Effect and safety of aromatase inhibitors for the treatment of short stature in male children and adolescents: a meta-analysis of randomized controlled trials.

This study is to evaluate the efficacy and safety of aromatase inhibitors (AIs) in the treatment of short stature in male children and adolescents. Pooled estimates of final or near-final height, predicted adult height (PAH), bone age, and potential side effects were calculated using a random-effects model or fixed-effects model. Our search identified 11 studies with a total of 463 participants. AI was associated with a significant increase in final or near-final height (weight mean difference (WMD)=3.61 cm, 95 % CI: 0.96, 6.26; p<0.001) and PAH (WMD=2.52 cm, 95 % CI: 0.32, 4.72; p=0.025) compared to other treatment. The use of AI showed an increased risk of minor side effects (risk ratio (RR)=2.90, 95 % CI: 1.15, 7.33; p=0.025), but no severe adverse effects were reported. Subgroup analysis, stratified by patient disease, revealed that AI significantly enhanced final or near-final height in both patients with idiopathic short stature (ISS) and those with constitutional delay of growth and puberty (CDGP). AIs may contribute to height increase in male children and adolescents with short stature, without significantly advancing bone age. However, the increased risk of minor side effects indicates the need for careful monitoring during AI therapy.

Fibrillin-1 Gene Variant p.Gly1754Ser Associated With Weill-Marchesani Syndrome Type 2: A Case Report.

Weill-Marchesani syndrome (WMS) is a rare connective tissue disorder characterized by severe short stature, small hands and feet, joint stiffness, eye abnormalities such as microspherophakia, ectopia of lenses, severe myopia, glaucoma, and heart defects. This case study describes a nine-year-old female child with WMS syndrome type 2 and heterozygous pathogenic variant p.Gly1754Ser in the fibrillin-1 gene, identified on whole exome sequencing. Two individuals with WMS with the p.Gly1754Ser variant have been previously reported in the medical literature. The present case is the fourteenth case of WMS type 2 with fibrillin-1 gene mutation in the medical literature, to the best of the author's knowledge.

Pycnodysostosis: Clinical Insights From Two Siblings.

Pycnodysostosis is a rare autosomal recessive bone disorder caused by mutations in the cathepsin K (CTSK) gene, characterized by increased bone density, short stature, and skeletal fragility. This study reports on two siblings from a consanguineous marriage, observed at the Mohammed VI University Hospital in Oujda, Morocco. Both patients presented with typical symptoms, including craniofacial dysmorphism and skeletal abnormalities. Radiographic findings confirmed increased bone density and acro-osteolysis. The cases highlight the importance of early and accurate diagnosis, comprehensive management to address the broad spectrum of clinical manifestations, and genetic counseling to inform family planning and manage the risk of recurrence in familial pycnodysostosis.

Factor analysis of traditional Chinese medicine symptoms for identification of syndrome patterns associated with idiopathic short stature in children.

Objectives: Diagnosing idiopathic short stature (ISS) in Traditional Chinese Medicine (TCM) remains challenging partly because the symptoms and syndrome patterns vary among ISS patients and studies. We aimed to use factor analysis of TCM symptoms to identify syndrome patterns associated with ISS in children on the basis of TCM theory. Materials and Methods: A cross-sectional study was conducted at Taipei Tzu Chi Hospital, New Taipei City, Taiwan, from October 1, 2014, to February 28, 2016. The study included 957 individuals who were newly diagnosed with ISS through simple random sampling. The outcome measures comprised 34 TCM symptoms related to children's growth, and these symptoms were assessed using a five-level self-report questionnaire, which was completed by children and their parents. A factor analysis was conducted for the extraction of underlying factors. Results: A total of 26 symptoms had factor loadings higher than the exact threshold value (0.4), and five factors were extracted. Factor 1, comprising seven symptoms, was interpreted as "yin deficiency and fire hyperactivity of kidney syndrome." Factor 2, which included eight symptoms, was interpreted as "phlegm dampness stagnation of spleen syndrome." Factor 4, which included five symptoms, was interpreted as "liver qi invading the spleen syndrome." Factor 5, which included four symptoms, was interpreted as "spleen-stomach weakness syndrome." Factor 3, which included four symptoms, was uninterpretable. Factors 1-5 accounted for 10%, 9%, 8%, 7%, and 6% of the total variance. Conclusion: Four major TCM syndrome patterns, namely, "yin deficiency and fire hyperactivity of kidney syndrome," "phlegm dampness stagnation of spleen syndrome," "Liver qi invading the spleen syndrome," and "spleen-stomach weakness syndrome" were identified and accounted for 40% of the total variance of the 34 TCM symptoms surveyed in children with ISS. Our findings may facilitate the diagnosis of ISS and the optimization of treatment strategies.

A feasibility study of magnetic resonance pelvimetry in women of short stature to identify the risk of cephalo-pelvic disproportion.

OBJECTIVE: To conduct a feasibility study to assess if MR Pelvimetry can be undertaken in short stature primigravidae, with a view to a main study to answer the question 'can MR pelvimetry be used to predict cephalo-pelvic disproportion (CPD) in women of short stature?'. STUDY DESIGN: This was a prospective single arm feasibility study. In the first phase, patient and public involvement was undertaken to assess acceptability of the study. In the second phase, primiparous women of ≤ 160 cm in height were selected from antenatal clinics. Obstetricians and midwives were asked to inform all eligible women about the study. Patients were approached in the third trimester and written information about the study provided. If the patient agreed to participate, they were invited for consent. MR scans were performed from 36 weeks gestation. Patients and their obstetricians were not informed of the results of the MR until after delivery (in view of NICE and WHO recommendations on pelvimetry). RESULTS: MR scans were performed on 21/35 (60%) participants who consented. The study was conducted without adverse events and was acceptable to all participants. Data were available from 19 patients; 7 (37%) of whom had caesarean section (CS) due to CPD, 7 (37%) had assisted vaginal birth (AVB), while 5 (26%) had spontaneous vaginal births (SVD). Two patients who had an elective CS were not included in the analysis. The pelvic measurements especially anatomical conjugate (inlet), transverse diameter (mid cavity) and anteroposterior diameter at the outlet were larger in the SVD group in comparison to in-labour CS /AVB. Interobserver MR scan measurements were comparable between radiologists: intraclass correlation coefficient (ICC) range 0.68 to 0.95. CONCLUSION: This feasibility study suggests that conducting a full study to answer the research question 'can MR pelvimetry predict CPD in women of short stature?'would be feasible and acceptable to patients. The recruitment, MR scan protocol, reporting, reliability of measures were all assessed and found acceptable for a trial. A trend was observed for smaller pelvic measurements in women who needed intervention compared with those who had a natural birth/SVD. With evidence from a full trial, this could have major implications for the management of short stature women, in terms of clinical practice and safety. KEY MESSAGES: A large trial would be feasible and acceptable to assess whether MR pelvimetry can predict CPD in women of short stature. Despite the small number of patients, a trend was observed for smaller pelvic measurements in women who needed intervention compared to those who had spontaneous vaginal birth. Evidence from a large trial could help inform clinical practice, and provide information and choice for women at risk of CPD.

Molecular diagnosis of patients with syndromic short stature identified by trio whole-exome sequencing.

Background: Short stature is a complex disorder with phenotypic and genetic heterogeneity. This study aimed to investigate clinical phenotypes and molecular basis of a cohort of patients with short stature. Methods: Trio whole-exome sequencing (Trio-WES) was performed to explore the genetic aetiology and obtain a molecular diagnosis in twenty Chinese probands with syndromic and isolated short stature. Results: Of the twenty probands, six (6/20, 30%) patients with syndromic short stature obtained a molecular diagnosis. One novel COMP pathogenic variant c.1359delC, p.N453fs*62 and one LZTR1 likely pathogenic variant c.509G>A, p.R170Q were identified in a patient with short stature and skeletal dysplasia. One novel de novo NAA15 pathogenic variant c.63T>G, p.Y21X and one novel de novo KMT2A pathogenic variant c.3516T>A, p.N1172K was identified in two probands with short stature, intellectual disability and abnormal behaviours, respectively. One patient with short stature, cataract, and muscle weakness had a de novo POLG pathogenic variant c.2863 T>C, p.Y955H. One PHEX pathogenic variant c.1104G>A, p.W368X was identified in a patient with short stature and rickets. Maternal uniparental disomy 7 (mUPD7) was pathogenic in a patient with pre and postnatal growth retardation, wide forehead, triangular face, micrognathia and clinodactyly. Thirteen patients with isolated short stature had negative results. Conclusion: Trio-WES is an important strategy for identifying genetic variants and UPD in patients with syndromic short stature, in which dual genetic variants are existent in some individuals. It is important to differentiate between syndromic and isolated short stature. Genetic testing has a high yield for syndromic patients but low for isolated patients.

A case with short stature and proteinuria: atypical presentation of a family with m.3243A>G mutation.

BACKGROUND: The mitochondrial DNA (mtDNA) m.3243A>G mutation is one of the most common pathogenic mtDNA variants. The phenotypes associated with this mutation range from asymptomatic induviduals to well-defined clinical syndromes, or non-syndromic mitochondrial disorders. Variable clinical features in pediatric cases may cause difficulty in diagnosis. Kidney involvement in this mutation is uncommon and reported on a case-by-case basis. Here, we report on a patient with m.3243A>G mutation, who presented with short stature and proteinuria, and his family, who share the same genotype but exhibit different heteroplasmy levels in different tissues and variable phenotypes. CASE PRESENTATION: A 15-year-old male patient was admitted to the pediatric endocrinology department with short stature. His examinations revealed nephrotic range proteinuria, hearing loss, impaired glucose tolerance, and Wolf-Parkinson-White syndrome. From family history, it was learned that diabetes mellitus (DM) and progressive sensorineural hearing loss were common in this family. The patient's mother, who had chronic kidney disease, DM, and hearing loss, had died suddenly for an unknown reason. Considering the family history, a genetic analysis was performed for mitochondrial disease. Mitochondrial DNA analysis revealed a m.3243A>G mutation with 47% heteroplasmy in blood, 62% heteroplasmy in buccal cells, and 96% heteroplasmy in urothelial cells in our patient. CONCLUSIONS: Short stature without any other complaint and renal involvement are rare findings in m.3243A>G mutation. In patients presenting with proteinuria, in the presence of conditions affecting many systems such as endocrine system pathologies, hearing loss, and cardiac pathologies, and in the presence of individuals with a similar family history of multiple organ involvement, mitochondrial diseases should be considered, and examined from this perspective. Our case illustrates the value of a detailed medical and family history.

The association between atopic dermatitis and linear growth in children- a systematic review.

To evaluate the association between atopic dermatitis (AD) and linear growth in children, and determine factors associated with compromised linear growth in children with AD. A PRISMA-compliant systematic review was conducted. Databases (PubMed, Embase, Scopus and Cochrane) were searched from inception to June 2024 for articles that reported a quantitative relationship between AD and linear growth in children (< 18 years old). Quality of included articles was assessed using the Joanna Briggs Institute Critical Appraisal Tools while quality of evidence in these studies was evaluated using Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. Fourteen studies (comprising 50,146 patients with AD) were included. Seven studies reported a strong positive or positive association between AD and reduced height standard deviation score (SDS) in children; the others reported no association. Only 3 studies had moderate quality of evidence, all of which reported an association between AD and poorer height SDS; the remaining 11 studies scored low in quality of evidence. Three studies reported the impact of AD on height to be transient. Secondary analysis showed AD severity, earlier AD onset, sleep disruption and, food restriction, to be risk factors for linear growth impairment in patients with AD. Topical steroid use was not associated with shorter stature in patients with AD. Conclusion: Current evidence on the association between childhood AD and poor linear growth is weak and inconsistent. However, patients with more severe AD, earlier disease onset, poorer sleep quality and higher nutritional restrictions appear more susceptible to linear growth impairment. What is known? • There is inconsistent evidence of the association between atopic dermatitis (AD) and linear growth in children in current literature, with some studies suggesting that AD may negatively impact linear height while other studies do not report similar associations. What is new? • There is no strong association between AD in childhood and poorer linear growth. • There may be a transient slowing of linear growth in children with AD, mimicking constitutional growth delay. • Children with severe AD, earlier disease onset, poorer sleep quality and nutritional restrictions may be at risk of more significant linear growth impairment. • Topical steroid use does not appear to contribute to shorter height in children with AD.

Unraveling the Genetic Puzzle: Could MAP3K7 Be a Candidate Gene for RASopathies? Case Presentation.

Noonan Syndrome (NS) diagnosis is challenging due to diverse clinical manifestations. Here, our case report highlights MAP3K7's novel role in NS. A 10.4-year-old female patient presented with short stature and suggestive clinical findings of RASopathy. Despite atypical facial features, the patient met two major diagnostic criteria of Van der Burgt.Initial genetic testing for known NS-associated genes did not find any variants. Later, whole exome sequencing (WES) discovered a unique de novo heterozygous variant (c.65C>A, p.(P22H)) in the MAP3K7. This variant, categorized as a variant of uncertain significance (VUS) by the American College of Medical Genetics and Genomics (ACMG) criteria, raised questions about its potential role in NS. The patient's clinical presentation deviated from classical manifestations of MAP3K7-associated syndromes, underscoring the genetic and molecular mechanisms' complexity. Notably, this is the first case reported to associate MAP3K7 variants with NS, advancing knowledge of the condition's genetic causes. Despite challenges in NS diagnosis, proper management, including recombinant growth hormone therapy, is crucial for optimizing growth potential. The case underscores MAP3K7 as a potential candidate gene for NS, and more functional genetic investigations are required to clarify the delicate interaction between genetic abnormalities, the RAS/MAPK pathway, and clinical manifestations observed in NS cases.

Short Stature in Klinefelter Syndrome From Aggrecan Mutation.

Despite tall stature being a characteristic feature of Klinefelter syndrome, occasional cases of short stature have been reported. These cases are often attributed to GH deficiency. This case report details a unique case of a 16-year-old male with Klinefelter syndrome exhibiting proportionate short stature resulting from a heterozygous, likely pathogenic, variant in the ACAN gene c.7141G > A (p.Asp2381Asn). This specific variant, previously identified once in a family with a recessive inheritance pattern is reported here for the first time in an individual with Klinefelter syndrome. This report emphasizes the importance of a thorough evaluation and consideration of genetic testing for an underlying diagnosis in short-statured individuals with Klinefelter syndrome. Timely detection would enable appropriate therapeutic interventions.

Evaluation of insulin-like growth factor-1 in apparently healthy infants and prepubertal Egyptian children with different nutritional statuses.

OBJECTIVES: to estimate insulin-like growth factor-1 (IGF-1) levels in apparently healthy infants and prepubertal children and compare results among different nutritional statuses. METHODS: Our cross-sectional work is a sub-study of a screening project for anemia and nutritional status. We included 252 apparently healthy infants and children with a mean age of 3.7 ± 1.3 years (1.1-6.6), with equal gender distribution. Data retrieved included breastfeeding and anthropometric measures. We tested the stored blood samples for IGF-1 levels. The sample size was reached when all kits were consumed. RESULTS: abnormal anthropometric measures were detected in 32.9%, either a single or multiple, and 86.5% were breastfed. Girls had significantly higher serum IGF-1 levels than boys (P: <0.001), which was noticeable in girls with abnormal nutritional status detected with anthropometry. Breastfeeding showed no significant association with IGF-1 levels. No significant difference was observed between IGF-1 levels between children with normal versus those with abnormal growth measures. Children with overweight or obesity had significantly lower IGF-1 than children with other body mass index (BMI) categories. Serum IGF-1 levels correlated positively with arm muscle area Z scores in infants and toddlers and weight and BMI Z scores in children between three and four. Also, IGF-1 correlated positively with the triceps skinfold Z score and arm muscle area Z score between four and five. CONCLUSIONS: Among studied infants and prepubertal children, serum IGF-1 was significantly higher in girls than boys and was considerably lower in children with overweight or obesity. Breastfeeding showed no association with IGF-1 levels.

Single-Center Experience in Patients with Mixed Gonadal Dysgenesis.

Mixed gonadal dysgenesis (MGD) is an uncommon chromosomal Disorder of Sexual Development (DSD). There is insufficient information regarding clinical findings and growth patterns. This study aimed to provide more information about mixed gonadal dysgenesis, which has not yet been sufficiently defined. Data from 10 patients diagnosed with mixed gonadal dysgenesis were retrospectively reviewed. Clinical presentations, complaints at admission, imaging, genetic results, and treatments received by the patients were examined. Gonadal status and the gender of the patients were reared and evaluated by a multidisciplinary council decision. If received, growth hormone treatment doses and height gains were examined. The patients' ages at admission range from 6 months to 17.5 years. The median height SDS of the patients was -0.75 (2.73), the mean body weight SDS was -0.49 (±1.46), and the mean body mass index (BMI) SDS was 0.26 (±0.97). The complaints at admission varied, including ambiguous genitalia, short stature, and absence of menstruation. Some patients are completely in the female phenotype, while some are inadequately virilized male phenotype. External Masculinization Score (EMS) ranges from 1 to 6.5. The decision to raise 6 patients as female and 4 patients as male was made by a multidisciplinary council. Growth hormone treatment was administered to patients raised as female and diagnosed with short stature. The height SDS gain in treated patients was 0.42 (±0.49). Due to its rarity and varied clinical presentation, our knowledge about mixed gonadal dysgenesis is limited. Therefore, early diagnosis and individualized treatment plans are crucial for this patient group.

The clinical and genetic aspects of six individuals with GH1 variants and isolated growth hormone deficiency type II.

Background: Isolated growth hormone deficiency type II (IGHD II) is an autosomal dominant disorder characterized by a GH1 gene variant resulting in a significant reduction in growth hormone (GH) secretion and a subsequent decrease of plasma insulin-like growth factor 1 (IGF-1) levels and eventual growth impairment. Objective: This study aimed to identify causative variants in six Chinese families with IGHD II, exploring both clinical and genetic characteristics. Methods: Detailed clinical data, including clinical presentations, physical charateristics, medical and family histories, as well as genetic test results, were systematically examined. Results: Six children, comprising four males and two females, with a mean age of 4.64 ± 1.15 years, exhibited short stature with a mean height of -3.95 ± 1.41 SDS. Four of them had a family history of short stature, while one patient presented with pulmonary hypertension. All children demonstrated GH deficiency in growth hormone stimulation tests (mean peak GH value: 2.83 ± 2.46 ng/mL). Exome sequencing for the six patients and targeted gene sequencing for their family members revealed heterozygous variants in the GH1 gene, including Exon2-5del, c.334T>C, c.291 + 1G>A, c.291 + 2T>A, 1.5 kb deletion, and 1.7 kb deletion, with four variants being novel. Four patients underwent human recombinant growth hormone (rhGH) replacement therapy, initiating treatment at a mean age of 4.6 ± 0.7 years. The mean height increase in patients was 1.21 ± 0.3 SDS in the first six months of treatment and 1.79 ± 0.15 SDS in the first year. Conclusion: Our findings contribute to expanding the genotypic and phenotypic spectra of individuals with IGHD II.

A long way to syndromic short stature.

BACKGROUND: Silver-Russell Syndrome (SRS, MIM #180860) is a clinically and genetically heterogeneous disorder characterized by intrauterine and postnatal growth retardation; SRS is also accompanied by dysmorphic features such as triangular facial appearance, broad forehead, body asymmetry and significant feeding difficulties. The incidence is unknown but estimated at 1:30,000-100,000 live births. The diagnosis of SRS is guided by specific criteria described in the Netchine-Harbison clinical scoring system (NH-CSS). CASE PRESENTATION: Hereby we describe four patients with syndromic short stature in whom, despite fitting the criteria for SRS genetic analysis (and one on them even meeting the clinical criteria for SRS), molecular analysis actually diagnosed a different syndrome. Some additional features such as hypotonia, microcephaly, developmental delay and/or intellectual disability, and family history of growth failure, were actually discordant with SRS in our cohort. CONCLUSIONS: The clinical resemblance of other short stature syndromes with SRS poses a risk of diagnostic failure, in particular when clinical SRS only criteria are met, allowing SRS diagnosis in the absence of a positive result of a genetic test. The presence of additional features atypical for SRS diagnosis becomes a red flag for a more extensive and thorough analysis. The signs relevant to the differential diagnosis should be valued as much as possible since a correct diagnosis of these patients is the only way to provide the appropriate care pathway, a thorough genetic counselling, prognosis definition, follow up setting, appropriate monitoring and care of possible medical problems.

Clinical Characteristics, Genetic Analysis, and Literature Review of Cornelia de Lange Syndrome Type 4 Associated With a RAD21 Variant.

BACKGROUND: Cornelia de Lange syndrome (CdLS) is an uncommon congenital developmental disorder distinguished by intellectual disorder and distinctive facial characteristics, with a minority of cases attributed to RAD21 variants. METHODS: A patient was admitted to the endocrinology department at Peking Union Medical College Hospital, where 2 mL of peripheral venous blood was collected from the patient and his parents. DNA was extracted for whole-exome sequencing (WES) analysis, and the genetic variation of the parents was confirmed through Sanger sequencing. RESULTS: A 13.3-year-old male patient with a height of 136.5 cm (-3.5 SDS) and a weight of 28.4 kg (-3.1 SDS) was found to have typical craniofacial features. WES revealed a pathogenic variant c.1143G>A (p.Trp381*) in the RAD21 gene. He was diagnosed with CdLS type 4 (OMIM #614701). We reviewed 36 patients with CdLS related to RAD21 gene variants reported worldwide from May 2012 to March 2024. Patient's variant status, clinical characteristics, and rhGH treatment response were summarized. Frameshift variants constituted the predominant variant type, representing 36% (13/36) of cases. Clinical features included verbal developmental delay and intellectual disorder observed in 94% of patients. CONCLUSION: This study reported the third case of CdLS type 4 in China caused by a RAD21 gene variant, enriching the genetic mutational spectrum.

Different growth patterns in two siblings with Schimke immuno-osseous-dysplasia.

Schimke immuno-osseous-dysplasia (SIOD) is an autosomal recessive systemic disease due to pathogenic variants in SMARCAL1. Manifestations include nephrotic syndrome (NS), kidney failure, T-cell dysfunction, vaso-occlusive disease, and disproportionate short stature, a general feature of this disease. Here, we present a markedly different growth pattern in two brothers with SIOD sharing the same homozygous R561C missense variant. The index patient presented at the age of 11 years with NS and severely disproportionate short stature, followed by kidney failure at the age of 16, and severely reduced adult height (z-score - 8.0). In contrast, the younger brother showed normal growth until the age of 8 years. Mild proteinuria was noted at the age of 4.5, followed by NS at 9.5 years, kidney failure at 11 years, progressive disproportionate stature, and reduced adult height (z-score - 4.5). Both brothers had comparable disproportion in adulthood (sitting height index z-score - 0.88 and - 1.44, respectively).

Small pituitary volume and central nervous system anomalies in Fanconi Anemia.

Introduction: Fanconi anemia (FA) is a genomic instability disorder associated with congenital abnormalities, including short stature and the presence of central nervous system anomalies, especially in the hypothalamic-pituitary area. Thus, differences in pituitary size could associate with the short stature observed in these patients. Our aim was to evaluate whether central nervous system abnormalities and pituitary gland volume correlate with height and hormone deficiencies in these patients. Methods: In this cross-sectional exploratory study 21 patients diagnosed with FA between 2017 and 2022 in a Spanish Reference Center were investigated. Magnetic resonance imaging (MRI) was performed and pituitary volume calculated and corelated with height and other endocrine parameters. Results: The percentage of abnormalities in our series was 81%, with a small pituitary (pituitary volume less than 1 SD) being the most frequent, followed by Chiari malformation type 1. The median value of pituitary volume was -1.03 SD (IQR: -1.56, -0.36). Short stature was found in 66.7% [CI95% 43-85.4]. Total volume (mm3) increases significantly with age and in pubertal stages. There were no differences between volume SD and pubertal stage, or the presence of endocrine deficiencies. No correlations were found between pituitary volume and the presence of short stature. The intraclass correlation index (ICC) average for volume was 0.85 [CI95% 0.61-0.94] indicating a good-to-excellent correlation of measurements. Discussion: Central nervous system anomalies are part of the FA phenotype, the most frequent after pituitary hypoplasia being posterior fossa abnormalities, which may have clinical repercussions in the patient. It is therefore necessary to identify those who could be candidates for neurosurgical intervention. The size of the pituitary gland is smaller in these patients, but this does not seem to be related to hormone deficiency and short stature or exposure to a low dose of total body irradiation.

Awareness-Raising Activities to Identify Children with Short Stature.

BACKGROUND: Although short stature is sometimes treatable in children, family members do not always realize that their children have short stature. To develop better educational materials for identifying short stature, we conducted a questionnaire survey on children with short stature. Using the results of the survey, we revised educational activities regarding short stature. METHODS: To assess the effectiveness of the revised activities, we examined changes in the numbers of consultations before and after the changes to the educational activities, the height of children examined after such changes, the test implementation rate, and the test results. RESULTS: After the start of direct promotion for school nursing staff in 2015, the number of outpatients with short stature who visited the hospital significantly increased (16.1/year before 2014 vs. 68.8/year after 2015; p = 0.02). The number of patients hospitalized for a growth hormone secretion stimulation test also significantly increased, from 9.3/year before 2014 to 47.0/year after 2015 (p = 0.02). However, 35% of families did not want to subject their child to a growth hormone stimulating test, even if their child was extremely short. CONCLUSIONS: Our revised educational activities for short stature among school nursing staff, school physicians, and nurses at health centers were more effective than conventional activities consisting of public relations magazines and lectures for the general public. It is important to provide proper explanations to enable a better understanding of hormone therapy.

Investigation of Serum Pro-Inflammatory Markers and Trace Elements Among Short Stature in Eastern Uttar Pradesh and Bihar Populations.

Purpose: Short stature is prevalent among children worldwide, particularly in developing countries. Various trace elements, including zinc, magnesium, iron, copper, chromium and selenium, are crucial for proper body development. The aim of this study is to explore the relationship between trace elements and TNF-α and IL-6 to elicit and possible pathway responsible for short stature. Methods: Two hundred and twenty samples were recruited for this study, 100 short statures and 120 controls were randomly selected. Six trace elements were measured using graphite furnace atomic absorption spectrometry. The concentrations of IL-6 and TNF-α in serum were assessed utilizing the Enzyme-Linked-Immunosorbent Assay (ELISA). Superoxide dismutase was also analysed to determine the oxidative stress response. Results: The study revealed notable distinctions in serum trace element levels of short stature. They exhibited significant lower levels of zinc and magnesium, alongside higher levels of copper. The altered Cu/Zn ratio seemed to have a positive correlation with short stature. Conversely, no significant disparities were observed in iron, chromium, and selenium levels. Furthermore, a significant rise was noted in proinflammatory marker TNF-α and cytokine IL-6. Additionally, superoxide dismutase was low in the short statures In silico study shows a high affinity of Zinc with TNF alpha. It may be suggested that inflammation at any time during childhood, with the rise in TNF alpha tightly binds with zinc and may have led to a decrease in zinc serum levels, altered redox homeostasis and resulted in short stature. Conclusion: The altered Cu/Zn ratio along with high TNF alpha and IL6 may be used as a marker for short stature in the initial years of growth in children before they reach maturity at the age of 18. Thereafter, introducing zinc supplementation could potentially enhance stature by mitigating TNF-alpha level. Further experimental studies will help to establish the exact role of zinc with TNF alpha in short stature.

Genetic analysis of the PAPP-A2 gene and evaluation of free IGF-1, IGFBP-5, and ALS concentrations in a group of 22 patients with idiopathic short stature.

INTRODUCTION: Short stature is one of the main reasons for consultation in outpatient clinics and paediatric endocrinology departments and is defined as height below the 3rd centile or less than -2 standard deviations (SDs). MATERIAL AND METHODS: The study's overarching aim was to analyse the PAPP-A2 gene at mutation sites described to date and at exons 3, 4, and 5, which encode the fragment of the catalytic domain with the active site of the pregnancy-associated plasma protein A2 (PAPP-A2) protein. The secondary aims of the study were clinical and auxological analysis of a group of patients with idiopathic short stature and biochemical analysis of growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis parameters not assessed as part of the routine diagnosis of short stature, such as free IGF-1, insulin-like growth factor binding protein 5 (IGFBP-5), and acid-labile subunit (ALS) levels. Molecular analysis of the PAPP-A2 gene was performed using polymerase chain reaction (PCR) and direct sequencing. Biochemical analysis of free IGF-1, IGFBP-5, and ALS was performed by enzyme-linked immunosorbent assay (ELISA). RESULTS: The mean height standard deviation score (HSDS) in the study group was -2.95. None of the patients exhibited previously described mutations in the PAPP-A2 gene or mutations in exons 3, 4, and 5 encoding the fragment of catalytic domain with the active site of the PAPP-A2 protein. In 4 patients, the known, non-pathogenic, heterozygotic polymorphism c.2328C>T(rs10913241) in exon 5 was found. CONCLUSIONS: Free IGF-1 levels correlate better with height and HSDS than total IGF-1 levels. The previously described mutations in the PAPP-A2 gene and mutations in exons 3, 4, and 5 encoding the fragment of catalytic domain with the active site of the PAPP-A2 protein were not detected; only the known and non-pathogenic, heterozygotic polymorphism c.2328C>T(rs10913241) in exon 5 of the PAPP-A2 gene was observed.