subspecialty care. Common causes of tall stature include familial tall stature, obesity, Klinefelter syndrome, Marfan syndrome, and precocious puberty. Although most children with short or tall stature have variants of normal growth, children who are more than three standard deviations from the mean for age are more likely to have underlying pathology. Evaluation for pathologic etiologies is guided by history and physical examination findings.

Most children with short or tall stature have normal variants of growth. The evaluation of potential pathologic causes of short or tall stature should be guided by the history and physical examination findings. 1 – 3

Evaluation of Growth

The first step in the evaluation of a child with suspected short or tall stature is to obtain accurate measurements and plot them on the appropriate growth chart. For infants and toddlers, weight, length, and head circumference should be plotted on a growth curve at every visit. For patients two to 20 years of age, weight, height, and body mass index should be plotted. Length should be measured using a horizontal rule in children younger than two years, and height should be measured using a wall-mounted stadiometer in children older than two years. Because children grow in spurts, two measurements at least three to six months apart, and preferably six to 12 months apart, are needed to accurately determine growth velocity. 4

The Centers for Disease Control and Prevention (CDC) and the American Academy of Pediatrics recommend using the World Health Organization (WHO) growth charts for children younger than two years and the CDC growth charts for children older than two years. 5 The CDC growth charts are a population-based reference that include data from bottle-fed and breastfed infants. Because the WHO growth charts are based on an international study of exclusively breastfed infants raised in optimal nutritional conditions, they are less likely to incorrectly identify breastfed infants as underweight. The CDC and WHO growth charts are available at http://www.cdc.gov/growthcharts/ and http://www.who.int/childgrowth/standards/en/ .

A newborn's size and growth are a result of the intrauterine environment, and growth hormone does not play a major role. Between six and 18 months of age, children exhibit catch-up or catch-down growth until they reach their genetically determined growth curve based on midparental height. By two years of age, growth hormone plays a predominant role. At this stage, children should track along a percentile, and variation should stay within two large bands on the growth chart. In adolescence, growth is affected by the onset of puberty, and sex hormones become the predominant factor in growth.

Variation from this normal pattern of growth may be a sign of pathologic conditions. Although most children with short or tall stature do not have a pathologic condition, extremes of height, especially beyond three standard deviations, require further workup.

MIDPARENTAL AND PROJECTED HEIGHT

Calculating the midparental height ( Table 1 ) is an important part of the evaluation because most short or tall children have short or tall parents. Projected height can be estimated by projecting the current growth curve to adulthood in children with normal bone age, or by using a bone age atlas in those with delayed bone age. Most children will have a projected adult height within 10 cm (4 in), or two standard deviations, of their midparental height. A projected height that differs from the midparental height by more than 10 cm suggests a possible pathologic condition. Short or tall parents may themselves have a pathologic reason for their height, especially if they are more than two standard deviations from the adult norm. 6 – 8

Growth velocity is a measurement of growth rate. Children with normal variants of height tend to have a normal growth velocity (5 cm [2 in] per year for children between five years of age and puberty) after catch-up or catch-down growth. A growth velocity that is less than normal should prompt further investigation. Table 2 includes normal growth velocity by age. 1 , 9

Bone age should be compared with chronologic age to narrow the differential diagnosis of short stature. 5 , 10 , 11 The traditional method compares a plain radiograph of the left wrist and hand to a database of norms, although various methods are now available. 10 – 12 Children with normal variations of growth may have advanced or delayed bone age, but a bone age that is more than two standard deviations from the mean for age is likely due to a pathologic condition.

Short Stature

Short stature is defined as a height more than two standard deviations below the mean for age, or less than the 3rd percentile. Idiopathic short stature is defined as a height less than two standard deviations below the mean for age without a known etiology.

Most children with short stature have normal variants such as familial short stature, constitutional delay of growth and puberty, or idiopathic short stature. Approximately 5% of children referred for evaluation of short stature have an identifiable pathologic cause. 13 The most common etiologies are growth hormone deficiency, hypothyroidism, celiac disease, and Turner syndrome. Other causes include renal, hepatic, and gastrointestinal diseases, and other genetic syndromes. 10 – 15

The initial evaluation of short stature ( Figure 1 ) should include a history and physical examination, accurate growth assessment, calculation of the growth velocity and midparental height, and radiography to evaluate bone age. 16 Drugs known to cause short stature include steroids (chronic use), attention-deficit/hyperactivity disorder medications, and anticonvulsants. Dysmorphic characteristics suggest a genetic disorder, whereas midline defects suggest an abnormality of the growth hormone axis. Table 3 includes the differential diagnosis of short stature. 1 , 2 , 4 , 16 – 18

If the initial evaluation suggests a genetic, endocrine, or gastrointestinal disorder, laboratory testing should be performed ( Table 4 ) . 1 , 3 , 13 , 14 , 16 , 19 , 20 In an asymptomatic child with short stature, an evaluation of the growth curve may provide clues to the underlying pathology. Underweight in a child with short stature suggests a systemic illness or malnutrition, whereas overweight suggests an endocrine disorder. 2 , 21

Different causes of short stature tend to fall within identifiable growth patterns, and a review of a child's growth curve and bone age should guide further evaluation. Children with familial short stature or idiopathic short stature have a bone age equivalent to their chronologic age, and children with constitutional delay of growth and puberty or endocrine disorders have a bone age that is less than their chronologic age. Because the bone age of a child with endocrine diseases will progressively fall behind chronologic age, calculating bone age every 12 months might be useful to differentiate constitutional delay of growth from endocrine diseases. 1

Children with endocrine disorders, such as growth hormone deficiency, hypothyroidism, or glucocorticoid excess, have normal to increased weight, whereas children with systemic disease tend to have decreased height and weight. 2 , 21

If findings from the initial evaluation do not suggest a diagnosis, laboratory testing may be performed ( Table 4 ) . 1 , 3 , 13 , 14 , 16 , 19 , 20 A retrospective study found that a complete laboratory evaluation of an asymptomatic child with idiopathic short stature is low yield and expensive. The two diseases that were most often identified in the studied cohort were celiac disease and an abnormality of the growth hormone axis. 3 If history and physical examination findings do not suggest a cause, a complete blood count, comprehensive metabolic panel, and measurement of bone age, insulinlike growth factor 1, and insulinlike growth factor binding protein 3 might be useful to screen for chronic disease and growth hormone deficiency. Karyotyping in girls might also be reasonable because short stature and delayed puberty may be the only symptoms in some girls with Turner syndrome.

Children with short stature and no identified cause and children with certain other identifiable causes of short stature should be referred to a pediatric endocrinologist. Table 5 lists the indications for referral. 2 , 6 , 22

SELECTED CAUSES

Constitutional Delay of Growth and Puberty . Children with this condition are born appropriate for gestational age, but will then fall to the 3rd percentile for height during catch-down growth. After this period, growth velocity will be normal and bone age delayed. 22 Children with this condition have delayed onset of puberty, resulting in a normal adult height.

Growth Hormone Deficiency . This condition may be congenital or acquired, and has an incidence of one in 3,000 to 9,000 children. 13 A history of head trauma, central nervous system infection, birth trauma, or cranial irradiation may suggest an acquired cause of growth hormone deficiency. Most infants with the congenital form are normal size at birth, but may have episodes of hypoglycemia or prolonged jaundice. Physical examination may reveal microphallus or midline craniofacial abnormalities. A child whose growth is initially normal but then falls progressively further off the growth curve may have growth hormone deficiency. Typically, children with this condition have a delayed bone age with a preserved or increased weight for age. The diagnosis can be made by a decreased insulinlike growth factor 1 or insulinlike growth factor binding protein 3, followed by negative growth hormone provocation test results. 23

Small for Gestational Age . Infants born small for gestational age typically have catch-up growth in the first 24 months, but 10% have a final height more than two standard deviations below the mean for age. 24 Children who do not have catch-up growth within the first six months or whose height is not within two standard deviations of the mean for age by two years of age may have a pathologic condition. It may take more than four years for a preterm infant who is born small for gestational age to attain a normal height. 24

Recombinant growth hormone is approved for a variety of conditions that cause short stature, including Turner syndrome, chronic renal failure, Prader-Willi syndrome, small for gestational age, Noonan syndrome, short stature homeobox-containing gene deficiency, and idiopathic short stature. It is administered through daily injections over several years. The injections are generally well tolerated, but rare adverse reactions have been reported. For children with idiopathic short stature, four years of treatment results in an increased height of 3.7 cm (1.46 in) and costs between $100,000 and $120,000. 25 , 26

Oxandrolone (Oxandrin) is an oral anabolic steroid that has been shown to increase height velocity but has little effect on final height. Insulinlike growth factor has been used in children with insulinlike growth factor deficiency. Although aromatase inhibitors have been used in children with idiopathic short stature, long-term effectiveness and safety data are not available. 27

Tall Stature

Tall stature is defined as a height more than two standard deviations above the mean for age (greater than the 97th percentile). Evaluation may also be needed in a child who has a normal height, but a projected height more than two standard deviations from the midparental height. Figure 2 is an algorithm for the evaluation of tall stature. 19 Although the percentage of children with tall stature is equal to that of children with short stature, children with tall stature are much less likely to be referred to subspecialty care.

Table 6 includes the differential diagnosis of tall stature. Constitutional advancement of growth in tall children is the equivalent of constitutional delay of growth and puberty in short children. 1 , 19 , 20 Children with constitutional advancement of growth have accelerated growth until two to four years of age and then track parallel to the growth curve. Puberty usually occurs early, leading to a near-normal height. 19

Obese children are tall for their age. 19 However, these children often have an early onset of puberty and therefore a near-normal final height. 20

Intervention is usually not needed in children with tall stature. High-dose sex steroids have been used to promote growth plate closure, but use has decreased over the past 20 years because of adverse effects. 28 Surgical destruction of the growth plates has also been performed, but this procedure is controversial. In patients with pituitary gigantism, octreotide (Sandostatin) and pegvisomant (Somavert) have been used to suppress the growth hormone. 19

Data Sources : We searched PubMed, Agency for Healthcare Research and Quality, Cochrane Database of Systematic Reviews, and National Guidelines Clearinghouse. Search terms included short stature, tall stature, and growth hormone. We did online searches of The New England Journal of Medicine , Pediatrics , American Family Physician , Pediatrics in Review , and the British Medical Journal to identify additional relevant articles. The bibliographies of review articles and textbook chapters were also reviewed for original research articles. The Pediatric Endocrine Society website was searched for consensus statements and clinical guidelines. Search dates: June and December 2014, and March 2015.

The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Army Medical Department or the U.S. Army Service at large.

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EDITORIAL article

Editorial: short stature: beyond growth hormone.

• 1 Department of Pediatrics, Second Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czechia
• 2 Endocrinology and Diabetes Unit, “Bambino Gesù” Children’s Hospital, Rome, Italy
• 3 Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
• 4 Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy
• 5 Institute for Maternal and Child Health IRCCS “Burlo Garofolo”, Trieste, Italy

Editorial on the Research Topic Short stature: beyond growth hormone

Short stature is the most common cause of referral to pediatric endocrinology units ( 1 ) and can be defined as a multifactorial condition regulated by genetic, epigenetic, and environmental factors ( 2 ). Traditionally, growth hormone (GH) has been considered the main regulator of growth. However, as understanding of short stature pathogenesis advances, a new concept has been proposed: the role of GH in the regulation of growth is only one of many factors influencing growth plate physiology ( 3 ). Moreover, the diagnostic methods currently used to diagnose GH deficiency (GHD) are known to have low specificity, leading to frequent false positive results ( 4 ). Children with diagnosed GHD are therefore believed to have variable etiology of their growth disorder, frequently independent of GH secretion ( 5 ).

One of the major topics in current pediatric endocrinology is whether it is possible to improve the poor accuracy of GH stimulation tests. One possibility might be the optimization of sex-steroid priming ( 6 ). Partepone et al. presented a comprehensive review regarding this topic. The authors highlighted a close link between sex steroids and GH secretion leading to a higher probability of false positive results in children with delayed onset of puberty and consequent GH overtreatment. The same mechanism, on the other hand, may lead to a non-physiological GH peak, resulting in missing the diagnosis in children with real GH deficiency (GHD) in case sex-steroid priming is performed. So far, there is no agreement Regarding the indication and management of sex-steroid priming. Another issue that might lead to an inaccurate diagnosis of GHD is bone age (BA) evaluation. Delayed BA is mandatory before making the GHD diagnosis in some countries ( 7 ), however, the subjective nature of the evaluation is considered its main disadvantage. Maratova et al. evaluated an automated software for BA evaluation and proved its good accuracy.

A lasting controversy in the current way to diagnose GHD was supported by Plachy et al. Using next-generation sequencing methods, the authors genetically examined children with isolated growth hormone deficiency (GHD) and familial short stature. Interestingly, the genetic results frequently did not correspond with the previous diagnosis of GHD – 67% of children with a clinical diagnosis of GHD and a genetic etiology of short stature had proven primary growth plate disorder. Another point of view on the same topic was presented by Lanzetta et al. In their retrospective analysis of children with a clinical and laboratory diagnosis of GHD, they compared children with or without an identifiable genetic, functional, or anatomical cause of GHD, namely definite GHD or short stature unresponsive to stimulation tests (SUS). These two groups differed significantly in pretreatment IGF-1 concentration and their increase after GH treatment initiation, in prevalence of pathological retesting, and of being overweight/obese at the end of treatment. However, the response to GH treatment in terms of near-adult height did not differ between the groups. Despite lasting doubts regarding the accuracy of GHD diagnostics, children diagnosed with “GHD” might profit from GH therapy even when another etiology of short stature is suspected.

The etiology of short stature other than GHD was covered by two other articles in our Research Topic. Mastromauro et al. wrote a review presenting growth hormone insensitivity (GHI) as a broad spectrum of disorders with a variable clinical picture. Since Laron described homozygous mutations in the gene for the GH receptor as the first mechanism causing GHI, many novel causes of GHI have been described, demonstrating the complexity of GHI and its role in the growth regulation. Another numerous and etiologically highly variable group of children are those born small for gestational age (SGA) with persistent short stature ( 8 ). In a retrospective study, Becker et al. compared clinical features and responses to GH treatment of SGA children with and without syndromic signs. They discovered that syndromic SGA children were shorter at the initiation of GH treatment, started GH therapy earlier, and reached a shorter adult height despite receiving higher doses of GH.

The etiology of growth disorders is, therefore, more complex than originally expected and is not just a matter of hormones. To understand it better, we must think far beyond GH.

Author contributions

LP: Writing – original draft, Writing – review & editing. AD: Writing – original draft, Writing – review & editing. GT: Writing – original draft, Writing – review & editing.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

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8. Toni L, Plachy L, Dusatkova P, Amaratunga SA, Elblova L, Sumnik Z, et al. The genetic landscape of children born small for gestational age with persistent short stature. Horm Res Pediatr . (2024) 97:40–52. doi: 10.1159/000530521

Keywords: endocrinological diseases, stimulation tests, growth hormone, genetics, short stature

Citation: Plachy L, Deodati A and Tornese G (2024) Editorial: Short stature: beyond growth hormone. Front. Endocrinol. 15:1403112. doi: 10.3389/fendo.2024.1403112

Received: 18 March 2024; Accepted: 22 March 2024; Published: 28 March 2024.

Edited and Reviewed by:

Copyright © 2024 Plachy, Deodati and Tornese. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Gianluca Tornese, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Short Stature in Children: Diagnosis, Management, and Treatment

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• Published Papers

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section " Clinical Pediatrics ".

Deadline for manuscript submissions: closed (25 June 2023) | Viewed by 6696

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Dear Colleagues,

Between 0.6% and 2.3% of healthy children are short. Short stature in children is the one of the most frequent reasons for consultation in a Pediatric Endocrinology Unit. Almost no patient has pathology and can be studied in primary care.

However, with the standard clinical and analytical evaluation, a diagnosis is not reached in some cases, which fall within the so-called idiopathic short stature.

Recent hormonal and genetic studies are making it possible to reduce the percentage of unknown causes and to approach the specific etiology with consequent improvement in genetic treatment and counseling.

Another prominent issue is the use of growth hormones, with indications approved (some very recently) by the EMA and FDA, although not always coincidently (such as idiopathic short stature) and with diverse inclusion criteria that invite the follow-up of these patients up to adult height and investigate predictive factors of response. Long-term follow-up is also important to ensure patients’ safety.

In this Special Issue, we aim to cover current knowledge regarding growth pathology, its endocrinological and genetic involvement, and the most appropriate therapeutic measures.

Dr. Juan Pedro López-Siguero Dr. José-Ignacio Labarta-Aizpún Guest Editors

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• Research article
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• Published: 28 March 2020

Final adult height of children with idiopathic short stature: a multicenter study on GH therapy alone started during peri-puberty

• Rui-min Chen 2 ,
• Shao-ke Chen 3 ,
• Ge-li Liu 4 ,
• Lin-qi Chen 5 ,
• Yu Yang 6 ,
• Xin-li Wang 7 ,
• Ya-guang Peng 8 &
• Chun-xiu Gong 1  

BMC Pediatrics volume  20 , Article number:  138 ( 2020 ) Cite this article

6009 Accesses

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To evaluate the efficacy of GH in improving FAH in ISS children in a multicenter study.

A real-world observation was carried out. Children with ISS in seven hospitals in China were enrolled. The height gains standard deviation score and the height gain over the target height were evaluated.

There were 344 ISS patients (217 boys and 127 girls). The baseline average age of boys and girls was 12.7 and 11.7 years, with bone age of 11.7 and 10.1 years, respectively. The baseline height SDS of boys and girls was − 3.07 and − 2.74, and the FAH SDS was − 1.91 and − 1.38, respectively. Compared with the baseline height SDS, the FAH SDS was significantly increased in both boys and girls (both P  = 0.0000). The FAH SDS was the highest (gain by 1.54 SD) in the ≥2y treatment course group. Two hundred eighteen patients (218/344, 63.4%) had a FAH SDS > − 2 SD. Among these patients, girls in the 1-2y treatment course group and ≥ 2y group had a FAH SDS higher than TH SDS. Even in the control group, a spontaneous catch-up growth of 1.16 SD was observed. A multivariate linear regression model was used to analyze the results, with FAH SDS as the dependent variable. It was found that the treatment course and baseline height SDS in the boys’ model were statistically significant ( P  < 0.05), whereas the baseline height SDS and baseline bone age significantly affected the girls’ FAH SDS ( P  < 0.05).

Conclusions

Both girls and boys of ISS improved FAH by GH therapy even if treatments begin over 10 years old and majority of them reached TH. Some peri-puberty ISS will have a spontaneous height gain. We recommend the course of GH treatment more than 2 years for girls, and longer courses for boys.

Peer Review reports

Idiopathic short status (ISS) is defined as a condition in which the height of an individual is more than 2SD score (SDS) below the corresponding mean height for a given age, sex, and population group without evidence of systemic, endocrine, nutritional, or chromosomal abnormalities. Children with ISS have normal birth weight and are GH sufficient [ 1 ]. The incidence of ISS (including constitutional delay of growth and puberty and familial short stature) is about 23 in 1000 [ 1 , 2 , 3 ]. In 2003, the US Food and Drug Administration approved growth hormone (GH) for the treatment of ISS patients (height < − 2.25 SD). The main purpose of GH therapy for ISS is to attain normal adult height and avoid daily life inconvenience and psychological problems caused by extreme or unacceptable short stature. However, few clinical studies have explored whether the final adult height (FAH) can reach the normal range after GH therapy. FAH is considered the golden indicator for evaluating the efficacy of GH therapy [ 4 , 5 ]. However, the predicted FAH following a short period of treatment is dynamic and cannot reflect the actual FAH. Owing to the heterogeneity of the treated ISS populations and the individualization of treatment, only a few randomized trials with small sample sizes have observed ISS until FAH [ 6 , 7 , 8 , 9 , 10 ]. A randomized study of FAH typically takes 8 years or more to complete and is often difficult to implement in clinical settings. Thus, most of the currently available studies only have small samples and are carried out in a single center. More studies are needed to confirm the efficacy of GH in the treatment of ISS.

In the clinical real world, many ISS children’s parents are willing to observe their children growth when they are young. As children grow older and become peri-puberty, more people come to see doctors. What is the effect of GH treatment alone in peri-puberty? Past literatures are not accurate. This is the first multicenter study in China on the efficacy of growth hormone alone in the treatment of elder children. In our current study, we followed up children with ISS diagnosed by the departments of pediatric endocrinology in seven tertiary hospitals in different regions of mainland China, and evaluated the efficacy of GH for ISS children until FAH.

Patients with ISS confirmed in the departments of pediatric endocrinology in seven tertiary hospitals, namely Beijing Children’s Hospital Affiliated to Capital Medical University, Fuzhou Children’s Hospital of Fujian Medical University Teaching Hospital, The second Affiliated Hospital of Guangxi Medical University, General Hospital of Tianjin Medical University, Children’s Hospital of Soochow University, Children’s Hospital of Jiangxi Province, and Third Hospital of Peking University, were enrolled in this study.

The inclusion criteria included: (a) body height less than − 2 SD of the height in the general population with the same race, age, sex, and other factors; (b) without systemic disease, endocrine disease, nutritional disease, or chromosomal abnormality; (c) with normal body length and weight at birth; (d) with a serum peak GH concentration > 7 ng/mL at peak GH stimulation test and normal insulin-like growth factor 1; (e) born before January 1, 2001; (f) had been treated with GH alone for ISS but the GH therapy had been withdrawn and FAH reached, regardless of whether the patient was in Tanner stage 1 at admission; and (g) informed consent was signed by parents and children older than 8 years.

The exclusion criteria included: (a) children who were treated with GnRHa (gonadotropin-releasing hormone agonist); and (b) obese children.

Regarding the concept of peri-puberty, there is no well-recognized age limit for its definition. Since the baseline Tanner stages differed in our research populations, the term peri-puberty was used in our study.

All patients and their parents signed informed consent for data collection.

A real-world observation was carried out. Clinical data including name, sex, date of birth, age at baseline, baseline height, baseline bone age based on Greulich-Pyle methodology, GH treatment course, age at last follow-up, FAH, and parents’ heights were recorded. The baseline height SD score (SDS), FAH SDS, and target height (TH) SDS were calculated. GH was subcutaneously injected at a dose of 0.15–0.2 IU/kg/day.

The height SD score (HtSDS) was calculated by referring to the 2005 Standard Deviations of Height and Weight for Children and Adolescents Aged 0–18 years in China [ 11 ].

Height standard deviation score (HtSDS) = (actual height − average height for children of the same sex and age) ÷ (SD of the heights for children of the same sex and age) [ 11 ].

TH (i.e., mid-parental target height) was as follows:

FAH was defined as follows: age at the last follow-up was > 15 years, height velocity was below 1 cm/year, and the GH therapy had been discontinued [ 12 ].

The primary endpoint was the difference between FAH SDS and baseline height SDS, i.e., the height SDS gain, expressed as △ 1HtSDS. The secondary endpoint was the difference between FAH SDS and TH SDS, i.e., the height gain over the TH ( △ 2HtSDS). △ 3HtSDS is baseline height SDS minus TH SDS. In addition, influencing factors of height SDS were analyzed.

The control group comprised patients who had been treated for less than 3 months. The remaining patients were divided into the 3-6 m group (treated for 3–6 months), 6-12 m group (treated for 6 months to 1 year), 1-2y group (treated for 1–2 years), and ≥ 2y group (treated for 2 or more years).

Patients were also stratified according to gender.

Screening flowchart:

Statistical analysis

Statistical analysis was performed using SPSS 20.0 software. A normal distribution test showed that all measurement data were normally distributed. Data are presented as mean ± SD. The means of two independent samples were compared by using the t test, and the comparisons of means among multiple groups were based on analysis of variance. The influencing factors of FAH SDS were analyzed by multivariate linear regression. A P value of less than 0.05 was considered significantly different.

General data

Among the 344 ISS patients in seven centers, there were 217 boys and 127 girls. The average age of boys and girls when starting the treatment (baseline) was 12.7 ± 1. 87 and 11.7 ± 1.61 years, with bone age of 11.7 ± 2.32 years and 10.1 ± 2.03 years, respectively. The growth stopped at the final follow-up visit, with a mean age of 18.5 ± 2.25 years for boys and 18.0 ± 2.02 years for girls (Table  1 ).

The baseline height SDS of boys and girls was − 3.07 and − 2.74, and the FAH SDS was − 1.91 and − 1.38, respectively. Compared with the baseline height SDS, the FAH SDS was significantly increased in both boys and girls (both P  = 0.0000) (Table  1 ).

Comparisons between FAH SDS and baseline height SDS

According to the treatment course, patients who had been treated for less than 3 months were designated the control group, and the remaining patients were divided into the 3-6 m, 6-12 m, 1-2y, and ≥ 2y groups. The average course of treatment was 2.92 years in the ≥2y group. The baseline height SDS and TH SDS were comparable among the five groups.

The baseline ages of the control group, 3-6 m group, and 6-12 m group were significantly larger than that of the ≥2y group.

The height gain SDS (i.e., between FAH SDS and baseline height SDS [ △ 1HtSDS]) was 1.16, 1.30, 1.00, 1.01, and 1.54 in each group; compared with the control group, the P value was 0.503, 0.492, 0.525, and 0.082, showing no significant difference. However, the FAH SDS was highest (increased by 1.54 SD) in the ≥2y group. The △ 1HtSDS showed a gradually increasing trend in the 6-12 m group, 1-2y group, and ≥ 2y group. Compared with the other two groups, the ≥2y group had significantly different △ 1HtSDS ( P  = 0.022). Even in the control group (regarded as an untreated group), a spontaneous catch-up growth of 1.16 SD was observed. However, the absolute height gain ( △ 1HtSDS) was clinically significantly higher in ≥2y group than in the control group (1.54 versus 1.16). In each group, there was significant difference between △ 2HtSDS and △ 3HtSDS. (Table 2 ; Fig.  1 and Supp. Figure 1 ).

Baseline height SDS, FAH SDS, and TH SDS in each group

Comparisons of FAH SDS and TH SDS

According to the Chinese Children Growth Standards, an SDS value of 1 is considered a clinically acceptable boundary value with practical clinical significance. Based on the gender stratification, the difference between FAH SDS and TH SDS was compared. The FAH SDS (− 1.913) was 1.079 lower than the TH SDS (− 0.834) (95% confidence interval [CI]: − 1.279 to − 0.878, P  > 0.05) in boys and 0.398 lower (95% CI: − 0.625 to − 0.170, P  < 0.001) in girls. Thus, the FAH SDS was closer to the TH SDS in girls after treatment.

Analysis of patients with FAH attaining normal height

In total, 218 patients (218/344, 63.4%) had a FAH SDS > − 2 SD, attaining the normal and non-short height (Table  3 ), comprising 118 boys (118/217, 54.4%) and 100 girls (100/127, 78.7%). Among these patients, girls in the 1-2y group and ≥ 2y group had a FAH SDS higher than TH SDS. FAH SDS was lower than TH SDS in all groups of boys who attained the normal and non-short height (Table  3 and Supp. Figure 2 ).

Compared with the pooled group with a FAH attaining the normal height, 8 of 10 girls and 11 of 31 boys in the control group attained the normal adult height. There was statistical significance between the number of boys in the control group and that in the pooled group ( P  = 0.049); that is, the number of boys in the control group attaining the normal height was smaller than that of boys in the pooled group reaching the normal height, while there was no significant difference between the control group and the pooled group.

Analysis of influencing factors of FAH

A multivariate linear regression model was used to analyze the results, with FAH SDS as the dependent variable and the baseline age, baseline bone age, baseline height SDS, treatment course, and TH as independent variables. It was found that treatment course and baseline height SDS in the boys’ model were statistically significant ( P  < 0.05), whereas the baseline height SDS and baseline bone age affected the girls’ FAH SDS (Table  4 ).

This is the first observational multicenter study with FAH results in China on the efficacy of growth hormone alone for ISS. It was an observational study based on the clinical reality and reflected the real-world situation. In addition to the follow-up of FAH, the difference between FAH SDS and baseline height SDS and between FAH height SDS and TH SDS was also evaluated. It was found that a treatment course of 2 years or more had better efficacy. Even for over 10 years old ISS children, GH therapy could improve FAH if the treatment course was long enough.

Randomized controlled trials (RCTs) have been recognized as high-quality research evidence because of their rigorous grouping/screening criteria and standardized treatment. However, sometimes RCTs do not actually reflect the clinical reality because the efficacy of GH for ISS varies greatly and the GH treatment is highly individualized in the true clinical setting. Although real-world retrospective studies are feasible, their data are limited by the natural characteristics of the treated children. In the study of short stature, it is difficult to find a control group without treatment: in clinical practice, few children will adhere to the follow-up protocol if no GH treatment is applied. In the current study, patients who had received GH treatment for less than 3 months were included in the control group, which was based on the following consideration: although GH is effective for a patient, such efficacy within a short period (3 months) can be neglected for the FAH; thus, the result of a short treatment course of up to 3 months is similar to that of natural growth. Our data comprised real-world clinical data, which may be used as evidence for long-term treatment of GH for ISS.

As known, the efficacy of GH in the treatment of ISS remains controversial. In a variety of prospective/retrospective, randomized/non-randomized, and controlled/non-controlled trials, some researchers concluded that GH treatment improved ISS while others considered it ineffective. The efficacies in these studies varied dramatically [ 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. Some meta-analyses showed that GH-treated ISS patients might gain more FAH than untreated children, but were still shorter than the normal populations. In the meta-analysis performed by Deodati and Canfarani, three RCTs that followed the ISS patients until FAH were included, among which the average treatment course was 4.6–6.2 years [ 8 ]. In these three RCTs the treated group gained 0.79 SDS (4.7 cm) more height than the control group without GH treatment. In the largest trial, the height attainment was 0.8 SDS (5 cm) more in the treatment group than in the control group. In the study by Sotos and Tokar, the height attainment was 1.9 SDS in the treatment group and only 0.49 SDS in the untreated control group [ 3 ]. Wit et al. evaluated 239 children treated with GH, of whom only 50 were followed up until FAH. The FAH increased by 1.52–1.85 SDS compared with baseline height [ 10 ]. In our current study, the FAH of boys and girls increased by 1.16 SD and 1.36 SD compared with baseline height, which is basically consistent with results reported in the literature. Compared with the 6 m-2y group, the ≥2y group had significantly more FAH gain over the baseline height. Therefore, GH treatment for more than 2 years can achieve better efficacy in ISS patients.

Our study showed that 54.4% of boys and 78.7% of girls had a FAH SDS > −2SD after GH treatment. This result explains that GH therapy is effective even in peri-puberty children. Among the girls who had been treated with GH > 2 years, their FAH was higher than TH. This further confirmed that GH therapy could improve FAH and longer the better. For boys, FAH SDS was lower than TH SDS in all groups although they attained the normal height. It may be that boys need to improve their height longer than girls. In the GeNeSIS observation study by Pfäffle and colleagues, including United States, Germany and France data, shows that most children achieved near adult height (NAH) within the normal range (height SDS > − 2) after GH treatment [ 19 ]. The main population of our study is Chinese Han children. It shows that the same results as in Europe and America, the efficacy of growth hormone is similar.

The average age of boys and girls at baseline was 12.7 ± 1.87 years and 11.7 ± 11.7 years, with bone age of 11.7 ± 2.32 years and 10.1 ± 10.02 years, respectively. The relatively late initiation of treatment reflected the real-world situation. Multivariate linear regression model analysis showed that FAH is influenced positively by baseline height SDS in the boys and girls, whereas negatively by baseline bone age in girls, which was consistent with previous findings [ 1 , 3 , 8 , 13 , 20 ]. Many previous studies have demonstrated that the age when starting GH treatment is an important factor for its efficacy [ 1 , 2 , 6 , 10 , 20 ]. In this regard, our patients might have benefited more from GH therapy if the treatment had started earlier.

And we notice in this study, even in the control group, there is a spontaneous height gain of 1.16 SD. Economic factors need to be taken into account in the treatment of ISS. In China, growth hormone therapy for ISS is covered by families themselves. Whether to treatment or not, as well as the course of treatment, is decided by parents after weighing the family economic and height expectations.

This study had some limitations: Although it was a multi-center observation study, 344 of 475 cases entered the final analysis. It reflects “real-world” clinical practice and can be considered reliable, but which is not represented in random clinical trials. The sample is not big enough when stratification by treatment duration, if there is a larger sample in each subgroup, it will be better to validate our findings.

In summary, both girls and boys of ISS improved FAH by GH therapy even if treatments begin over 10 years old and majority of them reached TH. Some peri-puberty ISS will have a spontaneous height gain. We recommend the course of GH treatment more than 2 years for girls, and longer courses for boys.

Availability of data and materials

The datasets generated and analyzed during the present study are available from the corresponding author on reasonable request.

Abbreviations

Idiopathic short status

Standard deviations

Growth hormone

Final adult height

Gonadotropin-releasing hormone agonist

Standard deviation score

Target height

Height standard deviation score

Confidence interval

Randomized controlled Trials

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Acknowledgements

The authors thank the patients, their families and the contributing physicians for their involvement in this study.

Not Applicable.

Author information

Authors and affiliations.

Department of Endocrine and Genetics and Metabolism, Beijing Children’s Hospital, Capital Medical University, National Centre for Children’s Health, No. 56 Nanlishi Road, Xicheng District, Beijing, 100045, China

Di Wu & Chun-xiu Gong

Department of Endocrinology, Fuzhou Children’s Hospital of Fujian Medical University Teaching Hospital, No.145, 817 Middle Road, Gulou District, Fuzhou, Fuzhou, 350005, Fujian Province, China

Rui-min Chen

Department of Pediatric, The second Affiliated Hospital of Guangxi Medical University, No.166, Daxuedong Road, Nanning, Guangxi, Nanning, 530007, Guangxi, China

Shao-ke Chen

Department of Pediatric, Tianjin Medical University General Hospital, No.154, Anshan Road, Heping District, Tianjin, 300052, Tianjin, China

Depatment of Endocrinology, Children’s Hospital of Soochow University, No. 92, Zhongnan Street, Gongyeyuan District, Suzhou, Suzhou, 215025, Jiangsu, China

Lin-qi Chen

Department of Endocrinology, Children’s Hospital of Jiangxi Province, No.122, Yangming Road, Donghu District, Nanchang, Jiangxi, Nanchang, 330006, Jiangxi, China

Department of Pediatric, Peking University Third Hospital, No.49, Huayuanbei Road, Haidian District, Beijing, Beijing, 100191, Beijing, China

Xin-li Wang

Center for Clinical Epidemiology and Evidence-Based Medicine, Beijing Children’s Hospital, Capital Medical University, National Centre for Children’s Health, No.56, Nanlishi Raod, Xicheng District, Beijing, Beijing, 100045, Beijing, China

Ya-guang Peng

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C.G. designed the investigation, data interpretation and revised the manuscript. D.W. performed most of the investigation, data analysis and wrote and revised the manuscript. R.C., S.C., G.L., L.C., Y.Y. and X.W. performed the investigation. Y.P. contributed to statistical analysis of data. All of the authors have read and approved the manuscript.

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Correspondence to Chun-xiu Gong .

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This study was approved by the ethics committee of National Center for Children’s Health & Beijing Children’s Hospital Affiliated to Capital Medical University. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All data published here are under the consent for publication. Written informed consent was obtained from all individual participants over 16 years old included in the study. A parent or guardian was on behalf of any participants under the age of 16 to write informed consent.

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Additional file 1: supp. figure 1..

△ 1HtSDS (i.e., FAH SDS minus baseline height SDS) in each group.

Additional file 2: Supp. Figure 2.

Comparisons of FAH SDS and TH SDS among girls in the pooled group with FAH SDS > − 2 SD.

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Wu, D., Chen, Rm., Chen, Sk. et al. Final adult height of children with idiopathic short stature: a multicenter study on GH therapy alone started during peri-puberty. BMC Pediatr 20 , 138 (2020). https://doi.org/10.1186/s12887-020-02034-8

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DOI : https://doi.org/10.1186/s12887-020-02034-8

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• Published: 04 November 2021

Short stature is associated with low flow-mediated vasodilation in Japanese men

• Takahiro Harada 1 ,
• Masato Kajikawa 2 ,
• Tatsuya Maruhashi 3 ,
• Shinji Kishimoto 3 ,
• Takayuki Yamaji 1 ,
• Yiming Han 3 ,
• Aya Mizobuchi 3 ,
• Yu Hashimoto 1 ,
• Kenichi Yoshimura 2 ,
• Yukiko Nakano 1 ,
• Kazuaki Chayama 4 ,
• Chikara Goto 5 ,
• Farina Mohamad Yusoff 3 ,
• Ayumu Nakashima 6 &
• Yukihito Higashi 2 , 3  

Hypertension Research volume  45 ,  pages 308–314 ( 2022 ) Cite this article

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A Comment to this article was published on 07 December 2021

An inverse association between height and the risk of cardiovascular disease has been reported. The objective of this study was to examine the association between height and endothelial function assessed by flow-mediated vasodilation (FMD). We evaluated cross-sectional associations of height with FMD in 7682 Japanese men. All participants were divided into four groups based on height: <155.0 cm, 155.0–164.9 cm, 165.0–174.9 cm, and ≥175.0 cm. Subjects in a lower quartile of FMD were defined as subjects having low FMD values. Univariate regression analysis revealed that height was significantly correlated with FMD ( r  = 0.14, p  < 0.001). FMD values were 4.6 ± 3.1% in the <155.0 cm group, 5.2 ± 3.1% in the 155.0–164.9 cm group, 5.7 ± 3.1% in the 165.0–174.9 cm group and 6.1 ± 3.2% in the ≥175.0 cm group. FMD significantly increased in relation to an increase in height. Multiple logistic regression analysis revealed that higher height groups were significantly associated with a decreased risk of low FMD value compared with the <155.0 cm group after adjustments for age, presence of hypertension, dyslipidemia, diabetes, current smoking, and brachial artery diameter. FMD was low in subjects with a short stature compared with that in subjects with tall stature. Individuals with a short stature may require intensive interventions to reduce the risk of cardiovascular events.

Clinical Trial Registration Information: URL for Clinical Trials: http://www.umin.ac.jp Registration Number for Clinical Trials: UMIN000012952.

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Acknowledgements

The authors would like to thank all of the patients who participated in this study. In addition, we thank Miki Kumiji, Megumi Wakisaka, Ki-ichiro Kawano and Satoko Michiyama for their excellent secretarial assistance; FMD-J investigators Takayuki Hidaka, MD, PhD; Shuji Nakamura, MD, PhD; Junko Soga, MD, PhD; Yuichi Fujii, MD, PhD; Naomi Idei, MD; Noritaka Fujimura, MD, PhD; Shinsuke Mikami, MD, PhD; Yumiko Iwamoto, MD; Akimichi Iwamoto, MD, PhD; Takeshi Matsumoto, MD, PhD; Nozomu Oda, MD, PhD (Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan); Kana Kanai, PhD; Haruka Morimoto, PhD (Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan); Tomohisa Sakashita, MD, PhD; Yoshiki Kudo, MD, PhD (Department of Obstetrics and Gynecology, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan); Taijiro Sueda, MD, PhD (Department of Surgery, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan); Hirofumi Tomiyama, MD, PhD, FAHA; Akira Yamashina, MD, PhD (Department of Cardiology, Tokyo Medical University, Tokyo, Japan); Bonpei Takase, MD, PhD, FAHA (Division of Biomedical Engineering, National Defense Medical College Research Institute, Tokorozawa, Japan); Takahide Kohro, MD, PhD (Department of Cardiology, Tokyo Medical University, Tokyo, Japan); Toru Suzuki, MD, PhD (Cardiovascular Medicine, University of Leicester, Leicester, UK); Tomoko Ishizu, MD, PhD (Cardiovascular Division, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan); Shinichiro Ueda, MD, PhD (Department of Clinical Pharmacology and Therapeutics, University of the Ryukyu School of Medicine, Okinawa, Japan); Tsutomu Yamazaki, MD, PhD (Clinical Research Support Center, Faculty of Medicine, The University of Tokyo, Tokyo, Japan); Tomoo Furumoto, MD, PhD (Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Hokkaido, Japan); Kazuomi Kario, MD, PhD (Division of Cardiovascular Medicine, Jichi Medical University School of Medicine, Tochigi, Japan); Teruo Inoue, MD, PhD (Department of Cardiovascular Medicine, Dokkyo Medical University, Mibu, Tochigi, Japan); Shinji Koba, MD, PhD (Department of Medicine, Division of Cardiology, Showa University School of Medicine, Tokyo, Japan); Kentaro Watanabe, MD, PhD (Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology (DNHMED), Yamagata University School of Medicine, Yamagata, Japan); Yasuhiko Takemoto, MD, PhD (Department of Internal Medicine and Cardiology, Osaka City University Graduate School of Medicine, Osaka, Japan); Takuzo Hano, MD, PhD (Department of Medical Education and Population-based Medicine, Postgraduate School of Medicine, Wakayama Medical University, Wakayama, Japan); Masataka Sata, MD, PhD (Department of Cardiovascular Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan); Yutaka Ishibashi, MD, PhD (Department of General Medicine, Shimane University Faculty of Medicine, Izumo, Japan); Koichi Node, MD, PhD (Department of Cardiovascular and Renal Medicine, Saga University, Saga, Japan); Koji Maemura, MD, PhD (Department of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan); Yusuke Ohya, MD, PhD (The Third Department of Internal Medicine, University of the Ryukyus, Okinawa, Japan); Taiji Furukawa, MD, PhD (Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan); Hiroshi Ito, MD, PhD (Department of Cardiovascular Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan); and Hisao Ikeda, MD, PhD (Faculty of Fukuoka Medical Technology, Teikyo University, Omuta, Japan).

This work was supported by JSPS KAKENHI (Grant Numbers 18590815 and 21590898 to YH and JP19K17599 to MK) and a Grant in Aid of Japanese Arteriosclerosis Prevention Fund (to YH).

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Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

Takahiro Harada, Takayuki Yamaji, Yu Hashimoto & Yukiko Nakano

Division of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan

Masato Kajikawa, Kenichi Yoshimura & Yukihito Higashi

Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

Tatsuya Maruhashi, Shinji Kishimoto, Yiming Han, Aya Mizobuchi, Farina Mohamad Yusoff & Yukihito Higashi

Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

Kazuaki Chayama

Department of Rehabilitation, Faculty of General Rehabilitation, Hiroshima International University, Hiroshima, Japan

Chikara Goto

Department of Stem Cell Biology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

Ayumu Nakashima

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The study was designed by TH, MK, and YH. Data correction was conducted by TH, TY, YH, MK, CG. YH, AM, FMY, SK, TM, and AN. Data analysis and interpretation were conducted by YN, KY, and KC. Manuscript was written and approved by all authors.

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Correspondence to Yukihito Higashi .

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Harada, T., Kajikawa, M., Maruhashi, T. et al. Short stature is associated with low flow-mediated vasodilation in Japanese men. Hypertens Res 45 , 308–314 (2022). https://doi.org/10.1038/s41440-021-00785-0

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Received : 29 July 2021

Revised : 02 September 2021

Accepted : 10 September 2021

Published : 04 November 2021

Issue Date : February 2022

DOI : https://doi.org/10.1038/s41440-021-00785-0

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• v.25(5); Sep-Oct 2021

Readdressing Short Stature in India: The “Long and the Short” of it

Kv raviteja.

Department of Endocrinology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

Bhanu Malhotra

Raman k. marwaha.

1 Department of Endocrinology, International Life Sciences Institute, New Delhi, India

Pinaki Dutta

Stature is one of the widely used indices of overall health and well-being in children. Short stature (SS) can be defined either on the basis of comparison with the normal population (less than 2 SD or the 3 rd centile) or with respect to the genetic potential (derived from parental stature) of a given individual. Deviation from standard height percentiles using calculated height velocity is one of the earliest indicators of short stature, irrespective of etiology. SS evaluation is one of the most comprehensive assessments in endocrinology and entails detailed history, physical examination, and biochemical, hormonal, radiological investigations, and genetic testing when indicated. It is also the clinical situation with multiple dilemmas, bearing in mind that 25% to 90% of children referred for short stature are not actually short, reassurance is the treatment of choice in nearly half the cases, and the limited scope of the use of growth hormone (GH) therapy in idiopathic short stature (ISS), Turner syndrome (TS), and skeletal dysplasias.[ 1 , 2 ]

SS is broadly divided into normal variant short stature (NVSS) (which includes constitutional delay of growth and puberty (CDGP) and familial short stature (FSS)) or pathological short stature (causes include endocrine, syndromic, or chronic-disease related). However, FSS is increasingly being classified as a pathological variant with the recognition of hitherto undiagnosed genetic conditions such as GH resistance (GHR), collagenopathies, RASopathies, and aggrecan gene mutations.[ 3 ] RASopathies denote developmental syndromes occurring due to germline mutations in the Ras–RAF–MEK–ERK/mitogen-activated protein kinase signaling pathway and include Noonan, Leopard, and the cardio-facio-cutaneous syndromes.[ 4 ] Aggrecan is a proteoglycan constituent of the growth plate cartilage and mutations in it have been found to be the underlying cause in a proportion of patients with FSS.[ 5 ] Current understanding implicates growth plate chondrocytes as one of the central parameters of both normal growth and normal variations of growth at the intraindividual (pubertal growth spurt) and interindividual (varied normal height in the population) levels. However, there is a lack of evidence on the trends in the etiological spectrum of SS across nationwide studies. Dynamicity in the prevalence and patterns of SS is expected, considering the change in nutritional status, recognition of endocrine causes in primary care settings as well as increasing focus on identifying genetic causes of underlying growth hormone deficiency (GHD) and/or hypopituitarism. Furthermore, whether the age of identification and diagnosis of SS is decreasing, suggesting improved surveillance or awareness of this chronic problem, remains unexplored.

Studies reporting the etiology of SS in community or outpatient settings in India were analyzed and stratified on the basis of duration of study and date of publication. There were four studies in the second decade of the twenty-first century, including our unpublished survey in 2191 school children in the community,[ 6 , 7 , 8 ] and two major studies in the first decade.[ 9 , 10 ] NVSS accounted for the most number of cases of SS. Hypothyroidism was the most common endocrine cause of SS and the second most common cause overall. This evidence was consistent, irrespective of the geographical location (north and south of the country) of the participants. On the other hand, there was a discrepancy in contemporary reports from north India itself, with one study reporting skeletal dysplasia as the most common etiology of SS, followed by ISS and TS in their cohort. The variance, despite a similar time frame and similar geographic location, is intriguing but may be indicative of the settings of the study (genetic referral clinic).[ 8 ]

Nationwide trends revealed a greater preponderance of pathological SS in the first decade of the twenty-first century, which has transitioned to NVSS over the second decade. The earlier predominance of pathological SS was uniform, irrespective of consecutive admissions or referral for SS.[ 11 ] This shift may possibly be due to increased awareness and access to health care, improved trends in nutrition as well as early diagnosis and management of chronic diseases and endocrinological conditions which are implicated in SS. The overall prevalence of hypopituitarism including GHD has seemingly halved with time, from 22.6% in the twentieth century to under 10% in more recent studies, but there are/is no similar evidence available for Turner's syndrome.[ 9 , 10 ] Pathological SS is expected to be more discernible owing to greater deviations of height from the normal or clinical features associated with the primary condition (systemic or syndromic disease or hormonal cause). Hence, improved knowledge about the problem may be one of the contributors to this transition. Inherent differences between community-based and clinic-based assessments are expected owing to referral bias, as children with greater severity of SS and pathologic causes are more likely to present in hospital settings. Etiological differences may also mirror the socio-economic and literacy status of the community as malnutrition and chronic diseases are more likely to affect children from the lower strata of society. This impact of nutrition on stature is well-evidenced by the fact that the earlier reported entity of GHR, of which poor nutritional status is a cause, is virtually absent from recent studies.[ 10 , 12 ] Interestingly, the prevalence of SS has remained virtually unchanged over the past two decades in India (varying from 2.8% to 3.7%). Furthermore, the variability in growth charts between different studies has not posed a significant effect on the overall prevalence of SS. Despite this reassuring data suggesting a transition to a predominantly physiological etiology of SS, the higher age at presentation in some reports is a cause of concern.[ 7 ]

The authors performed the largest community-based study in the country to generate normative reference range intervals for IGF-1. In this study, stature was assessed among other anthropometric parameters in healthy school-going children in the community between the ages of 5 and 18 years. The final enrolment was 2191 children, with 47.92% (n = 1050) girls. We found a 2.42% (n = 53) prevalence of short stature, as defined by height < 3rd centile on the revised Indian Academy of Pediatrics (IAP) growth charts,[ 13 ] and the mean age of diagnosis of SS was 11.8 ± 4.5 years. Based on gender, the prevalence of SS was 2.54% (n = 28) in boys at a mean age of 10.5 ± 4.4 years and 2.38% (n = 25) in girls at a mean age of 13.3 ± 4.2 years. In this SS cohort, low weight (60.7%) and normal weight (39.3%) was noted in boys, but in girls, the major proportion (72%) was constituted by normal-weight individuals. Prepubertal status was present in 58.6% of the boys and 20.8% of the girls. On analyzing the causes, CDGP was present in 28% of the boys irrespective of the chart used to compute bone age (Greulich Pyle (GP) or Tanner Whitehouse (TW) charts), but the prevalence was 12% in girls when using GP charts and 16% when using TW charts. Familial short stature (FSS) was present in a higher proportion in boys (25%) than in girls with SS (20%) when using the IAP criteria and 14.2% and 8% in boys and girls, respectively, when using the National Institute of Nutrition (NIN) criteria.[ 14 ] Among pathological causes of SS, hypothyroidism was more common in girls (16%) than boys (10.7%). The overall prevalence of celiac disease in the study (defined by IgA anti-TTG) was 1.55% (n = 34), but there were no cases among children with SS. This was most likely attributable to the early pick-up/detection as they were identified in the presymptomatic phase. It may also be due to the fact that the prevalence of the coeliac disease is higher in hospital settings as children with gastrointestinal symptoms or anemia are more likely to seek consultation than in community settings where asymptomatic individuals are much more likely. Its controversial to comment so early as the IGF-1 values mismatch yet to be sorted out soon

Our study provides interesting insights into the transition in the profile and etiology of SS, which is possibly reminiscent of an upsurge in economy, education, and access to basic health care in the country. Though the prevalence of SS has remained reasonably stable, it is the metamorphosis in the etiological profile that deserves attention. The gender difference between the age of SS in the community is also intriguing, with girls getting diagnosed at a more advanced chronological age than boys, probably reflecting the social fabric in the community. Prior studies conducted in hospital settings from the north reported a relative preponderance of celiac disease, also presenting with SS as a monosymptomatic presentation. The current report of almost similar overall prevalence of celiac disease, but none of them having SS probably points towards early detection or asymptomatic seropositivity, thereby averting long-term complications such as SS in these children. Among endocrine conditions, the prevalence of hypothyroidism has remained unchanged with time. Community-based data such as ours are the true indicators of the burden of the insidious problem of SS and have furnished contemporary evidence on the prevalence and etiological spectrum of SS.

Stature being a continuous accrual and cumulative phenomenon is usually diagnosed later than sooner. One of the early clues for the diagnosis of short stature is a derailment of height velocity, which can be easily obtained from regular anthropometric evaluations in school records. Encouraging and educating schools, institutions, vaccine centers, and primary health care providers about the importance of at least annual anthropometry is another area that may aid in timely diagnosis and referral to tertiary care centers. Furthermore, in children with chronic disease of any etiology, referral to the endocrinologist for further evaluation and ruling out concurrent treatable hormone deficiency such as hypothyroidism, growth hormone deficiency or resistance, can improve final adult height. National policies to target screening for childhood stunting in identified high-risk areas can also be employed.

The study received funding from the Endocrine Society of India (ESI) and Society of Endocrine Health Care for Elderly Adolescents and Children (SEHEAC).

Conflicts of interest

There are no conflicts of interest.

R EFERRENCES