Genetic disorders in the growth hormone - insulin-like growth factor-I axis

In the last few years, our knowledge of genetically determined causes of short stature has greatly increased by reports of challenging patients, who offered the opportunity to study genes that play a role in growth. Since the first paper that showed the etiology of Laron syndrome [Godowski PJ, et al: Proc Natl Acad Sci USA 1989;86:8083-8087], many mutations in the growth hormone (GH) receptor have been identified. Recently, new mutations or deletions have been found in several components of the GH-insulin-like growth factor-I (IGF-I) axis: a homozygous mutation of the GH1 gene, resulting in a bio-inactive GH; mutations in the STAT5b gene, which plays a major role in the GH signal transduction; a homozygous missense mutation in the IGF-I gene; heterozygous mutations in the IGF-I receptor gene and a homozygous deletion of the acid-labile subunit gene. In this mini review, we describe the clinical and biochemical features of these genetic defects. Genetic analysis has become essential in the diagnostic workup of a patient with short stature. However, regarding the time consuming nature of molecular analysis, it is important to carefully select the patient for specific genetic evaluation. To help in this selection process, we developed flowcharts, based on the recently described patients, that can be used as guidelines in the diagnostic process of patients with severe short stature of unknown origin.     

Common genetic variation in eight genes of the <Emphasis Type="Italic">GH</Emphasis>/<Emphasis Type="Italic">IGF1</Emphasis> axis does not contribute to adult height variation

Stature (adult height) is one of the most heritable human traits, yet few genes, if any, have been convincingly associated with adult height variation in the general population. Here, we selected 150 tag SNPs from eight candidate genes in the growth hormone (GH)/insulin-like growth factor-1 (IGF1) axis (GHR, GHRH, GHRHR, IGF1, IGFALS, IGFBP3, JAK2, STAT5B), and genotyped them in ∼2,200 individuals ascertained for short or tall stature. Nominally significant tag SNPs were then tested in three additional replication cohorts, including a family-based panel to rule out spurious associations owing to population stratification. Across the four height cohorts (N = 6,075 individuals), we did not observe any consistent associations between stature and common variants (≥5% minor allele frequency) in these eight genes, including a common deletion of the growth hormone receptor gene exon 3. Tests of epistatic interactions between these genes did not yield any results beyond those expected by chance. Although we have not tested all genes in the GH/IGF1 axis, our results indicate that common variation in these GH/IGF1 axis genes is not a major determinant of stature, and suggest that if common variation contributes to adult height variation in the general population, the variants are in other, possibly unanticipated genes. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Radiographic evaluation of children with growth disorders

Short stature as well as tall stature can have a wide variety of causes. Tall stature is usually experienced as a less important problem than short stature, but for both clinical presentations it is important to make a correct diagnosis as to etiology. The identification of the diagnosis frequently relies on radiological criteria. However, no international uniformity exists with respect to the radiographic evaluation of children with growth problems. We recommend that in patients with a possible diagnosis of a skeletal dysplasia a skeletal survey must be performed. In patients with a proportionate stature, radiographic analysis of the hand and wrist will be sufficient in most cases. However, whenever there are clinical abnormalities with a possible underlying bone anomaly, a modified skeletal survey is appropriate. The combination of clinical and biochemical features and an appropriate skeletal survey can often lead to the correct diagnosis and/or guide the subsequent molecular analysis.     

Polymorphism and mapping of the IGF1 gene,and absence of association with stature among African Pygmies

Summary Probes detecting restriction fragment length polymorphisms (RFLPs) in the insulinlike growth factor (IGF1) gene were isolated and allele frequencies in different human populations determined. No difference was detected between the distribution of IGF1 alleles in Pygmies versus non-Pygmy black Africans, despite the proposal that a defect in the IGF1 gene might be responsible for Pygmy short stature. This was supported by the absence of a correlation of IGF1 genotype with height in the C.A.R. Pygmies. Polymerase chain reaction (PCR) and direct sequencing failed to demonstrate an alteration in the region upstream the IGF1 start site in Pygmies. Linkage analysis demonstrated that IGF1 is tightly linked to the phenylalanine hydroxylase gene on chromosome 12q22–24.1.     

Plasma levels of insulin-like binding protein-2 in prepubertal short children and its diagnostic value in the evaluation of growth hormone deficiency

AIM: This study was designed to investigate whether determination of plasma insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2) levels could be of benefit in the evaluation of childhood growth hormone (GH) deficiency (GHD). METHOD: A retrospective analysis was performed on 91 prepubertal children referred for investigation of short stature. Maximal GH levels in plasma after provocative stimuli were between 1.0 and 93.0 mU/l, 6 subjects exhibiting peak values of <5 mU/l. Initially a GH peak of 20 mU/l was used as a cutoff limit to define GHD and idiopathic short stature (ISS) patients. The results of GH provocative tests were compared to age- and gender-based standard deviation scores (SDS) of plasma IGFBP-2, IGF-I, IGFBP-3 and the molar ratios of the latter two to IGFBP-2. The respective normative range values for these parameters were determined in plasma samples from 353 healthy children (i.e. 171 girls, 182 boys). RESULTS: Circulating IGFBP-2 levels did not correlate with height SDS, height velocity SDS or the peak GH levels after provocative stimuli. A weak negative relationship was found between IGFBP-2 and IGF-I. Plasma levels of IGFBP-2 in GHD patients were higher than those of ISS children, who had normal levels. Although at the optimal cutoff point of -0.71 SDS 91.5% of the GHD patients were identified correctly, a substantial proportion (71.9%) of the ISS subjects also had IGFBP-2 levels above this limit. The use of various combinations of IGFBP-2, IGF-I, IGFBP-3 and the derived ratios only slightly improved the diagnostic efficiency as compared to the results of the individual tests. Neither IGFBP-2 nor the IGFBP-3/IGFBP-2 and IGF-I/IGFBP-2 ratios were found to be related to the short- (1 year) or long-term (3 years) growth response to GH therapy. CONCLUSION: It is concluded that none of the tests investigated, either alone or in various combinations, are reliable in either predicting the peak GH level after provocative stimuli in prepubertal short children or in predicting their growth response to GH.     

De novo mutations in ARID1B associated with both syndromic and non-syndromic short stature

Background

Human height is a complex trait with a strong genetic basis. Recently, a significant association between rare copy number variations (CNVs) and short stature has been identified, and candidate genes in these rare CNVs are being explored. This study aims to evaluate the association between mutations in ARID1B gene and short stature, both the syndromic and non-syndromic form.

Results

Based on a case-control study of whole genome chromosome microarray analysis (CMA), three overlapping CNVs were identified in patients with developmental disorders who exhibited short stature. ARID1B, a causal gene for Coffin Siris syndrome, is the only gene encompassed by all three CNVs. A following retrospective genotype-phenotype analysis based on a literature review confirmed that short stature is a frequent feature in those Coffin-Siris syndrome patients with ARID1B mutations. Mutation screening of ARID1B coding regions was further conducted in a cohort of 48 non-syndromic short stature patients,andfour novel missense variants including two de novo mutations were found.

Conclusion

These results suggest that haploinsufficient mutations of ARID1B are associated with syndromic short stature including Coffin-Siris syndrome and intellectual disability, while rare missense variants in ARID1B are associated with non-syndromic short stature. This study supports the notion that mutations in genes related to syndromic short stature may exert milder effect and contribute to short stature in the general population.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-015-1898-1) contains supplementary material, which is available to authorized users.     

Growth hormone receptor sequence changes do not play a role in determining height in children with idiopathic short stature

BACKGROUND/AIMS: In children with short stature, in whom growth hormone deficiency has been excluded, the presence of a normal or elevated growth hormone concentration concomitant with low insulin-like growth factor I suggests growth hormone insensitivity (GHI). Previous reports suggest that heterozygous mutations in the growth hormone receptor gene (GHR) may account for about 5% of children with idiopathic short stature (ISS). In the present study we have attempted to determine whether mutations in the GHR explain the short stature and growth retardation in a cohort of children with ISS and characteristics suggesting GHI. METHODS: For the present study 33 children with clinical and biochemical characteristics of GHI were selected from a cohort of 150 children of short stature. Molecular analysis of the GHR was performed using a single-strand conformation polymorphism technique and sequencing. Ten different sequence changes in 19 (58%) out of 33 children were identified, 9 of them novel and 1 that had been described previously. RESULTS: Two changes were found in exons 2 and 6. The known polymorphism of exon 6 (G168) was significantly more common in the control subjects than in our study group (63.5 vs. 30%; p < 0.0001). In the intronic sequences 8 previously undescribed DNA changes were found. The screening of the affected children's family members revealed that both normal and short stature members carried the same variants. The study group did not significantly differ from the controls in retention (GHRfl) or exclusion (GHRd3) of exon 3. CONCLUSION: Our study suggests that sequence changes of the GHR are common in children with ISS. The presence of these sequence changes in the control subjects as well as in normal stature family members indicates that these changes represent a simple polymorphism of the GHR. Such DNA changes are more prevalent than previously recognized, and they do not seem to play a contributory role in the etiology of short stature.     

Exome sequencing reveals genetic architecture in patients with isolated or syndromic short stature

Short stature is among the most common endocrinological disease phenotypes of childhood and may occur as an isolated finding or in conjunction with other clinical manifestations. Although the diagnostic utility of clinical genetic testing in short stature has been implicated, the genetic architecture and the utility of genomic studies such as exome sequencing(ES) in a sizable cohort of patients with short stature have not been investigated systematically. In this study, we recruited 561 individuals with short stature from two centers in China during a 4-year period. We performed ES for all patients and available parents. All patients were retrospectively divided into two groups: an isolated short stature group(group I, n = 257) and an apparently syndromic short stature group(group II, n = 304). Causal variants were identified in 135 of 561(24.1%) patients. In group I, 29 of 257(11.3%) of the patients were solved by variants in 24 genes. In group II, 106 of 304(34.9%) patients were solved by variants in 57 genes. Genes involved in fundamental cellularprocess played an important role in the genetic architecture of syndromic short stature. Distinct genetic architectures and pathophysiological processes underlie isolated and syndromic short stature.     

Growth retardation, distinct oriental-like facies, glaucoma, brachydactyly, ventricular septal defect and speech disorder. An unknown entity.

A caucasian boy with distinct oriental-like facies, short stature, brachydactyly, congenital ventricular septal defect, glaucoma, and speech disorder is reported. Routine laboratory tests, karyotype, and hormonal profile (IGF 1, growth hormone during provocative testing, thyroid hormones, prolactin, gonadotrophins) were normal. Radiologic skeletal survey did not disclose any abnormality. Both parents were apparently normal, but short in stature.     

Next generation sequencing reveals novel homozygous frameshift in PUS7 and splice acceptor variants in AASS gene leading to intellectual disability,developmental delay,dysmorphic feature and microcephaly

Intellectual developmental disorder with abnormal behavior, microcephaly and short stature (IDDABS), (OMIM# 618342) is an autosomal recessive condition described as developmental delay, poor or absent speech, intellectual disability, short stature, mild to progressive microcephaly, delayed psychomotor development, hyperactivity, seizure, along with mild to swear aggressive behavior. Homozygous frameshift mutation in Pseudouridine Synthase 7, Putative; (PUS7) OMIM# 616,261 NM_019042.3 and splice acceptor variants in Alpha-Aminoadipic Semialdehyde Synthase; (AASS) OMIM# 605,113 NM_005763.3 was funded. Whole exome sequencing (WES) technique was used as tool to identify the molecular diagnostic test. Different bioinformatics analysis done for WES data and we identified two novel mutations one as frameshift mutation c.606_607delGA, p.Ser282CysfsTer9 in the PUS7 gene and splice acceptor variants c.1767–1 G > A in the AASS gene has been reported. The pattern of family segregation maintained the pathogenicity of this variation associated with abnormal behavior, intellectual developmental disorder, microcephaly along with short stature IDDABS. Further, the WES data was validated in the family having other affected individuals and healthy controls (n = 100) was done using Sanger sequencing. Finally, our results further explained the role of WES in the disease diagnosis and elucidated that the mutation in PUS7 and AASS genes may lead an important role for the development of IDDABS in Saudi family.     

Reproducibility in patterns of IGF generation with special reference to idiopathic short stature

BACKGROUND/AIM: Insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein 3 (IGFBP-3) generation tests are both sensitive and specific measures of growth hormone (GH) sensitivity. Recently, the question of reproducibility of IGF generation tests has been raised. We report our analysis of the correlation of low- and high-dose GH IGF-I and IGFBP-3 generation tests among patients with GH deficiency, GH insensitivity, and idiopathic short stature. METHODS: A total of 198 subjects were randomized to either high- or low-dose GH for 7 days; the alternate dose was received after a 2-week washout period. Samples were collected at baseline and on days 5 and 8 of GH administration. RESULTS: The serum concentrations of IGF-I and IGFBP-3 correlated significantly from one test to the other, regardless of the diagnosis. In normal subjects and patients with GH insensitivity and GH deficiency, the delta over baseline in IGF-I and IGFBP-3 in the low-dose test was highly predictive of the delta values in the high-dose test. The delta correlation was greatly diminished, however, in the patient population having idiopathic short stature. CONCLUSIONS: These observations support partial GH insensitivity effecting IGF-I generation specifically, as a possible etiology for idiopathic short stature, and thus such patients may warrant appropriate biochemical and/or molecular evaluation for partial GH insensitivity.     

环境因素对儿童特发性矮身材影响的临床研究

目的：探讨环境因素对儿童特发性矮身材的影响。方法：采用病例对照的研究方法,对100例特发性矮身材患者组和100例正常对照儿童组分别进行体格测量,问卷调查家庭基本情况、出生史、饮食习惯、生活方式、生长速率、家庭生活条件、经济状况、父母文化程度等环境因素资料进行Logistic回归分析。结果：家族矮小史、母亲文化程度、家庭经济状况、偏食、运动时间、留守儿童影响特发性矮身材的发生。结论：因素与儿童特发性矮身材有关,为特发性矮身材儿童早期干预提供临床依据。     

Regional differences in short stature in England between 2006 and 2019: A cross-sectional analysis from the National Child Measurement Programme

BackgroundShort stature, defined as height for age more than 2 standard deviations (SDs) below the population median, is an important indicator of child health. Short stature (often termed stunting) has been widely researched in low- and middle-income countries (LMICs), but less is known about the extent and burden in high-income settings. We aimed to map the prevalence of short stature in children aged 4–5 years in England between 2006 and 2019.Methods and findingsWe used data from the National Child Measurement Programme (NCMP) for the school years 2006–2007 to 2018–2019. All children attending state-maintained primary schools in England are invited to participate in the NCMP, and heights from a total of 7,062,071 children aged 4–5 years were analysed. We assessed short stature, defined as a height-for-age standard deviation score (SDS) below −2 using the United Kingdom WHO references, by sex, index of multiple deprivation (IMD), ethnicity, and region. Geographic clustering of short stature was analysed using spatial analysis in SaTScan. The prevalence of short stature in England was 1.93% (95% confidence interval (CI) 1.92–1.94). Ethnicity adjusted spatial analyses showed geographic heterogeneity of short stature, with high prevalence clusters more likely in the North and Midlands, leading to 4-fold variation between local authorities (LAs) with highest and lowest prevalence of short stature. Short stature was linearly associated with IMD, with almost 2-fold higher prevalence in the most compared with least deprived decile (2.56% (2.53–2.59) vs. 1.38% (1.35–1.41)). There was ethnic heterogeneity: Short stature prevalence was lowest in Black children (0.64% (0.61–0.67)) and highest in Indian children (2.52% (2.45–2.60)) and children in other ethnic categories (2.57% (2.51–2.64)). Girls were more likely to have short stature than boys (2.09% (2.07–2.10) vs. 1.77% (1.76–1.78), respectively). Short stature prevalence declined over time, from 2.03% (2.01–2.05) in 2006–2010 to 1.82% (1.80–1.84) in 2016–2019. Short stature declined at all levels of area deprivation, with faster declines in more deprived areas, but disparities by IMD quintile were persistent. This study was conducted cross-sectionally at an area level, and, therefore, we cannot make any inferences about the individual causes of short stature.ConclusionsIn this study, we observed a clear social gradient and striking regional variation in short stature across England, including a North–South divide. These findings provide impetus for further investigation into potential socioeconomic influences on height and the factors underlying regional variation.

Joanna Orr and coauthors investigate regional differences in short stature among children in England, between 2006-2019, using a cross-sectional analysis of the National Child Measurement Program data.     

Abnormal growth in noonan syndrome: genetic and endocrine features and optimal treatment

Noonan syndrome (NS) is a phenotypically heterogeneous syndrome which is frequently associated with short stature. Recent genetic investigations have identified mutations in five genes, namely PTPN11, KRAS, SOS1, NF1 and RAF1 in patients with the NS phenotype. PTPN11 is the commonest, being present in approximately 50% of cases. The degree of short stature in children does not associate closely with the presence of mutations, however some PTPN11-positive patients have decreased GH-dependent growth factors consistent with mild GH insensitivity. GH therapy, using doses similar to those approved for Turner syndrome (TS), induced short-term increases in height velocity over 1-3 years, and may improve final adult height with longer-term treatment.     

Genetic analysis of tall stature

Tall stature is less often experienced as an important problem than short stature. However, a correct diagnosis may be of eminent importance, especially when interventions are planned, or to know the natural history. Overgrowth can be caused by endocrine disorders and skeletal dysplasias, but also by several genetic syndromes. Despite a systematic diagnostic approach, there will be patients with tall stature who do not fit a known diagnosis. In this group of patients possibilities of genetic analysis do exist, but are not common practice. The FMR1 gene should be analyzed in patients with tall stature and mental retardation, and in these patients the NSD1 gene can be considered whenever some features of Sotos syndrome do exist. In tall patients without mental retardation and some features of Sotos or Beckwith-Wiedemann syndrome it may still be useful to look for mutations in the NSD1 gene, but also for changes in the 11p15 region. The various possibilities are discussed and placed in a flowchart.     

Views on Short Stature of Female vs Male Endocrine Pediatric Patients Undergoing Provocative Growth Hormone Testing and Their Parents

ObjectiveBoys outnumber girls in short stature evaluations and growth hormone treatment despite absence of gender differences in short stature prevalence. Family views on short stature influence medical management, but gender-based analysis of these views is lacking. This study explored endocrine patients’ and their parents’ perceptions of short stature and its impact on quality of life by patient gender.MethodsPatients aged 8 to 14 years undergoing provocative growth hormone testing and 1 parent each completed semistructured interviews. Clinical data were extracted by chart review.ResultsTwenty-four patient-parent dyads (6 female patients, 22 mothers; predominantly non-Hispanic White) participated. Six major themes emerged: (1) patients’ perceptions of their short stature were similar by gender, (2) physical experiences of short stature were similar by gender, (3) social experiences of short stature were both similar and different by gender, (4) parental perceptions of short stature as a factor limiting their child’s functionality were similar by gender, (5) concern about societal stigma related to short stature arose for both genders, and (6) patients’ perceptions of parental messaging about the import of their short stature were similar by gender.ConclusionOur data reveal more similarities than differences between genders in patient perceptions and patient and parent-reported experiences of short stature. Worry about stature-related stigma was noted for patients of both genders. Parental messaging about short stature emerged as an important area to explore further by patient gender. Our findings suggest that clinicians should be wary of making gender or stigma-based assumptions when evaluating children with short stature.     

FISH-deletion mapping defines a 270-kb short stature critical interval in the pseudoautosomal region PAR1 on human sex chromosomes

Deletions of the pseudoautosomal region (PAR1) of the sex chromosomes have recently been discovered in individuals with short stature, and a minimal common deletion region of 700 kb within PAR1 has subsequently been defined. We have cloned this entire region, which is bounded by the Xp/Yp telomere, as an overlapping cosmid contig. In the present study, we have used fluorescence in situ hybridization (FISH) to study four patients with X-chromosomal rearrangements, two with normal height and two with short stature. Genotype-phenotype correlations have narrowed down the the critical “short stature interval” to a 270-kb region containing the gene with an important role in growth. A minimal tiling path of 6–8 cosmids bridging this interval is now available for interphase and metaphase FISH and provides a valuable tool for diagnostic investigations of patients with idiopathic short stature. Received: 4 November 1996 / Accepted: 10 March 1997     

Selection signatures in Shetland ponies

Shetland ponies were selected for numerous traits including small stature, strength, hardiness and longevity. Despite the different selection criteria, Shetland ponies are well known for their small stature. We performed a selection signature analysis including genome‐wide SNPs of 75 Shetland ponies and 76 large‐sized horses. Based upon this dataset, we identified a selection signature on equine chromosome (ECA) 1 between 103.8 Mb and 108.5 Mb. A total of 33 annotated genes are located within this interval including the IGF1R gene at 104.2 Mb and the ADAMTS17 gene at 105.4 Mb. These two genes are well known to have a major impact on body height in numerous species including humans. Homozygosity mapping in the Shetland ponies identified a region with increased homozygosity between 107.4 Mb and 108.5 Mb. None of the annotated genes in this region have so far been associated with height. Thus, we cannot exclude the possibility that the identified selection signature on ECA1 is associated with some trait other than height, for which Shetland ponies were selected.     

Pure interstitial duplication of chromosome 7q (7q31.2-->q33) in a 4-year-old girl with growth restriction, short stature, speech delay and intellectual disability

We report the cytogenetic and molecular characterization of a 22.3-Mb pure interstitial duplication of chromosome 7q, dup(7)(q31.2-->q33) in a 4-year-old girl with growth restriction, short stature, speech delay, inguinal hernia, strabismus and intellectual disability. We speculate that the gene dosage increase effect of the ING3 and LEP genes may be partially responsible for the phenotype of growth restriction and short stature in this patient.     

Insulin-like growth factors as diagnostic tools in growth hormone deficiency during childhood and adolescence: the KIGS experience

Growth hormone (GH) deficiency in children covers a spectrum of disorders involving an impairment in GH secretion and a clinical syndrome characterized by permanent stunting of growth. Ascertaining impairments in GH secretion directly is complex, especially if GH deficiency (GHD) is isolated and not caused by congenital or acquired pituitary defects or genetic abnormalities. It has been established that the concentrations of GH-dependent peptides, such as insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3), are low in patients with GHD. Their levels are, however, also influenced by a multitude of factors, such as age, gender, height, liver function, nutritional status and other hormones. In addition, the type of complex formed, e.g. either binary or ternary, may influence the measurements of IGFs and their binding proteins. Therefore, levels of IGF-I and IGFBP-3 are generally lower in short children compared with age-matched norms. The reported diagnostic value of sub-normal basal levels of IGF-I and IGFBP-3 is, in terms of sensitivity and specificity, approximately 70%. Thus, definite proof of GHD can only be achieved by means of GH measurements. As the diagnosis of GHD is somewhat unlikely if IGF testing shows normal values, it is clearly advantageous to schedule these tests as part of the initial diagnostic work-up in short children, as their implementation is not only practical but also inexpensive. The Pfizer International Growth Database (KIGS) analysis of IGF-I (n = 2,750) and IGFBP-3 (n = 1,300) levels in children with idiopathic GHD shows that these two parameters are now firmly embedded in diagnostic strategies around the world.