Cause Of Short Stature Research Articles

From recognition to cause: analyzing parental knowledge of children’s short stature, preliminary study

Short stature (SS) is a condition where children's growth rates are below the 2.5th percentile for their age and gender. Early intervention is vital due to its association with reduced quality of life and mortality. This study examines the understanding of Qassimi parents regarding their child’s SS. We surveyed 384 Qassimi parents, including those with growing children and those without children willing to participate. Knowledge scores ranged from 0 to 8, with scores over 4 indicating good knowledge. Most of the study participants were Saudis, females, or holding a university degree. The mean score was 4.44 and almost 47% of respondents demonstrated good knowledge. All the study participants were aware of at least one cause of short stature. Of more than 20 causes of short stature, only 24.3% of the study participants could correctly identify 4 or more causes. Multivariable regression revealed that higher knowledge scores were significantly noted among participants younger than 40 years (p-value: < 0.001), students (p-value: < 0.001), unmarried (p-value: 0.001), and/or having no children (p-values: 0.001). Among respondents with children, individuals with children younger than 12 years had significantly better knowledge (p-value: 0.003). In contrast, knowledge was seemingly independent of gender, level of education, nationality, or family history (p-values: > 0.05). Although the knowledge status is overall moderate, it’s recommended to further start public health initiatives and educational programs, while paying special attention to population groups associated with lower knowledge level.

Slow growth and short stature in children with attention deficit hyperactivity disorder (ADHD): aretrospective study of 493 children who underwent growth hormone provocation testing at one tertiary paediatric endocrine centre.

We hypothesised that growth hormone (GH) deficiency (GHD) in children with attention deficit hyperactivity disorder (ADHD) is rare. This study aimed to determine any distinct clinical or biochemical parameters, including GH provocation testing, in children with ADHD on psychostimulants or idiopathic short stature (ISS). Retrospective cross-sectional study of children who had GH provocative testing between 1998 and 2013 at one tertiary paediatric endocrine centre. Clinical data included age, sex, anthropometry, pubertal staging, bone age, diagnostic code as per the European Society Paediatric Endocrinology (ESPE), GH provocation test results, thyroid function tests, serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein-3 (IGFBP-3) levels. Four hundred ninety-three subjects underwent GH provocation testing for investigation of short stature to exclude GHD during the study period. Fifty-one children hada diagnosis of ADHD. In the remaining children, the diagnosis was Idiopathic short stature (n=240), GHD +/- hypopituitarism (n=60), and 142 subjects had other causes of short stature. Children with ADHD were older, had higher height and weight SDS and were GH-sufficient. All 51 children with ADHD had a normal serum IGFBP-3, while 20 out of these 51 subjects had a low serum IGF-1. GHD in children with ADHD on psychostimulant medication is rare. GH testing in children with ADHD may not be necessary, particularly if serum IGFBP-3 is in thenormal range. We suggest IGFBP-3 could be used as a surrogate marker of GH sufficiency in children with ADHD. However, this needs to be confirmed with a larger study group.

Minimizing unnecessary brain magnetic resonance imaging in pediatric endocrinology: a retrospective cohort analysis.

Brain magnetic resonance imaging (MRI) is mandatory or highly recommended in many pediatric endocrinological conditions to detect causative anatomic anomalies and rule out neoplastic lesions. However, MRI can also show findings associated with the underlying clinical condition, as well as unrelated "incidentalomas". These latter findings are often abnormalities with a high incidence in the general population for which there is no clear literature regarding their management, especially in pediatric patients. The present study aimed to evaluate the number of unnecessary performed MRIs in pediatric endocrinology. Retrospective analysis on 584 MRI scans performed in 414 patients (254 growth hormone deficiency, 41 other causes of short stature, 116 central precocious puberty). The MRI scans were completely normal in 67% of the individuals, and the prevalence of individuals who underwent more than one MRI was 18%, with no significant differences among the groups. The overall prevalence of incidentalomas was 17%. Among 170 repeated MRI scans, 147 (86%) were not required according to a dedicated protocol. Only five patients (four GHD, one Noonan) correctly repeated the MRI. All the repeated MRI scans did not reveal any progression in the findings. If we include the MRIs performed in cases of OCSS other than Noonan syndrome (n=32) and girls with CPP older than 6 years (n=89), an additional 121 MRIs could have been avoided, leading to a total number of unnecessary MRIs to 268 (46%). Only a few specific neuroimaging findings in endocrinologic pediatric patients warrant further investigation, while too often repeated imaging is carried out unnecessarily. We advocate the importance of guidelines to reduce costs for both the healthcare system and patients' families, as well as to alleviate physical and psychological distress for patients and caregivers.

Clinical profiles and molecular genetic analyses of 98 Chinese children with short statures.

Short stature is one of the most prevalent endocrine disorders in children, and its genetic basis is a complex and actively researched subject. Currently, there is limited genetic research on exome sequencing for short stature, and more large-scale studies are necessary for further exploration. The retrospective study entailed investigation of 98 Chinese children with short statures (height SDS ≤ -2.5) of unknown etiologies recruited between 2017 and 2021. Whole-exome sequencing (WES) was performed on these patients to identify the potential genetic etiologies. The clinical data were reviewed retrospectively to assess the pathogenicity of the identified mutations. Additionally, 31 patients consented to and received recombinant human growth hormone (rhGH) therapy for 12 months. The short-term effects of rhGH treatment were evaluated across different etiologies of patients with short statures. The WES results were used to identify 31 different variants in 18 genes among 24 (24.5%) patients. Individuals with more severe short statures were more likely to have underlying genetic etiologies. Short stature accompanied by other phenotypes had significantly higher diagnostic yields than simple severe short stature. The rhGH therapy demonstrated efficacy in most children. Nevertheless, the treatment response was suboptimal in a boy diagnosed with 3M syndrome. WES is an important approach for confirming genetic disorders in patients with severe short statures of unknown etiologies, suggesting that it could be used as a primary diagnostic strategy. The administration of rhGH may not be suitable for all children with short statures, and the identification of the genetic cause of short stature by WES has significant guidance value for rhGH treatment.

The prevalence of celiac disease among children with short stature

Background and objectives: The most important characters of children are growth and development. There are many causes of short stature. Among causes of short stature celiac disease is the important reversible cause. Celiac disease can be diagnosed serologically or/and duodenal biopsy according to the level of serological tests or/and symptoms. The main objective of the study was to find the relation between having high tissue transglutaminase antibody and short stature Methods: This is a cross sectional study. From March 2021 to March 2022, consecutive sampling from of 79 children who presented to Helina center in Erbil city and Hawler teaching hospital (department of endocrinology) complaining to have short stature and recorded as short child. Tissue transglutaminase antibody were sent for all patients, and duodenal biopsy for selected cases were done. Result: Seventy-nine children with short stature were included in the study. Their mean age (SD) was 8.3 (3.3) years. The median was 8 years, and the age range was 1.1-16 years. More than half (54.4%) of the sample were aged 5-9 years, and 42 patients (53.2%) were females. The prevalence of celiac disease among children with short stature in our study was 13.9%, which is statistically is significant. The majority (69.6%) of the children had severe short stature (less than -2 Z score), and the rest had acceptable Z score. Conclusion: In conclusion, celiac disease should be considered in the differential diagnosis of patient who presents with short stature as it is not uncommon in our community. Sending for non-invasive investigations for diagnosing celiac disease is easier and simpler than other invasive procedures.

Safety considerations for the clinical application of recombinant human growth hormone

Recombinant human growth hormone (rhGH) is an effective therapeutic drug for improving short stature. Currently, rhGH can be used for various causes of short stature, including growth hormone deficiency, and the expansion of its clinical application has raised concerns about its safety. Based on existing evidence, when rhGH is used in a standardized manner for physiological replacement therapy, its safety profile is favorable. In clinical practice, attention should be focused on short-term safety during rhGH treatment, with the combination of literature evidence and clinical experience. There is still no definitive conclusion on the long-term safety due to insufficient duration of rhGH treatment. This paper reviews the possible adverse events that may occur during rhGH treatment and their risk control measures, aiming to help clinical physicians understand the overall safety of rhGH treatment and improve its clinical standardization.

Preliminary investigation into the genetic etiology of short stature in children through whole exon sequencing of the core family.

A comprehensive survey was carried out to investigate the genetic etiology of short stature in children by whole exon sequencing of a core family cohort to find and study mutations in multiple genes to assess their potential correlations to low height in children. The study included 56 pediatric patients from the Department of Pediatrics at the Zhangzhou Affiliated Hospital of Fujian Medical University. The participants met strict inclusion criteria, including age, Han Chinese ethnicity, low height standard deviation score, and the absence of known causes for short stature. Core pedigrees were identified using exome sequencing. After sequencing, variations were categorized and interpreted according to a variety of factors, including inheritance, location, type, and disease-causing gene databases. Variants were verified by Sanger sequencing. Most of the 97 gene mutations were missense. ACAN, PHEX, and COL2A1 were the most common gene mutations. Copy number variations were identified, particularly associated with the PHEX gene. Protein functional studies revealed that the mutations had a considerable influence on disease-promoting damage. The chromosomal locations with the highest enrichment of these genes were chr12, chr5, and chr2. In conclusion, the study revealed numerous genetic changes that may substantially impact physiological processes and disease. These findings establish the basis for further investigations into their diagnostic and therapeutic capabilities.

Clinical and laboratory characteristics but not response to treatment can distinguish children with definite growth hormone deficiency from short stature unresponsive to stimulation tests.

It has been proposed that not all children with short stature displaying an inadequate response to tests for growth hormone (GH) secretion truly suffer from GH deficiency (GHD). Only children with a monogenic cause of GHD or an identifiable combined hormonal deficiency or anatomical anomaly in the hypothalamic-pituitary axis should be considered definite GHD (dGHD). The remaining patients can be defined as a separate group of patients, "short stature unresponsive to stimulation tests" (SUS). The aim of this proof-of-concept study, was to assess whether SUS patients treated with rhGH exhibit any differences compared to GHD patients undergoing the same treatment. Retrospective analysis on 153 consecutive patients with short stature and pathological response to two GH stimulation tests. Patients with dGHD were defined as those with a clear genetic or anatomical hypothalamic-pituitary anomaly, as well as those with combined pituitary hormone deficiencies and those with a known insult to the hypothalamic-pituitary axis (i.e. total brain irradiation) (n=38, 25%); those without any of the previous anomalies were defined as SUS (n=115, 75%). At diagnosis, dGHD and SUS populations did not differ significantly in sex (F 32% vs 28%, p=0.68), age (11.9 vs 12.1, p=0.45), height SDS at diagnosis (-2.2 vs. -2.0, p=0.35) and prevalence of short stature (height <-2 SDS) (56% vs 51%, p=0.45). IGF-1 SDS were significantly lower in dGHD (-2.0 vs -1.3, p<0.01). After 1 year of treatment, the prevalence of short stature was significantly reduced in both groups (31% in dGHD vs. 21% in SUS, p<0.01) without any significant differences between groups (p=0.19), while the increase in IGF-1 SDS for bone age was greater in the dGHD category (+1.9 vs. +1.5, p<0.01), with no further difference in IGF-1 SDS between groups. At the last available follow-up, 59 patients had reached the near adult height (NAH) and underwent retesting for GHD. No differences in NAH were found (-0.3 vs. -0.4 SDS, 0% vs. 4% of short stature). The prevalence of pathological retesting was higher in dGHD (60% vs. 10%, p<0.01) as well as of overweight and obesity (67% vs. 26%). Stimulation tests and the equivalent benefit from rhGH therapy, cannot distinguish between dGHD and SUS populations. In addition, lower IGF-1 concentrations at baseline and their higher increase during treatment in dGHD patients, and the lack of pathological retesting upon reaching NAH in SUS patients, are facts that suggest that deficient GH secretion may not be the cause of short stature in the SUS studied population.

The Treatment of Growth Disorders in Childhood and Adolescence.

3% of all children are unusually short, and 3% are unusually tall. New approaches have broadened the range of therapeutic options in treating growth disorders. This review is based on publications retrieved by a selective review of the literature and on the authors' clinical experience. Pituitary growth hormone deficiency is treated with recombinant growth hormone. Long-acting preparations of this type became available recently, but their long-term safety and efficacy are still unknown. Vosoritide, a CNP analogue, has also been approved for the treatment of achondroplasia, and severe primary deficiency of insulin-like growth factor 1 (IGF-1) can be treated with recombinant IGF-1. In the treatment of excessively tall stature, new information on the safety of growth-attenuating treatment and an altered perception of above-average height in society have led to a change in management. There are new options for the treatment of rare causes of short stature, while new information on the safety of treatment strategies for excessive tallness have led to a reconsideration of surgical intervention. There is insufficient evidence on the benefits and risks of supraphysiological GH therapy and of newer treatment options for which there are as yet no robust data on adult height. Therefore, before any treatment is provided, physicians should give patients and their families detailed information and discuss their expectations from treatment and the goals that treatment can be expected to achieve.

A rare cause of short stature - A case report

A rare cause of short stature - A case report

SETD5 gene mutation as the cause of short stature

SETD5 gene mutation as the cause of short stature

Clinicoepidemiological Profile of Short Stature at A Tertiary Care Centre in Bangladesh

Background: Short stature (SS) is a common pediatric problem, which can cause psychosocial disturbances both in parents and children. The goal of the evaluation of a child with SS is to identify the subset of children with pathologic causes so that appropriate timely intervention can be made. Objective: The aim of the study was to study the clinical, epidemiological, and etiological profile of SS at a tertiary hospital of Bangladesh. Methods: This was a cross-sectional study and was conducted in the department of pediatric endocrinology, over a period of 1 year (January 2021-December 2021). A total of 100 children aged 3-14 years, with height &lt;-2SD below the mean height for age and sex were studied. Clinical history, examination, and laboratory evaluations were done to assess the cause of SS and the data were analyzed using appropriate statistical methods. Results: About 55% were female and 45% were male. The causes of SS were found to be familial SS (36%), constitutional growth delay of growth and puberty (12%), hypothyroidism (11%), growth hormone deficiency (8%), malnutrition (10%), chronic diseases (9%), genetic syndromes and skeletal problem (8%). Conclusion: The majority of short stature in children had normal variation of growth. Along with endocrine causes, chronic systemic illnesses and malnutrition still form a major bulk in the etiological profile of SS in Bangladesh. DS (Child) H J 2022; 38(2): 79-83

Role of genetic investigation in the diagnosis of short stature in a cohort of Italian children.

Short stature (SS) is defined as height more than 2 standard deviations below the mean for age and sex. Hypothyroidism, celiac disease, growth hormone deficiency, hormonal abnormalities, and genetic conditions are among its causes. A wide range of conditions often due to largely unknown genetic variants can elude conventional diagnostic workup. We used next-generation sequencing (NGS) to better understand the etiology of SS in a cohort of Italian children. The study sample was 125 children with SS of unknown origin referred to our Institute between 2015 and 2021. All had undergone complete auxological and hormonal investigations to exclude common causes of SS. Genetic analysis was performed using a NGS panel of 104 genes. Clinical data were reviewed to clarify the pathogenicity of the variants detected. In this cohort, 43 potentially causing variants were identified in 38 children. A syndromic genetic condition was diagnosed in 7: Noonan syndrome in 3, Leri-Weill syndrome in 3, and hypochondroplasia in 1. Moreover, 8 benign variants and other 37 like benign variants were found. In 88 children, 179 variants of uncertain significance (VUS) were identified. No variant was found in 16 children. Genetic analysis is a useful tool in the diagnostic workup of patients with SS, in adapting management and treatment, and in identifying syndromes with mild atypical clinical features. The role of VUS should not be underestimated, particularly when multiple VUS with possible mutual worsening effects are present in the same child.

Idiopathic Short Stature - A Case Report

Short stature in childhood is the most common reason for referral to pediatric endocrinologists. Idiopathic short stature is defined as ³2 SD below the corresponding mean height for a given age, sex, and population in a child with a normal birth size and normal body proportions and without evidence of any systemic, endocrine, nutritional, or chromosomal abnormalities. ISS children have normal GH responses to stimulation test and GH therapy has approved for the treatment of children with ISS. A six-year-old girl presented with not growing well in comparison to other peers since 6 months of her age. Her WAZ was -4.5 SD, HAZ was -7.7 SD, and projected height is far below parental target height. Bone age was 2-3 year and growth hormone stimulation showed normal growth hormone secretion. Here we reported a six-yearold girl diagnosed as a case of non-familial ISS and treated with growth hormone. Diagnosis of Idiopathic short stature was done by exclusion of other causes of short stature and growth hormone therapy was indicated.&#x0D; BANGLADESH J CHILD HEALTH 2022; VOL 46 (1) : 28-29

Exploring the Genetic Causes for Postnatal Growth Failure in Children Born Non-Small for Gestational Age.

The most common causes of short stature (SS) in children are familial short stature (FSS) and idiopathic short stature (ISS). Recently, growth plate dysfunction has been recognized as the genetic cause of FSS or ISS. The aim of this study was to investigate monogenic growth failure in patients with ISS and FSS. Targeted exome sequencing was performed in patients categorized as ISS or FSS and the subsequent response to growth hormone (GH) therapy was analyzed. We found 17 genetic causes involving 12 genes (NPR2, IHH, BBS1, COL1A1, COL2A1, TRPS1, MASP1, SPRED1, PTPTN11, ADNP, NADSYN1, and CERT1) and 2 copy number variants. A genetic cause was found in 45.5% and 35.7% of patients with FSS and ISS, respectively. The genetic yield in patients with syndromic and non-syndromic SS was 90% and 23.1%, respectively. In the 11 genetically confirmed patients, a gain in height from -2.6 to -1.3 standard deviations after 2 years of GH treatment was found. The overall diagnostic yield in this study was 41.7%. We identified several genetic causes involving paracrine signaling, the extracellular matrix, and basic intracellular processes. Identification of the causative gene may provide prognostic evidence for the use of GH therapy in non-SGA children.

Identification of a second genetic alteration in patients with SHOX deficiency individuals: a potential explanation for phenotype variability.

Our study aimed to assess the impact of genetic modifiers on the significant variation in phenotype that is observed in individuals with SHOX deficiency, which is the most prevalent monogenic cause of short stature. We performed a genetic analysis in 98 individuals from 48 families with SHOX deficiency with a target panel designed to capture the entire SHOX genomic region and 114 other genes that modulate growth and/or SHOX action. We prioritized rare potentially deleterious variants. We did not identify potential deleterious variants in the promoter or intronic regions of the SHOX genomic locus. In contrast, we found eight heterozygous variants in 11 individuals from nine families in genes with a potential role as genetic modifiers. In addition to a previously described Likely Pathogenic (LP) variant in CYP26C1 observed in two families, we identified LP variants in PTHLH and ACAN, and variants of uncertain significance in NPR2, RUNX2 and TP53 in more affected individuals from families with SHOX deficiency. Families with a SHOX alteration restricted to the regulatory region had a higher prevalence of a second likely pathogenic variant (27%) than families with an alteration compromising the SHOX coding region (2.9%, p= 0.04). In conclusion, variants in genes related to the growth plate have a potential role as genetic modifiers of the phenotype in individuals with SHOX deficiency. In individuals with SHOX alterations restricted to the regulatory region, a second alteration could be critical to determine the penetrance and expression of the phenotype.

The Growth Hormone Deficiency (GHD) Reversal Trial: effect on final height of discontinuation versus continuation of growth hormone treatment in pubertal children with isolated GHD—a non-inferiority Randomised Controlled Trial (RCT)

Background Growth hormone deficiency (GHD) is the commonest endocrine cause of short stature and may occur in isolation (I-GHD) or combined with other pituitary hormone deficiencies. Around 500 children are diagnosed with GHD every year in the UK, of whom 75% have I-GHD. Growth hormone (GH) therapy improves growth in children with GHD, with the goal of achieving a normal final height (FH). GH therapy is given as daily injections until adult FH is reached. However, in many children with I-GHD their condition reverses, with a normal peak GH detected in 64–82% when re-tested at FH. Therefore, at some point between diagnosis and FH, I-GHD must have reversed, possibly due to increase in sex hormones during puberty. Despite increasing evidence for frequent I-GHD reversal, daily GH injections are traditionally continued until FH is achieved.Methods/designEvidence suggests that I-GHD children who re-test normal in early puberty reach a FH comparable to that of children without GHD. The GHD Reversal study will include 138 children from routine endocrine clinics in twelve UK and five Austrian centres with I-GHD (original peak GH < 6.7 mcg/L) whose deficiency has reversed on early re-testing. Children will be randomised to either continue or discontinue GH therapy. This phase III, international, multicentre, open-label, randomised controlled, non-inferiority trial (including an internal pilot study) will assess whether children with early I-GHD reversal who stop GH therapy achieve non-inferior near FH SDS (primary outcome; inferiority margin 0.55 SD), target height (TH) minus near FH, HRQoL, bone health index and lipid profiles (secondary outcomes) than those continuing GH. In addition, the study will assess cost-effectiveness of GH discontinuation in the early retesting scenario.DiscussionIf this study shows that a significant proportion of children with presumed I-GHD reversal generate enough GH naturally in puberty to achieve a near FH within the target range, then this new care pathway would rapidly improve national/international practice. An assumed 50% reversal rate would provide potential UK health service cost savings of £1.8–4.6 million (€2.05–5.24 million)/year in drug costs alone. This new care pathway would also prevent children from having unnecessary daily GH injections and consequent exposure to potential adverse effects.Trial registrationEudraCT number: 2020-001006-39

A rare case of SCHMID metaphyseal chondrodysplasia associated with hypothyroidism,growth hormone deficiency and celiac disease: case report.

The authors present a rare case of 4-year-2-month-old boy referred to our Unit for harmonious short stature, he had a waddling gait, subtle micromelia, and hyperlordosis, no special facies. The skeletal scan made the diagnosis of SCHMID metaphyseal chondrodysplasia. The first laboratory workup showed elevated thyroid stimulating hormone and anti-tissue transglutaminase immunoglobulin A. The duodenal biopsies confirmed the diagnosis of coeliac disease. Treatment of levothyroxine was initiated with a gluten-free diet .6 years later, his re-evaluation showed a low insulin-like growth factor 1 and low growth hormone peaks confirming the diagnosis of growth hormone deficiency, Growth hormone therapy was initiated with an adjusted dose of levothyroxine. Other causes of short stature should not be missed when diagnosing chondrodysplasia, and further investigations should be carried out to detect other concomitant disorders since metaphyseal chondrodysplasia is a rare cause for short stature while hypothyroidism and coeliac disease are relatively common.

Two Rare Variants of Turner Syndrome with Isochromosome Structural Abnormalities

Background: Turner’ssyndrome (TS) is the most common cause of short stature and delayed puberty of female sex. Approximately half of the patients have its classic form of 45 XO, one fourth of patients are different mosaic forms and the remaining cases are structural abnormalities on X chromosome, among them most common structural abnormality is isochromosomeXq. These variant Turner’s can present with delayed menarche, amenorrhoea and infertility rather than classic manifestations of TS.Here we describetwo uncommon variants of TS, one is structural abnormality on X chromosome as 46X, iso(Xq) and another one is mosaic variety of TS including Isochromosome X as form of 45XO/46X, iso(Xq).Both of them presented with short stature and secondary amenorrhea without classic manifestations of TS. In TS with or without mosaicism, the frequency of isochromosome is reportedto be about 15-18%. Due to lack of classical manifestations of TS, diagnosis may be delayed and/or missed. So, female of short stature with secondary amenorrhoea should be searched for rare variants of TS by chromosomal analysis. J Medicine 2023; Vol. 34, No. 2(1) Supplement: 223

Better late than never - a very rare cause of short stature

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)