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Review

Idiopathic Short Stature: What to Expect from Genomic Investigations

by
Nathalia Liberatoscioli Menezes Andrade
1,
Laurana Polli Cellin
1,
Raissa Carneiro Rezende
1,
Gabriela Andrade Vasques
2 and
Alexander Augusto Lima Jorge
2,*
1
Unidade de Endocrinologia Genetica (LIM25), Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo 05403-000, Brazil
2
Unidade de Endocrinologia Genetica (LIM25) e Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular (LIM42), Hospital das Clinicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo 05403-000, Brazil
*
Author to whom correspondence should be addressed.
Endocrines 2023, 4(1), 1-17; https://doi.org/10.3390/endocrines4010001
Submission received: 1 November 2022 / Revised: 7 December 2022 / Accepted: 3 January 2023 / Published: 9 January 2023
(This article belongs to the Special Issue Growth and Growth Disorders)
Review Reports Versions Notes

Abstract

:
Short stature is a common concern for physicians caring for children. In traditional investigations, about 70% of children are healthy, without producing clinical and laboratory findings that justify their growth disorder, being classified as having constitutional short stature or idiopathic short stature (ISS). In such scenarios, the genetic approach has emerged as a great potential method to understand ISS. Over the last 30 years, several genes have been identified as being responsible for isolated short stature, with almost all of them being inherited in an autosomal-dominant pattern. Most of these defects are in genes related to the growth plate, followed by genes related to the growth hormone (GH)–insulin-like growth factor 1 (IGF1) axis and RAS-MAPK pathway. These patients usually do not have a specific phenotype, which hinders the use of a candidate gene approach. Through multigene sequencing analyses, it has been possible to provide an answer for short stature in 10–30% of these cases, with great impacts on treatment and follow-up, allowing the application of the concept of precision medicine in patients with ISS. This review highlights the historic aspects and provides an update on the monogenic causes of idiopathic short stature and suggests what to expect from genomic investigations in this field.

1. Introduction

Short stature is a common concern for physicians caring for children and is defined as having a height exceeding 2 standard deviations (SD) below the corresponding mean for a given age, sex, and population group. Based on this definition, short stature affects 2.3% of children [1]. In the traditional approach taken to investigate the cause of growth deficiencies, these children undergo an extensive medical evaluation searching for hormonal etiologies or other chronic medical conditions. However, previous studies have shown that a standard medical evaluation does not often lead to a diagnosis in a healthy child whose only positive finding based on anamnesis and a physical examination is short stature [2,3]. In about 70% of cases of short stature evaluations, the children are healthy, without clinical and laboratory findings that explain their growth disorder, being classified as having constitutional short stature or idiopathic short stature (ISS) [2,4,5]. This scenario has been changing with the improvement of the genetic sequencing techniques, which have made it possible to diagnose 10–30% of these children, providing an answer to the cause of their isolated short stature [6,7,8,9,10,11,12,13]. This review provides an update on the monogenic causes of idiopathic short stature and indicates what to expect from the genomic investigation in this field.

2. Materials and Methods

2.1. Search Strategy

We conducted a systematic literature review to identify studies reporting the use of genetic sequencing approaches in the investigation of idiopathic short stature. We searched the PubMed® databases and included studies from 1960 to November 2022.

2.2. Eligibility Criteria

We searched the literature for review, observational studies, and clinical studies that included genetic data about children classified as having idiopathic short stature. The key words “idiopathic short stature” and “genetics” were screened, and 6421 results were found. We excluded in this analysis books, documents, and papers that were not written in English, with 1026 results remaining. We considered as the most relevant articles those that encompassed large cohorts and used a multigene sequencing analysis for idiopathic short stature. We chose articles that addressed the term idiopathic short stature for the first time to discuss historical aspects and the most relevant articles that addressed genetic aspects related to idiopathic short stature in the last 20 years.

3. Historic Aspects of Idiopathic Short Stature

The term idiopathic is often used to relate to or to denote any disease or condition that arises spontaneously or without any known cause [14]. It is usually a diagnosis of exclusion, but it is unclear what minimum investigation should be carried out to define a condition as idiopathic. Therefore, many medical specialties have difficulties in defining this term [15]. In the context of short stature, it is hard to determine when the term idiopathic was first used in the medical literature concerning children with a growth disorder. To the best of our knowledge, the first time that this concept was reported was in 1964 in a paper that described the growth response to pituitary growth hormone (GH) [16]. In this study, the author explained the following: “The remainder of the patients could presumably be forced into various ill-defined groups, called primordial, ateliotic, constitutional, hypocaloric, or low-birth-weight dwarfs [16]. However, there is still much doubt if these terms delineate what has been posteriorly called “idiopathic growth failure”. In 1968, Edelmann et al. used the term “idiopathic growth retardation”, referring to children with growth retardation, with no determined etiology [17]. In the early 1970s, the term idiopathic short stature (ISS) appeared in the medical literature for the first time [18,19]. However, the term included patients with short stature regardless of birth weight or length, and it was generally used to describe growth disorders of an unknown cause. In 1996, after a consensus meeting, it was defined that children with ISS would be those with adequate birth weight and length for gestational age (>−2 SDS), without body disproportion, without evidence of chronic organic diseases, without psychiatric illnesses, with adequate nutrition, and without evidence of endocrine deficiencies, including GH [20]. Since then, the term has been widely used in clinical practice and was reinforced by the consensus study published in 2008 [21]. Nevertheless, these consensuses preceded the expansion of genetic studies in growth disorders [22]. Nowadays, more than 900 papers on PubMed address genetic studies involving children with ISS. Several of these studies described genes in which rare deleterious variants cause short stature without other characteristics or only with subtle phenotypes. These genes are mainly involved in the GH/insulin-like growth factor (IGF-1) axis and growth plate physiology [23], challenging the continued use of the term ISS.

4. Genetic Basis of Idiopathic Short Stature

Human height has a high degree of heritability, indicating that genetic factors are one of the main determinants of height [24]. Environmental aspects also contribute to height variability. Studies that evaluated the growth pattern of twins showed an increasing pattern of height heritability with age, being low in early childhood and up to 0.68–0.94 at older ages [25]. This genetic influence on height is attributed to a complex combination of multiple genes and variants in a typical pattern of a polygenic trait.
Based on these concepts, the genetic evaluation emerged as a great potential tool to understand ISS. In recent years, several genome-wide association studies (GWAS) have identified more than 12,000 common variants affecting adult height [21,24,26]. Each of these common variants (minor allele frequency (MAF) ≥ 5%) has a low impact on height variability (less than 1–2 mm), whereas rare variants (MAF < 1%) were associated with having a greater impact on height (around 20 mm) [27,28]. Thus, the combination of common and rare variants explains the height variability in the general population and those with short stature without other clinical manifestations in a polygenic model that is classically used to explain ISS [26,29].
In contrast to the polygenic nature presented above, more extreme phenotypes of short stature or syndromic growth disorders are often associated with monogenic conditions [30,31]. The first described monogenic cause of short stature was severe isolated growth hormone (GH) deficiency. In 1981, it was shown that a deletion of the GH1 gene caused complete GH deficiency and severe short stature [32]. In the last 40 years, hundreds of genes involved in syndromes associated with growth impairment have been identified [31]. These children and their families carried extremely rare variants with a great effect on the phenotype, usually with syndromic characteristics and Mendelian inheritance [28]. However, over the last 30 years, several genes have been identified as responsible for isolated short stature, almost all of them following an autosomal-dominant inheritance pattern [6,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47] (Table 1). This background is helping us better understand the genetic basis of short stature in non-syndromic individuals.

5. Genes Related to “Idiopathic Short Stature”: Monogenic Conditions

5.1. Genes Related to the GH-IGF1 Axis

The GH/IGF-1 axis is an essential postnatal growth regulator. One of the main criteria for classifying a child as having ISS is to exclude a diagnosis of GH deficiency [55]. The other axis defects are rare conditions, often causing extreme short stature and likely to be well characterized by the hormonal profile [56]. However, defects involving this axis can also cause remaining growth disorder phenotypes, often labeled as ISS.

5.1.1. GH1

In addition to the inherent difficulty in ruling out GH deficiency in children with short stature [22,57], the role of bioinactive GH molecules has long been postulated [58,59]. Specific mutations in GH1 make GH unable to activate its receptor but it retains its ability to be detected by GH assays. Few patients with biologically inactive GH have been described in the literature [60,61,62,63]. The patients usually have severe postnatal short stature (height SDS < −3) without significant dysmorphisms. A laboratory evaluation of these patients demonstrated a normal to elevated GH peak in stimulation tests and low levels of IGF-1 and IGFBP-3. The improvement in growth velocity and the increase in IGF-1 levels during short- and long-term rhGH therapy differentiates these children from those with insensitivity to GH [62]. Despite representing an extreme form of short stature, these patients can be classified as ISS, and only the identification of the genetic variant in GH1 allows the correct determination of the etiology of the growth disorder [35].

5.1.2. GHR

Classically, biallelic mutations in the GH receptor gene (GHR) cause complete insensitivity to GH (GHI) or Laron syndrome, a severe inability to respond to endogenous or exogenous GH with particular growth and metabolic effects [64]. Patients with the classical GHI phenotype have severe postnatal short stature, elevated basal and stimulated GH levels, and extremely low IGF-1/IGFBP-3 levels that do not increase after rhGH use. Studies in the 1990s suggested that children classified as having ISS could have partial forms of GHI, with low IGF-1 and GH binding protein (GHBP) values and high mean 12-h GH values [65]. In humans, GHBP is generated by the cleavage of GHR found on the cell surface, which reflects the expression of this receptor. Over the years, it has become clear that GH insensitivity occurs across a broad spectrum of severity [66]. In 1994, a GHR mutation was first reported in patients classified as ISS [33]. In this study, the author evaluated GHR in 14 ISS children with low GHBP and identified three patients with heterozygous and one with compound heterozygous GHR variants. Following this study, several others described patients with ISS and heterozygous variants of GHR. However, many of these variants would not be classified as pathogenic under the current criteria in variant analyses [67]. As GHR haploinsufficiency causes a slight reduction in height (around 4 cm) [68], only variants with a dominant negative effect can relate to short stature with autosomal dominant inheritance [69].

5.1.3. GHSR

Ghrelin is a brain–gut peptide that acts by binding to the growth hormone secretagogue receptor (GHSR) [70]. Beyond its action in energy metabolism and the regulation of appetite, this peptide was also related to bone formation and growth hormone release. The active form of GHSR is expressed predominantly in the pituitary and hypothalamus. Studies suggest that ghrelin regulates GH secretion, through GHSR, in an endocrine pathway distinct from GHRH and somatostatin, and contributes to the control of pulsatile GH release [71], with a high degree of constitutive activity in vitro. In 2006, Pantel et al. reported a GHSR missense variant in two unrelated families with short stature, demonstrating that this defect resulted in decreased receptor expression and selectively impaired the constitutive activity of the GHSR, whereas it preserved the ability for ghrelin response [38]. Homozygous and heterozygous defects in the GHSR gene were associated with ISS and with GH deficiencies of variable severity and penetrance. Both phenotypes were even described in the same family [38]. Additionally, heterozygous GHSR defects were also related to constitutional delays in growth and puberty [72]. This heterogeneity in the clinical presentation may be partially explained by the gene defects causing protein alterations that affect the binding affinity to ghrelin and the constitutive activity of the receptor itself. However, the role of GHSR variants in growth disorders is still a matter of debate.

5.1.4. STAT5B

The signal transducer and activator of transcription 5B (STAT5B) is an important cytoplasmic protein in the GHR signaling pathway. STAT5B is responsible for increases in the expression of several GHR-stimulated genes, such as IGF1, its binding protein (IGFBP-3), and the acid labile subunit (ALS) [73]. A homozygous inactivating mutation in the STAT5B gene was first described in 2003 as a rare cause of growth hormone insen sitivity in a patient with severe short stature and immunodysfunction [74]. Individuals heterozygous for loss-of-function (LoF) mutations in STAT5B have a mean negative impact of 3.9 cm in their height, usually resulting in their stature being within the normal range [75]. Collaborating with the idea of a spectrum of effects on height, in 2018, three heterozygous STAT5B mutations with dominant negative effects were described in eleven individuals from three unrelated families. The probands had variable degrees of short stature, with the laboratory evaluations being suggestive of mild GHI, elevated IgE, and eczema [46]. These data have identified STAT5B as a gene that can be associated with ISS.

5.1.5. IGF1 and IGF1R

IGF-1 is essential in intrauterine and postnatal growth, acting through a tyrosine kinase receptor, IGF-1R. Patients with LoF homozygous mutations in IGF1 or IGF1R experience prenatal-onset growth impairments, failure to thrive, microcephaly, and developmental delays [76]. While patients with IGF1 defects have extremely low levels of IGF-1, those with IGF1R defects show an elevation of this hormone. Both genetic defects cause normal to high concentrations of basal and stimulated GH [76]. The defects in heterozygosity in IGF1 or IGF1R have a much more variable clinical presentation. With the increase in cases with defects in these genes, some patients can be labeled as having ISS. Some cases of heterozygous LoF mutations in IGF1 were described; these patients had variable degrees of pre- and postnatal growth retardation with serum IGF-1 at the lower end of the normal range due to IGF1 haploinsufficiency [40]. Although most patients fit into the classification of children born small for gestational age (SGA) and have associated microcephaly, some patients may fit into the ISS classification. Heterozygous mutations in IGF1R were more frequent than in its ligand but showed similar broad clinical variability levels [77,78]. Some affected patients are born with weight and length within the lower reference limits and develop short stature during childhood, with normal to elevated IGF-1 values at baseline, which rise above the reference values during GH treatment [50,79]. Thus, heterozygous defects in IGF1 or IGF1R may be present in children classified as having ISS, being more likely in cases when the birth weight or length is at the lower limit of normality.

5.1.6. Ternary Complex Defects (IGFALS and PAPP-A2)

Most circulating IGF-1 is found in a ternary complex bound with IGFBP-3 and ALS (acid labile subunit). This complex is important in extending the serum IGF-1 half-life and decreasing its bioavailability at the tissue level [80]. Homozygous or compound heterozygous defects in the IGFALS cause human acid labile subunit (ALS) deficiencies. This condition causes a mild phenotype of GHI, characterized by moderate postnatal growth impairment, pubertal delay, normal or even increased GH, and a marked reduction in the levels of IGF-1 and IGFBP-3, which remain low after GH treatment [52,80,81] Heterozygous carriers of IGFALS gene mutations have a partial ALS deficiency, resulting in less than 1.0 SD of height loss and generally not causing short stature [82]. One study showed that the frequency of rare IGFALS variants in children with ISS is 3 times higher than in normal height controls, suggesting that defects in heterozygosity in this gene may contribute to short stature and low IGF-1 levels in some children with ISS [37].
Also related to the ternary complex, pregnancy-associated plasma protein A2 (PAPP-A2) is a serum and tissue protease responsible for the proteolysis of IGFBPs, releasing IGF-1 from the ternary complex [83]. PAPP-A2 specifically cleaves IGFBP-3 and -5, so the loss of PAPP-A2 function leads to increased serum concentrations of IGFBP-3 and IGFBP-5 and total concentrations of IGF-1, decreasing the bioactive IGF-1. Until now, few families with homozygous LoF mutations in PAPPA2 have been described [43,84]. In addition to their variable degrees of short stature, some patients had microcephaly, thin long bones, low bone mineral density, and insulin resistance. They also presented with markedly elevated serum concentrations of IGF-1 and IGFBP-3. As the clinical findings are relatively non-specific, some patients with PAPPA2 defects may be classified as having ISS if a more detailed hormonal assessment is not performed [83].

5.2. Genes That Regulate Growth Plate Physiology

Longitudinal growth depends on the endochondral ossification process in the growth plate. This process involves proliferation, hypertrophy, and the senescence of chondrocytes and cartilage matrix synthesis [85]. The regulation of the entire physiology of the growth plate involves several paracrine and autocrine factors, and defects in genes encoding any of these factors or their respective receptors, inherited in an autosomal dominant manner, can cause a variable phenotype form of isolated short stature with or without mild body disproportion [86]. In the last 20 years, growth-plate-related genes have become protagonists in studies related to ISS [87]. The most consistent and frequent findings were those involving short stature homeobox (SHOX) [34], natriuretic peptide receptor 2 (NPR2) [39], aggrecan (ACAN) [41], Indian hedgehog (IHH) [45], natriuretic peptide C (NPPC) [44], fibroblast growth factor receptor 3 (FGFR3) [42], and collagen-related genes [47]. Each of these genes is responsible for a small proportion of cases of isolated SS (up to 2%), but this proportion may be significantly higher in familial short stature [6,27].

5.2.1. SHOX

SHOX is located on the pseudoautosomal region of sex chromosomes and is expressed in hypertrophic chondrocytes in the growth plate. SHOX is a transcription factor that increases NPPB and inhibits the expression of FGFR3, stimulating and coordinating the proliferation and differentiation of chondrocytes. It also has an important role in the synthesis of the growth cartilage matrix through interactions with the SOX trio (SOX9, SOX5, and SOX6 genes) [49]. Since its first description in 1997, SHOX gene haploinsufficiency has become the leading monogenic cause of short stature (1–10% of non-syndromic short stature cases) [34,49].
It is known that defects in this gene comprise an enormous phenotypic variability ranging from isolated short stature with or without mild body disproportion to Leri–Weill dyschondrosteosis (LWD), a type of skeletal dysplasia characterized by mesomelia and Madelung deformity [88]. Despite being recognized, its phenotypic variability still needs to be better understood. Most genetic defects related to the SHOX gene (>70%) are deletions involving the whole gene or its regulatory regions. Although the genotype–phenotype correlation is still a matter of debate, deletions in downstream SHOX enhancers have been associated with a milder phenotype (variable degrees of short stature, with milder body disproportions and the absence of Madelung deformity) [89]. The growth impairments in SHOX haploinsufficiency are variable, but longitudinal follow-up studies suggest the presence of a growth retardation in early life with birth lengths in the lower range of normality, a relatively well-preserved prepubertal growth, an attenuated pubertal growth spurt, and a frequent short adult height. The loss of growth potential observed in these patients suggests an additional effect of estrogens in the presence of SHOX defects, which lead to premature fusion of the growth plate. A few studies suggest that recombinant human growth hormone (rhGH) therapy (with or without GnRH analog treatment) can improve the adult height of patients with SHOX haploinsufficiency by up to 1 SDS of height [90,91,92,93].

5.2.2. NPR2 and NPPC

In the last 10 years, the C-type natriuretic peptide (CNP) system and its receptor (NPR-B), encoded by the NPPC and NPR2 genes, respectively, have been identified as important regulators of the endochondral ossification process. The CNP/NPR-B system stimulates the proliferation and differentiation of chondrocytes and the synthesis of the growth plate matrix in an autocrine and paracrine manner. This action is partially explained by the inhibition of the FGFR3 pathway. Only two families, with short stature and small hand phenotypes, have been described as having heterozygous NPPC mutations [44]. In contrast, numerous descriptions of patients with homozygous NPR2 defects have been made.
Biallelic mutations in NPR2 lead to acromesomelic dysplasia of the Maroteaux type, a skeletal dysplasia characterized by severe mesomelic short stature and abnormalities in the phalanges and metacarpals [94]. Heterozygous mutations in NPR2 have been described in cohorts of children with idiopathic short stature (with frequency rates ranging from 1.8 to 13.6%) [82]. These patients have variable degrees of height deficit and progressive short stature with increasing loss of height potential with age [95]. In addition to short stature, these patients may also have mild body disproportion and nonspecific skeletal findings such as short metacarpals [39,96]. Treatment with rhGH promotes short-term height gains, but the data on the final height in treated patients are not yet available [97].

5.2.3. ACAN

Aggrecan, which is encoded by the ACAN gene, is a major proteoglycan component in the extracellular matrix of the growth plate and articular cartilage. Biallelic defects in ACAN cause Spondyloepimetaphyseal dysplasia, while alterations in the heterozygous state account for a less severe and more variable phenotype [98]. Since 2014, more than 100 variants have been described in the ACAN gene [41,99,100,101,102]. Usually, these patients have a severe to mild proportional short stature with advanced bone age in the prepubertal period, which leads to premature growth arrest after the onset of puberty, causing a deficit in adult height. The premature maturation of hypertrophic chondrocytes and the early invasion of growth plates by blood vessels and osteoblasts are proposed mechanisms for advanced bone age, early epiphyseal fusion, and premature growth arrest in patients with ACAN mutations [41]. Despite being a striking feature, it is not found in all patients [103]. Due to its presence in the articular cartilage, the patients may also present with early-onset osteoarthritis, which is more common by the fourth decade of life, mainly affecting the knees, with variable degrees of severity [102]. The limited data about growth patterns show that pubertal spurts may be impaired due to advancing bone age, which lead to a short adult height. Thus, these patients could benefit from puberty blocking and rhGH therapy [99,104].

5.2.4. IHH

The Indian hedgehog gene (IHH) is expressed in prehypertrophic cartilage chondrocytes and coordinates chondrocyte proliferation and differentiation during endochondral bone development [93]. Defects in the IHH gene have already been recognized as a cause of skeletal dysplasias in homozygosis (acrocapitofemoral dysplasia) and in heterozygosis (brachydactyly type A1, BDA1) [94]. More recently, heterozygous IHH mutations have been reported as a very frequent cause of short stature (frequency of 3.4%), with mild body disproportion and non-specific skeletal abnormalities such as brachymesophalangia-V (BMP-V, shortening of the middle phalanx of the fifth digit of varying degree) [33,95]. Despite being frequent in the general population (12.1%), BMP-V is a very common finding (64.3%) in hand radiographs of individuals with heterozygous mutations in IHH [33]. While the IHH mutations responsible for BDA1 are always missense and in the same domain of the protein, the mutations causing ISS are distributed throughout the gene and can also be LoF, suggesting a mechanism of haploinsufficiency. A short-term good response to rhGH has been described in these patients [33].

5.2.5. FGFR3

The fibroblast growth factor receptor-3 (FGFR3) pathway acts as a negative regulator of growth plate chondrogenesis. Heterozygous gain-of-function mutations in FGFR3 are recognized as causing achondroplasia and hypochondroplasia. Achondroplasia is clinically characterized by severe disproportionate short stature with rhizomelia [105]. On the other hand, hypochondroplasia is generally less severe and has a wider phenotypic variability [106]. Although body disproportion is expected in patients with hypochondroplasia, some children may not be diagnosed in the first evaluation. These children may not yet have radiographic findings suggestive of a skeletal defect or may have a slight body disproportion, which can only be recognized through the sitting height/total height ratio. As such, they are often classified as having idiopathic short stature, demonstrating the variable spectrum of the phenotype [107]. Corroborating this hypothesis, a recent study identified an activating mutation of FGFR3 causing autosomal proportional familial short stature without other specific findings [42].

5.2.6. COL2A1 and Other Collagen Genes

Collagens are the main structural components of the extracellular matrix, with type II collagen being the main collagen synthesized by chondrocytes. This type of collagen is found in the vitreous humor, inner ear, nucleus pulposus, and mainly in the growth cartilage, and is essential for the endochondral ossification process. Mutations in the COL2A1 gene interfere with the grouping of type II collagen molecules, causing varying degrees of skeletal dysplasia and some types of eye disorders. More than 16 syndromic conditions have been associated with collagen gene defects [108]. Some of these may present with short stature and unspecific skeletal alterations. However, due to the great variability and overlapping phenotypes, mainly in COL2A1, COL11A1, and COL11A2-related disorders, some mutations in collagen genes have already been reported in ISS cohorts [12,31,109,110,111]. In a recent study, Plachy et al. found 9 collagen genes variants (COL2A1, COL11A1) in 17 patients (11.5%) in a cohort of familial short stature patients that were treated with growth hormone therapy, reinforcing the role of these genes in genetic causes of short stature usually classified as idiopathic [47].

5.3. Genes Related to RAS-MAPK Pathway

Increased signal transduction through the mitogen-activated protein kinase (RAS-MAPK) cascade is a common molecular mechanism that characterizes a heterogeneous group of syndromes classified as RASopathies. Noonan syndrome is the main representative of this group and has short stature as one of its clinical criteria. However, there is a wide spectrum of genetic variability among individuals, and their phenotype–genotype correlations are not fully established, even within the same family. Another challenge in the diagnosis is that even in the presence of typical dysmorphisms, they can undergo changes according to age group, which often makes the clinical diagnosis even more difficult; these children can be classified as having idiopathic short stature due to their attenuated phenotype. Pathogenic variants in genes related to the RAS-MAPK pathway have already been identified in cohorts of patients with idiopathic short stature, with the diagnosis often being only possible using a genetic approach.

5.3.1. PTPN11

The protein–tyrosine phosphatase non-receptor type 11 gene (PTPN11) encodes the non-receptor Src-homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP2). SHP2 participates in multiple intracellular signaling pathways, including the Ras/MAPK cascade. Heterozygous mutations in PTPN11 cause Noonan syndrome (NS), characterized by reduced postnatal growth, congenital heart disease, and facial dysmorphisms [112]. Usually, children can also present with low serum IGF-1 levels, which reflects some degree of GH insensitivity [113]. Although most children harboring PTPN11 variants have some clinical features of Noonan syndrome, there is a wide variability in clinical presentation, even in patients with the same genetic variant [100]. In addition, some mutations have a less intense effect (hypomorphic) and a more discrete phenotype [114]. Based on this, PTPN11 variants have been increasingly described in studies evaluating multiple genes in ISS in children without other clinical criteria of Noonan syndrome [6,11,12,54]. This can be partially explained by the important changes in craniofacial features with age, which sometimes can make a clinical diagnosis of NS challenging. Children with PTPN11 variants in the milder end of the NS phenotypic spectrum can also be classified as having ISS. The identification of a pathogenic variant in PTPN11 in a child with isolated short stature has evident impacts on the follow-up and treatment.

5.3.2. NF1

Neurofibromin 1 (NF1) is a gene related to the RAS-MAPK pathway that encodes neurofibromin, a RAS-specific guanosine triphosphatase (GTPase)-activating protein that converts active GTP-bound RAS to inactive GDP-bound RAS. The inactivation of neurofibromin leads to the hyperactivation of RAS and contributes through other mediators to cell and growth proliferation related to the formation of tumors. The classic presentation of patients who carry variants in the NF1 gene includes café au lait spots, cutaneous or plexiform neurofibromas, and Lisch nodules in the iris. Intellectual disabilities, vasculopathies, optic gliomas, and increased risk of nervous system tumors, and short stature may be present, which can often suggest a Noonan-like phenotype [115]. Due to having the same phenotypic variability and the fact that the clinical features can change during childhood, NF1 variants have been found in cohorts of children with ISS, making it a gene to be enrolled in the genetic investigation of patients with isolated phenotypes [54]. Additionally, these data highlight the importance of a genetic diagnosis, as it has a great impact on the clinical follow-up as well as on the decision to start growth hormone therapy in these patients.

6. Conclusions and What to Expect from Genomic Investigations

In the last 20 years, the investigations of children with short stature have been changing considerably. The genetic approach has gained importance and emerged as a potential method to establish the etiology of growth impairment. Since the 1950s, when the karyotype technique was developed and explained chromosomal abnormalities such as Down’s syndrome and Turner’s syndrome, a lot has changed. The chromosome microarray analysis (CMA) technique became frequently used due to its greater sensitivity in detecting submicroscopic copy number variants (CNVs, deletions, and duplications). A CMA can reveal a pathogenic CNV in approximately 10% of growth disorders, mainly in children with syndromic short stature of an unknown cause [116]. The identification of point variants (single-nucleotide variants and small insertions and deletions) has also undergone great developments, migrating rapidly from Sanger sequencing to next-generation sequencing (NGS). This new technology allows the sequencing of multiple regions and genes simultaneously and can include an analysis of CNVs, an in-target gene panel, and whole-exome sequencing (WES) or whole-genome sequencing (WGS).
The use of NGS-based techniques improves the diagnostic yield and better explains the genetic basis of the isolated short stature phenotype for patients initially classified as having ISS. Although the current guidelines suggest that the genetic test should preferably be conducted in syndromic conditions or when it is possible to determine a candidate gene [22,117], this approach is being challenged. Children classified as having ISS infrequently show signs that reliably allow a candidate gene investigation, and for this reason the multigene approach is a logical strategy to assess them. Additionally, it has been increasingly shown that a significant number of children with ISS have a monogenic form of short stature (Table 2). The average diagnostic rate of the multigene approach in ISS is around 12.5% (ranging from 8.7 to 19.5%) [12]. Finally, the costs of genetic tests and their analysis have demonstrated substantial and rapid improvements. The perspective is that in the near future, according to Moore’s law, the price of human genome sequencing may drop quickly and considerably [118]. Consequently, a multigene approach (e.g., a targeted gene panel or WES) in children with ISS will soon become a good option, since it might save time and costs when used with other exams and provide an answer for a significant number of families about the cause of short stature, allowing the rapid identification of other affected family members.
Additionally, knowing the genetic basis of these patients’ short stature can allow precise genetic counseling and clinical follow-up. This is particularly relevant to children harboring variants in the RAS-MAPK pathway. Moreover, the use of rhGH therapy in ISS is controversial, and at some point the genetic studies can support the use of this therapy. It is accepted that children with SHOX haploinsufficiency can improve their adult height with rhGH therapy [91,93]. Some preliminary data have already associated with a good short-term response to rhGH treatment in patients with variants in the IHH [45], NPR2 [97], and ACAN [119] genes. The knowledge of the genetic basis of ISS has the potential to clarify the growth pattern and to trigger the development of specific treatment protocols, including the indication and the use of rhGH, natriuretic peptide analogs, or puberty modulators with the added benefit of permitting drug development through targeted therapy.
However, a substantial number of children with ISS remain undiagnosed, even after performing a WES analysis. Initially, we must remember that not every short child will be a short adult. Observational studies of children with ISS show that the majority show spontaneous catch-up growth [120]. These children are not expected to have genetic factors (mono- or polygenic) that cause short stature. Secondly, new genes associated with ISS need to be revealed. Furthermore, as height is a polygenic trait, it is expected that using a polygenic risk score (PRS) in combination with rare variants may increase the degree of knowledge about height determination, allowing the application of the concept of precision medicine in patients with ISS [26]. What we expect from the genomic investigation is that these diagnostic tools will be routinely offered and recommended in assessing children with ISS, so that we can close those gaps that remain open to so many families who seek our help.
Table
Table 2. A review of multigene approach studies on “idiopathic short stature”.
Table 2. A review of multigene approach studies on “idiopathic short stature”.
ReferenceTotal CohortISS CohortMethodologyDiagnostic Yield
(Total Cohort)		Diagnostic Yield
(ISS Cohort)		Discussion
Wang et al. (2013) [6]19214Target gene panel with 1077 genes4/192 (2%)3/14 (21.4%)Included syndromic children
Guo et al.
(2014) [7]		143Exome5/14 (35.7%)0Only genes related to syndromic short stature
Hattori et al. (2017) [8]8686Target gene panel with 10 genes18 (20.9%)18 (20.9%)Excluded SGA and syndromic children
Hauer et al. (2018) [9]20013Exome38/200 (19%)11/13 (84.6%)134 children initially classified as having ISS but included children born SGA and with syndromic features
Freire et al. (2019) [10]17955Target gene panel/exome8/55 (14.5%)8/55 (14.5%)Included only children with isolated short stature born SGA
Perchard et al. (2020) [11]26318Target gene panel27/263 (10%) 5/18 (27.8%)Included children with GH deficiency and dysmorphic features
Fan et al.
(2021) [13]		561257Exome135/561 (24%)11.3% (29/257)Included genes associated with hypopituitarism, skeletal dysplasia, and chronic and metabolic disorders with the positive results in the ISS group.
Sentchordi-Montané et al.
(2021) [12]		108108Target gene panel21/108 (19.4%)12/108 (11.1%)Skeletal dysplasia NGS panel and SHOX-related genes were excluded. Included children born SGA.
Andrade et al.
(2022) [121]		102102Target gene panel17/102 (16.7%)17/102 (16.7%)Only children classified as having ISS

Author Contributions

Conceptualization, A.A.L.J.; methodology and selection of manuscripts to be included in the review, A.A.L.J. and N.L.M.A.; writing—original draft preparation, N.L.M.A. and L.P.C.; writing—review and editing, R.C.R., G.A.V. and A.A.L.J.; supervision, A.A.L.J. and G.A.V. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by Grant 303294/2020-5 (to A.A.L.J.) from the National Council for Scientific and Technological Development (CNPq) and by Coordination of Superior Level Staff Improvement (CAPES; Finance Code 001 to N.L.M.A., L.P.C. and R.C.R.).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

A.A.L.J. received an independent research grant from BioMarin and consulting fees from Novo Nordisk. The other authors declare that they have no competing financial interest to declare.

References

  1. Visscher, P.M. Commentary: Height and Mendel’s theory: The long and the short of it. Int. J. Epidemiol. 2013, 42, 944–945. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Sisley, S.; Trujillo, M.V.; Khoury, J.; Backeljauw, P. Low Incidence of Pathology Detection and High Cost of Screening in the Evaluation of Asymptomatic Short Children. J. Pediatr. 2013, 163, 1045–1051. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Dauber, A. Genetic Testing for the Child With Short Stature—Has the Time Come To Change Our Diagnostic Paradigm? J. Clin. Endocrinol. Metab. 2019, 104, 2766–2769. [Google Scholar] [CrossRef] [PubMed]
  4. Lindsay, R.; Feldkamp, M.; Harris, D.; Robertson, J.; Rallison, M. Utah Growth Study: Growth standards and the prevalence of growth hormone deficiency. J. Pediatr. 1994, 125, 29–35. [Google Scholar] [CrossRef] [PubMed]
  5. Voss, L.D.; Mulligan, J.; Betts, P.R.; Wilkin, T.J. Poor growth in school entrants as an index of organic disease: The Wessex growth study. BMJ 1992, 305, 1400–1402. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Wang, S.R.; Carmichael, H.; Andrew, S.F.; Miller, T.C.; Moon, J.E.; Derr, M.A.; Hwa, V.; Hirschhorn, J.N.; Dauber, A. Large-Scale Pooled Next-Generation Sequencing of 1077 Genes to Identify Genetic Causes of Short Stature. J. Clin. Endocrinol. Metab. 2013, 98, E1428–E1437. [Google Scholar] [CrossRef] [Green Version]
  7. Guo, M.H.; Shen, Y.; Walvoord, E.C.; Miller, T.C.; Moon, J.E.; Hirschhorn, J.N.; Dauber, A. Whole Exome Sequencing to Identify Genetic Causes of Short Stature. Horm. Res. Paediatr. 2014, 82, 44–52. [Google Scholar] [CrossRef] [Green Version]
  8. Hattori, A.; Katoh-Fukui, Y.; Nakamura, A.; Matsubara, K.; Kamimaki, T.; Tanaka, H.; Dateki, S.; Adachi, M.; Muroya, K.; Yoshida, S.; et al. Next generation sequencing-based mutation screening of 86 patients with idiopathic short stature. Endocr. J. 2017, 64, 947–954. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  9. Hauer, N.N.; Popp, B.; Schoeller, E.; Schuhmann, S.; Heath, K.E.; Hisado-Oliva, A.; Klinger, P.; Kraus, C.; Trautmann, U.; Zenker, M.; et al. Clinical relevance of systematic phenotyping and exome sequencing in patients with short stature. Genet. Med. 2018, 20, 630–638. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  10. Freire, B.; Homma, T.K.; Funari, M.F.A.; Lerario, A.M.; Vasques, G.A.; Malaquias, A.C.; Arnhold, I.J.P.; Jorge, A.A.L. Multigene Sequencing Analysis of Children Born Small for Gestational Age With Isolated Short Stature. J. Clin. Endocrinol. Metab. 2019, 104, 2023–2030. [Google Scholar] [CrossRef] [PubMed]
  11. Perchard, R.; Murray, P.G.; Payton, A.; Highton, G.L.; Whatmore, A.; Clayton, P.E. Novel Mutations and Genes That Impact on Growth in Short Stature of Undefined Aetiology: The EPIGROW Study. J. Endocr. Soc. 2020, 4, bvaa105. [Google Scholar] [CrossRef] [PubMed]
  12. Sentchordi-Montané, L.; Benito-Sanz, S.; Aza-Carmona, M.; Díaz-González, F.; Modamio-Høybjør, S.; de la Torre, C.; Nevado, J.; Ruiz-Ocaña, P.; López, C.B.; Prieto, P.; et al. High prevalence of variants in skeletal dysplasia associated genes in individuals with short stature and minor skeletal anomalies. Eur. J. Endocrinol. 2021, 185, 691–705. [Google Scholar] [CrossRef] [PubMed]
  13. Fan, X.; Zhao, S.; Yu, C.; Wu, D.; Yan, Z.; Fan, L.; Song, Y.; Wang, Y.; Li, C.; Ming, Y.; et al. Exome sequencing reveals genetic architecture in patients with isolated or syndromic short stature. J. Genet. Genom. 2021, 48, 396–402. [Google Scholar] [CrossRef] [PubMed]
  14. Law, J.; Martin, E. Idiopathic. In Concise Medical Dictionary; Oxford University Press: Oxford, UK, 2010. [Google Scholar]
  15. Tirlapur, S.A.; Priest, L.; Daniels, J.P.; Khan, K.S. How do we define the term idiopathic? Curr. Opin. Obstet. Gynecol. 2013, 25, 468–473. [Google Scholar] [CrossRef]
  16. Soyka, L.F.; Ziskind, A.; Crawford, J.D. Treatment of Short Stature in Children and Adolescents with Human Pituitary Growth Hormone (Raben). N. Engl. J. Med. 1964, 271, 754–764. [Google Scholar] [CrossRef]
  17. Edelmann, C.M.; Houston, I.B.; Soriano, J.R.; Boichis, H.; Stark, H. Renal excretion of hydrogen ion in children with idiopathic growth retardation. J. Pediatr. 1968, 72, 443–451. [Google Scholar] [CrossRef]
  18. Spiegel, R.N.; Sather, A.; Hayles, A.B. Cephalometric study of children with various endocrine diseases. Am. J. Orthod. 1971, 59, 362–375. [Google Scholar] [CrossRef]
  19. Grunt, J.A.; Enriquez, A.R.; Daughaday, W.H.; Budd, S. Acute and Long-Term Responses to hGH in Children with Idiopathic Small-for-Dates Dwarfism. J. Clin. Endocrinol. Metab. 1972, 35, 157–168. [Google Scholar] [CrossRef]
  20. Ranke, M.B. Towards a Consensus on the Definition of Idiopathic Short Stature. Horm. Res. 1996, 45 (Suppl. 2), 64–66. [Google Scholar] [CrossRef]
  21. Cohen, P.; Rogol, A.; Deal, C.L.; Saenger, P.; Reiter, E.O.; Ross, J.L.; Chernausek, S.D.; Savage, M.O.; Wit, J.M. Consensus Statement on the Diagnosis and Treatment of Children with Idiopathic Short Stature: A Summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. J. Clin. Endocrinol. Metab. 2008, 93, 4210–4217. [Google Scholar] [CrossRef]
  22. Collett-Solberg, P.F.; Ambler, G.; Backeljauw, P.F.; Bidlingmaier, M.; Biller, B.M.; Boguszewski, M.C.; Cheung, P.T.; Choong, C.S.Y.; Cohen, L.E.; Cohen, P.; et al. Diagnosis, Genetics, and Therapy of Short Stature in Children: A Growth Hormone Research Society International Perspective. Horm. Res. Paediatr. 2019, 92, 1–14. [Google Scholar] [CrossRef] [PubMed]
  23. Inzaghi, E.; Reiter, E.; Cianfarani, S. The Challenge of Defining and Investigating the Causes of Idiopathic Short Stature and Finding an Effective Therapy. Horm. Res. Paediatr. 2019, 92, 71–83. [Google Scholar] [CrossRef] [PubMed]
  24. Silventoinen, K.; Sammalisto, S.; Perola, M.; Boomsma, D.I.; Cornes, B.K.; Davis, C.; Dunkel, L.; de Lange, M.; Harris, J.R.; Hjelmborg, J.V.; et al. Heritability of Adult Body Height: A Comparative Study of Twin Cohorts in Eight Countries. Twin Res. 2003, 6, 399–408. [Google Scholar] [CrossRef]
  25. Jelenkovic, A.; Sund, R.; Hur, Y.-M.; Yokoyama, Y.; Hjelmborg, J.; Möller, S.; Honda, C.; Magnusson, P.; Pedersen, N.; Ooki, S.; et al. Genetic and environmental influences on height from infancy to early adulthood: An individual-based pooled analysis of 45 twin cohorts. Sci. Rep. 2016, 6, 28496. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  26. Yengo, L.; Vedantam, S.; Marouli, E.; Sidorenko, J.; Bartell, E.; Sakaue, S.; Graff, M.; Eliasen, A.U.; Jiang, Y.; Raghavan, S.; et al. A saturated map of common genetic variants associated with human height. Nature 2022, 610, 704–712. [Google Scholar] [CrossRef]
  27. Dauber, A.; Rosenfeld, R.G.; Hirschhorn, J.N. Genetic Evaluation of Short Stature. J. Clin. Endocrinol. Metab. 2014, 99, 3080–3092. [Google Scholar] [CrossRef]
  28. Durand, C.; Rappold, G.A. Height matters—From monogenic disorders to normal variation. Nat. Rev. Endocrinol. 2013, 9, 171–177. [Google Scholar] [CrossRef]
  29. Marouli, E.; Graff, M.; Medina-Gomez, C.; Lo, K.S.; Wood, A.R.; Kjaer, T.R.; Fine, R.S.; Lu, Y.; Schurmann, C.; Highland, H.M.; et al. Rare and low-frequency coding variants alter human adult height. Nature 2017, 542, 186–190. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  30. Baron, J.; Sävendahl, L.; De Luca, F.; Dauber, A.; Phillip, M.; Wit, J.M.; Nilsson, O. Short and tall stature: A new paradigm emerges. Nat. Rev. Endocrinol. 2015, 11, 735–746. [Google Scholar] [CrossRef] [Green Version]
  31. Wit, J.M.; Oostdijk, W.; Losekoot, M.; van Duyvenvoorde, H.A.; Ruivenkamp, C.A.L.; Kant, S.G. MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature. Eur. J. Endocrinol. 2016, 174, R145–R173. [Google Scholar] [CrossRef]
  32. Phillips, J.A.; Hjelle, B.L.; Seeburg, P.H.; Zachmann, M. Molecular basis for familial isolated growth hormone deficiency. Proc. Natl. Acad. Sci. 1981, 78, 6372–6375. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Goddard, A.D.; Covello, R.; Luoh, S.-M.; Clackson, T.; Attie, K.M.; Gesundheit, N.; Rundle, A.C.; Wells, J.A.; Carlsson, L.M. Mutations of the Growth Hormone Receptor in Children with Idiopathic Short Stature. N. Engl. J. Med. 1995, 333, 1093–1098. [Google Scholar] [CrossRef] [PubMed]
  34. Rao, E.; Weiss, B.; Fukami, M.; Rump, A.; Niesler, B.; Mertz, A.; Muroya, K.; Binder, G.; Kirsch, S.; Winkelmann, M.; et al. Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nat. Genet. 1997, 16, 54–63. [Google Scholar] [CrossRef]
  35. Millar, D.S.; Lewis, M.D.; Horan, M.; Newsway, V.; Easter, T.E.; Gregory, J.W.; Fryklund, L.; Norin, M.; Crowne, E.C.; Davies, S.J.; et al. Novel mutations of the growth hormone 1 (GH1) gene disclosed by modulation of the clinical selection criteria for individuals with short stature. Hum. Mutat. 2003, 21, 424–440. [Google Scholar] [CrossRef] [PubMed]
  36. Abuzzahab, M.J.; Schneider, A.; Goddard, A.; Grigorescu, F.; Lautier, C.; Keller, E.; Kiess, W.; Klammt, J.; Kratzsch, J.; Osgood, D.; et al. IGF-I Receptor Mutations Resulting in Intrauterine and Postnatal Growth Retardation. N. Engl. J. Med. 2003, 349, 2211–2222. [Google Scholar] [CrossRef] [PubMed]
  37. Domené, H.M.; Scaglia, P.A.; Martínez, A.S.; Keselman, A.C.; Karabatas, L.M.; Pipman, V.R.; Bengolea, S.V.; Guida, M.C.; Ropelato, M.G.; Ballerini, M.G.; et al. Heterozygous IGFALS Gene Variants in Idiopathic Short Stature and Normal Children: Impact on Height and the IGF System. Horm. Res. Paediatr. 2013, 80, 413–423. [Google Scholar] [CrossRef] [PubMed]
  38. Pantel, J.; Legendre, M.; Cabrol, S.; Hilal, L.; Hajaji, Y.; Morisset, S.; Nivot, S.; Vie-Luton, M.-P.; Grouselle, D.; de Kerdanet, M.; et al. Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature. J. Clin. Investig. 2006, 116, 760–768. [Google Scholar] [CrossRef] [Green Version]
  39. Vasques, G.A.; Amano, N.; Docko, A.J.; Funari, M.F.A.; Quedas, E.P.S.; Nishi, M.Y.; Arnhold, I.J.P.; Hasegawa, T.; Jorge, A.A.L. Heterozygous Mutations in Natriuretic Peptide Receptor-B (NPR2) Gene as a Cause of Short Stature in Patients Initially Classified as Idiopathic Short Stature. J. Clin. Endocrinol. Metab. 2013, 98, E1636–E1644. [Google Scholar] [CrossRef] [Green Version]
  40. Batey, L.; Moon, J.; Yu, Y.; Wu, B.; Hirschhorn, J.N.; Shen, Y.; Dauber, A. A Novel Deletion of IGF1 in a Patient With Idiopathic Short Stature Provides Insight Into IGF1 Haploinsufficiency. J. Clin. Endocrinol. Metab. 2014, 99, E153–E159. [Google Scholar] [CrossRef]
  41. Nilsson, O.; Guo, M.H.; Dunbar, N.; Popovic, J.; Flynn, D.; Jacobsen, C.; Lui, J.C.; Hirschhorn, J.N.; Baron, J.; Dauber, A. Short Stature, Accelerated Bone Maturation, and Early Growth Cessation Due to Heterozygous Aggrecan Mutations. J. Clin. Endocrinol. Metab. 2014, 99, E1510–E1518. [Google Scholar] [CrossRef]
  42. Kant, S.G.; Cervenkova, I.; Balek, L.; Trantirek, L.; Santen, G.W.; de Vries, M.C.; van Duyvenvoorde, H.A.; van der Wielen, M.J.; Verkerk, A.J.; Uitterlinden, A.G.; et al. A novel variant of FGFR3 causes proportionate short stature. Eur. J. Endocrinol. 2015, 172, 763–770. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Dauber, A.; Muñoz-Calvo, M.T.; Barrios, V.; Domené, H.M.; Kloverpris, S.; Serra-Juhé, C.; Desikan, V.; Pozo, J.; Muzumdar, R.; Martos-Moreno, G.; et al. Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF -I availability. EMBO Mol. Med. 2016, 8, 363–374. [Google Scholar] [CrossRef] [PubMed]
  44. Hisado-Oliva, A.; Ruzafa-Martin, A.; Sentchordi, L.; Funari, M.F.; Bezanilla-López, C.; Alonso-Bernáldez, M.; Barraza-García, J.; Rodriguez-Zabala, M.; Lerario, A.M.; Benito-Sanz, S.; et al. Mutations in C-natriuretic peptide (NPPC): A novel cause of autosomal dominant short stature. Anesth. Analg. 2018, 20, 91–97. [Google Scholar] [CrossRef] [Green Version]
  45. Vasques, G.A.; Funari, M.F.A.; Ferreira, F.M.; Aza-Carmona, M.; Sentchordi-Montané, L.; Barraza-García, J.; Lerario, A.M.; Yamamoto, G.L.; Naslavsky, M.S.; Duarte, Y.A.O.; et al. IHH Gene Mutations Causing Short Stature With Nonspecific Skeletal Abnormalities and Response to Growth Hormone Therapy. J. Clin. Endocrinol. Metab. 2017, 103, 604–614. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Klammt, J.; Neumann, D.; Gevers, E.F.; Andrew, S.F.; Schwartz, I.D.; Rockstroh, D.; Colombo, R.; Sanchez, M.A.; Vokurkova, D.; Kowalczyk, J.; et al. Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation. Nat. Commun. 2018, 9, 2105. [Google Scholar] [CrossRef] [Green Version]
  47. Plachy, L.; Dusatkova, P.; Maratova, K.; Petruzelkova, L.; Elblova, L.; Kolouskova, S.; Snajderova, M.; Obermannova, B.; Zemkova, D.; Sumnik, Z.; et al. Familial Short Stature—A Novel Phenotype of Growth Plate Collagenopathies. J. Clin. Endocrinol. Metab. 2021, 106, 1742–1749. [Google Scholar] [CrossRef]
  48. El Kholy, M.; Mella, P.; Rashad, M.; Buzi, F.; Meazza, C.; Zahra, S.; Elsedfy, H. Growth Hormone/IGF-I Axis and Growth Hormone Receptor Mutations in Idiopathic Short Stature. Horm. Res. Paediatr. 2011, 76, 300–306. [Google Scholar] [CrossRef]
  49. Marchini, A.; Ogata, T.; Rappold, G.A. A Track Record on SHOX: From Basic Research to Complex Models and Therapy. Endocr. Rev. 2016, 37, 417–448. [Google Scholar] [CrossRef] [Green Version]
  50. Caliebe, J.; Broekman, S.; Boogaard, M.; Bosch, C.A.; Ruivenkamp, C.A.; Oostdijk, W.; Kant, S.; Binder, G.; Ranke, M.B.; Wit, J.M.; et al. IGF1, IGF1R and SHOX Mutation Analysis in Short Children Born Small for Gestational Age and Short Children with Normal Birth Size (Idiopathic Short Stature). Horm. Res. Paediatr. 2012, 77, 250–260. [Google Scholar] [CrossRef]
  51. Ester, W.A.; Van Duyvenvoorde, H.A.; De Wit, C.C.; Broekman, A.J.; Ruivenkamp, C.A.L.; Govaerts, L.C.P.; Wit, J.M.; Hokken-Koelega, A.C.S.; Losekoot, M. Two Short Children Born Small for Gestational Age with Insulin-Like Growth Factor 1 Receptor Haploinsufficiency Illustrate the Heterogeneity of Its Phenotype. J. Clin. Endocrinol. Metab. 2009, 94, 4717–4727. [Google Scholar] [CrossRef]
  52. Domené, H.M.; Bengolea, S.V.; Martínez, A.S.; Ropelato, M.G.; Pennisi, P.; Scaglia, P.; Heinrich, J.J.; Jasper, H.G. Deficiency of the Circulating Insulin-like Growth Factor System Associated with Inactivation of the Acid-Labile Subunit Gene. N. Engl. J. Med. 2004, 350, 570–577. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Inoue, H.; Kangawa, N.; Kinouchi, A.; Sakamoto, Y.; Kimura, C.; Horikawa, R.; Shigematsu, Y.; Itakura, M.; Ogata, T.; Fujieda, K.; et al. Identification and Functional Analysis of Novel Human Growth Hormone Secretagogue Receptor (GHSR) Gene Mutations in Japanese Subjects with Short Stature. J. Clin. Endocrinol. Metab. 2011, 96, E373–E378. [Google Scholar] [CrossRef] [Green Version]
  54. Plachy, L.; Strakova, V.; Elblova, L.; Obermannova, B.; Kolouskova, S.; Snajderova, M.; Zemkova, D.; Dusatkova, P.; Sumnik, Z.; Lebl, J.; et al. High Prevalence of Growth Plate Gene Variants in Children With Familial Short Stature Treated With GH. J. Clin. Endocrinol. Metab. 2019, 104, 4273–4281. [Google Scholar] [CrossRef] [PubMed]
  55. Collett-Solberg, P.F.; Jorge, A.A.; Boguszewski, M.C.; Miller, B.S.; Choong, C.S.Y.; Cohen, P.; Hoffman, A.R.; Luo, X.; Radovick, S.; Saenger, P. Growth hormone therapy in children; research and practice—A review. Growth Horm. IGF Res. 2018, 44, 20–32. [Google Scholar] [CrossRef] [PubMed]
  56. Vasques, G.A.; Andrade, N.L.M.; Correa, F.A.; Jorge, A.A.L. Update on new GH-IGF axis genetic defects. Arch. Endocrinol. Metab. 2019, 63, 608–617. [Google Scholar] [CrossRef] [Green Version]
  57. Sanguineti, N.; Braslavsky, D.; Scaglia, P.A.; Keselman, A.; Ballerini, M.G.; Ropelato, M.G.; Suco, S.; Vishnopolska, S.; Berenstein, A.J.; Jasper, H.; et al. p.R209H GH1 variant challenges short stature assessment. Growth Horm. IGF Res. 2019, 50, 23–26. [Google Scholar] [CrossRef]
  58. Kowarski, A.; Weldon, V.; Daughaday, W.; Schneider, J.; Ben-Galim, E. GROWTH FAILURE WITH NORMAL SERUM RIA-GH AND LOW SOMATOMEDIN ACTIVITY: SOMATOMEDIN RESTORATION AND GROWTH ACCELERATION AFTER EXOGENOUS GH. J. Clin. Endocrinol. Metab. 1978, 47, 461–466. [Google Scholar] [CrossRef]
  59. Mauras, N.; Walton, P.; Nicar, M.; Welch, S.; Rogol, A. Growth hormone stimulation testing in both short and normal statured children: Use of an immunofunctional assay. Pediatr. Res. 2000, 48, 614–618. [Google Scholar] [CrossRef] [Green Version]
  60. Takahashi, Y.; Kaji, H.; Okimura, Y.; Goji, K.; Abe, H.; Chihara, K. Short Stature Caused by a Mutant Growth Hormone. N. Engl. J. Med. 1996, 334, 432–436. [Google Scholar] [CrossRef]
  61. Takahashi, Y.; Shirono, H.; Arisaka, O.; Yagi, T.; Koga, J.; Kaji, H.; Okimura, Y.; Abe, H.; Tanaka, T.; Chihara, K. Biologically inactive growth hormone caused by an amino acid substitution. J. Clin. Investig. 1997, 100, 1159–1165. [Google Scholar] [CrossRef]
  62. Besson, A.; Salemi, S.; Deladoëy, J.; Vuissoz, J.-M.; Eblé, A.; Bidlingmaier, M.; Bürgi, S.; Honegger, U.; Flück, C.; Mullis, P.E. Short Stature Caused by a Biologically Inactive Mutant Growth Hormone (GH-C53S). J. Clin. Endocrinol. Metab. 2005, 90, 2493–2499. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Petkovic, V.; Miletta, M.C.; Boot, A.M.; Losekoot, M.; Flück, C.E.; Pandey, A.V.; Eblé, A.; Wit, J.M.; Mullis, P.E. Short stature in two siblings heterozygous for a novel bioinactive GH mutant (GH-P59S) suggesting that the mutant also affects secretion of the wild-type GH. Eur. J. Endocrinol. 2013, 168, K35–K43. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Laron, Z. Laron Syndrome (Primary Growth Hormone Resistance or Insensitivity): The Personal Experience 1958–2003. J. Clin. Endocrinol. Metab. 2004, 89, 1031–1044. [Google Scholar] [CrossRef] [Green Version]
  65. Attie, K.M.; Carlsson, L.M.; Rundle, A.C.; Sherman, B.M. Evidence for partial growth hormone insensitivity among patients with idiopathic short stature. J. Pediatr. 1995, 127, 244–250. [Google Scholar] [CrossRef] [PubMed]
  66. David, A.; Hwa, V.; Metherell, L.; Netchine, I.; Camacho-Hübner, C.; Clark, A.J.L.; Rosenfeld, R.G.; Savage, M.O. Evidence for a Continuum of Genetic, Phenotypic, and Biochemical Abnormalities in Children with Growth Hormone Insensitivity. Endocr. Rev. 2011, 32, 472–497. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Richards, S.; Aziz, N.; Bale, S.; Bick, D.; Das, S.; Gastier-Foster, J.; Grody, W.W.; Hegde, M.; Lyon, E.; Spector, E.; et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Anesth. Analg. 2015, 17, 405–424. [Google Scholar] [CrossRef] [Green Version]
  68. Zoledziewska, M.; Sidore, C.; Chiang, C.W.K.; Sanna, S.; Mulas, A.; Steri, A.M.; Busonero, F.; Marcus, J.; Marongiu, M.; Maschio, A.; et al. Height-reducing variants and selection for short stature in Sardinia. Nat. Genet. 2015, 47, 1352–1356. [Google Scholar] [CrossRef]
  69. Vairamani, K.; Merjaneh, L.; Casano-Sancho, P.; Sanli, M.E.; David, A.; Metherell, L.; Savage, M.O.; Del Pozo, J.S.; Backeljauw, P.F.; Rosenfeld, R.G.; et al. Novel Dominant-Negative GH Receptor Mutations Expands the Spectrum of GHI and IGF-I Deficiency. J. Endocr. Soc. 2017, 1, 345–358. [Google Scholar] [CrossRef]
  70. Kojima, M.; Hosoda, H.; Date, Y.; Nakazato, M.; Matsuo, H.; Kangawa, K. Ghrelin Is a Growth-Hormone-Releasing Acylated Peptide from Stomach. Nature 1999, 402, 656–660. [Google Scholar] [CrossRef]
  71. Howard, A.D.; Feighner, S.D.; Cully, D.F.; Arena, J.P.; Liberator, P.A.; Rosenblum, C.I.; Hamelin, M.; Hreniuk, D.L.; Palyha, O.C.; Anderson, J.; et al. A Receptor in Pituitary and Hypothalamus That Functions in Growth Hormone Release. Science 1996, 273, 974–977. [Google Scholar] [CrossRef]
  72. Pugliese-Pires, P.N.; Fortin, J.-P.; Arthur, T.; Latronico, A.C.; Mendonca, B.B.; Villares, S.M.F.; Arnhold, I.J.P.; Kopin, A.S.; Jorge, A.A.L. Novel inactivating mutations in the GH secretagogue receptor gene in patients with constitutional delay of growth and puberty. Eur. J. Endocrinol. 2011, 165, 233–241. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Levy, D.E.; Darnell, J.E., Jr. STATs: Transcriptional control and biological impact. Nat. Rev. Mol. Cell Biol. 2002, 3, 651–662. [Google Scholar] [CrossRef] [PubMed]
  74. Kofoed, E.M.; Hwa, V.; Little, B.; Woods, K.A.; Buckway, C.K.; Tsubaki, J.; Pratt, K.L.; Bezrodnik, L.; Jasper, H.; Tepper, A.; et al. Growth Hormone Insensitivity Associated with a STAT5b Mutation. N. Engl. J. Med. 2003, 349, 1139–1147. [Google Scholar] [CrossRef] [PubMed]
  75. Scalco, R.C.; Hwa, V.; Domené, H.M.; Jasper, H.G.; Belgorosky, A.; Marino, R.; Pereira, A.M.; A Tonelli, C.; Wit, J.M.; Rosenfeld, R.G.; et al. STAT5B mutations in heterozygous state have negative impact on height: Another clue in human stature heritability. Eur. J. Endocrinol. 2015, 173, 291–296. [Google Scholar] [CrossRef] [Green Version]
  76. Forbes, B.E.; Blyth, A.J.; Wit, J.M. Disorders of IGFs and IGF-1R signaling pathways. Mol. Cell. Endocrinol. 2020, 518, 111035. [Google Scholar] [CrossRef]
  77. Veenma, D.C.M.; Eussen, H.J.; Govaerts, L.C.P.; de Kort, S.W.K.; Odink, R.J.; Wouters, C.H.; Hokken-Koelega, A.C.S.; de Klein, A. Phenotype-genotype correlation in a familial IGF1R microdeletion case. J. Med. Genet. 2009, 47, 492–498. [Google Scholar] [CrossRef]
  78. Walenkamp, M.J.E.; Robers, J.M.L.; Wit, J.M.; Zandwijken, G.R.J.; van Duyvenvoorde, H.; Oostdijk, W.A.; Hokken-Koelega, A.C.S.; Kant, S.G.; Losekoot, M. Phenotypic Features and Response to GH Treatment of Patients With a Molecular Defect of the IGF-1 Receptor. J. Clin. Endocrinol. Metab. 2019, 104, 3157–3171. [Google Scholar] [CrossRef]
  79. Cabrera-Salcedo, C.; Hawkes, C.P.; Tyzinski, L.; Andrew, M.; Labilloy, G.; Campos, D.; Feld, A.; Deodati, A.; Hwa, V.; Hirschhorn, J.N.; et al. Targeted Searches of the Electronic Health Record and Genomics Identify an Etiology in Three Patients with Short Stature and High IGF-I Levels. Horm. Res. Paediatr. 2019, 92, 186–195. [Google Scholar] [CrossRef]
  80. Domené, S.; Domené, H.M. The role of acid-labile subunit (ALS) in the modulation of GH-IGF-I action. Mol. Cell. Endocrinol. 2020, 518, 111006. [Google Scholar] [CrossRef]
  81. Domené, H.M.; Hwa, V.; Jasper, H.G.; Rosenfeld, R.G. Acid-labile subunit (ALS) deficiency. Best Pract Res Clin Endocrinol Metab. 2011, 25, 101–113. [Google Scholar] [CrossRef]
  82. Fofanova-Gambetti, O.V.; Hwa, V.; Wit, J.M.; Domene, H.M.; Argente, J.; Bang, P.; Hoegler, W.; Kirsch, S.; Pihoker, C.; Chiu, H.K.; et al. Impact of Heterozygosity for Acid-Labile Subunit (IGFALS) Gene Mutations on Stature: Results from the International Acid-Labile Subunit Consortium. J. Clin. Endocrinol. Metab. 2010, 95, 4184–4191. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Argente, J.; Pérez-Jurado, L.A. Letter to the Editor: History and clinical implications of PAPP-A2 in human growth: When reflecting on idiopathic short stature leads to a specific and new diagnosis: Understanding the concept of “low IGF-I availability”. Growth Horm. IGF Res. 2018, 40, 17–19. [Google Scholar] [CrossRef] [PubMed]
  84. Babiker, A.; Al Noaim, K.; Al Swaid, A.; Al Fadhel, M.; Deeb, A.; Martín-Rivada, A.; Barrios, V.; Pérez-Jurado, L.A.; Alfares, A.; Al Alwan, I.; et al. Short stature with low insulin-like growth factor 1 availability due to pregnancy-associated plasma protein A2 deficiency in a Saudi family. Clin. Genet. 2021, 100, 601–606. [Google Scholar] [CrossRef]
  85. Lui, J.C.; Nilsson, O.; Baron, J. RECENT RESEARCH ON THE GROWTH PLATE: Recent insights into the regulation of the growth plate. J. Mol. Endocrinol. 2014, 53, T1–T9. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Nilsson, O.; Marino, R.; De Luca, F.; Phillip, M.; Baron, J. Endocrine Regulation of the Growth Plate. Horm. Res. Paediatr. 2005, 64, 157–165. [Google Scholar] [CrossRef] [PubMed]
  87. Vasques, G.A.; Andrade, N.L.M.; Jorge, A.A.L. Genetic causes of isolated short stature. Arq. Bras. De Endocrinol. Metabol. 2019, 63, 70–78. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Jorge, A.; Souza, S.C.; Nishi, M.Y.; Billerbeck, A.E.; Libório, D.C.C.; Kim, C.A.; Arnhold, I.J.P.; Mendonça, B.B.; Nishi, M.Y. SHOX mutations in idiopathic short stature and Leri-Weill dyschondrosteosis: Frequency and phenotypic variability. Clin. Endocrinol. 2006, 66, 130–135. [Google Scholar] [CrossRef]
  89. Funari, M.F.; de Barros, J.S.; Santana, L.S.; Lerario, A.M.; Freire, B.L.; Homma, T.K.; Vasques, G.A.; Mendonca, B.B.; Nishi, M.Y.; Jorge, A.A. Evaluation of SHOX defects in the era of next-generation sequencing. Clin. Genet. 2019, 96, 261–265. [Google Scholar] [CrossRef]
  90. Ogata, T.; Onigata, K.; Hotsubo, T.; Matsuo, N.; Rappold, G. Growth Hormone and Gonadotropin-Releasing Hormone Analog Therapy in Haploinsufficiency of SHOX. Endocr. J. 2001, 48, 317–322. [Google Scholar] [CrossRef] [Green Version]
  91. Blum, W.F.; Cao, D.; Hesse, V.; Fricke-Otto, S.; Ross, J.L.; Jones, C.; Quigley, C.A.; Binder, G. Height Gains in Response to Growth Hormone Treatment to Final Height Are Similar in Patients with SHOX Deficiency and Turner Syndrome. Horm. Res. Paediatr. 2009, 71, 167–172. [Google Scholar] [CrossRef]
  92. Blum, W.F.; Ross, J.L.; Zimmermann, A.G.; Quigley, C.A.; Child, C.J.; Kalifa, G.; Deal, C.; Drop, S.L.S.; Rappold, G.; Cutler, G.B., Jr. GH Treatment to Final Height Produces Similar Height Gains in Patients With SHOX Deficiency and Turner Syndrome: Results of a Multicenter Trial. J. Clin. Endocrinol. Metab. 2013, 98, E1383–E1392. [Google Scholar] [CrossRef] [PubMed]
  93. Dantas, N.C.; Funari, M.F.; Vasques, G.A.; Andrade, N.L.; Rezende, R.C.; Brito, V.; Scalco, R.C.; Arnhold, I.J.; Mendonca, B.B.; Jorge, A.A. Adult Height of Patients with SHOX Haploinsufficiency with or without GH Therapy: A Real-World Single-Center Study. Horm. Res. Paediatr. 2022, 95, 264–274. [Google Scholar] [CrossRef] [PubMed]
  94. Vasques, G.A.; Arnhold, I.J.; Jorge, A.A. Role of the Natriuretic Peptide System in Normal Growth and Growth Disorders. Horm. Res. Paediatr. 2014, 82, 222–229. [Google Scholar] [CrossRef]
  95. Hanley, P.C.; Kanwar, H.S.; Martineau, C.; Levine, M.A. Short Stature is Progressive in Patients with Heterozygous NPR2 Mutations. J. Clin. Endocrinol. Metab. 2020, 105, 3190–3202. [Google Scholar] [CrossRef] [PubMed]
  96. Hisado-Oliva, A.; Garre-Vázquez, A.I.; Santaolalla-Caballero, F.; Belinchón, A.; Barreda-Bonis, A.C.; Vasques, G.A.; Ramirez, J.; Luzuriaga, C.; Carlone, G.; González-Casado, I.; et al. Heterozygous NPR2 Mutations Cause Disproportionate Short Stature, Similar to Léri-Weill Dyschondrosteosis. J. Clin. Endocrinol. Metab. 2015, 100, E1133–E1142. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Plachy, L.; Dusatkova, P.; Maratova, K.; Petruzelkova, L.; Zemkova, D.; Elblova, L.; Kucerova, P.; Toni, L.; Kolouskova, S.; Snajderova, M.; et al. NPR2 Variants Are Frequent among Children with Familiar Short Stature and Respond Well to Growth Hormone Therapy. J. Clin. Endocrinol. Metab. 2020, 105, e746–e752. [Google Scholar] [CrossRef]
  98. Gibson, B.G.; Briggs, M.D. The aggrecanopathies; an evolving phenotypic spectrum of human genetic skeletal diseases. Orphanet J. Rare Dis. 2016, 11, 86. [Google Scholar] [CrossRef] [Green Version]
  99. Gkourogianni, A.; Andrew, M.; Tyzinski, L.; Crocker, M.; Douglas, J.; Dunbar, N.; Fairchild, J.; Funari, M.F.A.; Heath, K.; Jorge, A.A.L.; et al. Clinical Characterization of Patients With Autosomal Dominant Short Stature due to Aggrecan Mutations. J. Clin. Endocrinol. Metab. 2016, 102, 460–469. [Google Scholar] [CrossRef]
  100. Hauer, N.N.; Sticht, H.; Boppudi, S.; Büttner, C.; Kraus, C.; Trautmann, U.; Zenker, M.; Zweier, C.; Wiesener, A.; Jamra, R.A.; et al. Genetic screening confirms heterozygous mutations in ACAN as a major cause of idiopathic short stature. Sci. Rep. 2017, 7, 12225. [Google Scholar] [CrossRef] [Green Version]
  101. Lin, L.; Li, M.; Luo, J.; Li, P.; Zhou, S.; Yang, Y.; Chen, K.; Weng, Y.; Ge, X.; Mireguli, M.; et al. A High Proportion of Novel ACAN Mutations and Their Prevalence in a Large Cohort of Chinese Short Stature Children. J. Clin. Endocrinol. Metab. 2021, 106, e2711–e2719. [Google Scholar] [CrossRef]
  102. Wu, S.; Wang, C.; Cao, Q.; Zhu, Z.; Liu, Q.; Gu, X.; Zheng, B.; Zhou, W.; Jia, Z.; Gu, W.; et al. The Spectrum of ACAN Gene Mutations in a Selected Chinese Cohort of Short Stature: Genotype-Phenotype Correlation. Front. Genet. 2022, 13, 891040. [Google Scholar] [CrossRef] [PubMed]
  103. Alexandrou, E.; Dauber, A.; Tyzinski, L.; Hwa, V.; Andrew, M.; Kim, H.; Elangovan, S.; Gubanich, P.; Taylor-Haas, J.A.; Paterno, M.; et al. Clinical phenotype and musculoskeletal characteristics of patients with aggrecan deficiency. Am. J. Med. Genet. Part A 2022, 188, 1193–1203. [Google Scholar] [CrossRef]
  104. Muthuvel, G.; Dauber, A.; Alexandrou, E.; Tyzinski, L.; Andrew, M.; Hwa, V.; Backeljauw, P. Treatment of Short Stature in Aggrecan-deficient Patients With Recombinant Human Growth Hormone: 1-Year Response. J. Clin. Endocrinol. Metab. 2021, 107, e2103–e2109. [Google Scholar] [CrossRef] [PubMed]
  105. Horton, W.A.; Hall, J.G.; Hecht, J.T. Achondroplasia. Lancet 2007, 370, 162–172. [Google Scholar] [CrossRef]
  106. Rousseau, F.; Bonaventure, J.; Legeai-Mallet, L.; Schmidt, H.; Weissenbach, J.; Maroteaux, P.; Munnich, A.; Le Merrer, M. Clinical and genetic heterogeneity of hypochondroplasia. J. Med. Genet. 1996, 33, 749–752. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  107. Mamada, M.; Yorifuji, T.; Kurokawa, K.; Kawai, M.; Momoi, T.; Nakahata, T. Prevalence of Mutations in the FGFR3 Gene in Individuals with Idiopathic Short Stature. Clin. Pediatr. Endocrinol. 2006, 15, 61–64. [Google Scholar] [CrossRef] [Green Version]
  108. Deng, H.; Huang, X.; Yuan, L. Molecular genetics of the COL2A1-related disorders. Mutat. Res. Mol. Mech. Mutagen. 2016, 768, 1–13. [Google Scholar] [CrossRef]
  109. Nishimura, G.; Haga, N.; Kitoh, H.; Tanaka, Y.; Sonoda, T.; Kitamura, M.; Shirahama, S.; Itoh, T.; Nakashima, E.; Ohashi, H.; et al. The phenotypic spectrum of COL2A1 mutations. Hum. Mutat. 2005, 26, 36–43. [Google Scholar] [CrossRef]
  110. Chen, M.; Miao, H.; Liang, H.; Ke, X.; Yang, H.; Gong, F.; Wang, L.; Duan, L.; Chen, S.; Pan, H.; et al. Clinical Characteristics of Short-Stature Patients With Collagen Gene Mutation and the Therapeutic Response to rhGH. Front. Endocrinol. 2022, 13, 820001. [Google Scholar] [CrossRef]
  111. Yang, L.; Zhang, C.; Wang, W.; Wang, J.; Xiao, Y.; Lu, W.; Ma, X.; Chen, L.; Ni, J.; Wang, D.; et al. Pathogenic gene screening in 91 Chinese patients with short stature of unknown etiology with a targeted next-generation sequencing panel. BMC Med. Genet. 2018, 19, 212. [Google Scholar] [CrossRef]
  112. Tartaglia, M.; Kalidas, K.; Shaw, A.; Song, X.; Musat, D.L.; van der Burgt, I.; Brunner, H.G.; Bertola, D.R.; Crosby, A.; Ion, A.; et al. PTPN11 Mutations in Noonan Syndrome: Molecular Spectrum, Genotype-Phenotype Correlation, and Phenotypic Heterogeneity. Am. J. Hum. Genet. 2002, 70, 1555–1563. [Google Scholar] [CrossRef] [Green Version]
  113. Malaquias, A.C.; Jorge, A.A. Activation of the MAPK pathway (RASopathies) and partial growth hormone insensitivity. Mol. Cell. Endocrinol. 2021, 519, 111040. [Google Scholar] [CrossRef] [PubMed]
  114. Pannone, L.; Bocchinfuso, G.; Flex, E.; Rossi, C.; Baldassarre, G.; Lissewski, C.; Pantaleoni, F.; Consoli, F.; Lepri, F.; Magliozzi, M.; et al. Structural, Functional, and Clinical Characterization of a Novel PTPN11 Mutation Cluster Underlying Noonan Syndrome. Hum. Mutat. 2017, 38, 451–459. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Pasmant, E.; Vidaud, M.; Vidaud, D.; Wolkenstein, P. Neurofibromatosis type 1: From genotype to phenotype. J. Med. Genet. 2012, 49, 483–489. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  116. Homma, T.K.; Krepischi, A.C.; Furuya, T.K.; Honjo, R.S.; Malaquias, A.C.; Bertola, D.R.; Costa, S.S.; Canton, A.P.; Roela, R.A.; Freire, B.; et al. Recurrent Copy Number Variants Associated with Syndromic Short Stature of Unknown Cause. Horm. Res. Paediatr. 2017, 89, 13–21. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  117. Mintz, C.S.; Seaver, L.H.; Irons, M.; Grimberg, A.; Lozano, R. Focused Revision: ACMG practice resource: Genetic evaluation of short stature. Genet. Med. 2021, 23, 813–815. [Google Scholar] [CrossRef]
  118. Hayden, E.C. Technology: The $1,000 genome. Nature 2014, 507, 294–295. [Google Scholar] [CrossRef] [Green Version]
  119. Van Der Steen, M.; Pfundt, R.; Maas, S.J.; Bakker-van Waarde, W.M.; Odink, R.J.; Hokken-Koelega, A.C. ACAN Gene Mutations in Short Children Born SGA and Response to Growth Hormone Treatment. J. Clin. Endocrinol. Metab. 2016, 102, 1458–1467. [Google Scholar] [CrossRef] [Green Version]
  120. Greco, L.; Power, C.; Peckham, C. Adult outcome of normal children who are short or underweight at age 7 years. BMJ 1995, 310, 696–700. [Google Scholar] [CrossRef] [Green Version]
  121. Andrade, N.L.M.; Funari, M.F.D.A.; Malaquias, A.C.; Collett-Solberg, P.F.; Gomes, N.; Scalco, R.; Dantas, N.C.B.; Rezende, R.C.; Tiburcio, A.M.F.P.; Souza, M.A.R.; et al. Diagnostic yield of a multigene sequencing approach in children classified as idiopathic short stature. Endocr. Connect. 2022, 11, e220214. [Google Scholar] [CrossRef]
Table
Table 1. The genes related to “idiopathic short stature” as a monogenic component.
Table 1. The genes related to “idiopathic short stature” as a monogenic component.
GeneYear of Description in ISSPrevalence in ISSEvidenceObservationRef
GHR19955%LimitedLaboratory findings suggestive of partial GH insensitivity[33,48]
SHOX19972.4%DefinitiveShort stature with mild body disproportion[49]
GH12003No dataLimitedSevere postnatal short stature, normal to elevated GH peaks in stimulation tests, and low levels of IGF-1 and IGFBP-3[35]
IGF1R2003No dataModeratedThe majority were born small for their gestational age and had high levels of IGF-1[36,50,51]
IGFALS2004No dataLimitedSevere deficiency of IGF1 and IGFBP-3, disproportional to the severity of short stature[52]
GHSR2006Only case reportLimitedAssociated with GHD and short stature in the same family[38,53]
NPR220132 to 13.6%StrongProportional or disproportional short stature and unspecified skeletal findings at
time of X-ray of bone age 		[39]
PTPN112013Only case reportLimitedShort stature with or without mild phenotype of Noonan syndrome[6]
IGF12013No dataLimitedVariable degree of pre- and postnatal growth retardation with serum IGF-1 at the lower end of normal[40]
ACAN2014No dataModeratedShort stature with or without advanced bone age[41]
FGFR32015Only one case reportLimitedOnly one family described with proportional short stature[42]
PAPP-A22016Only case reportLimitedHigh levels of IGF-1 and IGFPB-3[43]
NPPC2018No dataLimitedBrachydactyly[44]
IHH20183.3%ModeratedProportional or disproportional short stature, with or without unspecific skeletal findings as shortening of middle phalanges of the 2nd and 5th digits [45]
STAT5B2018Only case reportLimitedEczema and laboratory results suggestive of partial GH insensitivity[46]
NF12019No dataLimitedShort stature without clinical features of neurofibromatosis[54]
COL2A120215.7%LimitedUnspecific skeletal findings and disproportionate short stature[47]
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Andrade, N.L.M.; Cellin, L.P.; Rezende, R.C.; Vasques, G.A.; Jorge, A.A.L. Idiopathic Short Stature: What to Expect from Genomic Investigations. Endocrines 2023, 4, 1-17. https://doi.org/10.3390/endocrines4010001

AMA Style

Andrade NLM, Cellin LP, Rezende RC, Vasques GA, Jorge AAL. Idiopathic Short Stature: What to Expect from Genomic Investigations. Endocrines. 2023; 4(1):1-17. https://doi.org/10.3390/endocrines4010001

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Andrade, Nathalia Liberatoscioli Menezes, Laurana Polli Cellin, Raissa Carneiro Rezende, Gabriela Andrade Vasques, and Alexander Augusto Lima Jorge. 2023. "Idiopathic Short Stature: What to Expect from Genomic Investigations" Endocrines 4, no. 1: 1-17. https://doi.org/10.3390/endocrines4010001

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