Topics on Continuous Training

J.I. Labarta Aizpún

Head of the Pediatrics Department. Endocrinology Unit. Professor of Pediatrics. Miguel Servet University Hospital. Zaragoza

Abstract Short stature is a very common cause of referral. There are many causes of growth failure, but the great majority of cases are due to normal variants and only in a minority of cases an underlying disease is found. Pathological growth failure includes the consideration not only of short stature, but also growth velocity, genetic height and estimation of adult height. Idiopathic short stature is a broad concept difficult to define and in the last years new genes related to the development of the growth cartilage have been implicated. The diagnostic process should be stepwise and aims to differentiate between short stature that is a variant of normal and pathological short stature, identify the cause, and initiate treatment as soon as possible. A complete medical history and examination, together with a careful assessment of auxology, bone age, and basic complementary tests, allow the diagnosis to be guided without the need for advanced studies. Treatment with recombinant human growth hormone (rhGH) should be carried out under the indicated conditions and doses and started as soon as possible during prepuberty. This review presents the state of the art regarding differential diagnosis and therapeutic possibilities.

 

Resumen La talla baja es un motivo frecuente de consulta. Las causas son múltiples, pero, en la mayoría de las ocasiones, se trata de variaciones normales del crecimiento y, muy pocas veces, se identifica una etiología responsable. El concepto de hipocrecimiento patológico incluye valorar no solamente la talla, sino también la velocidad de crecimiento, la talla genética y la estimación de la talla adulta. La talla baja idiopática es un concepto amplio y de difícil definición y, en los últimos años, se han identificado anomalías en genes implicados en el desarrollo del cartílago de crecimiento. El proceso diagnóstico debe ser escalonado y tiene por objetivo diferenciar una talla baja variante de la normalidad de una talla baja patológica, identificar la causa e instaurar un tratamiento lo antes posible. Una historia clínica y exploración completa, junto con una juiciosa valoración de la auxología, edad ósea y pruebas complementarias básicas, permiten orientar el diagnóstico sin necesidad de estudios avanzados. El tratamiento con hormona de crecimiento recombinante humana (rhGH) se debe realizar en las condiciones y dosis indicadas e iniciarlo lo antes posible durante la prepubertad. En esta revisión se realiza una actualización del tema, tanto a nivel del diagnóstico diferencial como de las posibilidades de tratamiento.

 

Key words: Short stature; Growth failure; Growth hormone.

Palabras clave: Talla baja; Retraso de crecimiento; Hormona de crecimiento.

 

 

Pediatr Integral 2025; XXIX (4): 249 – 271

 

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Short stature

https://doi.org/10.63149/j.pedint.44

Introduction

Short stature (SS) is one of the main reasons for consultation, and growth assessment is a highly sensitive indicator of a child’s health status. Human growth is a dynamic process subject to multifactorial regulation, and height variation in the population is explained by genetic factors and, to a lesser extent, by environmental factors. The GH-IGF-I axis is the most important endocrine system in the regulation of postnatal growth.

The assessment of a child’s growth is a very sensitive indicator of their health and well-being, and its evaluation is part of well-child monitoring programs. Short stature (SS) is one of the main reasons for consultation, hence the importance of performing a correct assessment to adequately direct the diagnostic process and differentiate pathological SS from non-pathological SS, which is a variant of normal human growth and maturation rates(1,2).

Human growth is a dynamic, continuous, non-linear process regulated by multiple factors, which can be classified as exogenous (nutrition, physical activity, affectivity, psychosocial influence) and endogenous (genetic, hormonal, metabolic, and tissue receptivity at the growth plate level). Approximately 80% of the variation in adult height found in the population depends on genetic factors, and the remaining 20% is explained by environmental factors that are responsible for the difference in height between populations and the secular acceleration of growth. This genetic dependence is attributed to the combined participation of multiple genes, making adult height a polygenic trait. The maturation rate of an individual is also conditioned by genetic factors. Environmental factors, such as nutrition, stress, affectivity, and socioeconomic conditions, can influence growth and the maturation rate, such that unfavorable conditions determine a lower adult height and a later puberty(3).

The GH-IGF-I axis It is the most important endocrine system in the regulation of growth(4,5). Growth hormone (GH) has direct growth-stimulating actions and most of them are mediated by the action of IGF-I (insulin-like growth factor number I) produced in the liver. IGF-I is the main postnatal growth factor and exerts mitogenic and anabolic actions on most cells. IGF-I circulates in the blood bound to carrier proteins or IGF binding proteins (IGFBPs). The most important IGFBP in serum is IGFBP-3, which together with the acid-labile subunit (ALS) and IGF-I forms a ternary complex that transports IGF-I to the tissues. At the peripheral level, proteases break down the IGFBP complexes and allow the release of free IGF-I into the tissues. Both IGF-I and IGFBP-3 and the acid-labile subunit are proteins produced in the liver that depend on the secretion and action of GH. In recent years, progress has been made in the understanding of the peripheral bioavailability of IGF-I, and the role of pappalysins, specifically pappalysin-2 (PAPP-A2, pregnancy-associated plasma protein 2), which acts as a proteolytic enzyme that breaks down the ternary complex of IGF-IGFBP-3-ALS, facilitating the release of IGF-I into the tissues. Stanniocalcins are peptides that regulate, in turn, the action of pappalysins, and are therefore also involved in the regulation of the peripheral action of IGF-I(6). GH and nutritional status are the two most important regulatory factors of hepatic secretion of IGF-I and IGFBP-3. Other hormonal systems involved in the regulation of IGF-I levels are insulin, thyroid hormones, glucocorticoids and sex steroids. Malnutrition, conditions such as anorexia and celiac disease, chronic inflammatory diseases such as Crohn’s disease or juvenile chronic arthritis, decrease the levels of IGF-I and IGFBP-3, despite normal GH secretion, indicating the existence of a secondary resistance to GH(2). In the growth cartilage, in addition to the endocrine action of IGF-I and GH, other growth factors and proteins produced by the chondrocytes themselves and which have autocrine and/or paracrine action also intervene, such as IGF-I, FGF (fibroblast growth factor), TGFβ (transforming growth factor), CNP (C-natriuretic peptide or C-type natriuretic peptide), PTHrP (PTH-related protein), cytokines, extracellular matrix proteins and bone morphogenetic proteins (BMP)(3,5).

The concept of short stature and growth failure

While short stature is a static and statistical concept, growth failure is defined based on growth rate, genetic height, and expected adult height. Most short statures presented to the clinic are normal growth variants, and only in approximately 15-20% is an underlying cause or pathology found.

Height follows a normal distribution, and by definition, 2.3% and 0.6% of healthy individuals have a height that is 2 SD and 2.5 SD below the mean for age and sex in a given population, respectively. This indicates that many children referred for SS testing do not have pathology and are at the extreme end of the normal curve. To correctly assess growth and identify pathological growth, three parameters must be considered: a) height relative to the mean (SD or percentile position); b) comparison of height relative to genetic height (GH); and c) growth velocity (GV) adjusted for age, sex, and pubertal stage, where a height loss greater than 0.3 SD/year is considered greater than expected based on physiological growth variability. SS is a static concept based on a statistical criterion defined as a height below normal, while growth failure is a broader concept and involves assessing growth rate and future expectations for adult height. The most frequently used criteria for describing SS/growth failure are: a) height less than -2 SD for age and sex on charts appropriate for the population studied; b) normal height (within ±2 SD) but 2 SD below genetic height (GH); c) an estimated adult height 2 SD below the individual’s genetic height; and d) decreased growth velocity, including a growth velocity less than -1 SD (~25th percentile) for age and sex, sustained over a period of more than 2 years. This concept includes situations where a child does not have SS but may have pathological growth failure(4,5).

The prevalence of growth failure is difficult to establish, but it is thought that approximately 3-5% of the child population may exhibit SS at any given stage of their growth. There is no reason to believe that the prevalence of SS varies depending on the origin of the population studied, with the exception of growth failure due to nutritional or deficiency causes in underprivileged countries. The prevalence of pathological SS is between 1.5% and 40%, depending on the severity of the auxological inclusion criteria, but it is accepted that approximately 15-20% of SS cases have a known cause(5), while the vast majority are variants of normal or non-pathological SS.

Etiology and classification of short stature

Growth disorders have a multitude of causes and are classified as disorders with primary or intrinsic involvement of the growth plate, disorders with secondary involvement of the growth plate due to alterations in the nutritional-hormonal-metabolic environment, and disorders of unknown cause. Idiopathic SS is a difficult and controversial concept to define, largely dependent on the tests performed. In recent years, genetic studies have made it possible to identify genetic abnormalities in genes related to growth plate development in patients with short stature who were previously considered idiopathic.

Height variation in the normal population is mostly related to variants in genes involved in the growth cartilage and, for this reason, many authors prefer to categorize SS based on whether the growth cartilage involvement is primary, due to the affectation of the genes involved in its function, or secondary to other processes(7). Table I(8) presents the different etiologies according to the classification proposed by the European Society of Pediatric Endocrinology(8), which divides them into 3 large groups: a) growth failure of primary origin, due to defects or anomalies intrinsic to the growth cartilage; b) secondary growth failure, caused by all those processes that determine an alteration of the nutritional-hormonal-metabolic environment in the growth cartilage; and c) growth failure of unknown cause, in what has been called idiopathic short stature (ISS).

 

Primary growth failure

Growth failure of prenatal origin

Prenatal growth can be affected by numerous maternal (tobacco, alcohol, drugs, systemic diseases), placental (uterine-placental insufficiency), and fetal (infections, chromosomal abnormalities, gene abnormalities) factors; however, in most cases, no cause is identified and the term idiopathic intrauterine growth restriction is used. The concept of small for gestational age (SGA) is not always synonymous with intrauterine growth restriction, as some children may be considered SGA without having undergone intrauterine growth restriction if their genetic potential and growth percentile have been within low percentiles throughout pregnancy (constitutional SGA). The term intrauterine growth restriction should describe fetuses in which there is clear evidence of growth restriction; it is more of an obstetric concept, which includes the determination of fetal growth in two stages and the verification of growth cessation. The term SGA is defined as a newborn (NB) whose birth weight and/or length is ≥2 SD below the mean for their gestational age(9). Most SGA newborns show catch-up growth, which is most intense in the first six months, and 80-90% reach a normal length in early childhood, between ±2 SD, although they are often below their family range. At 2 years of age, 13-15% of these children have a length below -2 SD; after the first two years of life, catch-up growth is rare, except in premature newborns. The group of SGA newborns without spontaneous catch-up growth should be followed, as they may be candidates for treatment with recombinant human growth hormone (rhGH). GH does not play a primary role in prenatal growth, which at the hormonal level depends more on insulin and insulin-like growth factors-1 and -2 (IGF-I and IGF-II). The group of growth retardation of prenatal origin should include disorders linked to insulin deficiency and IGF-I synthesis or action due to mutations in the genes IGF1 and IGF1R, respectively(10).

Syndromes associated with growth failure

Various syndromes are known to be associated with growth retardation(10,11). SS is frequently of prenatal origin, resulting in an intrinsic growth disturbance. In this group of patients, clinical examination is essential to guide the diagnosis (Table II)(3,4).

 

 

Skeletal dysplasias

More than 400 types of bone dysplasias (BD) are described and classified according to clinical, radiological, biochemical, and molecular criteria, and more than 350 genes are involved. BDs have a combined incidence of 1:5,000 live births and represent 5% of children born with a congenital defect. BDs frequently present with short stature in childhood, but due to their clinical heterogeneity, symptoms can range from premature arthritis with normal stature to patients with severe short stature with death in the perinatal period. The spine and extremities are usually affected, but it is also necessary to rule out involvement of other organs and systems, such as vision, hearing, neurological impairment, or cardiorespiratory function. The key sign is disproportionate SS with abnormalities of the body segments(12).

Achondroplasia, which is due to a mutation in the gene FGFR3 (4p16.3) with an autosomal dominant pattern and complete penetrance, and hypochondroplasia, a milder form of achondroplasia and also linked to the gene FGFR3, are the most frequent BDs and are easily identified clinically due to their growth failure, shortening of limbs, rhizomelia, curvature of the legs and frequent genu varum(13). Hypochondroplasia does not have the characteristic facial appearance of achondroplasia and its growth stunting is less, and it can be confused with and diagnosed as familial idiopathic SS. Other less common BDs are multiple epiphyseal dysplasia, in which at least five genes have been implicated (COMP, COL9A1, COL9A2, COL9A3 and MATN3), and Maroteaux’s acromesomelic dysplasia, which is linked to a loss of function of both alleles of the NPR2 gene.

SHOX gene is located in the pseudoautosomal region of the short arm of the X and Y chromosomes, and is predominantly expressed in the 1st and 2nd pharyngeal arch, distal humerus (elbow), distal ulna and radius (wrist), proximal tibia and distal femur (knee) and regulates the differentiation and proliferation of chondrocytes. Mutations or deletions in homozygosity or compound heterozygosity are very rare and are associated with Langer’s mesomelic dysplasia, very severe BD with very short stature (-6 SD), severe shortening of the limbs and aplasia of the ulna and fibula. Haploinsufficiency of the SHOX gene by mutation or deletion in heterozygosity of the SHOX gene or its regulatory region PAR1 is responsible for Léri-Weill dyschondrosteosis and also for some clinical manifestations of Turner syndrome. Léri-Weill dyschondrosteosis is characterized by mesomelic undergrowth (shortening of the forearms), cubitus valgus, Madelung deformity, shortening of the metacarpals and metatarsals, high-arched palate, micrognathia, and a short neck; these manifestations are more marked in women and after puberty, due to the influence of estrogen. The phenotypic variability is wide, so the clinical spectrum is a continuum ranging from severe forms, with disproportionate SS, to mild forms, with proportionate SS with minor skeletal and radiological abnormalities without Madelung deformity. Up to 2-15% of idiopathic short stature is associated with heterozygous mutations in the SHOX gene. In table III(14), the clinical pictures associated with SHOX gene abnormalities are presented(14).

 

Secondary growth failure

Chronic diseases and malnutrition

In developed countries, malnutrition as a cause of growth retardation is usually linked to chronic pathologies with inadequate diets and nutrient intake. Restrictive diets, whether or not associated with excessive exercise, and eating disorders such as anorexia nervosa, can lead, depending on the severity and duration, to protein-calorie malnutrition and impaired growth. Malnutrition is accompanied by a state of secondary GH resistance with decreased levels of IGF-I and IGFBP-3 and normal or elevated GH secretion. Recurrent infections (gastrointestinal, parasitic) are a common cause of growth retardation in underdeveloped countries. In our setting, the presence of recurrent infections should raise the possibility of underlying immunodeficiency (primary or secondary) or associated malformations. It is estimated that ~10% of pathological SS causes are secondary to chronic disease. The growth pattern is similar, with an initial impact on weight development and body mass index (BMI) and, subsequently, a decrease in growth velocity, a drop in height, as well as delayed puberty and bone age. The release of the noxa and appropriate treatment produce a recovery growth, which may be total or partial(15).

Endocrine diseases

Endocrine disorders account for approximately 5% of the causes of pathological SS. In addition to GH-IGF axis disorders, these include hypothyroidism and chronic hypercortisolism (Cushing’s syndrome), which can be caused by the pituitary (Cushing’s disease) or adrenal (ACTH-independent hypercortisolism), or, most commonly, by chronic corticosteroid administration. In the latter case, the severity of growth retardation depends on the type of corticosteroid, dose, duration, administration regimen, and individual sensitivity. Other endocrine causes include pseudohypoparathyroidism and poorly controlled diabetes. Endocrine-caused growth failure includes clinical situations of excess of sexual steroids (precocious puberty, congenital adrenal hyperplasia, exogenous administration of steroids) that present a transient hypergrowth, acceleration of bone age and premature closure of growth cartilages and end with adult height below normal(16).

GH-IGF axis disorders

Growth retardation due to alterations in the GH-IGF axis accounts for 2-5% of cases of postnatal SS. GH deficiency (GHD) can be genetic or acquired, isolated or associated with other hormonal deficiencies. GHD has an incidence of 1:3,400 and a prevalence of 1:29,000. Most GHD are idiopathic, and only 20% have an organic cause. Among the idiopathic GHD group, embryological abnormalities at the pituitary level can be found, such as pituitary hypoplasia, hypoplastic or absent stalk, and ectopic neurohypophysis(17).

Between 3-30% of cases of selective GHD are familial or genetic. Most mutations involve the GH genes (GH1) or to the hypothalamic GH-releasing hormone receptor (GHRHR) and, to date, no patients with mutations in the GHRH gene have been identified. Heterozygous mutations in genes HESX1 and SOX3 are a rare cause of selective GHD. It is important to consider that some cases of panhypopituitarism initially present as isolated GHD and eventually develop the other hormonal deficiencies. Recessive and dominant mutations have been described in the GH secretagogue receptor type 1 gene (GHSR), whose natural ligand is ghrelin, in patients with partial idiopathic GHD. GHD associated with agammaglobulinemia is caused by an affectation in the BTK (Bruton agammaglobulinemia tyrosine kinase) gene. The clinical manifestations of GHD depend on its severity. The most common manifestations are progressive growth retardation, loss of height, decreased growth velocity, and, frequently, delayed bone age. Delayed bone age is not always observed, as premature adrenarche or precocious/advanced puberty may coexist, or the patient comes from a family with a rapid maturation rate. Severe forms are accompanied by a characteristic phenotype (central adiposity, doll-like face, acromicria, high-pitched voice, decreased muscle mass). In the neonatal age, if other pituitary deficits are present, patients present with hypoglycemia, micropenis, with or without cryptorchidism, prolonged jaundice, and elevated liver enzymes(18).

As with selective GHD, most cases of multiple hormonal deficiencies are idiopathic, and in 20-25% of cases, a responsible gene is identified. Many of the transcription factors involved in the secretion of pituitary hormones are not specific to the pituitary gland and participate in the ontogeny of other organs, so they are frequently associated with other malformations. The mode and timing of presentation of the different hormonal axes can vary, so they can appear at later ages; generally speaking, TSH and GH deficiencies are the “earliest,” while FSH, LH, PRL, and ACTH impairment can be “late” and manifest in adulthood. The genes most frequently involved in multiple hormone deficiencies are HESX1 (septo-optic dysplasia), PROP1, POU1F1 (TSH, GH and prolactin deficiency), RIEG (Rieger syndrome), LHX3, LHX4, SOX3 (X-linked GHD with psychomotor delay), GLI2 (holoprosencephaly), GLI3 (Pallister-Hall syndrome), OTX2, FGF8 (holoprosencephaly), FGFR1 (eye defects, corpus callosum hypoplasia) and IGSF1 (TSH, GH and prolactin deficiency with macroorchidism)(18,19).

Inactive GH refers to an immunologically reactive, but structurally abnormal and biologically inactive, GH molecule produced by a pathogenic variant in the GH1 gene. It is characterized by a progressive growth retardation with normal or high serum levels of GH, since they produce immunologically detectable GH, but biologically inactive, which is why it is associated with decreased levels of IGF-I and IGFBP-3, a positive response in the IGF-I generation test (rhGH administration for 5 days with a 50% increase in basal IGF-I levels), since the GH receptor is normal, and a good response to treatment with rhGH(5,17).

Primary IGF-I deficiency or primary GH insensitivity syndrome is a rare condition that presents with a very characteristic and severe phenotype; it is included within the postnatal growth retardation, with a proportionate appearance. These conditions are characterized by normal or increased GH secretion with very low levels of IGF-I and IGFBP-3 in the absence of systemic disease, malnutrition, chronic inflammation, liver damage or other comorbidity that justifies a lower production of IGF-I due to secondary insensitivity. They present with severe SS, decreased growth velocity and a characteristic phenotype (facies with midfacial hypoplasia, broad forehead, central adiposity), although partial or variable severity forms are currently accepted. Laron syndrome due to affectation of the GH receptor gene (GHR) was identified 50 years ago and represents the extreme form of insensitivity, but today less severe forms and partial insensitivity are accepted. GH action and biological signal transmission require protein phosphorylation, including STAT5b (signal transducer and activator of transcription 5B), also involved in immune function, and therefore, deficiency of this factor is associated with recurrent lung and skin infections. Other proteins responsible for transmitting the GH signal are known, such as STAT3, also involved in immune function, the interleukin 2 receptor (ILRG2 gene) and phosphatidylinositol 3 kinase (PIK3R1 gene)(35). The primary defect of the acid-labile subunit (ALS) results in a lower bioavailability of IGF-I at the peripheral level and is associated with very low serum levels of IGF-I, IGFBP-3 and ALS; the phenotype is not as severe and its growth pattern may resemble constitutional growth retardation. The mutation of the IGF1 gene can determine a severe decrease in IGF-I, which causes severe prenatal and postnatal delay, microcephaly, sensorineural hearing loss, retromicrognathia and mental retardation, reflecting the important role of IGF-I in prenatal growth and in the development of the central nervous system (CNS). Growth retardation due to bioinactive IGF-I due to a mutation in the IGF1 gene has also been described, which associates elevated levels of IGF-I, but biologically inactive. IGF-I resistance is due to heterozygous mutations in the IGF-I type 1 receptor gene (IGF1R), which are responsible for isolated cases of pre- and postnatal growth retardation, and recent studies indicate that they are present in up to 2% of SGAs with SS. Patients with mutations in the IGF2 gene present a phenotype similar to Silver-Russell syndrome, indicating that IGF-II plays a role in postnatal growth in addition to its function in fetal growth. Recently, a new syndrome due to mutations in the PAPPA2 gene has been described and involves a deficiency of a protease of the IGF-I transport protein (IGFBP-3), which, when deficient, prevents the release of IGF-I from the ternary complex. It occurs with elevated GH and total IGF-I, IGFBP-3 and ALS, and a decrease in free IGF-I due to lower bioavailability at the peripheral level(20). The classification of GH-IGF axis disorders is presented in table IV(19,20).

 

Psychosocial disorders and iatrogenic growth retardation

Situations of emotional deprivation (neglect, abandonment, bullying, abuse) are associated, depending on the degree and duration, with growth and pubertal delays due to secondary functional hypopituitarism. Treatments for cancer can lead to impaired growth; total body irradiation, in addition to affecting the pituitary gland, leads to reduced growth of the trunk, resulting in disharmonious growth retardation; chemotherapy and drugs that block cellular tyrosine kinase activity can also slow growth. Treatments that suppress appetite can cause reduced growth rates.

Growth disorders of unknown cause: idiopathic short stature

The term idiopathic short stature (ISS) is an arbitrary and controversial concept, since establishing the etiology of a patient is closely related to the extent of complementary studies. The classic definition of ISS includes any child with height ≥2 SD below the mean for age, sex and population group, normal prenatal growth assessed by normal length and weight for gestational age, absence of endocrine disease, which includes demonstration of normal GH secretion, absence of chronic diseases, chromosomal abnormalities, nutritional and/or emotional deficiencies, normal physical examination and normal body proportions. From a conceptual point of view, ISS has been subdivided into familial ISS and non-familial ISS, and in turn, both groups can be subclassified into children with delayed puberty and children with normal puberty. ISS has been the subject of extensive reviews and its concept has been subject to debate and discussion over the last years(21).

The ISS group includes children with normal variants of short stature (NVSS), which include familial short stature (FSS), constitutional delay of growth and puberty (CDGP), and mixed cases. Furthermore, the ISS concept includes patients who, while meeting the criteria of the previous definition, present minor skeletal or phenotypic abnormalities that may go unnoticed without a thorough examination, and who reach a short adult height that is lower than their genetic height. This group of patients is not part of the “classic” NVSS concept and would be forms of pathological SS with a cause not identified with standard studies, in which an advanced study is required to ensure that they are truly “idiopathic.” It is estimated that approximately 60-80% of children who consult for SS fall into the ISS group, and of these, the vast majority would be NVSS and the rest would be pathological ISS(22).

Normal variants of short stature

The term familial short stature (FSS) includes healthy individuals with short stature, who have a normal maturational rhythm (normal bone age and puberty), normal growth velocity, have a history of SS in first-degree relatives, and reach a short adult height commensurate with their genetic makeup. The diagnosis of FSS is made by exclusion, and it is important to emphasize that short parents do not always mean simple FSS, since the presence of this finding does not exclude the possibility that the child may present other causes of growth retardation or that the parents carry a genetic abnormality of variable expressivity.

The concept of constitutional delay of growth and puberty (CDGP) includes children with slow maturation and an adequate growth velocity, but who, from 7-8 years of age, experience a decrease in growth velocity, which becomes very evident in the peripubertal ages, with delayed bone age and the onset of puberty. A history of pubertal delay in the father (late shaving age, late growth spurt) and/or in the mother (late menarche) is very common. The growth pattern of these children is very characteristic and can be summarized as follows: a) normal weight and length at birth; b) normal growth velocity during the first 12-18 months of life with a subsequent decline until 2-4 years of age, when height is within its genetic range; c) from 2-4 years of age, growth velocity reaches a normal rate, but below average; d) significant prepubertal decrease in growth velocity; e) delayed height for chronological age, but not for bone age, which presents a delay ≥2 years; and f) late pubertal growth spurt, but in line with bone age, characterized by a shorter time interval from the onset of puberty to the start of the growth spurt and by a less intense peak growth velocity. All children spontaneously, although late, reach complete pubertal maturation, and most achieve a normal adult height appropriate for the family; although, in a variable percentage (~20%), adult height is between 0.6 and 1.5 SDS below their GH. Patients with associated FSS and/or a decreased growth velocity throughout childhood and during the prepubertal period are at greater risk of not reaching their GH; conversely, children with a family history of tall stature tend to match or exceed their GH. A definitive diagnosis of CDGP cannot be made until the late onset of puberty is confirmed (≥13-14 years in males and ≥12-13 years in females)(14,25). The clinical characteristics of NVSS are presented in table V(1,16,23).

 

Pathological idiopathic short stature

Population genome studies have shown that most of the genes involved in height variability are related to the growth plate and endochondral ossification. These genes include the SHOX (short stature homeobox gene Xp22.33 and Yp11.2); NPR2 (natriuretic peptide receptor 2; 9p13); FGFR3 (fibroblast growth factor receptor 3; 4p16.3), NPPC (natriuretic peptide precursor C; 2q37); ACAN (aggrecan; 15q26.1) and IHH (Indian hedgehog homolog; 2q35). These are genes whose mutations in a state of homozygosity or compound heterozygosity determine a specific BD, while pathogenic variants in heterozygosity determine SS without apparent disproportion and with minor and nonspecific clinical and skeletal signs. As these genes are inherited in a dominant manner, a history of SS in one of the parents is frequent. These patients would form the group of pathological ISS and, once their cause is identified, would leave the ISS group and would become part of the growth failure due to primary involvement of the growth cartilage. The haploinsufficiency of the SHOX gene is present in 2-15% of patients with apparent ISS, and suggestive clinical findings would include the variable presence of minor skeletal abnormalities such as limb shortening, high-arched palate, micrognathia, cubitus valgus, tibial curvature, and a stocky appearance. Radiologically, these patients may present with minor findings such as altered bone alignment of the wrist bones, triquetrum deformity of the carpal bones, or triangular deformity of the radial head, but not all patients present with all these findings, and there may be patients who do not show radiographic abnormalities (Table III)(14). Patients with heterozygous involvement of the ACAN gene present short adult stature and a growth pattern characterized by accelerated bone age and premature closure of growth cartilages. The ACAN gene encodes a proteoglycan called aggrecan, which is a component of the extracellular matrix of the growth plate and articular cartilage. They have a mostly proportionate habit, although the arm span is greater than the height in some patients. These patients associate early-onset osteoarthritis, lordosis, and early lumbar herniation(5,22).

Diagnosis

The diagnostic process should be step-by-step and aims to differentiate normal variant SS from pathological SS and identify the cause as early as possible to initiate early treatment. A detailed clinical history, a thorough examination, and a correct interpretation of auxological and bone age data are the first steps in establishing a suspected diagnosis and guiding the appropriate testing.

In many cases, a diagnosis cannot be reached through clinical history and physical examination, so basic complementary testing must be performed to rule out systemic diseases. There is no consensus on which tests to perform, and they usually offer very low diagnostic yield. When an abnormality of the GH-IGF axis is suspected, IGF-I measurement is the first test to perform. Diagnosis of GHD in childhood is straightforward in severe forms. However, diagnosis of idiopathic GHD, which is the most common form, requires correct and judicious interpretation of clinical, auxological, radiological, and hormonal data (IGF-I levels and GH stimulation test), as there is no specific test. In cases of idiopathic SS that show minor skeletal abnormalities and/or mild dysmorphisms, especially if they are severe forms and there is a family history of short stature, a genetic cause should be suspected and advanced genetic studies should be performed in collaboration with a clinical geneticist for correct interpretation of the results, as they offer high diagnostic yield.

The causes of SS are multiple, and differential diagnosis requires a series of well-structured, step-by-step procedures before proceeding with complementary studies. Most cases are NVSS, and not every child requires the same range of complementary tests, since, in most cases, a thorough clinical history and physical examination will suffice to establish a diagnosis. In the diagnostic approach to SS, one could refer to five levels of examination(23,24).

Step 1: Medical history and physical examination

The first level would be based on a detailed clinical history and physical examination aimed at finding data that help identify a known cause responsible for the growth failure (Table VI)(24,25). Perinatal history inquiring about pregnancy and delivery, maternal illnesses, prenatal growth, weight, length and head circumference at birth, to identify whether the origin of the growth retardation is prenatal (idiopathic or secondary intrauterine growth retardation) or postnatal. It is necessary to assess the family history and ask for growth and puberty data from parents and relatives. The child’s genetic potential or “path” must be determined, and this is done by calculating the GT, which is the height that a son or daughter should reach assuming optimal and similar health conditions in both generations. There are different methods for calculating GT, but the most commonly used formula is obtained by calculating the average parental height adjusted by sex (Tanner formula); for women, it is [(father’s height + mother’s height) – 13] / 2; and for men, it is [(father’s height + mother’s height) + 13] / 2. GT ± 8.5 cm corresponds to the 3rd and 97th percentiles of adult height estimates, and a child is said to be short for their family when it is ≥ 2 SDs from the GT. Tanner’s formula underestimates the GT in the case of short parents and overestimates it in the case of tall parents. In these cases, another GT formula would be accepted: [(father’s height SD + mother’s height SD) / 2] x 0.72(24,25).

 

Personal history must be made to rule out symptoms of systemic disease (chronic diarrhea, bloody stools, abdominal pain, anorexia, recurrent infections, chronic cough, dyspnea, arthralgia, arthritis, fatigue, slowness, weight loss, hypertension, virilization, headache and neurological symptoms) and to perform a nutritional, psychiatric and emotional history. Physical examination includes comprehensive auxology. Length is defined below the age of 2; children at this age should be measured supine using an infant stadiometer. Height is defined above the age of 3 and should be measured using a well-calibrated stadiometer. Between the ages of 2 and 3, both methods are used to calculate previous and future growth velocity using the same methodology. In addition to length/height, weight, head circumference, body mass index, sitting height, sitting height/height ratio, arm span, and a study of body segments [upper segment (US) and lower segment (LS)] should also be assessed. In children under 2–3 years of age, the fontanelle and dentition (indicative of developmental rhythm) should also be examined, and nutritional status is assessed using the weight-for-length ratio. In older children, pubertal development should be assessed according to Tanner’s stages, since it is very important to relate growth velocity to pubertal stage. The child should be examined to determine whether or not he or she has started puberty (4 mL testes in boys and breasts with a stage II glandular button in girls) and, in turn, what stage of puberty he or she is in, since the pubertal growth spurt occurs in girls in the initial stages of puberty (Tanner II-III), while in boys it occurs in the advanced stages (Tanner III-IV). When assessing growth, the choice of appropriate charts is very important, and the use of updated national charts is recommended, especially those based on longitudinal studies. In Spain, the most commonly used charts for assessing growth are those from the 2010 Spanish Cross-Sectional Study(26). In their absence and below 2 years of age, the charts from the World Health Organization (2006) should be used; this is especially accepted for nutritional assessment, and above this age, the use of the CDC charts is recommended (Centers for Disease Control and Prevention)(5,25).

For a correct auxological assessment three parameters need to be considered: height relative to the mean (SD or percentile position); comparison of height relative to genetic height; and growth velocity adjusted for age, sex, and pubertal stage. Studies are often performed unnecessarily and when the situation requires them. Table VII(25) presents the auxological criteria based on which a SS study should be initiated to rule out pathological SS(24,25).

 

The clinical history may show key signs that allow us to think about the existence of GHD, such as hypoglycemia, prolonged neonatal jaundice, micropenis, history of cranial irradiation, CNS trauma or infection, consanguinity or involvement of a first-degree relative, and craniofacial midline abnormalities. Physical examination reveals proportionate short stature, central adiposity, broad forehead, midfacial and/or nasal root hypoplasia, a graceful doll-like appearance, and acromicria of the hands and feet. In many cases, only short stature is identified, and the auxological criteria for suspecting GHD are as follows: a) severely short stature less than -3 SD; b) height more than 1.5 SD below the mean parental height; c) height less than -2 SD and growth velocity for one or more years below -1 SD or a height loss greater than 0.5 SD for one year in children over 2 years of age; d) in the absence of short stature, a growth velocity of less than -2 SD for one year or less than -1.5 SD on a sustained basis or a height loss of more than 1.5 SD for 2 years; and e) signs indicative of intracranial injury or multiple pituitary deficiency or GH deficiency in the newborn(17-19).

The physical examination should include a search for signs of facial dysmorphia or phenotypic features and body proportions that suggest a specific syndrome. Measuring body segments can indicate disharmonious or disproportionate growth retardation and is equivalent to indicating an abnormality in the relationship between sitting height (SH) and standing height. SH (distance between vertex and coccyx) gives an idea of trunk length. The SH/height ratio is 0.7 at birth and 0.5 when skeletal maturation is reached. A high sitting height/standing height ratio, greater than 0.55, indicates SS due to limb shortening (achondroplasia-type BD, hypochondroplasia, Turner syndrome, hypophosphatemic rickets); whereas a low ratio indicates SS due to trunk shortening (spondyloepiphyseal BD, post-spinal radiotherapy BD, scoliosis). This ratio can be expressed in SD according to reference standards, and disproportionate SS can be suspected if the ratio is above or below 1 SD. Measuring the lower segment (LS) (distance between the pubic symphysis and the floor) is less precise than calculating the SH, but it is also used clinically to diagnose disproportionate SS. The upper segment (US) is calculated by subtracting height from LS. References exist for the upper segment/lower segment ratio. Normal values for the US/LS vary with age: in newborns it is 1.7; in the first few years it is >1; at 10 years of age it is equal to 1; and over 10 years of age it is <1. A reduced US/LS ratio suggests shortening of the spine, and when it is increased, shortening of the lower limbs. Measuring the arm span (the distance between the fingertips with the arms fully extended and abducted at 90°) can identify upper extremity shortening. Arm span, in newborns, is 2.5 cm shorter than length; in childhood, it is equal to height; and in adolescence, it is 2 cm longer than height in males and 4 cm longer than height in females. Upon examination, when there is a difference greater than 4 cm, upper extremity shortening should be suspected. Similarly, measurements of the forearm or leg can be performed to identify mesomelic shortening of the upper or lower extremities according to reference standards. Physical examination and history taking are very important, since up to 25% of children with pathological SS may not be identified by auxological criteria and hence the importance of assessing the phenotype, dysmorphisms, associated pathology and personal clinical history(5,23,24).

Serial measurements allow for the calculation of the growth velocity over a minimum period of 6 months, ideally 1 year. A thorough reconstruction of the child’s growth pattern up to the present is essential. Growth velocity (GV) can also be expressed in SD for age and sex and by percentile. It is accepted that a GV below the 25th percentile (~ -1 SD) maintained for one year is indicative of a possible growth disorder, and when it is below the 10th percentile, it requires a special study.

It is important to carry out a bone age (BA) (hand and wrist X-ray, usually of the left or non-dominant hand). There are different methods for its assessment, but the most commonly used is the Greulich and Pyle atlas, which is an observer-dependent method with high variability. BA provides information on the patient’s residual growth and helps guide the diagnosis. Based on bone age and using Bailey-Pinneau tables, the predicted adult height (PAH) can be calculated. Automated methods that reduce variability also allow for the calculation of PAH. PAH is indicative and serves as a developmental parameter, although it is unreliable when there is a significant advancement or delay in BA or in BD and syndromic SS. A delayed BA suggests CDGP, GH deficiency, nutritional deficiency, or chronic systemic disease. In contrast, an advanced BA indicates premature maturation (precocious puberty, adrenal hyperandrogenism). In primary growth disorders (syndromes, BD), BA is usually consistent with chronological age. Hand and wrist radiographs also serve to rule out skeletal abnormalities indicative of minor syndromes or BD (brachydactyly, shortening of the 4th metacarpal in pseudohypoparathyroidism, Turner syndrome, Madelung deformity due to haploinsufficiency of the SHOX gene).

Step 2: Targeted complementary examination

The second level of examination would focus on specific investigations based on the examination findings. When BD is suspected (disproportionate SS or SS significantly below the patient’s genetic height), a radiographic examination is required, which should include the skull, spine, thorax, pelvis, long bones, and left hand. Clinical signs that should raise suspicion of BD include macrocephaly, shortening of limbs or a body segment, severe undergrowth, limited joint movement, thoracic abnormalities, kyphosis and/or scoliosis, genu valgum/varus, brachydactyly, and, often, a positive family history due to the dominant nature of many of these abnormalities. A thorough clinical examination is required before the radiological examination, which should include height, weight, head circumference, arm span, sitting height, and the sitting height/height ratio or upper segment/lower segment ratio. All of this will allow the identification of BDs with trunk shortness (spondyloepiphyseal dysplasia, mucopolysaccharidosis) or limb shortening (achondroplasia, hypochondroplasia, pseudoachondroplasia, Léri-Weill dyschondrosteosis, metaphyseal dysplasia) and, in turn, the latter can be classified as rhizomelic, mesomelic, or acromelic, depending on whether the limb shortening is proximal (femur and humerus), middle (radius, ulna, tibia, fibula), or distal (hands and feet), respectively. Radiological studies allow them to be classified as epiphyseal, metaphyseal, or diaphyseal BDs, determine the affected regions, and rule out bone mineralization abnormalities. BDs do not always present with obvious disproportionate SS, as they vary in expression. Some mild forms of BD may have minor skeletal abnormalities that go unnoticed, and in these cases, they can be included in the ISS group and form part of the differential diagnosis. There are many syndromes associated with growth retardation that can be diagnosed clinically through a thorough physical examination (Table II)(3,4); many of these syndromes are linked to specific genetic abnormalities, so genetic testing should be performed in a targeted manner(14,24).

Step 3: General complementary examination

In most cases, a specific diagnosis is not reached through physical examination and clinical history, so complementary testing should be performed. Various treatment protocols have been proposed in this regard, but there is no international consensus (Table VIII)(24). In healthy children with short stature and no specific medical history of interest, with a normal physical examination and who maintain a growth velocity greater than 5 cm/year, the diagnostic yield of the tests performed is very low (less than 2%), since the vast majority of them did not have any abnormalities in the study performed, indicating the low incidence of pathology in healthy children with short stature and a normal physical examination. It is agreed that all children with SS should have a thyroid function test, celiac disease screening, and IGF-I levels. If the history and examination suggest a specific cause of the growth retardation, specific complementary tests should be performed (sweat test if suspected cystic fibrosis, 24-hour urinary free cortisol if hypercortisolism due to Cushing’s disease or syndrome is suspected, or stool parasites if intestinal parasitosis is suspected).

 

Step 4: Advanced complementary examination: study of the GH-IGF axis

Determination of IGF-I is the first test performed when GHD is suspected, with decreased values suggesting its diagnosis. However, variations with age, pubertal stage, sex, nutritional status, and body mass index, and the limitations of the methodology for performing a robust and consistent IGF-I determination, as well as the absence of generally applicable reference values, limit its usefulness and make its interpretation difficult. Before the age of 3, the range of normal IGF-I values includes the method’s lowest detection level, so there is an overlap of values between normal and deficient children. Therefore, at this age, the predictive value of IGFBP-3 is considered higher, but, beyond that age, its sensitivity is lower than that of IGF-I. Decreased IGF-I and IGFBP-3 values make GHD highly likely, but other pathologies must be ruled out, such as malnutrition, hypothyroidism, and GH insensitivity. In turn, when associated with delayed development and puberty, the IGF-I level should be interpreted in relation to the child’s pubertal stage (bone age) and not in relation to their chronological age. As a diagnostic parameter for GHD, IGF-I has variable sensitivity and specificity depending on the study; the cutoff level with the best sensitivity and specificity is -1.65 SDS. IGF-I alone is of little value and should always be interpreted in combination with the rest of the examination. An isolated IGF-I measurement below -2 SD has a sensitivity of 65% and a specificity of 80% as a diagnostic value for GHD, so up to 35% of children with GHD have normal IGF-I levels. IGF-I measurement can help select patients for study, as a very low probability of presenting GHD has been described in children with IGF-I above -1 SD (14%) or 0 SD (4%). The combination of IGF-I and growth velocity increases sensitivity to 95% and specificity to 96%. In a child with SS and normal growth velocity (≥25th centile), having a normal IGF-I (≥50th centile) makes the diagnosis of GHD very unlikely(27).

If auxology and IGF-I levels suggest GHD, the next step is measurement of GH secretion using a stimulation test. The pulsatile nature of GH secretion requires stimulation tests, but they have many limitations. These are non-physiological stimuli with low specificity and reproducibility, and can produce a high number of false positives. Normative values adjusted for age, sex, pubertal stage, BMI, or even for each type of stimulus are lacking. Their use is not recommended in early childhood, where variability and limitations are greatest. To date, there are no randomized controlled studies at adult height that correlate GH levels in stimulation tests with the response to rhGH treatment until adult height. Cut-off points have been established arbitrarily and have varied historically from 3-5-7-10 ng/mL. The current methodology for determining GH in serum based on more specific monoclonal antibodies has led to a modification of the cut-off level from 10 ng/mL to 7 ng/mL. At present, the cut-off level that allows us to differentiate normality vs. deficiency is still not known with certainty. In the peripubertal age, it is difficult to establish whether an insufficient GH response is indicative of GHD, and it is essential to differentiate it from constitutional growth retardation. This is based on auxology, the degree of height delay for the child’s genetic height, and the study of the growth pattern, which must be interpreted according to the child’s maturation rate and with appropriate reference standards. To differentiate between these two situations, a study of the GH-IGF axis has traditionally been proposed after a short course of sex steroids (priming), but since there are no normal criteria for interpreting the results, its use is controversial. Some patients with auxological criteria compatible with GHD have decreased IGF-I levels and GH levels in stimulation tests above the cutoff point. These children do not have a classic GH deficiency, but do have an abnormality in the GH-IGF axis and, after excluding other pathologies, would be candidates for treatment with rhGH(27,28).

Brain MRI focusing on the hypothalamic-pituitary area may be helpful in diagnosing GHD. Hypothalamic-pituitary abnormalities suggestive of GHD include empty sella and absence of the anterior pituitary gland, ectopic neurohypophysis, hypoplasia or absence of the pituitary stalk or pituitary gland. MRI is indicated in any child, even in the absence of SS, who presents with an abrupt arrest of growth velocity and/or signs of intracranial hypertension to rule out a tumor in the hypothalamic-pituitary area. The isolated presence of pituitary hypoplasia is not sufficient to diagnose GHD, although it indicates the need for further work-up(19).

In children with suspected GHD, clinical guidelines continue to recommend stimulation testing, but they also recommend against basing the diagnosis of GHD solely on stimulation test results, implicitly acknowledging the lack of sensitivity and specificity. One way to reduce false positives from stimulation tests is to auxologically select patients for study. The combination of height less than -2 SD, growth velocity less than -1 SD, and height ≥1.5 SD below genetic height offers high sensitivity and specificity for a stimulation test cutoff of 7 ng/mL as a diagnostic criterion for GHD. There are special clinical situations where testing is not necessary, such as in newborns (baseline GH level less than 7 ng/mL) or in patients with severe auxological criteria associated with a hypothalamic-pituitary malformation or congenital or acquired hypopituitarism. Severe GHD is easily identifiable, but the diagnosis of idiopathic GHD is always challenging, as the difference between idiopathic SS and idiopathic GHD is problematic; therefore, the diagnosis of idiopathic GHD in childhood should be based on clinical judgment, including auxological, radiological and hormonal parameters, as well as the physician’s experience(28).

A decrease in IGF-I levels with normal or elevated GH secretion should lead to consideration of two situations: inactive GH or a GH insensitivity or resistance syndrome(20,28). GH insensitivity or resistance syndromes may be primary or of genetic origin, or secondary to protein-calorie malnutrition or a chronic systemic disease. Primary forms are very rare conditions due to genetic defects at the level of the GH receptor or postreceptor in the GH biological signal transmission chain, with very severe auxology and characteristic abnormalities of the GH-IGF axis. In secondary forms, there is a postreceptor dysfunction due to malnutrition. A differential diagnosis of GH-IGF axis disorders is presented in table IX(19,20).

 

Step 5: Advanced complementary examination: genetic studies

The last level of examination involves carrying out genetic studies that allow the identification of the cause of the growth retardation in cases where a specific diagnosis has not been made and who are classified as pathological ISS, since the study performed up to that point has been normal. Patients classified as ISS who show skeletal abnormalities and/or minor nonspecific dysmorphisms raise suspicion of a genetic cause. Genetic studies should be performed as a final diagnostic test and always after a rigorous clinical examination. There are a series of clinical data that make a genetic cause more likely (Table X)(3,10).

 

Genetic studies, such as cGH array, multiplex ligation-dependent probe amplification (MLPA), Single Nucleotide Polymorphism (SNP)-array, clinical exome panel, exome trio, and whole genome, should be performed under diagnostic suspicion and in collaboration with the clinical geneticist for correct interpretation of the results. Currently, genetic studies have allowed us to understand the involvement of new growth plate regulatory genes, which in homozygosity or compound heterozygosity are presented as BD, while in heterozygosity they are presented as ISS (SHOX, NPR2, NPPC, IHH, FBN1, BMP2, FGFR3, ACAN). Table III(14) presents the clinical findings that should lead to suspicion of ISS associated with an anomaly of the SHOX gene and if this is negative, mutations in other genes should be sought, such as NPR2 (similar clinical phenotype without Madelung deformity), IHH (small hands, shortening of the middle phalanx of the 4th and 5th fingers) or NPCC (small hands, moderate brachydactyly). Each of these genes represents a small percentage of children with ISS, but this percentage is higher in cases with a history of SS in their parents, since they are genes that are inherited in an autosomal dominant manner. The prevalence of pathogenic abnormalities in copy number variants (CNVs) in patients with SS and psychomotor retardation, intellectual disability or additional malformations ranges between 10-15%. Performing targeted clinical exome or exome trio analysis in patients with pathological growth failure without an identified cause has a high diagnostic yield (25-50%)(5,24).

Treatment

Treatment of SS depends on the underlying cause and should be guided by etiology.

rhGH should be used under the indicated clinical conditions and at the recommended doses. Predictors of a good long-term response and adult height gain include starting treatment at an early age, prepubertal treatment duration, and response within the first year. rhGH is effective and safe with a very low incidence of complications. Long-acting GH administered weekly demonstrates an efficacy and safety profile that is not inferior to daily rhGH, which is why international agencies have approved its indication for GH deficiency in childhood, starting at 3 years of age. NVSS, FSS, and CDGP do not usually require any type of treatment once other causes of SS have been excluded and a differential diagnosis with idiopathic GHD has been made, which is often difficult. In some cases of CDGP, the patient may have significant psychological impairment, and in this case, which is more common in males than females, treatment with a short course of sex steroids can be offered. It is very difficult to correct a height deficit during puberty, and the use of LHRH analogues or aromatase inhibitors to delay bone maturation and increase growth potential is controversial and should be performed by a pediatric endocrinologist expert in growth on an individual basis. Recombinant IGF-I is indicated in cases of primary IGF-I deficiency. Vosoritide is an analogue of CNP (C-natriuretic peptide) which is indicated in patients with achondroplasia, as it improves growth and body proportions.

SS itself is not a disease, but rather a symptom of an underlying process. Therefore, treatment for SS depends on the etiology. Treatment for secondary growth retardation is aimed at treating the underlying disease and improving nutrition. In the case of psychosocial growth retardation, which is complex and difficult to diagnose, family attitudes should be modified and optimal nutrition should be ensured. Drugs are available that can influence growth (rhGH, rhIGF-I, sex steroids, CNP analogues (C-natriuretic peptide), modifying pubertal development and increasing growth potential (LHRH analogues, aromatase inhibitors) and surgical techniques that allow bone lengthening.

Growth hormone

Recombinant human growth hormone (rhGH) has a history of more than 40 years since its production in 1981 and subsequent indication in 1985 for GH deficiency (GHD) in childhood. Treatment with recombinant human GH (rhGH) has been available since 1985; previously, GH extracted from cadaveric pituitary gland was used, but this was discarded due to its association with Creutzfeldt-Jacobs disease. The greater availability of rhGH has allowed the indications to be extended to other non-deficiency conditions (Table XI)(29,30). In many chronic diseases, such as inflammatory bowel disease, juvenile chronic arthritis or chronic corticosteroid therapy, rhGH has been used with the aim of improving growth, but, except for chronic kidney failure, the indication is not approved for the rest of the situations(29,30). The goal of rhGH treatment is to normalize height as quickly as possible (catch-up growth), ensure normal growth and pubertal development, and achieve a normal adult height for the population and commensurate with TG. Its use is contraindicated in cases of poorly controlled systemic disease, active oncological disease, and/or epiphyseal closure. rhGH is administered subcutaneously, daily, at night, has a dose-dependent effect, and is well tolerated. It should be monitored by a pediatric endocrinologist; follow-up is usually performed every 3–6 months with clinical tests (height, weight, BMI, growth velocity, pubertal development), and annual monitoring of bone age, PAH assessment, determination of IGF-1 levels, which should be maintained within normal limits, thyroid function, and metabolic control (HbA1C, lipids) is recommended. Treatment is continued until adult height is reached and is discontinued when a BA ≥ 14 years in women or ≥ 16 years in men is reached and there is a GV ≤ 2 cm/year. In cases of multiple hormonal deficiency, treatment of the corresponding hormonal deficiencies should be carried out(31).

 

Treatment with rhGH raises unresolved issues, including variability in response and the difficulty in differentiating responding patients with significant height gain from non-responders. Regardless of the clinical condition, starting treatment at an early age, the number of years in prepubertal age, and response in the first year are very important predictors of a good long-term response. In prepubertal children diagnosed with GH deficiency, a height gain of 0.5 SD in the first year is associated with a final height gain of 1 SD. Poor response may be due to various causes, such as poor adherence, inadequate diagnosis and dosage, concomitant pathology or comorbidity requiring specific treatment (hypothyroidism, celiac disease, poor nutrition or low-calorie diet), low sensitivity to the action of rhGH, or even an unknown cause. Recognizing a poor response is an essential part of treatment. The family and patient should be educated and motivated regarding the need for good compliance. Treatment with rhGH is safe at indicated doses, with a low incidence of side effects. Pharmacovigilance studies have been conducted to verify the safety of the treatment. Adverse effects that may occur include lipoatrophy if injection sites are not rotated, arthralgia, edema, prepubertal gynecomastia, increased nevi, hyperglycemia due to decreased insulin sensitivity, and partial hypothyroidism due to interference with the action of TRH and/or increased peripheral conversion of T4 to T3; all of these are rare, mild, and disappear upon dose reduction or temporary discontinuation of treatment. Potential treatment complications include benign cranial hypertension, femoral capitis epiphysiolysis, and progression of scoliosis, which, in the absence of risk factors, are very rare (<1:1,000 children on treatment). No association has been demonstrated between the use of rhGH and the development of neoplasia in children without an increased risk of cancer. There is insufficient evidence to conclude that rhGH increases the risk of malignancy in children with a risk factor for malignancy, although its use is not recommended in these patients. An increased risk of developing a second tumor has been described in patients with a history of childhood cancer treated with rhGH; this risk decreases with prolonged observation, and a causal relationship is difficult to establish given the presence of other factors, especially prior radiotherapy. Therefore, there is insufficient evidence to recommend against rhGH treatment(31).

GH has different actions; at the bone level, it stimulates longitudinal growth, bone remodeling, endochondral ossification, and calcium apposition, but at the metabolic level, it promotes protein anabolism and lean mass gain, stimulates cardiac function and maximum aerobic capacity, and decreases fat mass and inhibits glucose uptake and lipogenesis. These actions at different levels have meant that its indications are not limited to a growth-stimulating effect (e.g., GH deficiency in adolescence, GH deficiency in adulthood). GHD should be re-evaluated upon reaching adult height; most idiopathic GHD are transient, but severe GHD, combined hypopituitarism, and deficits are frequently permanent forms, as are genetic defects. Discontinuation of rhGH treatment in adolescents with a permanent form of GHD is associated with an increase in cardiovascular risk factors (increased visceral fat, increased total cholesterol, LDL cholesterol, and decreased HDL cholesterol), decreased lean body mass gain, and decreased bone mass gain. Treatment with rhGH should be restarted in adolescence after appropriate clinical reassessment and evaluation(29-31).

Long-acting growth hormone (LGH)

Despite the accumulated experience with rhGH treatment, there are several unresolved gaps, including poor adherence and the impact that chronic daily injection treatment has on children and their families. In this regard, the potential benefits of weekly rhGH are lower injection frequency, potentially improved clinical outcomes by improving adherence, a reduced disease burden for patients, families, and caregivers, and improved tolerability and acceptance of treatment, all of which would result in improved quality of life for the patient and their carers. Clinical trials have shown a sustained effect over time with progressive normalization of height, with the patient reaching a normal height for the population and within their genetic range. Studies demonstrate a clear beneficial effect on variables measuring disease burden and treatment experience. The incidence of adverse effects is similar to that of daily rhGH, and IGF-1 levels increase in a dose-dependent manner, as do IGFBP-3 levels, and remain within the normal range. The three LGH molecules that have shown a non-inferior effect to daily rhGH in phase II and phase III trials for GH deficiency in childhood are somatrogon, lonapegsomatropin, and somapacitan. Weekly LGH demonstrates an efficacy and safety profile that is non-inferior to daily rhGH, which is why international agencies have approved its indication for GH deficiency in childhood, starting at 3 years of age. In 2023, the Spanish Agency for Medicines and Medical Devices (AEMPS) approved the use of somatrogon at a dose of 0.66 mg/kg/week. LGH is not currently indicated for other SS conditions, such as Turner syndrome or SGA, although clinical trials are underway. There is no doubt that a new era in the use of GH has opened with the approval of LGH, which may bring significant benefits to the quality of life of patients and their families. Real-life follow-up studies should be conducted to verify the benefit of LGH on adherence and quality of life and demonstrate that this therapeutic alternative is cost-effective and safe in the long term(32).

Idiopathic short stature

The NVSS, FSS and CDGP do not usually require any type of treatment once other causes of SS have been excluded and a differential diagnosis with idiopathic GHD has been made, which is often difficult. It is usually sufficient to explain the situation to the family and reinforce psychological support for the child, informing them of the benign nature of the condition, the absence of disease, and the expected normal progression of growth and puberty until reaching an adult height commensurate with their family. Clinical follow-up is aimed at providing reassurance to the family and the patient. In some cases of CDGP, and when accompanied by obvious delayed height and puberty, the patient may have psychological impairment that must be assessed; this is more common in males than in females. Those cases with psychological impairment and emotional (lower self-esteem, academic failure) and social (isolation) repercussions are candidates for hormonal treatment. If this occurs, a short course of sex steroids for 4-6 months would be indicated to induce pubertal development and stimulate growth. In men, low doses of testosterone esters are administered in the form of depot (propionate) preparations at a dose of 50 mg/month intramuscularly starting at 14 years of chronological age or 12 years of bone age, for a period of 3-6 months. Testosterone stimulates growth without accelerating bone age or compromising adult height, induces the appearance of secondary sexual characteristics and, since gonadotropins are not inhibited at low doses, pubertal development is favored. It is not considered necessary to initiate treatment below this age due to the risk of accelerating bone age. The first treatment cycle should be followed by a period of clinical observation (6 months). Oxandrolone, a non-steroidal anabolic steroid, has fallen into disuse, and clinical trials have been conducted with new-generation aromatase inhibitors (letrozole) with promising results. Its indication is less frequent in women, and low doses of estrogen are recommended starting at 13 years of chronological age or 11 years of bone age. 17β-estradiol (oral 5 mcg/kg/d or preferably transdermal 3.1-6.2 mcg/alternate days, equivalent to 1/8-1/4 of a 25 mcg patch) is used for a short period of 4 months with monitoring of bone age. It is known that treatment with sex steroids to induce puberty, when started after the age of 14 in boys or 12 in girls, has no impact on adult height, but provides significant psychological support(15,16).

In 2003, the FDA approved the indication use of rhGH in ISS, for children with SS ≤ -2.25 SD below the mean who have a growth velocity that makes it very unlikely they will reach normal adult height and in whom other causes of SS have been excluded at a dose of 0.035-0.050 mg/kg/day. The EMA, European Medical Agency, has not approved this indication. There is controversy regarding the degree of effectiveness of rhGH, and significant variability in response is accepted, consistent with the heterogeneity of patients categorized as ISS. Compared with the untreated control population, a mean height gain of 0.65 SD was observed, representing 4-5 cm, which is lower than that observed in other clinical conditions. A meta-analysis found an adult height gain of 4-6 cm, with a range between 2.3 and 8.7 cm, and a mean gain of 1 cm per year of treatment. Some authors suggest starting treatment at a dose of 0.034 and increasing the dose to 0.067 mg/kg/day. The strongest predictors of a better response to adult height have been an early age at initiation of treatment (<9 years), a higher dose, better length at birth, greater delay in bone age, and greater height deficit with respect to the TG. Since treatment response varies, and because response in the first year correlates with better long-term response, it is proposed to assess height gain at 12 months and, if the gain is less than 0.3-0.5 SD, to reconsider continuing treatment. Whether the resulting adult height gain is cost-effective and beneficial to the patient’s psychological well-being is open to debate(29-31).

Treatment of short stature during puberty

Regardless of the etiology of growth retardation, the possibilities of increasing growth potential during puberty are limited by the inexorable tempo of fusion of the growth plates that limits the residual growth time, and clinical experience dictates that it is very difficult to correct a height deficit during puberty. The increase in height during puberty only accounts for 17% and 12% of adult height in males and females, respectively. Since many patients present late with severe short stature at the onset of puberty, one of the objectives is to increase this percentage of height gain. There are several clinical observations that support the idea that adult height is dependent on the tempo and the level of exposure of the growth cartilage to estrogens. Patients with high exposure reach a smaller adult height than genetically expected, as occurs in precocious puberty, and conversely, patients with lower exposure, as in hypogonadism, reach a relatively tall adult height. Estradiol is the most important hormonal factor in the maturation of the growth cartilage in both men and women. There are two strategies to reduce the exposure of the growth cartilage to estrogens in order to delay bone maturation and increase growth potential: either through LHRH analogues (LHRH-a), by inhibiting gonadotropin release, or by peripherally blocking the conversion of testosterone to estradiol through aromatase inhibitors (AI)(33).

There is sufficient evidence to suggest that LHRH-a can halt puberty, delay bone maturation and epiphyseal closure, and increase adult height in patients with central precocious puberty. Treatment with LHRH-a in children with ISS and normal or advanced puberty has not demonstrated significant and clinically relevant efficacy in improving adult height, so the use of LHRH-a is not indicated. In patients with advanced puberty and rapid progression, individualized assessment could be made based on the degree of impairment in adult height. The combination of LHRH-a and rhGH has been proposed as an option to improve adult height in patients with severely impaired growth during puberty, always balancing benefits and disadvantages, especially in the psychological and bone health areas. In patients with SS (GHD, SGA) receiving rhGH treatment and whose height at the onset of puberty is below normal and who present premature puberty with significant AHP involvement, the addition of LHRH-a could be considered, especially in girls, for a minimum period of 2-3 years, since it is associated with an adult height gain of 6 to 9 cm and allows them to reach their GT. Since most of the evidence has been obtained from uncontrolled studies and the number of randomized clinical trials is limited, some authors consider its indication controversial. This option should be made on an individual basis by a pediatric endocrinologist expert in growth, sharing the decision with the family due to the psychological impact of halting puberty.

A selective way to prolong the growth period in puberty is to prevent the action of estrogens at the growth cartilage level by means of AIs; this has the advantage over the use of LHRH-a that it does not stop pubertal progression. AIs are not approved for any pediatric indication, but are approved for the treatment of breast cancer, and have been used off-label in different situations of pathological SS in men, either alone or in combination with rhGH. Studies of AIs in ISS and CDGP are limited, and although they demonstrate a slowing of BA and a significant improvement in AHP of +5 cm, there are few studies at adult height and the results are not always consistent. The use of AIs in combination with rhGH has been studied in patients with ISS and GHD. Patients receiving combination therapy (rhGH + anastrozole) show significantly slower progression of BA than those receiving rhGH alone and a significantly greater height gain relative to the growth prognosis, demonstrating that combining an AI with rhGH treatment increases growth potential. The studies have limitations, the main one being the lack of data at adult height. The possible side effects of AIs are related to the decrease in estradiol levels and a possible impact on the morphology of the vertebral bodies and the lipid profile, although short-term treatment of less than 2-3 years has not demonstrated any impact on bone mineral density.

Regarding the use of AIs in Pediatrics, the Cochrane group has conducted a systematic review and concluded that current evidence indicates that the use of AIs improves short-term growth results, but there is not enough evidence to indicate an increase in adult height due to the scarcity of studies with adequate methodology. The lack of data on adult height makes it impossible to draw firm conclusions and it is considered a controversial treatment. The use of AIs should be individualized, performed by experienced pediatric endocrinologists, in boys with pathological short stature at the beginning of puberty and significant involvement of the AHP, not in prepuberty, with a bone age greater than 12 years and less than 14.5 years. A short treatment duration of 2-3 years is recommended, in combination with rhGH, since it allows to improve growth and long-term response. Its use is not recommended in women, since when LH levels increase they can develop ovarian cysts. The use of medication “off-label” does not imply that it is illegal or contraindicated, as long as its use is supported by studies and after consent and information to the family and patient of the benefits, risks and expected results. The use of AI in pediatrics must be very individualized and cautious(33).

Insulin-like growth factor type I (IGF-I)

Recombinant IGF-I was approved in 2007 for patients with primary IGF-I deficiency (primary/genetic abnormalities of the GH receptor, in its post-receptor intracellular signaling pathways STAT5B, genetic IGF-I deficiency, PAPP-A2 deficiency, ALS deficiency) who meet the following criteria: height ≤ -3 SD, decreased growth velocity ≤ 10th percentile, normal or elevated GH secretion and IGF-I levels below the 2.5th percentile for age- and sex-adjusted values, absence of secondary disease (malnutrition, hypothyroidism) that would justify secondary insensitivity to GH, and IGF-I generation test with no increase in IGF-I levels after rhGH administration. It is also indicated in patients with genetic GHD type IA (absence of GH) who, after rhGH administration, synthesize neutralizing anti-GH antibodies and are therefore resistant to rhGH treatment. The recommended dose is 40-80 mcg/kg/day, in two subcutaneous doses. Side effects include hypoglycemia, adenoid and tonsillar hypertrophy (snoring, sleep apnea, hearing loss), lipohypertrophy, benign cranial hypertension, subcutaneous tissue growth and facial changes, visceromegaly, arthralgia, and muscle pain. It is recommended to administer with meals to avoid hypoglycemia. Clinical experience has focused primarily on primary GH receptor deficiency, and a positive response has been observed, with variable height gain (0.8-4.3 SD), which is less than that observed in GH deficiency treated with rhGH. This lower response is attributed to the absence of restoration of the physiology of the IGF system, since the levels of IGFBP-3 and ALS are not normalized, and to an absence of the direct action of GH at the level of chondrocytes, which would mean less differentiation of the same and less local autocrine production of IGF-I(34).

Bone dysplasias

Surgical lengthening of the long bones (tibia, humerus, femur) has been used in the treatment of severe SS due to BD with a dual objective: to increase adult height and improve segment proportionality. In severe SS not associated with BD, its indication is more controversial. Regarding the lengthening of the lower limbs (femur and tibia) and upper limbs (humerus), different options have been described, and their indication, age at which they are performed, and the technique used is discussed. Lengthening of the lower limbs between 14 and 40 cm aims to increase standing height, improving the variables of proportionality, functionality, and quality of life dependent on the lower segment. Similarly, lengthening of the upper limbs, with elongations between 8 and 10 cm, allows for an increase in arm length and, therefore, improves the variables of body proportionality and functionality dependent on the upper segment. Significant increases in height are achieved, but these procedures frequently involve complications and incidents, requiring prolonged follow-up and not always achieving satisfactory functional results. Therefore, patients and families must be fully informed beforehand about the advantages and disadvantages, and the patient must be highly motivated; they should only be performed by centers with proven experience(13).

In 2022, the AEMPS approved the indication of vosoritide for achondroplasia in patients older than 2 years of age and with open epiphyses, and the indication was subsequently extended to 4 months of age and older. Achondroplasia is the most common cause of SS associated with BD, with an estimated incidence of 1/10,000-1/30,000 live births. It is caused by an activating mutation in the FGFR3 gene which determines a gain of receptor function and overactivation of the MAPK signaling pathway (mitogen-activated protein kinase), inhibiting the proliferation and differentiation of growth plate chondrocytes. Vosoritide is an analogue of CNP (C-natriuretic peptide) which, upon binding to its receptor, inhibits MAPK activity and leads to increased chondrocyte differentiation and proliferation. Trials have shown an increase in annual growth rate of 1.57 cm/year in the treated group vs the control group, which is maintained over the years and produces a net gain in height. In addition, an improvement in body proportions is evident. The approved treatment is 15 mcg/kg/day, is maintained until the epiphyses close, and is well tolerated with a good safety profile. Phase III clinical trials are being conducted in patients with hypochondroplasia with encouraging results(35).

Role of the Primary Care pediatrician

Primary care pediatricians play a fundamental role in monitoring the growth of healthy children and in the early detection of growth disorders. Good communication and coordination between primary care and specialized care is essential for early diagnosis and treatment of growth disorders. Although there is no established consensus regarding which tests should be performed in primary care and when to refer children with short stature to specialized care, the functions of the primary care pediatrician can be summarized as follows:

• Monitor the growth and development of healthy children as an indicator of health and well-being. In addition to monitoring height, weight, and BMI, they should also check for normal pubertal development, both in terms of onset and progression.

• When faced with a child with SS, it is important to know how to differentiate between NVSS and possible pathological SS. It is important to have the foundation for a complete history and physical examination, an auxological assessment, and an accurate interpretation of the growth curve to suggest FSS and/or CDGP.

• Carrying out basic general complementary tests to confirm the suspected diagnosis of NVSS and rule out other systemic diseases.

• Refer cases with suspected pathological SS and those children diagnosed with NVSS who have marked growth retardation and/or a poor prognosis for adult height and/or whose progression is not as expected to the reference Pediatric Endocrinology Unit.

• Monitor children with an established diagnosis of NVSS and provide children, parents, and caregivers with realistic information about growth expectations.

Growth and development is a complex process that spans from the fetal period to the end of adolescence, involving a multitude of factors. Proper monitoring of this process is a very useful clinical tool for detecting diseases at different levels.

Conflict of interest

There is no conflict of interest in the preparation of this manuscript nor source of funding.

Bibliography

The asterisks show the author’s opinion that the article is of interest.

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Recommended bibliography

– Wit JM, Kamp GA, Oostdijk W. Towards a rational and efficient diagnostic approach in children referred for growth failure to the general paediatrician. Horm Res Pediatr. 2019; 91: 223-40.

A must-read article. This is an excellent review of the topic, which addresses the differential diagnosis of short stature in a very informative and academic manner. It was written by a Dutch research group with a strong tradition in growth studies and has a very clinical approach. The reader will enjoy it.

– Collett-Solberg PF, Ambler G, Backeljauw P, Bidlingmaier M, Biller BMK, Boguszewski MCS, et al. Diagnosis, genetics and therapy of short stature in children: a Growth Hormone Research Society International Perspective. Horm Res Pediatr. 2019; 92:1-14.

This is an article elaborated after the meeting of a group of experts from the Growth Hormone Research Society. Easy to read with clear messages about when to begin a study for short stature, tests to perform, patient selection for genetic testing, and management of children on rhGH treatment.

– Grimberg A, DiVall SA, Polychronakos C, Allen DB, Cohen LE, Quintos JB, et al. Guidelines for Growth Hormone and Insulin-like Growth Factor-I treatment in children and adolescents: growth hormone deficiency, idiopathic short stature and primary insulin-like growth factor-I deficiency. Horm Res Pediatr. 2016; 86: 361-97.

This is a clinical guide elaborated by the Pediatric Endocrine Society, regarding the diagnosis and treatment of GH deficiency, idiopathic short stature, and primary IGF-I deficiency. It establishes recommendations based on the GRADE system, making it a mandatory article for good clinical practice. Highly recommended.