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Kidney transplantation in children with end‐stage kidney disease significantly enhances survival and quality of life but poses unique challenges related to chronic immunosuppressive therapy. In fact, despite being essential for preventing organ rejection, immunosuppressive therapy can have significant side effects specific to pediatric patients, such as adverse impacts on physiological growth, puberty, and fertility. The resulting short stature and delayed or incomplete pubertal development can profoundly affect young patients' psychological and social well‐being, impacting self‐esteem and overall quality of life, and may significantly hamper compliance and therapeutic adherence. Most studies on immunosuppression in pediatric kidney transplant recipients focus on general side effects and outcomes like long‐term graft survival or acute complications. On the other side, there is limited evidence in the current literature on the specific issues of growth, puberty, and fertility in this patient population. In this pragmatic review, we aimed to summarize the most relevant information available on these critical aspects of post‐transplant management in pediatric patients, also providing some practical indications on management strategies for minimizing these often neglected but still important complications. [ABSTRACT FROM AUTHOR]

Purpose: Growth hormone deficiency (GHD) causes growth disturbances during childhood. The most recommended treatment of GHD is the administration of recombinant human growth hormone (rhGH). Recent studies have proved that well-nourished GHD children respond better to rhGH therapy compared to undernourished individuals. The aim of this study was to analyze nutritional status along with height velocity in GHD children during the first two years of rhGH therapy, and to estimate the optimal BMI z-score range in which these children achieve the best growth results. Methods: This retrospective analysis included 80 prepubertal idiopathic GHD children treated with rhGH. Anthropometric data were obtained from medical records made at an initial visit and then follow-up visits after 12 and 24 months of treatment. The body mass index (BMI) was calculated and standardized into z-score, basing on Cole's LMS method. Then, the BMI z-score was analyzed in relation to the parameters of growth response. Results: The higher the BMI z-score at treatment entry, the greater the increase in height during the first twelve months of rhGH therapy. BMI z-score ≥0 noted at the beginning of each year of the treatment are associated with significantly better growth increments throughout the first and the second years of the therapy. Conclusion: Prepubertal idiopathic GHD children with BMI z-score below 0 would probably benefit from the improvement of their nutritional status prior to the rhGH treatment beginning. It seems that increasing BMI z-score to obtain values between 0 and 1 would be optimal for the growth process. [ABSTRACT FROM AUTHOR]

Objective: Autosomal‐recessive hypophosphataemic rickets type 2 (ARHR2) is a rare disease that is reported in survivors of generalized arterial calcification of infancy (GACI). Design, Patients and Measurement: The objective of this study was to characterize a multicenter paediatric cohort with ARHR2 due to ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1) deficiency and with a diagnosis of GACI or GACI‐related findings. The clinical, biochemical and genetic characteristics of the patients were retrospectively retrieved. Results: We identified 18 patients from 13 families diagnosed with ARHR2. Fifteen of the patients had an ENPP1 variation confirmed with genetic analyses, and three were siblings of one of these patients, who had clinically diagnosed hypophosphataemic rickets (HRs) with the same presentation. From nine centres, 18 patients, of whom 12 (66.7%) were females, were included in the study. The mean age at diagnosis was 4.2 ± 2.2 (1.6–9) years. The most frequently reported clinical findings on admission were limb deformities (66.6%) and short stature (44.4%). At diagnosis, the mean height SD was −2.2 ± 1.3. Five of the patients were diagnosed with GACI in the neonatal period and treated with bisphosphonates. Other patients were initially diagnosed with ARHR2, but after the detection of a biallelic variant in the ENPP1 gene, it was understood that they previously had clinical findings associated with GACI. Three patients had hearing loss, and two had cervical fusion. After the treatment of HRs, one patient developed calcification, and one developed intimal proliferation. Conclusion: ARHR2 represents one manifestation of ENPP1 deficiency that usually manifests later in life than GACI. The history of calcifications or comorbidities that might be associated with GACI will facilitate the diagnosis in patients with ARHR2, and patients receiving calcitriol and phosphate medication should be carefully monitored for signs of calcification or intimal proliferation. [ABSTRACT FROM AUTHOR]

Introduction: Studies investigating the risk factors associated with unfavorable maternal/neonatal outcomes in cases of shoulder dystocia are scarce. This study aims to uncover the predictive factors that give rise to unfavorable outcomes within the context of shoulder dystocia. Materials and methods: Medical records of pregnancies complicated by shoulder dystocia was obtained between 2008–2022 from a single tertiary center. This study involved the comparison of sociodemographic, sonographic, and delivery characteristics among pregnancies complicated by shoulder dystocia resulting in favorable vs. unfavorable maternal/neonatal outcomes. Results: A total of 275 pregnancies were analyzed, with 111 (40.3%) classified as unfavorable outcomes and 164 (59.7%) as favorable outcomes. Employing a multivariable regression analysis, several independent associations were identified with unfavorable maternal/neonatal outcomes. Specifically, short maternal stature, pre-gestational diabetes, vacuum extraction, Wood's screw maneuver, and macrosomia merged as significant predictors of unfavorable maternal/neonatal outcomes. Conclusion: Short maternal stature, pre-gestational diabetes, vacuum extraction, Wood's screw maneuver, and macrosomia may all contribute to poor maternal/neonatal outcomes in shoulder dystocia cases. This knowledge allows clinicians to improve their decision-making, patient care, and counseling. [ABSTRACT FROM AUTHOR]

Context Rare patients with short stature and growth hormone (GH) resistance have dominant-negative variants in the GH receptor. We describe a patient with GH resistance due to elevated levels of GH binding protein and demonstrate the potential for a precision medicine intervention. Objective To determine whether high-dose GH can overcome GH resistance in this specific patient resulting in normal insulin-like growth factor (IGF)-1 levels and improved growth rates. Methods Single patient trial of ascending doses of GH followed by a dose stable phase: total 12 months of treatment. The patient has a heterozygous variant in the GH receptor resulting in elevated levels of GH binding protein manifesting as GH resistance and severe short stature. Daily subcutaneous GH was administered, starting at 50 µg/kg/day and escalating to 250 µg/kg/day until goal IGF-1 achieved. The subject continued on 250 µg/kg/day for a total treatment duration of 12 months. The primary outcome measure was the dose of GH required to achieve an IGF-1 level above the midpoint of the normal range. Secondary endpoints included height velocity and the change in height SDS during the first year of treatment. Results A dose of GH of 250 µg/kg/day achieved the target IGF-1 level. The patient's annualized height velocity was 8.7 cm/year, an increase of 3.4 cm/year from baseline, resulting in a 0.81 SD gain in height. Conclusion A precision medicine approach of extremely high dose GH was able to overcome GH resistance in a patient with a dominant-negative variant in the GH receptor resulting in elevated GH binding protein levels. [ABSTRACT FROM AUTHOR]

Context Patients with Turner syndrome (TS) often present with short stature and ovarian insufficiency. The optimal method of pubertal induction to maximize adult height (AH) is unknown. Objective To identify variables related to pubertal induction that are associated with growth and AH. Methods This retrospective cohort analysis of patients attending a specialized TS clinic at a quaternary children's hospital included patients with TS (n = 107) who attended the clinic between 2015 and 2021. Among them, 51 received estradiol for pubertal induction. Main outcome measures were changes in height SD score (ΔHeightSDS) during pubertal induction and AH. Age at pubertal induction, bone age delay, mid-parental height (MPH), growth hormone treatment, and karyotype were assessed as predictors of AH and ΔHeightSDS. Associations between karyotype and comorbidities were also assessed. Results AH was predicted by MPH (0.8 cm/cm, P =.0001) and bone age delay (−1.84 cm/year, P =.006). ΔHeightSDS was predicted by growth hormone dose (0.09 SDS/mg/m2/week; P =.017), bone age delay (−1.37 SDS/year; P =.003), and age at pubertal induction (0.44 SDS/year; P =.001). There was an interaction between bone age delay and pubertal induction age (P =.013), with the combination of younger age at pubertal induction and a less-delayed bone age associated with a lower ΔHeightSDS. Karyotype did not influence AH or ΔHeightSDS but did affect rates of other comorbidities. Conclusion Decisions around timing of pubertal induction in patients with TS should be tailored to the individual. The current approach to estrogen supplementation needs to be refined in order to facilitate pubertal induction in a physiological manner without compromising height. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Anthropometric measurements are crucial in pediatric critical care, but the impact of height on ICU outcomes is underexplored despite a substantial number of short-for-age children in ICUs. Previous studies suggest that short stature increases the risk of poor clinical outcomes. This study examines the relationship between short stature and ICU outcomes. Methods: We conducted a retrospective cohort study using a Japanese nationwide database (the Japanese Intensive Care Patient Database; JIPAD), which included pediatric patients under 16 years admitted to ICUs from April 2015 to March 2020. Height standard deviation scores (SD scores) were calculated based on age and sex. Short-stature patients were defined as height SD score < − 2. The primary outcome was all-cause ICU mortality, and the secondary outcome was the length of stay in ICU. Results: Out of 6,377 pediatric patients, 27.2% were classified as having short stature. The ICU mortality rate was significantly higher in the short-stature group compared to the normal-height group (3.6% vs. 1.4%, p < 0.01). Multivariable logistic regression showed that short stature was independently associated with increased ICU mortality (OR = 2.73, 95% CI 1.81–4.11). Additionally, the Fine–Gray subdistribution hazards model indicated that short stature was associated with a lower chance of ICU discharge for each additional day (HR 0.85, 95% CI 0.81–0.90, p < 0.01). Conclusions: Short stature is a significant risk factor for increased ICU mortality and prolonged ICU stay in critically ill children. Height should be considered in risk assessments and management strategies in pediatric intensive care to improve outcomes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

We report a case of a 16-year-old girl presenting to our clinic with decreased visual acuity and increased intraocular pressure in both eyes. The ophthalmological examination revealed best-corrected visual acuity (BCVA) of 0.3 in the right eye (R.E.) and 0.4 in the left eye (L.E.) and intraocular pressure (IOP) of 46 mmHg in the R.E. and 42 mmHg in the L.E., with a 360° closed angle on gonioscopy, pupillary block due to bulging, a hyper-spherical lens and high corneal thickness, without ectopia lentis or cataract. The eyes responded poorly to pharmacological mydriasis; therefore, the lens equator could not be visualised. The patient had a history of pulmonary stenosis, short stature and no significant cognitive deficits. These elements point to the diagnosis of Weill–Marchesani syndrome, and the ophthalmological management was surgical, including lens extraction and the installation of a capsular tension ring, an intraocular lens and a Shunt ExPress implantation. Evolution was favourable, with improved BCVA of 0.7 in the R.E. and 0.63 in the L.E. and IOP of 14 mmHg in the R.E. and 13 mmHg in the L.E., without topical or systemic treatment at the 6-month follow-up. Weill–Marchesani syndrome has a complex presentation, with ophthalmological, musculoskeletal, cardiac and psychiatric manifestations. Usually, this leads to a need for a multidisciplinary approach. The ophthalmologic symptoms are often the cause of presentation to a specialist, and glaucoma is the most threatening of the ocular pathologies, with possible evolution into irreversible blindness; therefore, prompt surgery and careful follow-up become key components of the treatment plan. As a take-home message, we encourage a high degree of suspicion of Weill–Marchesani syndrome in such cases. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Commercial hybrids are the main germplasm source for developing maize lines in breeding programs in Brazil; additionally, nitrogen (N) is one the major limiting maize production in Brazilian tropical areas. Here, we assessed the combining ability among ten commercial hybrids under contrasting N inputs and selected the best parental hybrids to develop breeding populations for optimal and N-stress environments. We evaluated the 45 F1 crosses for agronomic traits under contrasting N inputs and over two summer seasons. A mixed model approach was used to estimate the variance components of general combining ability (GCA) and specific combining ability (SCA) as well as to predict the GCA and SCA effects. N-stress caused a reduction in GY (33.25%) of F1 crosses averaged across seasons. We found presence of combining ability (GCA and SCA) x N input interaction for grain yield (GY), days to pollen and plant stature. The parental hybrids showed differences in GCA for cycle and plant stature but not for GY, irrespective of N inputs. Additionally, the variance components of SCA were not significant (P>0.10) for GY under LN, whereas SCA was the major component accounting for variation among F1 crosses under HN. Based on estimates of GCA effects for cycle and plant height, we selected the hybrids BAL188, BM3061, GNZ7210, BRS1060 and DKB390 as sources of favorable alleles for earlier maturing and shorter stature maize for both N conditions and suggested that hybrids GNZ7201 and DKB390, and AG1051 and NS70, which presented very small estimates of SCA for GY, must be recombined to develop two synthetic populations to begin a reciprocal recurrent selection program, mainly for non N-stress environments. [ABSTRACT FROM AUTHOR]

Background: Acromesomelic chondrodysplasias are a rare subgroup of the clinically and genetically heterogeneous osteochondrodysplasias that are characterised by abnormalities in the limb development and short stature. Here, we report a 2‐year‐old boy, offspring of consanguineous parents, with acromesomelic dysplasia and postaxial polydactyly in which exome sequencing identified a novel homozygous missense variant in BMPR1B. The patient showed skeletal malformation of both hands and feet that included complex brachydactyly with the thumbs most severely affected, postaxial polydactyly of both hands, shortened toes as well as a bilateral hypoplasia of the fibula. Methods: Whole trio exome sequencing was conducted to identify potential genetic variants in the patient. Results: The analysis identified the biallelic variant NM_001203.3:c.821A > G;p.(Gln274Arg) in BMPR1B, a gene encoding bone morphogenetic protein receptor 1B. Conclusion: The skeletal phenotype can be brought in line with the phenotypes of previously reported cases of BMPR1B‐associated chondrodysplasias. However, the postaxial polydactyly described here is a novel clinical finding in a BMPR1B‐related case; notably, it has previously been reported in other acromesomelic dysplasia cases caused by homozygous pathogenic variants in GDF5—a gene which encodes for growth differentiation factor 5, a high‐affinity ligand to BMPR1B. [ABSTRACT FROM AUTHOR]

Bardet–Biedl syndrome (BBS) is an inherited ciliopathy affecting multiple organs and systems with wide clinical and genetic heterogeneity. To date, biallelic variants of the LZTFL1 gene have been reported only in six patients with BBS. We identified a homozygous LZTFL1 nonsense variant in a boy presenting with classical BBS features. In addition, he showed a more pronounced cognitive impairment than previously reported subjects and severe short stature, matching the phenotype displayed by some other patients with LZTFL1 variants and lztfl1 knock‐out mice. This case report contributes to a better understanding of the clinical spectrum associated with LZTFL1 pathogenic variants, and highlights possible genotype–phenotype correlations. [ABSTRACT FROM AUTHOR]

Cutaneous-skeletal hypophosphatemia syndrome (CSHS) is a rare disorder characterized by the presence of melanocytic nevi, dysplastic cortical bony lesions, and fibroblast growth factor 23 (FGF23)-mediated hypophosphatemic rickets. Herein, we describe the diagnosis of an 8-year-old girl presenting with short stature, reduced lower limb mobility, and abnormal gait due to muscle weakness and constant pain in the legs. Biochemical parameters demonstrated hypophosphatemia, hyperphosphaturia, slight increase in parathyroid hormone (PTH), high levels of alkaline phosphatase, and elevated FGF23. Burosumab improved phosphate-wasting, serum phosphorus, alkaline phosphatase, and PTH, followed by a significant mineralization in vertebral bodies evidenced by radiographic assessment. Our report shows a long-term follow-up of CSHS with a notable improvement promoted by an anti-FGF23 therapy. [ABSTRACT FROM AUTHOR]

Vitamin D-dependent rickets type 1A is caused by pathogenic variants of CYP27B1 gene, which is inherited in autosomal recessive pattern. These variants lead to defective 1α-hydroxylase enzymatic activity, leading to impaired renal formation of 1,25(OH)2 vitamin D. We report a case of a 16-year-old Asian male patient, with short stature and progressive bone deformity, whose biochemical parameters revealed low levels of 1,25(OH)2 vitamin D, low serum calcium levels, along with high phosphorus and raised levels of intact parathyroid hormone. These biochemical parameters suggested the diagnosis of pseudohypoparathyroidism. The patient also had concurrent extrapulmonary tuberculosis during the time of presentation to our endocrine unit. However, on molecular testing, it was revealed that the patient was harboring pathogenic variants of the CYP27B1 gene, in a compound heterozygous manner, with a novel missense mutation in exon 6 of the CYP27B1 gene, c.1136G > C (p.Arg379Thr), suggesting the diagnosis of vitamin D-dependent rickets type 1A. The cause of high phosphorus at the time of presentation, which led to a diagnostic dilemma of pseudohypoparathyroidism, was later explained by presence of active extra pulmonary tuberculosis. This report describes a case of vitamin D-dependent rickets type 1A, mimicking pseudohypoparathyroidism owing to presence of concurrent illness like extrapulmonary tuberculosis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Premise: Seed dispersal is a critical process impacting individual plants and their communities. Plants have evolved numerous strategies and structures to disperse their seeds, but the evolutionary drivers of this diversity remain poorly understood in most lineages. We tested the hypothesis that the evolution of wind dispersal traits within the melicgrasses (Poaceae: Meliceae Link ex Endl.) was correlated with occupation of open and disturbed habitats. Methods: To evaluate wind dispersal potential, we collected seed dispersal structures (diaspores) from 24 melicgrass species and measured falling velocity and estimated dispersal distances. Species' affinity for open and disturbed habitats were recorded using georeferenced occurrence records and land cover maps. To test whether habitat preference and dispersal traits were correlated, we used phylogenetically informed multilevel models. Results: Melicgrasses display several distinct morphologies associated with wind dispersal, suggesting likely convergence. Open habitat taxa had slower‐falling diaspores, consistent with increased wind dispersal potential. However, their shorter stature meant that dispersal distances, at a given wind speed, were not higher than those of their forest‐occupying relatives. Species with affinities for disturbed sites had slower‐falling diaspores and greater wind dispersal distances, largely explained by lighter diaspores. Conclusions: Our results are consistent with the hypothesized evolutionary relationship between habitat preference and dispersal strategy. However, phylogenetic inertia and other plant functions (e.g., water conservation) likely shaped dispersal trait evolution in melicgrasses. It remains unclear if dispersal trait changes were precipitated by or predated changing habitat preferences. Nevertheless, our study provides promising results and a framework for disentangling dispersal strategy evolution. [ABSTRACT FROM AUTHOR]

Noonan syndro me is a rare autosomal dominant congenital abnormality associated with a gene defect located on the short arm of chromosome 12. It is characterized by dysmorphic facies, webbed neck, short stature, lymphatic obstruction, cardiac anomalies, and intellectual disability. Prenatal diagnosis of Noonan syndrome is rare because there are no pathognomonic sonographic signs. Studies on the prenatal sonographic features of Noonan syndrome have been reported in very limited numbers. This case series of severe fetal Noonan syndrome, together with a literature review, was conducted to establish prenatal sonographic features highly suggestive of Noonan syndrome to facilitate early detection by clinicians. This study reveals that Noonan syndrome has a relatively specific pattern, which facilitates prenatal molecular genetic diagnosis. Increased nuchal translucency (NT) in the late first trimester and fluid collection in the early second trimester could be warning signs for follow-up, prompting further investigation to detect late-onset features and leading to molecular genetic confirmation. Most structural abnormalities appear in the second trimester, with progressive changes noted throughout gestation. This review better characterizes the sonographic features of fetal Noonan syndrome based on a larger sample size, illustrating a wider spectrum of prenatal phenotypes, including lymphatic drainage disorders, cardiac abnormalities, polyhydramnios, and absent ductus venosus. [ABSTRACT FROM AUTHOR]

SOFT syndrome (Short stature-Onychodysplasia-Facial dysmorphism-hypoTrichosis) is a rare primordial dwarfism syndrome caused by biallelic variants in POC1A encoding a centriolar protein. To refine the phenotypic spectrum of SOFT syndrome, recently shown to include metabolic features, we conducted a systematic review of all published cases (19 studies, including 42 patients). The SOFT tetrad affected only 24 patients (57%), while all cases presented with short stature from birth (median height: -5.5SDS([-8.5]-[-2.8])/adult height: 132.5 cm(103.5–148)), which was most often disproportionate (90.5%), with relative macrocephaly. Bone involvement resulted in short hands and feet (100%), brachydactyly (92.5%), metaphyseal (92%) or epiphyseal (84%) anomalies, and/or sacrum/pelvis hypoplasia (58%). Serum IGF-I was increased (median IGF-I level: + 2 SDS ([-0.5]-[+ 3])). Recombinant human growth hormone (rhGH) therapy was stopped for absence/poor growth response (7/9 patients, 78%) and/or hyperglycemia (4/9 patients, 45%). Among 11 patients evaluated, 10 (91%) presented with central distribution of fat (73%), clinical (64%) and/or biological insulin resistance (IR) (100%, median HOMA-IR: 18), dyslipidemia (80%), and hepatic steatosis (100%). Glucose tolerance abnormalities affected 58% of patients aged over 10 years. Patients harbored biallelic missense (52.4%) or truncating (45.2%) POC1A variants. Biallelic null variants, affecting 36% of patients, were less frequently associated with the SOFT tetrad (33% vs 70% respectively, p = 0.027) as compared to other variants, without difference in the prevalence of metabolic abnormalities. POC1A should be sequenced in children with short stature, altered glucose/insulin homeostasis and/or centripetal fat distribution. In patients with SOFT syndrome, rhGH treatment is not indicated, and IR-related complications should be regularly screened and monitored. PROSPERO registration: CRD42023460876. [ABSTRACT FROM AUTHOR]

Achondroplasia, the most common form of inherited disproportionate short stature, is caused by mutations in the fibroblast growth factor receptor 3 gene. The typical clinical features of achondroplasia include short stature, rhizomelic disproportion, joint hyperlaxity, spinal deformity and deformity of the upper and lower limbs. The latter are among the challenges of state-of-the-art orthopaedic treatment plans and significantly contribute to the burden of the disease in individuals with achondroplasia. Multidisciplinary preoperative individual decision-making concerning surgical interventions should be considered. New medical treatments for achondroplasia have been developed and (some) have been approved for clinical use in several countries. While the number of research articles on achondroplasia is increasing rapidly, many unknown or controversial orthopaedic topics remain. Furthermore, in view of new medical developments with improvements in growth and potentially other effects, the timing and algorithms of orthopaedic treatments (e.g. guided growth, limb lengthening and deformity correction) need to be re-evaluated. While standing height is the primary research focus in medical therapy, it is crucial to comprehensively assess orthopaedic parameters in this multifactorial disease. The current treatment of patients with achondroplasia requires specialised multidisciplinary centres with transitional care and individual orthopaedic counselling. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: Height age (HA) and bone age (BA) delay is well known in the patients with short stature. Therefore assessing pituitary hypoplasia based on chronological age (CA) might cause overdiagnosis of pituitary hypoplasia. We aimed to investigate the diagnostic and prognostic value of the PH and PV based on CA, HA, or BA in the patients with GHD. Methods: Fifty-seven patients with severe and 40 patients with partial GHD and 39 patients with ISS assigned to the study. For defining the most accurate diagnosis of pituitary hypoplasia, PH and PV were evaluated based on CA, BA and HA. The relationship of each method with clinical features was examined. Results: The mean PV was significantly larger in patients with ISS compared to the GH-deficient patients. PV was more correlated with clinical features including height SDS, stimulated GH concentration, IGF-1 and IGFBP-3 SDS, height velocity before and after rGH therapy. We found BA-based PV could discriminate GHD from ISS (Sensitivity: 17%, specificity: 98%, positive predictive value: 94%, negative predictive value: 39%), compared to the other methods based on PH or PV respect to CA and HA. 3% of patients with ISS, 17% of patients with GHD had pituitary hypoplasia based on PV-BA. Conclusion: PV based on BA, has the most accurate diagnostic value for defining pituitary hypoplasia. But it should be kept in mind that there might be still misdiagnosed patients by this method. PV is also a significant predictor for the rGH response. [ABSTRACT FROM AUTHOR]

Ghosal hematodiaphyseal dysplasia (GHDD) is an autosomal recessive disorder characterized by diaphyseal dysplasia of long bones, bone marrow fibrosis, and steroid-responsive anemia. Patients with this disease have a mutation in the thromboxane-AS1 (TBXAS1) gene located on chromosome 7q33.34. They present with short stature, varying grades of myelofibrosis, and, hence cytopenias. Patients with the above presentation were evaluated through clinical presentation, X-ray of long bones, bone marrow examinations, and confirmed by genetic testing. In this article, we present two cases: The first case is a 3-year-old boy who presented with progressive pallor and ecchymotic patches for a year. On investigation, he had bicytopenia and bone marrow fibrosis. His anemia was steroid responsive and was finally diagnosed as GHDD. The second case is a 20-month-old girl who presented with blood in stools, developmental delay, anemia, and increased intensity of long bones on X-ray. Since other investigations were normal, suspicion of GHDD was raised, and a genetic workup was conducted which suggested mutation in TBXAS1 gene, confirming the diagnosis of GHDD. Children with refractory anemia and cortical thickening on skeletogram should always be evaluated for dysplasias. Timely treatment with steroids reduces transfusion requirements and halts bone damage, thus leading to better growth and improved quality of life. [ABSTRACT FROM AUTHOR]

The increased availability of recombinant human GH (rhGH), albeit at a relatively high cost, has increased a demand for treatment of children and adolescents of normal height to increase their adult stature. There are no scientific reports on the efficacy and safety of rhGH therapy in this condition; therefore, the authors comment on the possible causes and consequences based on their personal opinion and experience. As in gigantism, when GH action and end-organ are normal, enough GH is expected to result in increased growth velocity. Short-term adverse effects related to rhGH therapy for approved indications of short stature in children have been very rare. Data on long-term adverse effects are still scarce. A small increase in height might be statistically significant but not functionally or socially relevant. Considering that an increase in height represents more a desire than a need, physicians should emphasize the normality and qualities of these children, discuss with families the alternatives, such as counseling, and refrain from supporting the concept that taller is better. [ABSTRACT FROM AUTHOR]

Several evidence gaps exist regarding the use of long-acting polyethylene glycol recombinant human growth hormone (PEG-rhGH) in children with idiopathic short stature (ISS), particularly studies conducted in real-world settings, with long-term follow-up, involving varied dosing regimens, and in comparison with daily rhGH. The study aimed to evaluate the effectiveness, safety, and adherence of once-weekly PEG-rhGH for catch-up growth in children with prepubertal ISS compared to daily rhGH. A real-world retrospective cohort study was conducted in prepubertal children with ISS in China. Children who voluntarily received once-weekly PEG-rhGH or daily rhGH were included and were followed up for 2 years. Ninety-five children were included, 47 received PEG-rhGH 0.2–0.3 mg/kg weekly and 48 received daily rhGH. Outcome measures included effectiveness in catch-up growth, adverse events, and treatment adherence. Height velocity increased significantly in both groups during rhGH therapy. In children who received PEG-rhGH treatment, height velocity was 10.59 ± 1.37 cm/year and 8.75 ± 0.86 cm/year in the first and second year, respectively, which were significantly more than those who received daily rhGH (9.80 ± 1.05 cm/year, P = 0.002, and 8.03 ± 0.89 cm/year, P < 0.001). The height standard deviation score improved at the end of the second year for all children (P < 0.001). However, children who received PEG-rhGH showed more excellent improvement than those with daily rhGH (1.65 ± 0.38 vs. 1.50 ± 0.36, P = 0.001). In children who received PEG-rhGH, lower missed doses were observed than those with daily rhGH (0.75 ± 1.06 vs. 4.4 ± 2.0, P < 0.001). No serious adverse events were observed. Conclusion: PEG-rhGH demonstrated superior effectiveness and adherence compared to daily rhGH in the treatment of children with ISS. The safety profiles were similar between the two treatments. What is Known: • Recombinant human growth hormone (rhGH) has been used to increase adult height in children with idiopathic short stature (ISS), and its safety profile is comparable to other indications for growth hormone treatment. • The use of long-acting rhGH in children with ISS is still an area of uncertainty. What is New: • This 2-year real-world study provides new evidence that PEGylated rhGH (PEG-rhGH) is more effective than daily rhGH in promoting catch-up growth in children with ISS. • PEG-rhGH also demonstrated superior treatment adherence compared to daily rhGH in children with ISS. • The safety profiles of PEG-rhGH and daily rhGH were found to be similar. [ABSTRACT FROM AUTHOR]

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Context Insufficient efficacy and safety data for off-label use of aromatase inhibitors to augment height in boys with short stature. Objective To compare anastrozole and letrozole in treatment of idiopathic short stature in pubertal boys. Design Open-label trial with 2 treatment arms. Setting Pediatric Endocrine Clinic at Stanford. Participants A total of 79 pubertal males ≥10 years with bone age (BA) ≤ 14 years, predicted adult height (PAH) < 5th percentile or >10 cm below mid-parental height. Intervention Anastrozole 1.0 mg or letrozole 2.5 mg daily for up to 3 years. Main Outcome Measures Annual hormone levels and growth parameters during treatment and a year posttherapy; annual BA and PAH (primary outcome measure); spine x-rays and dual energy X-ray absorptiometry at baseline and 2 years. Results Compared with anastrozole (n = 35), letrozole (n = 30) resulted in higher testosterone levels, lower estradiol and IGF-1 levels, and slower growth velocity and BA advance. The PAH increase observed at year 1 in both groups did not persist at years 2 and 3. Change in PAH from baseline was not different between treatment groups. In groups combined, PAH gain over 3 years vs baseline was +1.3 cm (P =.043) in linear mixed models. Conclusion Letrozole caused greater deviations than anastrozole in hormone levels, growth velocity, and BA advancement, but no group differences in PAH or side effects were found. Change in PAH after 2 to 3 years of treatment was minimal. The efficacy of AI as monotherapy for height augmentation in pubertal boys with idiopathic short stature may be limited, and safety remains an issue. [ABSTRACT FROM AUTHOR]

Background: CWC27-related spliceosomeopathy is a rare autosomal recessive disorder with only 14 patients have been reported. It is characterized by retinal degeneration, short stature, skeletal anomalies, and neurological defects. We described the clinical features of a Chinese patient with CWC27-related spliceosomeopathy and identified the pathogenic variant. Methods: The affected subject underwent detailed ophthalmic examinations. Systemic abnormalities were assessed, including body height, craniofacial morphology, oral cavity, hands, feet, hair and skin. Genomic DNA was isolated from peripheral blood and sequenced by next-generation sequencing. Sanger sequencing was performed for validation and segregation. Results: The patient had poor vision, nyctalopia and nystagmus from childhood. Fundoscopy revealed extensive chorioretinal atrophy with numerous scattered greyish pigmentation. Severe circular areas of macular atrophy were observed. Optical coherent tomography showed reduced retinal thickness with nearly absent ellipsoid zone and retinal pigment epithelium. In addition, craniofacial abnormalities, short statue, brachydactyly, dental anomalies, cafe-au-lait spots, scant hair, absent eyebrows and thin eyelashes were documented. Genetic analysis revealed a novel homozygous novel small deletion c.1133delG(p.G378Efs*12) in CWC27 (NM_005869.2). Conclusions: We present a patient with early-onset retinitis pigmentosa and marked syndromic features. A novel CWC27 pathogenic variant was identified. Our findings broaden the clinical and mutation spectrum of CWC27-related spliceosomeopathy, and could be helpful in diagnosis of this rare disease. [ABSTRACT FROM AUTHOR]

Background: Geleophysic dysplasia (GD) and Weill–Marchesani syndrome (WMS) are two rare genetic disorders that are classified as acromelic dysplasias and have many common features that overlap clinically and genetically in some patients. Both diseases are characterized by acromelic features, including short stature, brachydactyly, joint limitations, and cardiac involvement. WMS is distinguished from GD mainly by ocular abnormalities, including high myopia, microspherophakia, ectopia lentis, and glaucoma and the absence of the life-threatening airway stenosis and early lethality. These two syndromes are allelic diseases of the FBN1 gene, with the gene families including A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS) and latent transforming growth factor-beta-binding protein (LTBP). Although the ADAMTSL2 gene has been associated only with GD within the acromelic dysplasias, there have been reports of patients with ADAMTSL2-related GD exhibiting ocular abnormalities that resemble WMS. Methods and Results: We present a 24-year-old female patient with microspherophakia, ectopia lentis, myopia, short stature, joint stiffness, thick skin, short hands and feet, and cardiac valve disease consistent with WMS. The virtual panel analysis, including WMS and GD-related genes, revealed a homozygous c.493 G>A (p.Ala165Thr) variant in the ADAMTSL2 gene (NM_014694.4), which has been previously reported in a geleophysic dysplasia patient. Conclusions: Mounting evidence suggests that GD and WMS may be allelic diseases of the ADAMTSL2 gene. [ABSTRACT FROM AUTHOR]

Variants in more than 60 different genes, most of which code for podocyte‐related proteins, have been found to be associated with monogenic forms of nephrotic syndrome (NS). Biallelic variants in DAAM2, a member of the formin family, were recently identified to cause autosomal recessive (AR) NS type 24 in four unrelated families with steroid‐resistant nephrotic syndrome (SRNS). This case report represents only the fifth reported family of DAAM2‐associated NS and the first from India, with two sibs who presented with a complex phenotype characterized by steroid‐resistant nephrotic syndrome, short stature, dysmorphic facial features, deep‐set toenails, myopia, increased thickness of the calvarium of the skull, and sloping ribs. Both sibs were found to have a homozygous likely pathogenic nonsense variant c.196C>T (p.Arg66Ter; NM_001201427.2) in exon 3 of the DAAM2 gene through whole exome sequencing. The dysmorphic features could possibly be part of the DAAM2‐related phenotype which has hitherto not been reported or could represent a blended phenotype, with the extrarenal manifestations resulting from a yet to be identified coexisting genetic condition. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Postnatal growth failure is often attributed to dysregulated somatotropin action, however marked genetic and phenotypic heterogeneity exist. We report five patients from three families who present with short stature, immune dysfunction, atopic eczema and gastrointestinal pathology associated with recessive variants in QSOX2. QSOX2 encodes a nuclear membrane protein linked to disulphide isomerase and oxidoreductase activity. Loss of QSOX2 disrupts Growth hormone-mediated STAT5B nuclear translocation despite enhanced Growth hormone-induced STAT5B phosphorylation. Moreover, patient-derived dermal fibroblasts demonstrate Growth hormone-induced mitochondriopathy and reduced mitochondrial membrane potential. Located at the nuclear membrane, QSOX2 acts as a gatekeeper for regulating stabilisation and import of phosphorylated-STAT5B. Altogether, QSOX2 deficiency modulates human growth by impairing Growth hormone-STAT5B downstream activities and mitochondrial dynamics, which contribute to multi-system dysfunction. Furthermore, our work suggests that therapeutic recombinant insulin-like growth factor-1 may circumvent the Growth hormone-STAT5B dysregulation induced by pathological QSOX2 variants and potentially alleviate organ specific disease. Defects in growth hormone (GH) action account for a substantial percentage of endocrine causes of growth failure. Here, the authors report that QSOX2 deficiency modulates human growth by impairing GH-STAT5B downstream activities and mitochondrial dynamics, contributing to multi-system dysfunction. [ABSTRACT FROM AUTHOR]

Background: Epilepsy during recombinant human growth hormone (rhGH) therapy is rare in children. The potential association between rhGH treatment and epilepsy remains unclear. Methods: We retrospectively analyzed the clinical data of two Chinese boys who experienced epilepsy during the use of rhGH and reviewed the relevant literature. Results: Case 1, an 8-year and 2-month-old boy, was diagnosed with short stature, malnutrition, and congenital hypothyroidism. He was on levothyroxine sodium tablets for a long time. Recurrent febrile convulsions were present at 6-7 years. Electroencephalogram and magnetic resonance imaging (MRI) showed no abnormality, and no treatment was given. He was diagnosed with complex febrile convulsions. The boy started rhGH treatment (approximately 0.15 IU/kg/day, sc, qd) at 8 years and 4 months. Epilepsy occurred three times during the 6 months of rhGH treatment. Electroencephalography confirmed a definitive diagnosis of epilepsy. Then, he discontinued rhGH treatment at 8 years and 11 months and started taking levetiracetam (0.25 g, po, bid) for antiepileptic therapy. Epilepsy was well-controlled 4 months later. He continued rhGH treatment at 10 years and 3 months and has been on rhGH treatment until now, with no recurrence of epilepsy. He has been taking levetiracetam to date. Case 2, a 9-year and 1-month-old boy, was diagnosed with central precocious puberty, predicted short final height, and overweight. He started treatment with triptorelin (3.75 mg, im, q4w) and rhGH (approximately 0.15 IU/kg/day, sc, qd) at 9 years and 3 months. He tended to fall repeatedly when he was approximately 10 years old. Electroencephalography showed a few medium- to high-amplitude sharp waves and sporadic sharp slow waves in the left middle temporal region, sometimes involving the left posterior temporal region. He was diagnosed with epilepsy. Triptorelin discontinuance provided no symptom relief, which worsened further. Subsequently, he withdrew from rhGH treatment, and the symptoms occurred occasionally within a week and stopped after 15 days. The electroencephalogram returned to normal. No further seizures occurred during follow-up to date. Conclusion: During the use of rhGH in short-stature children with complex febrile convulsions or underlying lesions related to neurological impairment or those being treated with antiepileptic drugs, epilepsy may be induced. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: Retrospective analysis on 584 MRI scans performed in 414 patients (254 growth hormone deficiency, 41 other causes of short stature, 116 central precocious puberty). Results: 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%). Conclusions: 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. [ABSTRACT FROM AUTHOR]

Recombinant human growth hormone therapy (rhGH) has been widely accepted as the safe treatment for short stature in children with such genetic syndromes as Prader–Willi syndrome and Turner or Noonan syndrome. Some patients with short stature and rare genetic syndromes are treated with rhGH as growth hormone-deficient individuals or as children born small for their gestational age. After years of experience with this therapy in syndromic short stature, it has been proved that there are some aspects of long-term rhGH treatment beyond growth promotion, which can justify rhGH use in these individuals. This paper summarizes the data of a literature review of the effects of rhGH treatment beyond growth promotion in selected genetic syndromes. We chose three of the most common syndromes, Prader–Willi, Turner, and Noonan, in which rhGH treatment is indicated, and three rarer syndromes, Silver–Russel, Kabuki, and Duchenne muscular dystrophy, in which rhGH treatment is not widely indicated. Many studies have shown a significant impact of rhGH therapy on body composition, resting energy expenditure, insulin sensitivity, muscle tonus, motor function, and mental and behavioral development. Growth promotion is undoubtedly the primary benefit of rhGH therapy; nevertheless, especially with genetic syndromes, the additional effects should also be considered as important indications for this treatment. [ABSTRACT FROM AUTHOR]

Background: Achondroplasia is the most common form of skeletal disorder with disproportionate short stature. Vosoritide is the first disease-specific, precision pharmacotherapy to increase growth velocity in children with achondroplasia. Limb surgery is a standard approach to increase height and arm span, improve proportionality and functionality, as well as correcting deformities. The aim of this study was to gain expert opinion on the combined use of vosoritide and limb surgery in children and adolescents with achondroplasia. Methods: An international expert panel of 17 clinicians and orthopaedic surgeons was convened, and a modified Delphi process undertaken. The panel reviewed 120 statements for wording, removed any unnecessary statements, and added any that they felt were missing. There were 26 statements identified as facts that were not included in subsequent rounds of voting. A total of 97 statements were rated on a ten-point scale where 1 was 'Completely disagree' and 10 'Completely agree'. A score of ≥ 7 was identified as agreement, and ≤ 4 as disagreement. All experts who scored a statement ≤ 4 were invited to provide comments. Results: There was 100% agreement with several statements including, "Achieve a target height, arm span or upper limb length to improve daily activities" (mean level of agreement [LoA] 9.47, range 8–10), the "Involvement of a multidisciplinary team in a specialist centre to follow up the patient" (mean LoA 9.67, range 7–10), "Planning a treatment strategy based on age and pubertal stage" (mean LoA 9.60, range 8–10), and "Identification of short- and long-term goals, based on individualised treatment planning" (mean LoA 9.27, range 7–10), among others. The sequence of a combined approach and potential impact on the physes caused disagreement, largely due to a lack of available data. Conclusions: It is clear from the range of responses that this modified Delphi process is only the beginning of new considerations, now that a medical therapy for achondroplasia is available. Until data on a combined treatment approach are available, sharing expert opinion is a vital way of providing support and guidance to the clinical community. [ABSTRACT FROM AUTHOR]

Background: Recently, the C3-epimer of 25-hydroxyvitamin D [C3-epi-25(OH)D] has become a topic of interest among 25-hydroxyvitamin D [25(OH)D] metabolites. Although it can lead to an overestimation of vitamin D storage, its relationship with disease occurrence remains controversial, possibly related to the great extent of tracking of 25(OH)D by C3-epi-25(OH)D over time. This study aimed to investigate the differential performance of C3-epi-25(OH)D3 and its percentage [%C3-epi-25(OH)D3] with respect to 20 common paediatric diseases. Methods: This study involved 805 healthy children and adolescents and 2962 patients with common paediatric diseases. We investigated sex, age, and seasonal differences in C3-epi-25(OH)D3 and %C3-epi-25(OH)D3 levels; their variations on 20 common paediatric diseases; and their degree of correlation with 25(OH)D3 levels and various diseases. Results: Among the healthy underage participants, C3-epi-25(OH)D3 and %C3-epi-25(OH)D3 changed similarly, with no sex differences. Moreover, their levels were higher in the infant period than in the other periods (t = 5.329–5.833, t = 4.640–5.711, all Padj < 0.001), and in spring and summer than in autumn and winter (t = 3.495–6.061, t = 3.495–5.658, all Padj < 0.01). Under healthy and disease conditions, C3-epi-25(OH)D3 was positively correlated with 25(OH)D3 (ρ = 0.318 ~ 0.678, all P < 0.017), whereas %C3-epi-25(OH)D3 was not, except in patients with nephrotic syndrome (ρ=-0.393, P = 0.001). Before and after adjusting for 25(OH)D3, the relationship of C3-epi-25(OH)D3 with the diseases was notably different. However, it was almost consistent for %C3-epi-25(OH)D3. Our results indicated that %C3-epi-25(OH)D3 was associated with short stature, nephrotic syndrome, lymphocytic leukaemia, rickets, paediatric malnutrition, and hypovitaminosis D (OR = 0.80 ~ 1.21, all P < 0.05). Conclusions: The %C3-epi-25(OH)D3 can correct the properties of C3-epi-25(OH)D3 to better track 25(OH)D3 and may be more suitable for exploring its pathological relevance. Further detailed studies of each disease should be conducted. [ABSTRACT FROM AUTHOR]

Introduction: Most infants born as small for gestational age (SGA) demonstrate catch up growth by 2–4  years, but some fail to do so. This failure is associated with several health risks, including neuropsychological development issues. However, data on the morphological characteristics of the brains of infants born as SGA without achieving catch up growth are lacking. This study aims to determine the structural aspects of the brains of children born as SGA without catch up growth. Methods: We conducted voxel- and surface-based morphometric analyses of 1.5-T  T1-weighted brain images scanned from eight infants born as SGA who could not achieve catch up growth by 3  years and sixteen individuals with idiopathic short stature (ISS) to exclude body size effects. Growth hormone (GH) secretion stimulation tests were used to rule out GH deficiency in all SGA and ISS cases. The magnetic resonance imaging data were assessed using Levene’s test for equality of variances and a two-tailed unpaired t-test for equality of means. The Benjamini–Hochberg procedure was used to apply discovery rate correction for multiple comparisons. Results: Morphometric analyses of both t-statical map and surface-based analyses using general linear multiple analysis determined decreased left insula thickness and volume in SGA without catch up growth compared with ISS. Conclusion: The brain scans of patients with SGA who lack catch up growth indicated distinct morphological disparities when compared to those with ISS. The discernible features of brain morphology observed in patients born as SGA without catch up growth may improve understanding of the association of SGA without catch up growth with both intellectual and psychological outcomes. [ABSTRACT FROM AUTHOR]

Background: The main clinical features of pseudohypoparathyroidism (PHP)/inactivating parathyroid hormone/parathyroid hormone-related protein signaling disorders (iPPSD), including parathyroid hormone (PTH) resistance, brachydactyly and short stature, develop during middle and late childhood. Very few studies have addressed hearing loss in PHP/iPPSD patients, and these studies have yielded widely divergent conclusions. The aim of our study was to assess hearing and determine the predictive factors of hearing loss in patients with PHP/iPPSD. Methods: Our retrospective cohort study was conducted between March 2019 and May 2020 in the Otolaryngology Department and the calcium phosphate reference center for rare diseases in Bicêtre Paris-Saclay Hospital, France. We retrospectively collected data from patients with PHP/iPPSDs (age, sex, genetic mutations, height, body mass index (BMI), PTH resistance, presence or absence of ectopic ossifications and brachydactyly). All patients underwent auditory investigations, including tonal and vocal audiometry. The primary outcome was the pure tone average (PTA). The PTA was compared with the norm according to the International Organization for Standardization. Hearing loss was defined as a PTA ≥ 20 db. Results: The median age of the patients was 15.6 years [9.5, 28.5]. Thirty-six patients were diagnosed with iPPSD2, and eight were diagnosed with iPPSD3. Twenty-six of them (59%) were female. Hearing impairment was confirmed in 17 patients (39%). The mean PTA and the mean SRT of the deaf ears were 40 ± 26 db and 31 ± 14 db. The mean difference in the PTA between the patients and the normal controls was 11.4 db (p = 0.00002). Short stature and the presence of ectopic ossifications were two significant predictive factors of hearing loss (p = 0.009 and p = 0.03, respectively). Sex, BMI, PTH resistance, mutation category and brachydactyly were not associated with an increased risk of hearing loss (p = 0.19, p = 0.41, p = 0.13, p = 0.50, p = 0.19, respectively). Conclusion: Our study confirmed the frequency of hearing loss in patients with PHP/iPPSD disease (prevalence = 39%). A diagnosis of PHP/iPPSD should trigger auditory investigations and follow-up, especially when short stature and/or ectopic ossifications are present. [ABSTRACT FROM AUTHOR]

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. Therewere 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 systemanomalies are part of the FA phenotype, the most frequent after pituitary hypoplasia being posterior fossa abnormalities, whichmay 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. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction associated fatty liver disease (MAFLD) is a common cause of liver disease in children and adolescents. The relationship between insulin resistance (IR) and MAFLD in children with short stature remains largely unknown. The present study was to investigate the relationship between the triglyceride–glucose (TyG) index and alanine aminotransferase (ALT) levels in children with short stature. A total of 1754 children with short stature were enrolled. Anthropometric, biochemical and hormonal indexes were collected through physical measurement examinations and laboratory tests. A nonlinear association was found between the TyG index and ALT. The inflection point of the curve was at a TyG index of 8.24. In multivariate piecewise linear regression, only when the TyG index was greater than 8.24 was there a significant positive association between the TyG index and ALT (β 5.75, 95% CI 3.30, 8.19; P < 0.001). However, when the TyG index was less than 8.24, there was no significant association between the TyG index and ALT (β −0.57, 95% CI −1.84, 0.71; P = 0.382). This study demonstrated a nonlinear relationship between TyG index and ALT in children with short stature. This finding suggests that a high TyG index is associated with elevated ALT in children with short stature. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This article aims to understand the impact of a condition causing multiple benign neoplasms on a historical individual, and increase understanding of disease processes using a paleopathological case. We present the case of an adult male from the Balizhuang site in Weifang City, Changle County, Shandong Province, China, dated by the burial artifacts to the Qing period (1644–1911 CE). The individual has multiple bony growths found on both long and flat bones, which were also observed radiographically. Imaging revealed that the lesions show continuity with the medullary cavity of the host bone. The individual also exhibited short stature, upper limb length asymmetry, and hip and ankle deformities. Conditions included in a differential diagnosis are myositis ossificans, parosteal osteosarcoma, and osteochondroma, with multiple osteochondromas (MO) being the most likely diagnosis. We also present historical texts suggesting the presence of osteochondromas in China. This may be the first case of adult MO reported in Chinese bioarcheology, helping to expand paleopathological data on benign tumors. [ABSTRACT FROM AUTHOR]

Objective: 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. Materials and Methods: 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. Results: 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). Conclusion: 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. [ABSTRACT FROM AUTHOR]

Introduction: Heterozygous variants in the ACAN gene may underlie disproportionate short stature with characteristically accelerated bone age (BA) maturation and/or early-onset osteoarthritis (OA). Methods: The objective of this study was to describe phenotype, analyze genotype-phenotype correlations, and assess the response of growth hormone (GH) treatment in children with a heterozygous ACAN variant. Thirty-six subjects (23 boys, 13 girls) with ACAN deficiency and treated for ≥1 year with GH were identified in the Dutch National Registry of GH treatment in children. Results: We identified 25 different heterozygous ACAN variants in 36 subjects. Median (interquartile range) height SDS at start of GH was −2.6 SDS (−3.2 to −2.2). Characteristic features such as disproportion, advanced BA, early-onset OA, and dysmorphic features like midface hypoplasia and brachydactyly were present in the majority of children, but in ∼20%, no specific features were reported. Subjects with a truncating ACAN variant had a shorter height SDS compared to subjects with a non-truncating variant (−2.8 SDS and −2.1 SDS, respectively, p = 0.002). After 3 years of GH, height gain SDS in prepubertal children was 1.0 SDS (0.9–1.4). In pubertal children, height SDS remained relatively stable. Conclusion: The phenotype of subjects with pathogenic heterozygous ACAN variants is highly variable, and genetic testing for ACAN deficiency should be considered in any child with significant short stature, even in the absence of disproportion, specific dysmorphic features, or BA advancement. Furthermore, children with ACAN deficiency may benefit from GH with a modest but significant response, which is sustained during 3 years of treatment. [ABSTRACT FROM AUTHOR]

We report growth hormone (GH) deficiency due to presumed GH releasing hormone (GHRH) resistance in an adolescent with pseudohypoparathyroidism type 1B (PHP1B) due to paternal uniparental disomy of chromosome 20 (patUPD20). A male patient aged 11 years 10 months with obesity and mild developmental delay was found to have hypocalcemia, hyperphosphatemia, and an elevated parathyroid hormone level. History included muscle cramps and leg pain with activity. Examination showed round facies, short stature, and obesity. He was in puberty and bone age was advanced by > 2 years. Detailed genetic workup, including nucleotide sequence analysis of GNAS exons 1-13 and STX16 , methylation-sensitive multiplex ligation-dependent probe amplification and analysis of several microsatellite markers for chromosome 20, established the diagnosis of PHP1B due to patUPD20. Muscle cramps and hypocalcemia resolved with calcium carbonate, ergocalciferol, and calcitriol treatment. He was short with linear growth deceleration at around age 13 years. Peak GH concentration was insufficient following stimulation testing. Growth velocity improved with human GH treatment. Although rare, resistance to GHRH can occur in PHP1B and patients with this disorder should be evaluated for GH insufficiency if they present with short stature and reduced growth velocity. Treatment with recombinant human GH may improve growth velocity in such patients. [ABSTRACT FROM AUTHOR]

Skeletal disorders encompass a wide array of conditions, many of which are associated with short stature. Among these, Desbuquois dysplasia is a rare but severe condition characterized by profound dwarfism, distinct facial features, joint hypermobility with multiple dislocations, and unique vertebral and metaphyseal anomalies. Desbuquois dysplasia is inherited in an autosomal recessive manner, with both the DBQD1 (MIM 251450) and DBQD2 (MIM 615777) forms resulting from biallelic mutations. Specifically, DBQD1 is associated with homozygous or compound heterozygous mutations in the CANT1 gene, while DBQD2 can result from mutations in either the CANT1 or XYLT1 genes. This review synthesizes the findings of 111 published case reports, including 54 cases of DBQD1, 39 cases of DBQD2, and 14 cases of the Kim variant (DDKV). Patients in this cohort had a median birth weight of 2505 g, a median length of 40 cm, and a median occipitofrontal circumference of 33 cm. The review highlights the phenotypic variations across Desbuquois dysplasia subtypes, particularly in facial characteristics, joint dislocations, and bone deformities. Genetic analyses revealed a considerable diversity in mutations, with over 35% of cases involving missense mutations, primarily affecting the CANT1 gene. Additionally, approximately 60% of patients had a history of parental consanguinity, indicating a potential genetic predisposition in certain populations. The identified mutations included deletions, insertions, and nucleotide substitutions, many of which resulted in premature stop codons and the production of truncated, likely nonfunctional proteins. These findings underscore the genetic and clinical complexity of Desbuquois dysplasia, highlighting the importance of early diagnosis and the potential for personalized therapeutic approaches. Continued research is essential to uncover the underlying mechanisms of this disorder and improve outcomes for affected individuals through targeted treatments. [ABSTRACT FROM AUTHOR]

Achondroplasia (ACH; MIM #100,800), caused by a heterozygous gain of function pathogenic variant in the fibroblast growth factor receptor 3 gene (FGFR3; MIM*134,934), is the most prevalent and most readily identifiable cause of disproportionate short stature that is compatible with life. In addition, individuals with achondroplasia face significant medical, functional, and psychosocial challenges throughout their lives. This study assessed associated morbidities in patients with achondroplasia at a single center in Turkey. In this study, the clinical findings and associated morbidities of a group of patients with achondroplasia (n = 68) with clinical multidisciplinary follow-up at a single center between the years 2005–2023 are evaluated retrospectively. A total of 68 patients, 30 male (44.1%) and 38 female (55.9%), were evaluated. In the majority (84.2%) of patients, shortness of extremities was detected in the prenatal period at an average of 28.7 gestational weeks (± 3.6 SDS) with the aid of ultrasonography. More than half (n = 34/63, 54%) of the patients had a father of advanced paternal age (≥ 35 years). Among the complications, respiratory system manifestations, including obstructive sleep apnea (70%), ear-nose-throat manifestations including adenoid hypertrophy (56.6%) and otitis media (54.7%), neurological manifestations due to foramen magnum stenosis (53.2%), and skeletal manifestations including scoliosis (28.8%), are represented among the most common. The mortality rate was 7.3% (n = 5/68). Conclusion: This study not only represents the first retrospective analysis of the associated morbidities of patients with achondroplasia from a single center in Turkey but also will provide a reference point for future studies. [ABSTRACT FROM AUTHOR]