List of Abbreviations
ICP – intracranial pressure
IUGR – intrauterine growth restriction
ISS – idiopathic short stature
IGF-1 – insulin-like growth factor I
MRI – magnetic resonance imaging
FT4 – free thyroxine
GH – growth hormone
TSH – thyroid-stimulating hormone
IRI – immunoreactive insulin
HbA1c – glycated hemoglobin
SD (standard deviation) – standard deviation
SDS (standard deviation score) – standard deviation score
Terms and Definitions
Short stature – height below the 3rd percentile (height SDS less than -2) for the corresponding age and sex.
Growth rate – absolute change in body length over time (most often calculated per 1 year).
Idiopathic growth delay – a condition characterized by short stature (height SDS less than -2 or below the 3rd percentile) for the corresponding sex and age, in which known causes of short stature are excluded.
SDS (standard deviation score) – standard deviation score – an integral indicator used to assess how well a child's individual height matches reference values for the corresponding age and sex. The SDS shows how many standard (sigma) deviations the difference between the mean normal and measured values represents.
Bone age – a criterion of biological maturity of the organism, determined by the degree of skeletal ossification.
Pubertal status – the presence and stage of development of secondary sexual characteristics at the time of the child's examination.
Puberty – a transitional period between childhood and sexual maturity, a process of physical, hormonal, physiological, and psychological changes in an adolescent's body that promote the development of secondary sexual characteristics and lead to individual reproductive maturity.
Body mass index (BMI) – a value used to assess the degree of correspondence between body weight and height. Calculated by the formula: (BMI = weight (kg)) ⁄ height (m)2.
1. Brief information on the disease or condition
1.1 Definition of the disease or condition
Idiopathic growth delay [ICD code E34.3] – a condition characterized by short stature (height SDS less than -2 or below the 3rd percentile) for the corresponding sex and age, with all known causes of short stature excluded [1].
Criteria for idiopathic short stature:
normal birth length and weight of the child;
absence of body proportions disproportions;
absence of chronic somatic diseases (cardiac, renal, or other organ disorders) in the stage of decompensation;
absence of psycho-emotional (stress) factors;
absence of nutritional factors;
absence of endocrinopathies, including growth hormone deficiency.
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
The very term "idiopathic" indicates that the cause of the pathology is unknown. Therefore, the term "idiopathic short stature" (ISS) includes both unrecognized pathology (endocrine disorders, syndromic and bone disorders, consequences of malnutrition, psychological or psychiatric disorders, etc.) and variants of normal development. ISS represents a heterogeneous group of short children with high genetic and phenotypic variability. Short stature may be caused by the influence of genetic and epigenetic factors, as well as environmental factors. According to various studies, including those using genetic technologies, about 25 – 49% of children diagnosed with "idiopathic short stature" have genetic disorders. The most common are gene mutations: SHOX, ACAN, NPR2, as well as genetic defects in genes of the growth hormone-insulin-like growth factor 1 (GH-IGF-1) axis system [2,3].
Syndromic growth delay is an inherent component of over 2,000 different syndromes. Turner syndrome is the most common (1:2,500–3,000 live-born girls), caused by structural anomalies of the X chromosome. Noonan syndrome occurs with equal frequency in children of both sexes (1:1,000–2,000) and is characterized by a normal karyotype (both sporadic and familial variants are possible). Clinical manifestations of Noonan syndrome depend on the genetic nature of the disease; forme fruste variants are frequent, in which growth delay is regarded as a variant of ISS. In such cases, in-depth hormonal and molecular-genetic studies are required [4].
In international and domestic pediatric practice, several other names belonging to this category are also used: constitutional growth delay, constitutional short stature, constitutional delay of growth and puberty, normal variant short stature, familial short stature, familial delay of growth and puberty, etc. [2,3,5].
The diagnosis of "idiopathic short stature" is valid until the cause of the observed growth disorders is identified. Once the cause is established, this diagnosis is no longer applied.
1.3 Epidemiology of the Disease or Condition
From a statistical standpoint, height is characterized by a normal distribution among the population; based on this, about 2% of the population in the general population are short. In most cases (60–80%), the cause of short stature remains unknown, which is why ISS is diagnosed [1,3]. Only in 3.0–5.0% of cases in short children with height indicators below the third percentile is it possible to detect endocrine disorders, such as GH deficiency, hypothyroidism, hypercortisolism, etc., or syndromic pathology. In 9.5% of cases, the cause of short stature is other factors (malnutrition, psychological or psychiatric disorders, etc.), and in 15%, reduced birth weight and length indicators are detected [6].
1.4 Features of Coding the Disease or Condition
ICD E34.3 – Short stature [dwarfism], not elsewhere classified.
1.5 Classification of the disease or condition
In accordance with the classification adopted by the European Society for Paediatric Endocrinology (ESPE) in 2007 and approved for use by the International Consensus in 2008, two forms of idiopathic short stature are distinguished: familial and non-familial. In the familial form, the child is short compared to the corresponding sex and age, but remains within the mid-parental height range. In the non-familial form, the child is short compared to the corresponding sex and age, as well as compared to their parents: their height SDS upon examination is significantly (by 2 SD (standard deviation) or more) lower than the mid-parental height SDS [1,7].
After 13 years for girls and 14 years for boys, both forms are subdivided into short stature with or without delayed puberty. Delayed puberty is diagnosed in girls at 13 years if there is no breast development; in boys at 14 years if testicular volume is less than 4 ml. Non-familial short stature with delayed puberty is also called constitutional delay of growth and puberty [1,7].
Classification of ISS [1]:
a) Familial short stature:
- with delayed puberty;
- without delayed puberty.
b) Non-familial short stature:
- with delayed puberty (constitutional delay of growth and puberty);
- without delayed puberty.
Parental height is used as a distinguishing criterion. For this, the mid-parental (genetically predicted) height is calculated using the Tanner formula:
The limits of mid-parental height may vary within ± 10 cm for boys and within ± 7 cm for girls.
Comments: short stature can be defined as familial if the child's height corresponds to the mid-parental height in the presence of at least one short relative, even if this relative is not a parent of the child (uncles, aunts, grandfathers, grandmothers). Men under 163 cm and women under 150 cm are considered short.
1.6 Clinical presentation of the disease or condition
Idiopathic short stature is characterized by a child's short stature with normal body proportions and the absence of identified pathology as its possible cause, while the child's height SDS is -2 or lower compared to the average height indicators for children of this age and sex. In addition, the growth rate is reduced to -2 SDS or less during one year of observation compared to the population mean for the corresponding chronological age and sex; OR the growth rate is less than -1.5 SD during two years of observation compared to the population mean for the corresponding chronological age and sex [8-12].
Comments: growth rate analysis makes it possible to identify the first signs of growth retardation. To assess the growth rate, data from at least two accurate measurements must be available. To minimize calculation errors, it is preferable that the interval between measurements is at least 6 months [12–14].
SDS (Standard Deviation Score) is an integral indicator used to assess the conformity of a child's individual anthropometric parameter with reference data for the corresponding age and sex. SDS indicates how many standard (sigma) deviations (SD) the difference between the arithmetic mean and the measured value constitutes [12,14].
SDS = (x – X)/SD, where
x is the individual anthropometric parameter of the child (height, growth velocity, body weight, etc.),
X is the mean corresponding parameter for a given chronological age and sex,
SD is the standard deviation of the parameter for a given chronological age and sex,
SDS = –2 SD corresponds to the 3rd percentile,
SDS = 0 corresponds to the 50th percentile,
SDS = +2 SD corresponds to the 97th percentile.
2. Diagnostics, medical indications and contraindications for diagnostic methods
Idiopathic short stature is a diagnosis of exclusion. Once a specific cause of growth retardation is established, the diagnosis of “idiopathic short stature” is no longer applied.
Criteria for establishing the diagnosis/condition:
1) anamnesis data,
2) results of physical examination, including anthropometry,
3) laboratory test data,
4) results of instrumental examination.
The algorithm for diagnosing idiopathic short stature is presented in Appendix B.
2.1 Complaints and Anamnesis
Assessment of the health status and anthropometric data of any child with short stature should begin with a thorough collection of anamnesis (history of life, family history, history of present illness). Taking the history of the present illness is important for understanding the potential etiology of growth retardation and correctly interpreting the clinical picture at the time of examination.
It is recommended to analyze the anamnestic data of a child with suspected ISS: features of the course of pregnancy and childbirth (e.g., infectious diseases suffered by the mother during pregnancy, hypertension, drug treatment, etc.), the child's condition at birth according to the Apgar score, the presence of postpartum complications, etc., as well as data on birth weight and length (in accordance with gestational age and sex) during the initial consultation/examination of a child with suspected ISS for the purpose of differential diagnosis of ISS and growth retardation due to IUGR (intrauterine growth restriction) [15,16].
(Level of Evidence C, Grade of Recommendation 5)
It is recommended to analyze the anamnestic data of a child with suspected ISS: the presence of severe malformations and chronic diseases (e.g., chronic renal failure, chronic gastrointestinal diseases leading to malabsorption, celiac disease, central nervous system, blood, or liver diseases, cardiovascular and bronchopulmonary malformations, systemic inflammatory diseases, etc.) for the purpose of differential diagnosis of ISS and somatogenic growth retardation [1,5,16,17].
(Level of Evidence C, Grade of Recommendation 5)
It is recommended to determine (by collecting anamnesis and analyzing medical documentation) the age of onset of growth lag (decrease in growth rate) in a child with suspected ISS for the purpose of differential diagnosis of ISS with growth retardation due to IUGR, syndromic short stature, and somatogenic growth retardation [1,5,13,15,16].
(Level of Evidence C, Grade of Recommendation 5)
It is recommended to assess the psychoemotional state of a child with suspected ISS, which can be judged by their sociability, degree of socialization, academic performance, parents' involvement in their life, etc., for the purpose of differential diagnosis of ISS with growth retardation caused by deprivation or psychosocial reasons [17–19].
(Level of Evidence C, Grade of Recommendation 5)
It is recommended to analyze the family history of a patient with suspected ISS: height of the mother and father (if possible - measured during the examination), calculation of mid-parental height [13,14]; timing of puberty in parents and close relatives (menarche in women, appearance of body hair, growth spurt, age of final height achievement, etc.); presence of short relatives (especially with a height of –2 SDS and below) and features of their phenotype (this may require studying family photos); and also ascertaining the presence of consanguineous marriages in order to exclude bone dysplasias, hereditary diseases, and syndromes associated with short stature [9,12,20].
(Level of Evidence C, Grade of Recommendation 5)
Comments: in a number of cases, in parents (more often in men) of children with ISS, a similar developmental variant can be detected: short stature from 2 years of age just below the 3rd percentile throughout childhood, later onset of puberty (lagging behind peers by 2–4 years), and postponed growth spurt with the achievement of normal final height.
2.2 Physical Examination
Like all stages of examining a child, the physical examination is aimed at identifying the cause of short stature, first of all, measuring and analyzing anthropometric parameters.
It is recommended to mandatory carry out anthropometric measurements (body length/height, sitting height, body weight, BMI), calculate height SDS, growth velocity, growth velocity SDS, and body mass index SDS, and mandatory plot individual growth charts for children with suspected ISS in order to detect short stature, assess its severity, and determine growth dynamics [9,12,14].
(Level of Evidence C, Grade of Recommendation 5)
Comments. In children under 2 years of age, height is measured in the supine position. In case of measuring height in the standing position, 0.7 cm must be added to the obtained value.
In children older than 2 years, height is measured in the standing position. If this procedure is not feasible, height is measured in the supine position, and 0.7 cm must be subtracted from the obtained value.
Percentile tables are used to plot the individual growth chart (Appendix A3).
Growth velocity and growth velocity SDS are most informative in prepubertal children. In children older than 10–11 years, the assessment of these parameters may be associated with significant errors due to the rapid dynamics of growth velocity at this age and the varying timing of puberty onset [14].
Idiopathic short stature is diagnosed when a child's height is below –2 SD, in the absence of another identified cause of short stature [1,2,8–12].
It is recommended to examine a child with suspected ISS when the height SDS value is greater than –2 (i.e., in the absence of significant growth retardation), but with a growth velocity of –2 SDS or less for 1 year compared to the population mean for the corresponding chronological age and sex; OR with a growth velocity of –1.5 SDS or less for two years compared to the population mean for the corresponding chronological age and sex. Growth dynamics should be assessed by an endocrinologist/pediatrician using the same calibrated stadiometer, with a time interval between measurements of at least six months [13].
(Level of Evidence C, Grade of Recommendation 5)
It is recommended to calculate the ratio of the "upper" and "lower body segments" in children with suspected ISS and compare it with the standards for the corresponding sex and age in order to identify disproportionate physique typical of chondrodysplasias and certain variants of syndromic short stature [1,12,14,16,21].
(Level of Evidence C, Grade of Recommendation 5)
Comments: calculation of the "lower segment" = standing height – sitting height.
Body proportionality is assessed for the differential diagnosis of various forms of skeletal dysplasias. Measuring the upper-to-lower body segment ratio, a small arm span, or short forearms allows for the suspicion of a number of conditions, including those due to SHOX gene haploinsufficiency (Turner and Leri-Weill syndromes), but can also occur in 16% of children with short stature [8,21]. Normal body segment ratio values are presented in Appendix A3, Table 1. With a proportional physique, the arm span equals the height.
It is recommended to search for dysmorphic features in children with suspected ISS in order to exclude congenital syndromes and bone dysplasias (hypochondroplasia, spondyloepiphyseal dysplasia, etc.) associated with short stature [16,22].
(Level of Evidence C, Grade of Recommendation 5)
It is recommended to assess sexual status (pubertal stages) in children with suspected ISS in order to exclude disorders of sex development (e.g., gonadal dysgenesis) and delayed puberty within the framework of constitutional delay of growth and puberty [23,24].
(Level of Evidence C, Grade of Recommendation 5)
It is recommended to assess the psychological status of children with suspected ISS in order to detect deprivation or psychosocial growth retardation [17–19].
(Level of Evidence C, Grade of Recommendation 5)
2.3 Laboratory Diagnostics
It is recommended to perform a complete blood count, urinalysis, general general-clinical blood chemistry test (study of creatinine, urea, total protein, ionized calcium, inorganic phosphorus, total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase levels in the blood), and determine the levels of antibodies to gliadin (AGA-IgA) and tissue transglutaminase in the blood (IgA anti-tTG) in children with suspected ISS to exclude somatic pathology that could be the cause of short stature [1,6,9,12,53].
(Level of Evidence C, Grade of Recommendation 5)
Comments: recommended laboratory tests are presented in Appendix A3, tab. 2.
It is recommended to test serum levels of thyroid-stimulating hormone (TSH) and free thyroxine (fT4) in children with suspected short stature to rule out hypothyroidism as a cause of short stature [9,25,26].
(Level of Evidence C, Grade of Recommendation 5)
It is recommended to measure blood levels of insulin-like growth factor 1 (IGF-1) [27–29], as well as growth hormone (GH) levels during GH stimulation tests in children with suspected short stature to rule out growth hormone deficiency in accordance with the current National Consensus on the Diagnosis of GH Deficiency and the collection of guidelines "Federal Clinical Guidelines for the Diagnosis and Treatment of Hypopituitarism in Children and Adolescents" [20].
(Level of Evidence C, Grade of Recommendation 5)
Comments: GH stimulation tests are performed to rule out growth hormone deficiency in accordance with the Russian National Consensus on the Diagnosis and Treatment of Hypopituitarism in Children and Adolescents and the collection "Federal Clinical Guidelines for the Diagnosis and Treatment of Hypopituitarism in Children and Adolescents". If a normal GH peak is observed in a single test, a second test is not required, and the diagnosis of GH deficiency is ruled out [20].
IGF-1 is an important parameter in the evaluation of any child with short stature. However, its level depends on the child's age, sex, nutrition, thyroid status, pubertal status, and the presence of endocrine (e.g., diabetes mellitus) and somatic (e.g., liver and kidney disorders) diseases. IGF-1 is reduced in 25–50% of children with short stature. A normal IGF-1 level calls into question but does not rule out GH deficiency. IGF-1 measurement is also necessary during somatotropin** therapy to assess patient compliance and sensitivity to growth hormone, as well as to monitor treatment safety.
2.4 Instrumental Diagnostics
Bone age determination is important both for diagnosis, dynamic monitoring during treatment, and final adult height prediction. Bone age makes it possible to assess the child's remaining growth potential. The height percentile corresponding to the bone age assessment roughly corresponds to the final height percentile.
It is recommended to perform a posteroanterior radiograph of the wrist in children with suspected short stature to assess bone age and predict final height [1,3,5].
(Level of Evidence C, Grade of Recommendation 5)
Comments: Bone age is usually determined using the Greulich-Pyle method with a radiological atlas (W. Greulich, S. Pyle, 1959) or the Tanner-Whitehouse method (TW2) [1,3,5,54]. In short stature, bone age typically lags behind chronological age by an average of 1.5–2 years (ranging from 0 to 4 years) in the prepubertal period, and the degree of its delay correlates with the severity of height deficit [30–33].
If bone deformations are detected on radiographs (e.g., Madelung deformity, brachydactyly, shortening of metacarpal bones, etc.), further evaluation is required to identify chondrodysplasias, rickets-like disorders, SHOX gene pathology, pseudohypoparathyroidism, etc. [3,34].
Prediction of final adult height is calculated using the Bayley-Pinneau (BP) and Tanner-Whitehouse (TW) methods.
It is recommended to assess the ratio of bone age to chronological age (BA/CA) in children with short stature receiving growth hormone therapy in order to monitor skeletal maturation rates and timely predict the risk of premature epiphyseal fusion, which can lead to a decrease in the final height prognosis [39].
(Level of Evidence C, Grade of Recommendation 5)
Comments: The BA/CA ratio is a critical indicator of the "biological cost" of height gain. Normally, during treatment, this index should approach 1.0. Acceleration of skeletal maturation (BA/CA > 1.0) indicates an excessive drug dose or the onset of precocious puberty, which shortens the time window for therapy [39].
As an alternative method for assessing treatment efficacy, height SDS for chronological age (SDS CA) and height SDS for bone age (SDS BA), along with their ratio, can be used. Height SDS for bone age is a key indicator for preserving growth potential: normally, under effective treatment, height SDS for chronological age should increase (Δ SDS CA > 0), while height SDS for bone age should remain stable or increase.
A decrease in height SDS for bone age during therapy may indicate excessive acceleration of skeletal maturation (ossification outpacing linear growth), which potentially leads to premature closure of growth plates and a reduced final height prognosis. Calculating this ratio allows the physician to timely identify cases of inappropriate dose selection or the development of precocious puberty during treatment [39,53].
It is not recommended to perform brain magnetic resonance imaging in short children for the diagnosis of short stature [1,3,5].
(Level of Evidence C, Grade of Recommendation 5)
It is recommended to perform brain magnetic resonance imaging in children with short stature prior to initiating somatotropin** therapy [1,3,5].
(Level of Evidence C, Grade of Recommendation 5)
Comments: There is no compelling evidence necessitating brain magnetic resonance imaging in the diagnosis of short stature; according to international consensuses, this study is not required for short stature.
2.5 Other Procedures
It is recommended to perform a cytogenetic study (karyotyping) in all girls with short stature, regardless of the presence or absence of phenotypic features of Turner syndrome, to rule out this pathology [1,5,9,12,13,53].
(Level of Evidence C, Grade of Recommendation 5)
Molecular genetic testing
Over the past decade, the development of sequencing technologies has significantly expanded the possibilities for identifying the genetic etiology of short stature [53]. The diagnostic yield of genetic testing in unexplained short stature varies depending on the patient's phenotype and the methodology used. Specifically, the diagnostic yield of exome sequencing (ES) is 15.1% in children with isolated short stature, 50.8% in syndromic forms, and reaches 69.8% in patients with clinical signs of skeletal dysplasias [53].
It is recommended to perform genetic testing in a child with short stature if the evaluation reveals any of the following features: severe short stature (height < -3 SDS); microcephaly; macrocephaly (absolute or relative); or body disproportion (sitting height-to-height ratio or arm span-to-height ratio exceeding ± 2.5 SDS) [53].
(Level of Evidence C, Grade of Recommendation 5)
It is recommended to perform genetic testing in short children with clinical signs indicating concomitant syndromic pathology [53].
(Level of Evidence C, Grade of Recommendation 5)
It is recommended to perform genetic testing in a short child presenting with major malformations and/or neurodevelopmental disorders [53].
(Level of Evidence C, Grade of Recommendation 5)
It is recommended to perform genetic testing in a child with short stature who has clinical or radiological skeletal anomalies [53].
(Level of Evidence C, Grade of Recommendation 5)
It is recommended to perform genetic testing in a child with short stature if the family history indicates an autosomal dominant, autosomal recessive, X-linked, or mitochondrial inheritance pattern, or if the child's height SDS is significantly lower than that of both parents [53].
(Level of Evidence C, Grade of Recommendation 5)
It is recommended to conduct a thorough clinical evaluation for imprinting disorders followed by specific DNA methylation testing (if suspected) in children born small for gestational age (SGA) with persistent isolated or non-isolated short stature of undetermined etiology [53].
(Level of Evidence C, Grade of Recommendation 5)
It is recommended to perform comprehensive genetic testing for children with SGA status (with persistent short stature of undetermined etiology) for diagnostic purposes and to identify rare genetic conditions where recombinant growth hormone therapy is contraindicated, if such treatment is being considered [53].
(Level of Evidence C, Grade of Recommendation 5)
It is recommended to perform genetic testing using next-generation sequencing methods (exome/genome or targeted gene panel) in a short child with severe growth hormone deficiency and/or anatomical abnormalities of the hypothalamo-pituitary region associated with genetic causes [53].
(Level of Evidence C, Grade of Recommendation 5)
It is recommended to use a targeted gene panel or first-line candidate gene sequencing in a short child with characteristic clinical and laboratory signs of growth hormone (GH) or IGF-1 insensitivity [53].
(Level of Evidence C, Grade of Recommendation 5)
It is not recommended to perform genetic testing (aside from basic laboratory screening, including karyotype/Turner syndrome testing in girls) in a child with isolated short stature suspected of having constitutional delay of growth and puberty (CDGP) or in cases of well-founded suspicion of a polygenic etiology of short stature [53].
(Level of Evidence C, Grade of Recommendation 5)
Comments: prior to initiating genetic testing, the potential benefits and risks of testing should be thoroughly discussed with the family on an individual basis. Close collaboration between clinical laboratory geneticists, medical geneticists, and pediatric endocrinologists is recommended when determining indications for genetic tests and interpreting their results. Genetic counseling is recommended for every family undergoing genetic testing [53]. If new clinical signs appear in a patient, available genetic data should be re-analyzed. In children with persistent short stature of unclear etiology who have previously undergone genetic testing, it is recommended to periodically consider re-analyzing genetic data, taking into account improvements in bioinformatics and new genetic discoveries [53].
3. Treatment, including drug and non-drug therapies, diet therapy, and pain management
3.1 Conservative Treatment
Dynamic observation of children with ISS is recommended as an acceptable management approach [35,36].
(Level of Evidence C, Grade of Recommendation 5)
Comments: the absence of drug therapy for ISS is an acceptable management strategy, since this form of growth retardation is not a disease, and its association with adult quality of life is weak and insufficiently studied [35,36].
It is recommended that a medical board of pediatric endocrinologists consider initiating trial therapy with #somatropin** in a child with ISS (height SDS below -2.25) to improve height prognosis, provided that:
- there is marked concern from the child and/or parents/legal representatives regarding growth retardation,
- there is a strong desire for such therapy on the part of the patient themselves and their parents/legal representatives, certified by a signed informed consent [1,17,38].
(Level of Evidence C, Grade of Recommendation 5)
Comments: the main goal of treatment is to achieve a normal final height for the given population. Foreign literature contains data indicating an improvement in the psychological state of children against the background of increased growth parameters when using #somatropin**; currently, there are no domestic data on the quality of life of children with ISS before and after treatment with #somatropin** [17–19].
To make a decision on starting therapy, the physician must provide the patient with the most complete information possible about the expected growth effects and assess the patient's readiness to adhere to the prescribed treatment. It is desirable that the patient and their parents are consulted by a psychologist to objectively assess the impact of short stature on the child's quality of life. It is important to distinguish between the patient's actual self-assessment of quality of life and the quality of life of the child as perceived by the parents. Therapy is not recommended for a child who is not concerned about their height.
Since the use of #somatropin** for ISS is off-label, the decision to initiate it must be made by a medical board and accompanied by informed consent signed by the parents. After starting therapy, the patient must be regularly examined by an endocrinologist and a psychologist.
The optimal age to start #somatropin** therapy is the prepubertal period.
A decreased or normal IGF-1 level is neither an indication nor a contraindication for #somatropin** therapy in ISS.
On average, over 7 years of #somatropin** therapy, the gain in final height in children with ISS averages 3–4 cm when using a calculated dose of 0.033 mg/kg/day and 7–8 cm with a dose of 0.05 mg/kg/day. The final height SDS of children with ISS receiving #somatropin** treatment is -1.77 SDS, and in those not receiving this treatment: -2.34 [38]. Individual response to #somatropin** therapy varies greatly among patients, up to a complete lack of response, of which the patient and their parents must be informed before treatment begins [1].
A calculated starting dose of #somatropin** of 0.033 mg/kg/day (0.24 mg/kg/week) is recommended for children with ISS who have received medical board approval for trial therapy to improve height prognosis [30–32].
(LoE B, GoR 2)
Comments: it is hypothesized that in most children with ISS, along with a partially reduced endogenous spontaneous GH secretion, sensitivity to GH is also reduced, which can be overcome by administering exogenous #somatropin** in replacement (0.033 mg/kg/day) and supraphysiological doses (0.05 mg/kg/day) [30–33]. Currently, there are no reliable predictors of the growth response to #somatropin** in children with ISS [31]: no correlation has been found between the growth effect of #somatropin** and parameters such as height SDS, baseline IGF-1 level, #somatropin** dose, or stimulation test results [30,39,40]. Higher doses (0.07 mg/kg/day and above) lead to accelerated bone maturation and negate the efficacy of therapy [30–33].
For this purpose, #somatropin** is used off-label.
It is recommended to titrate the dose of #somatropin** to achieve a high-normal IGF-1 level (upper half of the reference range for the corresponding sex and age according to the standards of the assay kit and laboratory performing the analysis) in children with ISS who have received medical board approval for trial therapy with #somatropin**, during its further use to improve height prognosis [1,2,41].
(LoE A, GoR 1)
Comments: if there is a good growth response, it is advisable to continue #somatropin** treatment at the same dose [1,2].
If IGF-1 exceeds the upper limit of normal, a reduction in the #somatropin** dose is recommended.
It is recommended to continue medical board-approved #somatropin** therapy, provided it is effective, in children with ISS to improve height prognosis [1,2].
(Level of Evidence C, Grade of Recommendation 5)
Comments: the best criterion for treatment efficacy is ∆ height SDS. In addition, changes in growth velocity (in cm/year and growth velocity SD) and bone age progression are evaluated. Absolute height gain (in cm) is not considered as a criterion because it depends on age and sex.
Therapy is considered effective if:
• ∆ height SDS > 0.3–0.5 after 1 year of therapy,
• increase in growth velocity by more than 3 cm/year,
• growth velocity SDS > +1,
• BA/CA ≤ 1.
An unsatisfactory growth response may be the result of low compliance, incorrect storage conditions or administration technique, or growth hormone insensitivity. If there is a good growth response, continuing #somatropin** treatment at the same dose is indicated [1,2].
The physician must actively involve the family in discussing the child's management strategy and provide a realistic assessment of expected treatment outcomes, taking into account the variability of the clinical result.
It is recommended that a medical board of pediatric endocrinologists consider adding trial therapy with prolonged gonadotropin-releasing hormone analogues (#triptorelin**, #leuprorelin**) 3.75 mg/28 days intramuscularly to #somatropin** in a child with ISS who has onset of puberty and an unfavorable height prognosis (subject to written consent from the patient and/or their parents/legal representatives) in order to delay puberty and improve final height prognosis [42,45].
(LoE A, GoR 1)
Comments: isolated clinical studies have shown that combination treatment with gonadotropin-releasing hormone analogues and #somatropin** was effective in children with ISS at Tanner stages 2–3. Suppression of puberty and bone maturation by gonadotropin-releasing hormone analogues with simultaneous increase in growth velocity using #somatropin** preparations led to an increase in predicted adult height without obvious side effects. At the same time, this combination currently has experimental status [34,39–42].
For this purpose, gonadotropin-releasing hormone analogues are used off-label.
It is recommended that a medical board of pediatric endocrinologists consider adding trial therapy with aromatase inhibitors (#letrozole 2.5 mg orally daily or #anastrozole 1 mg orally daily) to #somatropin** in boys with ISS who have onset of puberty and an unfavorable height prognosis (subject to written consent from the patient and/or their parents/legal representatives) in order to delay bone maturation and improve final height prognosis [46].
(LoE A, GoR 1)
Comments: considering the important role of estrogens in epiphyseal fusion, attempts are being made to improve the final height of male patients with ISS by suppressing the conversion of testosterone to estradiol using aromatase inhibitors [46,47]. Currently, this combination has experimental status.
For this purpose, aromatase inhibitors are used off-label.
It is recommended to discontinue medical board-approved #somatropin** therapy in children with ISS upon reaching near-final height (decrease in growth velocity to less than 2 cm/year and/or epiphyseal fusion (reaching a bone age of 14 years in girls and 16 years in boys [1,2]).
(Level of Evidence C, Grade of Recommendation 5)
Comments: therapy with #somatropin** can be discontinued once a final height above -2 SDS is reached. Treatment may also be stopped earlier if the child and/or their parents are satisfied with the height achieved or do not wish to continue therapy for other reasons. Discontinuation of treatment is advisable if, despite high IGF-1 levels, the growth response to treatment remains unsatisfactory [15,36].
3.2 Alternative treatments for idiopathic short stature
It is recommended that a medical board of pediatric endocrinologists evaluates the possibility of using #testosterone** in boys with constitutional delay of growth and puberty who have mild growth retardation (SDS > –2.5) and significant bone maturation delay (3 years or more) to accelerate growth velocity. International practice uses #testosterone enanthate** at 50–100 mg IM once a month [15,48]. However, in the Russian Federation, due to the unavailability of #testosterone enanthate** preparations, it is standard practice to use #testosterone (mixture of esters)** in an equivalent dose [48].
(Level of Evidence C, Grade of Recommendation 5)
Comments: the goal of this therapy is to increase growth velocity by accelerating the onset of puberty compared to how the child would develop naturally. Final height is not significantly altered by this.
For this purpose, #testosterone** preparations are used off-label.
#Testosterone** preparations are used exclusively in boys older than 14 years with a height below the 3rd percentile, in prepuberty or early puberty (testicular volume < 6 cm3), with a basal testosterone level of less than 3.5 nmol/L.
4. Medical Rehabilitation and Sanatorium-Resort Treatment
Not required.
5. Prevention and Dispensary Observation
According to literature data, the incidence of adverse effects associated with #somatropin** therapy in patients with idiopathic short stature is comparable to that in children with true GH deficiency or those treated for other conditions. At the same time, considering that higher doses of #somatropin** may be used in patients with idiopathic short stature, and taking into account potential therapy risks, careful observation and monitoring of both treatment efficacy and safety are required [3,12,32].
It is recommended to perform mandatory anthropometric measurements (body length/height, sitting height, body weight, BMI), compare the child's growth indicators with age-related norms by calculating anthropometric parameters (height SDS, growth velocity, growth velocity SDS, BMI SDS), and construct an individual growth chart for children with idiopathic short stature in order to assess treatment efficacy, detect increasing skeletal disproportion, and adjust the #somatropin** dose [3,9,12].
(Level of Evidence C, Grade of Recommendation 5)
It is recommended to assess sexual status (pubertal stages) to monitor the onset and progression of puberty; in cases of stage 2–3 puberty and an unfavorable growth prognosis, a medical board should consider the possibility of prescribing additional treatment with prolonged gonadotropin-releasing hormone analogues [36].
(Level of Evidence C, Grade of Recommendation 5)
For this purpose, gonadotropin-releasing hormone analogues are used off-label.
It is recommended that children with idiopathic short stature receiving #somatropin** therapy be followed up by an orthopedic trauma surgeon every 1–2 years to detect adverse events such as scoliosis and slipped capital femoral epiphysis, and to take timely measures for their management [3,9,12].
(Level of Evidence C, Grade of Recommendation 5)
It is recommended that children with idiopathic short stature receiving #somatropin** therapy be followed up by an otorhinolaryngologist every 1–2 years to detect adverse events such as tonsillar hypertrophy, and to take timely measures for their management [3,9,12].
(Level of Evidence C, Grade of Recommendation 5)
It is recommended to perform a direct-projection radiograph of the wrist once a year (every 6 months during late puberty) in children with idiopathic short stature to determine bone age in order to predict growth potential [3,5,13].
(Level of Evidence C, Grade of Recommendation 5)
It is recommended to test blood insulin-like growth factor I levels once every 6 months in children with idiopathic short stature receiving #somatropin** therapy to assess compliance, dose adequacy, as well as treatment efficacy and safety [40,41,50].
(Level of Evidence C, Grade of Recommendation 5)
It is recommended to test blood glucose and glycated hemoglobin levels once every 6 months in children with idiopathic short stature receiving #somatropin** therapy to assess carbohydrate metabolism in order to evaluate treatment safety [3,5,51].
(Level of Evidence C, Grade of Recommendation 5)
It is recommended to consult an ophthalmologist with fundus examination once a year in children with idiopathic short stature receiving #somatropin** therapy to evaluate treatment safety [52].
(Level of Evidence C, Grade of Recommendation 5)
It is recommended to immediately perform magnetic resonance imaging in children with idiopathic short stature receiving #somatropin** therapy if the patient develops neurological symptoms or if a brain space-occupying lesion is suspected, in order to take urgent management measures [52].
(Level of Evidence C, Grade of Recommendation 5)
Comments: currently, there is no evidence of brain tumor development associated with #somatropin** therapy; therefore, routine brain magnetic resonance imaging is not indicated for patients with idiopathic short stature receiving #somatropin** treatment [1,3,5].
6. Organization of Medical Care
Indications for hospitalization in a medical organization:
1) Planned hospitalization is necessary for stimulation tests if required by the specific clinical case. In addition, planned hospitalization may be required to perform brain magnetic resonance imaging in a young child if necessitated by the clinical case at hand;
2) Planned hospitalization is also possible after initiating #somatropin** therapy to monitor treatment progress every 6–12 months.
Indications for patient discharge from a medical organization
1) Patient discharge is possible after clinical and laboratory evaluation.
7. Additional Information
The optimal age to initiate therapy is early prepuberty (from 5 years of age until the onset of puberty). The later treatment is started, the smaller the expected final height gain [1].
Criteria for Evaluating the Quality of Medical Care
№ | Quality criteria | Evaluation of compliance (yes/no) | |
|---|---|---|---|
1. | Height measurement and height SDS assessment performed | (yes/no) | |
2. | Sitting height measurement with proportionality assessment performed | (yes/no) | |
3. | Growth velocity calculation for the preceding 6–12 months performed (if growth data available) | (yes/no) | |
4. | Body weight measurement performed | (yes/no) | |
5. | Assessment of sexual development (pubertal stages) performed | (yes/no) | |
6. | Wrist radiography with bone age assessment performed | (yes/no) | |
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Appendix A1. Working Group Composition
LEADERS:
Valentina Aleksandrovna Peterkova – Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences, Scientific Director of the Institute of Pediatric Endocrinology at the Academician I. I. Dedov National Medical Research Center for Endocrinology of the Russian Ministry of Health, Head of the Department of Pediatric Endocrinology and Diabetology at the Institute of Higher and Continuing Professional Education of the Academician I. I. Dedov National Medical Research Center for Endocrinology of the Russian Ministry of Health, Chief freelance pediatric specialist endocrinologist of the Russian Ministry of Health.
Olga B. Bezlepkina – D.Sc. (Med.), Deputy Director of the Center – Director of the Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health, Professor at the Department of Pediatric Endocrinology and Diabetology, Institute of Higher and Continuing Professional Education, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.
TEXT AUTHORS:
Maria S. Pankratova – Ph.D. (Med.), Leading Researcher, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health, Associate Professor at the Department of Pediatric Endocrinology and Diabetology, Institute of Higher and Continuing Professional Education, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.
Elena V. Nagaeva – MD, PhD, Head of the Department of Thyroidology, Reproductive and Somatic Development, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health, Associate Professor at the Department of Pediatric Endocrinology and Diabetology, Institute of Higher and Continuing Professional Education, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.
Maria V. Vorontsova – PhD, Leading Researcher at the National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.
Alisa V. Vitebskaya – PhD, Associate Professor at the Department of Children's Diseases, N.F. Filatov Clinical Institute of Children's Health, I.M. Sechenov First Moscow State Medical University (Sechenov University) of the Russian Ministry of Health.
Oleg A. Malievsky – MD, PhD, Professor at the Department of Hospital Pediatrics, Bashkir State Medical University of the Russian Ministry of Health, Chief Freelance Pediatric Endocrinologist of the Volga Federal District.
Elizaveta N. Raykina – Pediatric Endocrinologist at the National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.
EXPERTS:
Elena B. Bashnina – MD, PhD, Professor at the Department of Endocrinology named after Academician V.G. Baranov, North-Western State Medical University named after I.I. Mechnikov, Chief Freelance Pediatric Endocrinologist of the North-Western Federal District.
Galina A. Galkina – MD, PhD, Head of the Pediatric Endocrinology Department, Research Institute of Obstetrics and Pediatrics, Rostov State Medical University of the Russian Ministry of Health, Chief Freelance Pediatric Endocrinologist of Rostov Oblast, Chief Freelance Pediatric Endocrinologist of the Southern Federal District.
Alexey V. Kiyaev – MD, PhD, Professor at the Department of Hospital Pediatrics, Ural State Medical University of the Russian Ministry of Health, Head of the Center for Pediatric Endocrinology, Regional Children's Clinical Hospital, Chief Freelance Pediatric Endocrinologist of Sverdlovsk Oblast, Chief Freelance Pediatric Endocrinologist of the Ural Federal District.
Anna A. Kolodkina – Head of the Department of Hereditary Diseases and Early Childhood Endocrinopathies, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health, PhD.
Irina B. Kostrova – Head of the Pediatric Endocrinology Department, N.M. Kuraev Children's Republican Clinical Hospital, Chief Freelance Pediatric Endocrinologist of the Republic of Dagestan, Chief Freelance Pediatric Endocrinologist of the North-Caucasian Federal District.
Elena E. Petryaykina – MD, PhD, Director of the Russian Children's Clinical Hospital, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Chief freelance pediatric endocrinologist of Moscow, Chief freelance pediatric endocrinologist of the Central Federal District.
Lyubov N. Samsonova – MD, PhD, Head of the Department of Pediatric Endocrinology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health.
Tatyana E. Taranushenko – MD, PhD, Head of the Department of Pediatrics, Institute of Postgraduate Education, Professor V.F. Voino-Yasenetsky Krasnoyarsk State Medical University of the Russian Ministry of Health, Chief Freelance Pediatric Endocrinologist of Krasnoyarsk Krai, Chief Freelance Pediatric Endocrinologist of the Siberian Federal District.
Tatyana Yu. Shiryaeva – PhD, Leading Researcher at the Department of Thyroidology, Reproductive and Somatic Development, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology named after Academician I.I. Dedov of the Russian Ministry of Health.
Anatoly N. Tyulpakov – MD, PhD, Associate Professor, Head of the Department of Endocrine Disease Genetics, Research Centre for Medical Genetics named after Academician N.P. Bochkov of the Ministry of Science and Higher Education of Russia, pediatric endocrinologist at the Russian Children's Clinical Hospital, Pirogov Russian National Research Medical University of the Russian Ministry of Health.
Igor S. Chugunov – Head of the Pediatric Endocrine Tumor Department, Institute of Pediatric Endocrinology, National Medical Research Center for Endocrinology of the Russian Ministry of Health, PhD.
Conflict of interest: the authors of the clinical guidelines declare no conflict of interest. For the final edition and quality control, the guidelines were re-evaluated by the members of the working group, who concluded that all comments and feedback from experts have been taken into account, and the risk of bias in the development of the guidelines has been minimized.
Appendix A2. Methodology for Developing Clinical Guidelines
Target audience for these clinical guidelines:
Pediatricians;
Pediatric endocrinologists;
Endocrinologists.
Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)
LoE | Definition |
|---|---|
1 | Systematic reviews of studies with reference standard control or systematic reviews of randomized controlled trials with meta-analysis |
2 | Individual studies with reference standard control or individual randomized controlled trials and systematic reviews of studies of any design, except randomized controlled trials, with meta-analysis |
3 | Studies without consecutive reference standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case report |
5 | Only justification of mechanism of action or expert opinion is available |
Table 2. Scale for grading levels of evidence (LE) for preventive, therapeutic, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)
LoE | Definition |
|---|---|
1 | Systematic review of RCTs with meta-analysis |
2 | Individual RCTs and systematic reviews of studies of any design except RCTs, with meta-analysis |
3 | Non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case reports or case series, case-control studies |
5 | Only justification of the mechanism of action of the intervention (preclinical studies) or expert opinion is available |
Table 3. Scale for assessing grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)
GoR | Definition |
|---|---|
A | Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or acceptable methodological quality, and their conclusions on the outcomes of interest are consistent) |
B | Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or acceptable methodological quality, and/or their conclusions on the outcomes of interest are inconsistent) |
C | Weak recommendation (lack of adequate quality evidence (all considered efficacy criteria (outcomes) are unimportant, all studies are of low methodological quality, and their conclusions on the outcomes of interest are inconsistent) |
Procedure for updating clinical guidelines.
The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.
Appendix A3. Reference Materials
Current instructions for medicinal products mentioned in the clinical guidelines are available at http://grls.rosminzdrav.ru
Order of the Ministry of Health of the Russian Federation No. 583n dated October 29, 2024 'On approval of the Procedure for the provision of medical care in the profile of "pediatric endocrinology".'
Table 4. Normal upper-to-lower segment ratios (Kaplan S., 1989)
Age | Boys | Girls | Age | Boys | Girls |
|---|---|---|---|---|---|
0,5-1,4 | 1,81 | 1,86 | 9,5-10,4 | 1,12 | 1,11 |
1,5-2,4 | 1,61 | 1,80 | 10,5-11,4 | 1,10 | 1,08 |
2,5-3,4 | 1,47 | 1,44 | 11,5-12,4 | 1,07 | 1,07 |
3,5-4,4 | 1,36 | 1,36 | 12,5-13,4 | 1,06 | 1,07 |
4,5-5,4 | 1,30 | 1,29 | 13,5-14,4 | 1,04 | 1,09 |
5,5-6,4 | 1,25 | 1,24 | 14,5-15,4 | 1,05 | 1,10 |
6,5-7,4 | 1,20 | 1,21 | 15,5-16,4 | 1,07 | 1,12 |
7,5-8,4 | 1,16 | 1,16 | 16,5-17,4 | 1,08 | 1,12 |
8,5-9,4 | 1,13 | 1,14 | 17,5-18,4 | 1,09 | 1,12 |
Comments: when assessing body proportions in children with significant bone maturation delay, it is recommended to use the child's «bone age».
Figure 2. Height and weight percentile charts (boys, 0–36 months)
Table 5. Laboratory tests used in the evaluation of short children with suspected ISS to rule out other causes of short stature.
Laboratory tests | Excluded diseases/conditions |
|---|---|
Complete blood count (CBC) | Anemias, infectious diseases associated with signs of inflammation – chronic intestinal diseases (e.g., Crohn's disease) |
Urinalysis | Renal pathology |
General routine blood chemistry: serum iron level test, blood ferritin level test | Anemias, nutritional disorders, malabsorption, celiac disease |
General routine blood chemistry: blood ionized calcium level test, blood inorganic phosphorus level test, blood alkaline phosphatase activity assay | Disorders of calcium-phosphorus metabolism |
General routine blood chemistry: blood potassium level test, blood sodium level test, blood chlorides level test | Acidosis, including of renal origin |
General routine blood chemistry: blood creatinine level test, blood urea level test | Chronic renal failure |
General routine blood chemistry: blood alanine aminotransferase activity assay, blood aspartate aminotransferase activity assay, total bilirubin level test, free and conjugated bilirubin level test, total protein level test | Liver pathology |
Blood endomysial antibody assay (IgA EmA), blood tissue transglutaminase antibody assay (IgA anti-tissue transglutaminase, total IgA) | Celiac disease |
Blood serum free thyroxine (FT4) level test, blood thyroid-stimulating hormone (TSH) level test | Hypothyroidism |
Insulin-like growth factor I blood test | GH deficiency |
Appendix B. Physician Action Algorithms
Appendix C. Patient Information
If growth delay compared to peers is suspected, parents should immediately consult a pediatrician to evaluate linear development and identify the cause of short stature (if present).
When evaluating a child with growth retardation, the physician analyzes history data:
child development history, including data on chronic diseases, psycho-emotional shocks, and nutritional disorders;
pregnancy and childbirth history, physical examination results including anthropometric measurements, as well as laboratory and instrumental tests.
Short stature may be caused by a specific pathology or represent a variant of normal development. Therefore, during a medical visit, in addition to analyzing child development data, a family history review may be required, including information on chronic diseases and the onset and progression of puberty (which may also involve measuring the parents' height and reviewing family photographs).
Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools
Not applicable.