Genetic Causes Of Short Stature Research Articles

Long-acting PEGylated growth hormone in children with idiopathic short stature: time to reconsider our diagnostic and treatment policy?

Idiopathic short stature (ISS) is a diagnosis of exclusion, and therefore each child with short stature or slow growth referred to a paediatrician deserves a full medical history and physical examination, as well as radiological and laboratory screening tests. In patients with an increased likelihood of a genetic cause, genetic testing is indicated. Idiopathic short stature is an approved indication for recombinant human growth hormone (rhGH) in the USA but not in most other parts of the world. In a recent article published in this journal, Luo et al reported on the 1-year's results of a multicentre randomized controlled trial (n = 360) on the efficacy and safety of two dosages of long-acting PEGylated rhGH (PEG-rhGH, Jintrolong®) (0.1 or 0.2 mg/kg body weight per week, respectively) in children with ISS compared with an untreated control group. The growth response to the higher dosage was similar to reported data on daily rhGH. In this commentary, we discuss whether the recent data on genetic causes of short stature in children who initially were labelled ISS, and data on the long-term safety of daily rhGH, may influence the balance between risks and benefits of rhGH treatment in children with ISS. We further discuss the pharmacokinetic and -dynamic profile of PEG-rhGH and its potential consequences for long-term safety.

A new era of genetic diagnosis for short stature children: A review

Children with short stature are often presented to pediatric endocrinologists. Short stature is defined as the height that is more than two standard deviations below the corresponding mean height for a specific age and sex in a reference population. Endocrine dysfunctions, including growth hormone deficiency/insensitivity, hypothyroidism, cortisol excess, precocious puberty, chronic disease (renal disease, diabetes mellitus, or inflammatory disease), and genetic disorders, should be assessed in patients presenting with short stature. In addition to medical history, physical examination, endocrine study, skeletal survey, and genetic testing are important for identifying the cause of short stature. Based on the next-generation sequencing analysis in patients with short stature, different genes that are unrelated to syndromic or non-syndromic short stature were identified. In particular, the genetic causes of short stature disrupting the growth plates and the pituitary-insulin-like growth factor axis have expanded. In recent years, the molecular level of chondrogenesis in the growth plates, including paracrine signals, extracellular matrix, and fundamental intracellular signals, has been reported. Moreover, new insights into the molecular pathogenesis of short stature are emerging. This article aimed to review the genetic causes of primary growth impairment in idiopathic short stature conditions.

Novel Insights Into the Genetic Causes of Short Stature in Children.

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

Síndrome de Morquio A: diagnóstico diferencial na baixa estatura desproporcionada na infância

Short stature is defined as a condition in which the height of the individuals is below the third percentile or two standard deviations below the expected average for children of the same age and sex. Bone dysplasias are an important group in the differential diagnosis in children with short stature and, among them, Morquio A syndrome, a genetic-metabolic disease, characterized by an enzyme deficiency and lysosomal accumulation with a direct impact on bone development and cartilaginous. Often, this pathology goes unnoticed by the endocrinologist or pediatrician when evaluating children with short stature, mainly because the classical signs and symptoms of the disease are not yet evident. Morquio A syndrome is not curable, but early diagnosis and treatment make it possible to prevent disease progression and provide better quality of life for patients. The currently available treatments are hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (TRE). In addition, due to the various disabling comorbidities that can arise with evolution, a multidisciplinary approach is essential. Knowledge of genetic causes of short stature due to alteration in bone development is fundamental for the clinical suspicion of this group of diseases. This article aims to report the case of three siblings with the syndrome, whose diagnosis of two of these patients took more than two decades to be established.

Detection of Del/Dup Inside SHOX/PAR1 Region in Children and Young Adults with Idiopathic Short Stature.

Short stature is a common growth disorder defined as a body height two standard deviations (SD) or more below the mean for a given age, gender, and population. A large part of the cases remains unexplained and is referred to as having idiopathic short stature (ISS). One of the leading genetic causes of short stature is variants of short stature homeobox-containing gene (SHOX) and is considered to be responsible for 2–15% of ISS. We aimed to analyse the regulatory and coding region of SHOX in Slovenian children and young adults with ISS and to investigate the pathogenicity of detected variants. Our cohort included 75 children and young adults with ISS. Multiplex ligation-dependent probe amplification (MLPA) was performed in all participants for the detection of larger copy number variations (CNVs). Sanger sequencing was undertaken for the detection of point variants, small deletions, and insertions. A total of one deletion and two duplications were discovered using the MLPA technique. Only one of these four variants was identified as disease-causing and occurred in one individual, which represents 1.3% of the cohort. With Sanger sequencing, two variants were discovered, but none of them appeared to have a pathogenic effect on height. According to the results, in the Slovenian population of children and young adults with ISS, SHOX deficiency is less frequent than expected considering existing data from other populations.

Genetic evaluation in children with short stature.

Short stature is a common clinical manifestation in children. Yet, a cause is often unidentifiable in the majority of children with short stature by a routine screening approach. The purpose of this review is to describe the optimal genetic approach for evaluating short stature, challenges of genetic testing, and recent advances in genetic testing for short stature. Genetic testing, such as karyotype, chromosomal microarray, targeted gene sequencing, or exome sequencing, has served to identify the underlying genetic causes of short stature. When determining which short stature patient would benefit from genetic evaluation, it is important to consider whether the patient would have a single identifiable genetic cause. Specific diagnoses permit clinicians to predict responses to growth hormone treatment, to understand the phenotypic spectrum, and to understand any associated co-morbidities. The continued progress in the field of genetics and enhanced capabilities provided by genetic testing methods expands the ability of physicians to evaluate children with short stature for underlying genetic defects. Continued effort is needed to elaborate new genetic causes of linear growth disorders, therefore, we expand the list of known genes for short stature, which will subsequently increase the rate of genetic diagnosis for children with short stature.

Focused Revision: ACMG practice resource: Genetic evaluation of short stature

Focused Revision: ACMG practice resource: Genetic evaluation of short stature

Short Stature in Children Visiting Endocrine Out Patient Department of Kanti Children’s Hospital, Nepal

Introduction: The causes of Short Stature in children are different in different countries. It can vary from endocrine to non-endocrine. This study was conducted to identify the causes of short stature in children who are brought in Endocrine Out Patient Department of Kanti Children’s Hospital.
 Methods: This is a retrospective study done at Endocrine Out Patient Department of Kanti Children’s Hospital for ten year duration. One Hundred and Twenty five Children who were brought with chief complain of not gaining height were included. Children’s were evaluated for causes of short stature.
 Results: Male and Female ratio was 1.2:1. The commonest cause seen was Familial Short Stature 41(32.8%), Constitutional 22(17.6%), Hypothyroidism 20 (16%), Syndromic 13 (10.4%), Skeletal Dysplasia 10 (8%), Malnutrition 10 (8%), Chronic Diseases 7 (5.6%) and Growth Hormone Deficiency 2 (1.6%).
 Conclusions: This study showed Familial and Constitutional short stature as leading cause of short stature. Hypothyroidism and Malnutrition account for significant percentage which are treatable cause. Down’s syndrome(40%) and Turner Syndrome(7.6%) are the main genetic causes of short stature.

Decifrare la bassa statura nei bambini

Short stature is the most common cause of referral to paediatricians. Only a minority of children with short stature have an underlying pathology. Although well-established diagnostic and management paradigms do exist, recent advances in molecular technologies have significantly improved our understanding of the genetic causes of short stature. Therefore, after the exclusion of nutritional, hormonal, inflammatory or systemic disorders, or skeletal dysplasias and syndromes, genetic causes should be ever supposed and genetic evaluation considered. An appropriate diagnosis of short stature should be performed as early as possible and personalized treatment should be started in a timely manner. Novel treatment approaches have been also proposed both as diagnostic tools and as therapeutic agents to optimize the approach to short stature. Therefore, detailed characterization of children with poor growth is necessary to perform a tailored diagnostic and therapeutic workup with the aim to decipher the causes of short stature better.

Detection of <i>SHOX</i> Gene Variations in Patients with Skeletal Abnormalities with or without Short Stature

Objective:SHOX gene mutations constitute one of the genetic causes of short stature. The clinical phenotype includes variable degrees of growth impairment, such as Langer mesomelic dysplasia (LMD), Léri-Weill dyschondrosteosis (LWD) or idiopathic short stature (ISS). The aim of this study was to describe the clinical features and molecular results of SHOX deficiency in a group of Turkish patients who had skeletal findings with and without short stature.Methods:Forty-six patients with ISS, disproportionate short stature or skeletal findings without short stature from 35 different families were included. SHOX gene analysis was performed using Sanger sequencing and multiplex ligation-dependent probe amplification analysis.Results:Three different point mutations (two nonsense, one frameshift) and one whole SHOX gene deletion were detected in 15 patients from four different families. While 4/15 patients had LMD, the remaining patients had clinical features compatible with LWD. Madelung’s deformity, cubitus valgus, muscular hypertrophy and short forearm were the most common phenotypic features, as well as short stature. Additionally, hearing loss was detected in two patients with LMD.Conclusion:This study has presented the clinical spectrum and molecular findings of 15 patients with SHOX gene mutations or deletions. SHOX deficiency should be especially considered in patients who have disproportionate short stature or forearm anomalies with or without short stature. Although most of the patients had partial or whole gene deletions, SHOX gene sequencing should be performed in suspected cases. Furthermore, conductive hearing loss may rarely accompany these clinical manifestations.

Whole-Exome Sequencing in Idiopathic Short Stature: Rare Mutations Affecting Growth.

Idiopathic short stature (ISS) is a common diagnosis of exclusion in patients with short stature (SS). In this article, we aimed to identify the genetic causes of SS in patients with ISS and investigate treatment options. Fourteen children with diagnosis of ISS were identified, and whole-exome sequencing (WES) was subsequently conducted on blood-derived DNA. Five patients were correctly diagnosed with ISS and four had rare mutations that have not been previously reported. Four patients had mutations known to cause SS and one had a mutation that was known not to affect height. WES can help identify rare mutations implicated in ISS.

Evaluation and management of a child with short stature.

Growth monitoring is a fundamental approach to evaluate a child's health and it is part of preventive programs to timely identify and treat a possible disease. Height and weight measurements, calculation of height velocity over time are main instruments to discover pathological deviations. Short stature is defined as a height that is greater than or equal 2 standard deviations (SDS) below the mean height for reference children comparable for sex and age. According to the International Classification of Pediatric Endocrine Diagnosis (ICPED) the possible causes of short stature could be divided into three groups: primary growth disorders (intrinsic diseases of the growth plate), secondary growth disorders (diseases that interfere on the growth plate setting) and the idiopathic short stature in which no possible cause is identified. The etiology of short stature is not always a disease, but it could be a variant of normal growth. Furthermore, to date there are new advances in the genetic causes of short stature. A detailed evaluation of a child with growth impairment should include an accurate history, a standardize physical examination, general and specific laboratory evaluations, radiologic investigations and genetic testing. Short stature could represent an important threat for physical and psychological health in a child, so a prompt identification of abnormal growth deviations offers the possibility to early treat the possible cause of shortness. This review aimed to discuss a practical approach to a child with short stature on the bases of the most recent scientific evidence.

Genetics of Growth Disorders-Which Patients Require Genetic Testing?

The second 360° European Meeting on Growth Hormone Disorders, held in Barcelona, Spain, in June 2017, included a session entitled Pragmatism vs. Curiosity in Genetic Diagnosis of Growth Disorders, which examined current concepts of genetics and growth in the clinical setting, in terms of both growth failure and overgrowth. For patients with short stature, multiple genes have been identified that result in GH deficiency, which may be isolated or associated with additional pituitary hormone deficiencies, or in growth hormone resistance, primary insulin-like growth factor (IGF) acid-labile subunit deficiency, IGF-I deficiency, IGF-II deficiency, IGF-I resistance, and primary PAPP-A2 deficiency. While genetic causes of short stature were previously thought to primarily be associated with the GH–IGF-I axis, it is now established that multiple genetic anomalies not associated with the GH–IGF-I axis can result in short stature. A number of genetic anomalies have also been shown to be associated with overgrowth, some of which involve the GH–IGF-I axis. In patients with overgrowth in combination with an intellectual disability, two predominant gene families, the epigenetic regulator genes, and PI3K/AKT pathway genes, have now been identified. Specific processes should be followed for decisions on which patients require genetic testing and which genes should be examined for anomalies. The decision to carry out genetic testing should be directed by the clinical process, not merely for research purposes. The intention of genetic testing should be to direct the clinical options for management of the growth disorder.

SUN-038 Role Of The Satb 1 Gene In Growth Across Species: Findings In A Cohort Of Patients With Short Stature And In A Knockout Zebrafish Model

Background: Short stature is a common pediatric disorder, affecting 3% of the population; however, the identification of its cause is limited by its largely variable clinical presentation and genetic heterogeneity. Identification of novel genetic causes of short stature is of great importance to customize the therapeutic approach of this entity. The especial AT-rich sequence binding protein1 gene (SATB1) encodes a chromatin organizer with important roles in cell growth and immunosuppression. SATB1 is highly expressed in the pituitary gland, where it regulates the differentiation of PIT1 positive cells. Indeed, the conditional knockout of Satb1 in the mouse pituitary decreases growth hormone expression, leading to reduced growth. Aim: To investigate the putative role of SATB1 in growth in a cohort of individuals with short stature and in a zebrafish knockout (KO) model. Methods: We obtained germline DNA samples from a cohort of 287 Brazilian patients diagnosed with short stature (height <2 SDS for age and sex), including 52 patients small for gestational age (SGA), 5 cases with growth hormone deficiency (GHD), 10 cases with syndromic short stature and 220 cases with idiopathic short stature. All cases were screened for SATB1 copy number variations (CNVs) using droplet digital PCR, and 190 cases were screened for mutations via Sanger sequencing. In silico predictions were retrieved from the Varsome browser. All variants were annotated to RefSeq NM_002971.5. Using CRISPR-Cas9, we generated two lines of zebrafish satb1 bearing frameshift mutations; both lines were crossed to obtain full KOs. Growth was monitored from 3 to 12 weeks post-fertilization (wpf) and expression of pituitary hormones was analyzed at 6 wpf by quantitative PCR. Results: No variants predicted as damaging were found in the short stature cohort. Nevertheless, variants of uncertain significance (VUS, mostly intronic) were found in 11% of our cohort, in which 57% of the individuals that carry a VUS presented familial short stature while 43% were non-familial. Interestingly, the variant c.515+112G>A was identified in 3/33 (9.1%) of SGA patients, but only in 2/143 (1.4%) of ISS patients. No CNVs were observed. In the zebrafish model, satb1 knockout led to significantly smaller size at 3 wpf, compared with heterozygous and wild type controls (median standard length: 6.6, 7.4, and 7.8 cm, and mean weight: 2.7, 4.3, and 4.6 mg, respectively, P<0.05 for all comparisons). At 6 wpf, we identified a trend for lower gh1 expression in the KOs vs. heterozygous zebrafish (relative quantification: 0.68 vs. 1.79, P=0.06). Conclusion: Our results support a role for SATB1 in regulating growth hormone production across species. Although loss of SATB1 function could theoretically lead to growth hormone deficiency in humans, defects in this gene do not seem to play a crucial role in the height of individuals with short stature.

New developments in the genetic diagnosis of short stature.

Genome-wide approaches including genome-wide association studies as well as exome and genome sequencing represent powerful new approaches that have improved our ability to identify genetic causes of human disorders. The purpose of this review is to describe recent advances in the genetic causes of short stature. In addition to SHOX deficiency which is one of the most common causes of isolated short stature, PAPPA2, ACAN, NPPC, NPR2, PTPN11 (and other rasopathies), FBN1, IHH and BMP2 have been identified in isolated growth disorders with or without other mild skeletal findings. In addition, novel genetic causes of syndromic short stature have been discovered, including pathogenic variants in BRCA1, DONSON, AMMECR1, NFIX, SLC25A24, and FN1. Isolated growth disorders are often monogenic. Specific genetic causes typically have specific biochemical and/or phenotype characteristics which are diagnostically helpful. Identification of additional subjects with a specific genetic cause of short stature often leads to a broadening of the known clinical spectrum for that condition. The identification of novel genetic causes of short stature has provided important insights into the underlying molecular mechanisms of growth failure.

Genetic short stature

Adult height and growth patterns are largely genetically programmed. Studies in twins have indicated that the heritability of height is high (>80%), suggesting that genetic variation is the main determinant of stature. Height exhibits a normal (Gaussian) distribution according to sex, age, and ancestry. Short stature is usually defined as a height which is 2 standard deviations (S.D.) less than the mean height of a specific population. This definition includes 2.3% of the population and usually includes healthy individuals. In this group of short stature non-syndromic conditions, the genetic influence occurs polygenically or oligogenically. As a rule, each common genetic variant accounts for a small effect (1mm) on individual height variation. Recently, several studies demonstrated that some rare variants can cause greater effect on height, without causing a syndromic condition. In more extreme cases, height SDS below 2.5 or 3 (which would comprise approximately 0.6 and 0.1% of the population, respectively) is frequently associated with syndromic conditions and are usually caused by a monogenic defect. More than 1,000 inherited/genetic diseases have growth disorder as an important phenotype. These conditions are usually responsible for syndromic short stature. In the coming years, we expect to discover several genetic causes of short stature, thereby explaining the phenotype of what we currently classify as short stature of unknown cause. These discoveries will have a profound impact on the follow-up and treatment of these children.

Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis

Familial growth hormone deficiency provides an opportunity to identify new genetic causes of short stature. Here we combine linkage analysis with whole-genome resequencing in patients with growth hormone deficiency and maternally inherited gingival fibromatosis. We report that patients from three unrelated families harbor either of two missense mutations, c.347G>T p.(Arg116Leu) or c.1106C>T p.(Pro369Leu), in KCNQ1, a gene previously implicated in the long QT interval syndrome. Kcnq1 is expressed in hypothalamic GHRH neurons and pituitary somatotropes. Co-expressing KCNQ1 with the KCNE2 β-subunit shows that both KCNQ1 mutants increase current levels in patch clamp analyses and are associated with reduced pituitary hormone secretion from AtT-20 cells. In conclusion, our results reveal a role for the KCNQ1 potassium channel in the regulation of human growth, and show that growth hormone deficiency associated with maternally inherited gingival fibromatosis is an allelic disorder with cardiac arrhythmia syndromes caused by KCNQ1 mutations.

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature.

The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3, and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFκB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T3/T4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. Heterozygous NPR2 or SHOX defects may be found in ∼3% of short children, and also rasopathies (e.g., Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal abnormalities, CNVs, and imprinting disorders.

Whole Exome Sequencing to Identify Genetic Causes of Short Stature

Background/Aims: Short stature is a common reason for presentation to pediatric endocrinology clinics. However, for most patients, no cause for the short stature can be identified. As genetics plays a strong role in height, we sought to identify known and novel genetic causes of short stature. Methods: We recruited 14 children with severe short stature of unknown etiology. We conducted whole exome sequencing of the patients and their family members. We used an analysis pipeline to identify rare non-synonymous genetic variants that cause the short stature. Results: We identified a genetic cause of short stature in 5 of the 14 patients. This included cases of floating-harbor syndrome, Kenny-Caffey syndrome, the progeroid form of Ehlers-Danlos syndrome, as well as 2 cases of the 3-M syndrome. For the remaining patients, we have generated lists of candidate variants. Conclusions: Whole exome sequencing can help identify genetic causes of short stature in the context of defined genetic syndromes, but may be less effective in identifying novel genetic causes of short stature in individual families. Utilized in the clinic, whole exome sequencing can provide clinically relevant diagnoses for these patients. Rare syndromic causes of short stature may be underrecognized and underdiagnosed in pediatric endocrinology clinics.

Genome-wide screening of copy number variants in children born small for gestational age reveals several candidate genes involved in growth pathways.

The etiology of prenatal-onset short stature with postnatal persistence is heterogeneous. Submicroscopic chromosomal imbalances, known as copy number variants (CNVs), may play a role in growth disorders. To analyze the CNVs present in a group of patients born small for gestational age (SGA) without a known cause. A total of 51 patients with prenatal and postnatal growth retardation associated with dysmorphic features and/or developmental delay, but without criteria for the diagnosis of known syndromes, were selected. Array-based comparative genomic hybridization was performed using DNA obtained from all patients. The pathogenicity of CNVs was assessed by considering the following criteria: inheritance; gene content; overlap with genomic coordinates for a known genomic imbalance syndrome; and overlap with CNVs previously identified in other patients with prenatal-onset short stature. In 17 of the 51 patients, 18 CNVs were identified. None of these imbalances has been reported in healthy individuals. Nine CNVs, found in eight patients (16%), were categorized as pathogenic or probably pathogenic. Deletions found in three patients overlapped with known microdeletion syndromes (4q, 10q26, and 22q11.2). These imbalances are de novo, gene rich and affect several candidate genes or genomic regions that may be involved in the mechanisms of growth regulation. Pathogenic CNVs in the selected patients born SGA were common (at least 16%), showing that rare CNVs are probably among the genetic causes of short stature in SGA patients and revealing genomic regions possibly implicated in this condition.