Search

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]

Background: Children with nephrotic syndrome are at risk of obesity and growth impairment from repeated steroid treatment. However, incidence and risk factors for obesity and short stature remain uncertain, which is a barrier to preventative care. Our aim was to determine risk, timing, and predictors of obesity and short stature among children with nephrotic syndrome. Methods: We evaluated obesity and longitudinal growth among children (1–18 years) enrolled in Insight into Nephrotic Syndrome: Investigating Genes, Health, and Therapeutics. We included children with nephrotic syndrome diagnosed between 1996–2019 from the Greater Toronto Area, Canada, excluding congenital or secondary nephrotic syndrome. Primary outcomes were obesity (body mass index Z-score ≥ + 2) and short stature (height Z-score ≤ -2). We evaluated prevalence of obesity and short stature at enrolment (< 1-year from diagnosis) and incidence during follow-up. Cox proportional hazards models determined the association between nephrotic syndrome classification and new-onset obesity and short stature. Results: We included 531 children with nephrotic syndrome (30% frequently relapsing by 1-year). At enrolment, obesity prevalence was 23.5%, 51.8% were overweight, and 4.9% had short stature. Cumulative incidence of new-onset obesity and short stature over median 4.1-year follow-up was 17.7% and 3.3% respectively. Children with frequently relapsing or steroid dependent nephrotic syndrome within 1-year of diagnosis were at increased risk of new-onset short stature (unadjusted hazard ratio 3.99, 95%CI 1.26–12.62) but not obesity (adjusted hazard ratio 1.56, 95%CI 0.95–2.56). Children with ≥ 7 and ≥ 15 total relapses were more likely to develop obesity and short stature, respectively. Conclusions: Obesity is common among children with nephrotic syndrome early after diagnosis. Although short stature was uncommon overall, children with frequently relapsing or steroid dependent disease are at increased risk of developing short stature. Effective relapse prevention may reduce steroid toxicity and the risk of developing obesity or short stature. [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]

Osteogenesis imperfecta (OI) is a genetic disorder characterized by bone fragility and fractures, short stature, dental abnormalities, hearing loss, scoliosis, and chronic pain. Despite a growing literature on the functional outcomes of OI, limited research has explicitly examined the psychosocial outcomes of pain within OI. Adults with OI (N = 15) were interviewed to understand pain-related experiences through a thematic analysis of semi-structured interview data. Research team members, genetic research experts, and OI clinicians developed an interview guide focused on topics related to pain and mental health challenges. Participants' transcripts were coded by two independent coders; codes were then merged across coders and quotation outputs were subsequently abstracted (paraphrased then thematically classified) to identify common themes. Themes related to pain management variability regarding pain type, pain risk management and accessibility, pain outcomes (e.g., behavior, cognitive, affective), and pain exacerbating factors (e.g., individual, contextual) were identified. Participants reported chronic and acute pain, and despite the inaccessibility and stigmatization of pain medications (e.g., opioids), pharmacological treatments were the most common pain management approach. Participants reported negative pain outcomes, such as limited daily functioning and activity participation, fear, anger, anxiety, depression, and difficulty concentrating. Lastly, participants suggested that lack of physician and community knowledge on chronic pain in OI indirectly exacerbates both subjective pain intensity and outcomes. Although limited by a small, nondiverse sample, the current study provides valuable exploration of the unique pain experiences of adults with OI that may have implications for proactive management, treatment development, and clinician training. [ABSTRACT FROM AUTHOR]

Spondyloocular syndrome (SOS) is a rare autosomal recessive skeletal and ocular disorder with variable phenotypes. It is caused by pathogenic mutation in the XYLT2 gene, which encodes the enzyme xylo-transferase, necessary for the synthesis of proteoglycan. It is characterized by generalized osteoporosis, short stature, hearing impairment, eye abnormalities, and cardiac defects. Till date only 24 cases have been reported worldwide with no cases documented from India. We subjected the patient to relevant biochemical investigations and Dual Energy X-ray Absorptiometry (DEXA) scan along with Next Generation Clinical Exome Sequencing (NGCES). We report a case of 23-year-old male who presented with recurrent long bone fractures, congenital heart defects, eye abnormalities (bilateral corneal opacities and atrophic bulbi), and short stature. In addition, our patient also had genu valgum and right-sided hydrocele which have never been reported in SOS till date. On genetic analysis, NGCES revealed a novel pathogenic frameshift variant c.191_192 delCA, p.(Thr64fs*22) in the XYLT2 gene. The patient is doing well on six monthly zoledronic acid infusions. [ABSTRACT FROM AUTHOR]

KBG syndrome is a rare genetic disorder caused by heterozygous pathogenic variants in ANKRD11. Affected individuals have developmental delay, short stature, characteristic facial features, and other dysmorphic findings. To date, a spectrum of unspecific neuroradiological defects has been reported in KBG patients, such as cortical defects, white matter abnormalities, corpus callosum, and cerebellar vermis hypoplasia. Deep clinical and neuroradiological phenotyping and genotype of a patient presenting with mild cognitive and behavioral problems were obtained after written informed consent. We herein describe the first KBG patient presenting with cerebellar heterotopia, a heterogeneous malformation characterized by the presence of clusters of neurons within the white matter of cerebellar hemispheres. This novel association broadens the neuroradiological spectrum of KBG syndrome, and further prompts to investigate the potential functions of ANKRD11 in cerebellar development. [ABSTRACT FROM AUTHOR]

A minority of children born small for gestational age (SGA) may experience catch-up growth failure and remain short in adulthood. However, the underlying causes and mechanisms of this phenomenon are not yet fully comprehended. We reviewed the present state of research concerning the growth hormone-insulin-like growth factor axis and growth plate in SGA children who fail to achieve catch-up growth. Additionally, we explored the factors influencing catch-up growth in SGA children and potential molecular mechanisms involved. Furthermore, we considered the potential benefits of supplementary nutrition, specific dietary patterns, probiotics and drug therapy in facilitating catch-up growth. [ABSTRACT FROM AUTHOR]

Context: Growth hormone (GH) deficiency in a child with short stature is diagnosed by GH secretion provocative tests. When the test response is considered adequate, the short stature is considered idiopathic (ISS). Objective: To determine the effect of GH provocative tests on the growth rate in children with idiopathic short stature. Design: Children with short stature with a normal response to at least one GH provocative test were enrolled. Height and growth velocity were measured prior to and after stimulus tests during the follow-up. Methods: Height, mid-parental height, body weight, and body mass index were measured. The height and growth rate were converted to percentiles and Standard Deviation Scores (SDS) using reference ranges standardized by age and sex. GH provocative tests employed arginine or clonidine as secretagogues. Results: Fourty-six children of both genders were enrolled. In thirty-six children, height was measured at the time of testing and on an average time prior to and after the tests of 210 days and 180 days respectively. After testing the children displayed a 3.4-fold increase in their estimated 90-day growth rate. The median (inter-quartile range, IQR) 90 days growth of children pre-and post-tests were 0.7 (0.2–1.0) cm and 2.4 (1.7–3.1) cm respectively with a mean 3,4-fold increase (p < 0.0001). The median (IQR) 90 days growth of children pre- and post-tests calculated as standard deviation scores (SDS) were −4.0 (−5.4–−2.1) SDS and 0.1 (−1.9–1.4) SDS respectively (p < 0.0001). Ten children with ISS were observed for about 5 months before the GH provocative tests. A small increase in the growth rate was seen only in 2 out of 10 children before testing while it increased in all of them after the tests. The difference in the median growth rate at the first and the second observation was not significant (p = 0.219). Conclusions: Two sequential somatotropic axis provocative tests increase the growth rate in children with idiopathic short stature. The duration of this effect is yet to be determined. [ABSTRACT FROM AUTHOR]

We describe 'Boldrewood', a new accession of watercress (Nasturtium officinale R. Br.) that was initially found to be of short stature with high antioxidant capacity (Payne et al. 2015). This was of particular commercial interest because it offered the potential to develop a novel watercress product with fork-friendly size and improved health-benefits. In two commercial trials comparing Boldrewood to a control, we confirmed that Boldrewood exhibits a dwarf phenotype with a significantly shorter stem and consistently produced more leaves per stem area alongside comparable crop biomass. The antioxidant and chemopreventive capacity of Boldrewood were comparable to the commercial crop. For the first time, we observed a novel increase in glucosinolate concentrations and cytotoxicity to cancer cells, characterised as decreased IC50 (half-maximal concentration of an inhibitor), associated with increased crop age at harvest. This suggests that a slower-growing and longer to harvest crop provides a significant improvement in health benefits gained in this leafy crop which is already known to be highly nutrient dense and with considerable chemopreventive ability. [ABSTRACT FROM AUTHOR]

Background: Craniopharyngioma is a common intracranial tumour in children. Clinical manifestations are related to hypothalamic/pituitary deficiencies, visual impairment, and increased intracranial pressure. Defects in pituitary function cause shortages of growth hormone, gonadotropin, corticotropin, thyrotropin, and vasopressin, resulting in short stature, delayed puberty, feebleness, lethargy, polyuria, etc. However, manifestations involving precocious puberty (PP) are rare. Case report: In both patients, surgical resection was performed after the diagnosis of craniopharyngioma, and breast development occurred postoperatively at one month in one patient and at one year and three months in the other patient. Central precocious puberty (CPP) was diagnosed via relevant examinations. Leuprorelin was injected subcutaneously every 28 days, and changes in height, weight, bone age, gonadal ultrasound and sex hormones were recorded. During the follow-up of the two children, the sex hormone levels were significantly reduced, and significant acceleration in bone age was not observed. Conclusions: CPP was induced by craniopharyngioma surgery, and treatment with gonadotropin-releasing hormone analogues (GnRHa) inhibited sexual development and bone age progression. More attention should be given to monitoring for CPP during long-term follow-up of craniopharyngiomas in the clinic. [ABSTRACT FROM AUTHOR]

Background: There is no appropriate tool to predict recombinant human growth hormone (rhGH) response before therapy initiation in short-stature children in late puberty. The current study aimed to explore the associations between magnetic resonance imaging (MRI) stages of the knee growth plates and rhGH response in short-stature children in late puberty. Methods: In this prospective cohort study, short-stature children in late puberty were treated with rhGH and followed up for 6 months. We proposed a novel knee MRI staging system according to the growth plate states of distal femurs or proximal tibias and divided the participants into three groups: unclosed growth plate group, marginally closed growth plate group, and nearly closed growth plate group. The primary outcomes were height gain and growth velocity (GV), which were assessed three months later. Results: Fifty participants were enrolled, including 23 boys and 27 girls. GV and height gain after 6 months of rhGH therapy decreased successively in the three groups with an increased degree of growth plate fusion, especially when grouped by proximal tibias (GV1-3 mon from 9.38 to 6.08 to 4.56 cm/year, GV4-6 mon from 6.75 to 4.92 to 3.25 cm/year, and height gain from 4.03 to 2.75 to 1.95 cm, all P < 0.001). Moreover, the MRI stages of growth plates independently served as a significant variable for GV and height gain after therapy, especially when grouped by proximal tibias (all P < 0.01). Conclusion: The MRI staging method is expected to be an effective tool for predicting rhGH response before therapy initiation in short-stature children in late puberty. [ABSTRACT FROM AUTHOR]

Patients with Aarskog–Scott syndrome (AAS) have short stature, facial anomalies, skeletal deformities, and genitourinary malformations. FYVE, RhoGEF, and PH domain-containing 1 (FGD1) is the only known causative gene of AAS. However, the diagnosis of AAS remains difficult, and specific treatments are still absent. Patients suspected with AAS were recruited, and clinical information was collected. Genetic testing and functional analysis were carried out for the diagnosis. By literature review, we summarized the clinical and genetic characteristics of FGD1-related AAS and analyzed the genotype–phenotype correlation. Five patients were recruited, and four novel FGD1 variants were identified. The diagnosis of AAS was confirmed by genetic analysis and functional study. Three patients treated with growth hormone showed improved heights during the follow-up period. By literature review, clinical features of AAS patients with FGD1 variants were summarized. Regarding FGD1 variations, substitutions were the most common form, and among them, missense variants were the most frequent. Moreover, we found patients with drastic variants showed higher incidences of foot and genitourinary malformations. Missense variants in DH domain were related to a lower incidence of cryptorchidism. Conclusion: We reported four novel pathogenic FGD1 variations in AAS patients and confirmed the efficacy and safety of growth hormone treatment in FGD1-related AAS patients with growth hormone deficiency. Additionally, our literature review suggested the crucial role of DH domain in FGD1 function. What is Known: • Aarskog–Scott syndrome is a rare genetic disease, and the only known cause is the variant in FGD1 gene. The typical clinical manifestations of AAS include facial, skeletal, and urogenital deformities and short stature. What is New: • We reported four novel FGD1 variants and reported the treatment of growth hormone in FGD1-related AAS patients. Our genotype–phenotype correlation analysis suggested the crucial role of DH domain in FGD1 function. [ABSTRACT FROM AUTHOR]

Background and Objective: Vosoritide is a recently approved therapy for achondroplasia, the most common form of disproportionate short stature, that has been shown to be well tolerated and effective in increasing linear growth. This study aimed to develop a population pharmacokinetic (PPK) model to characterize pharmacokinetics (PK) of vosoritide and establish a weight-band dosing regimen. Methods: A PPK model was developed using data from five clinical trials in children with achondroplasia (aged 0.95−15 years) who received daily per-kg doses of vosoritide. The model was used to simulate expected exposures in children with a refined weight-band dosing regimen. Simulated exposure was compared with the observed exposure from the pivotal clinical trial to evaluate appropriateness of the weight-band dosing regimen. Results: A one-compartment model with a change-point first-order absorption and first-order elimination accurately described PK of vosoritide in children with achondroplasia. Body weight was found to be a predictor of vosoritide's clearance and volume of distribution. Additionally, it was observed that dosing solution concentration and duration of treatment influenced bioavailability. The weight-band dosing regimen resulted in simulated exposures that were within the range demonstrated to be well tolerated and effective in the pivotal clinical trial and showed improved consistency in drug exposure across the achondroplasia population. Conclusions: The weight-band dosing regimen reduced the number of recommended dose levels by body weight and is expected to simplify dosing for children with achondroplasia and their caregivers. Clinical Trial Registration: NCT02055157, NCT02724228, NCT03197766, NCT03424018, and NCT03583697. [ABSTRACT FROM AUTHOR]

To study the presentation and plan of treatment of patient with Rosai Dorfman Disease. Rosai-Dorfman disease(RDD), is rare, non-neoplastic, multisystemic histiocytic disorder. Nodal form is more common. It's self-limiting disorder of unknown etiology. Symptomatic treatment is mainstay. Bardet–Biedl syndrome (BBS) is rare ciliopathic, autosomal-recessive disorder, affecting multiple organs. Characterized by marked central obesity, retinal dystrophy, polydactyly, mental retardation, hypogonadism and renal dysfunction. Treatment is symptomatic with hormone supplementation & regular follow-ups. 10 year male presented with swelling over left side of neck and intermittent fever since 2 years, diminished vision in night since 5 years. History of similar complaints on right side 5 years back. Fine needle aspiration cytology(FNAC)-features consistent with Rosai Dorfman Disease. Examination showed short stature, squint eyes, polydactyly. Multiple palpable neck nodes of variable sizes. Ophthalmic evaluation showed Retinitis Pigmentosa. Paediatric consultation for syndromic evaluation, features were consistent with Bardet Biedel syndrome. Since the presentation is same as that of opposite side in past, because of recurrence of symptoms even with regular antibiotic and steroid therapy, and no local recurrence of disease on right side, surgical excision is planned for the patient. Rosai-Dorfman disease and Bardet–Biedl syndrome are rare disorders presenting many diagnostic and therapeutic challenges. High degree of clinical suspicion (RDD & BBS) with typical histopathological features (RDD) are diagnostic. Symptomatic treatment is useful and surgical excision can be done for recurrent/ complicated cases of RDD while symptomatic treatment with regular follow-up for BBS. [ABSTRACT FROM AUTHOR]

The aim of the study was to determine the relationship between flatfoot morphology and body mass and height in children aged 6–12 years. A total of 6471 Chinese children (mean age 9.0 ± 1.9 years, 41% female) were assessed for foot morphometry, body height, and body mass index. Foot morphology, including foot length, width, girth, arch height, hallux valgus angle, and rearfoot valgus angle, was measured using a 3D laser scanner. Flatfoot evaluations were conducted using the Sztriter–Godunov index (KY) from footprints. All measurements were analyzed by age and sex using the mean values of the left and right sides. Comparisons were performed between flatfoot groups, between body mass index (BMI) groups, and between body height groups. The study revealed a significant decrease in the incidence of bipedal flatfoot with age (p < 0.001), whereas the prevalence of obesity remained consistent (p > 0.05). Bipedal flatfoot was associated with distinct morphological changes, including lower arches, reduced instep height, diminished ankle heights and a greater rearfoot valgus angle (p < 0.05). When comparing the BMI groups, overweight children had larger and thicker feet (p < 0.05), but no differences were found in arch height and ankle height (p > 0.05). When comparing the body height groups, short-statured children had a shorter feet girth, shorter arches, and shorter ankle height (p < 0.05), but no differences were found in the rearfoot valgus angle (p > 0.05). Conclusion: The main characteristics of flat feet include lower arches and instep heights and ankle heights but higher rearfoot valgus angles. In general, overweight children's feet do not have the common features of flat feet. In contrast, short children had similar features of flatfoot except for rearfoot valgus. Assessment of posture, such as rearfoot valgus, can be critical in identifying children with flat feet. What is Known: • The morphology of children's feet is associated with body growth, but the relationship between flatfeet and body mass and height remains controversial. What is New: • Three-dimensional foot measurement shows that body mass is generally not associated with flatfeet, while short children have lower arches but no rearfoot valgus. [ABSTRACT FROM AUTHOR]

Various agrochemicals have been shown to affect diatom growth, physiology, and the structure and diversity of the assemblage. This research aims to study the structural and functional parameters of the benthic diatom assemblage, including indices, ecological traits, nuclear, and frustule abnormalities during the colonization period when exposed to different levels of agricultural impact in lowland streams. To achieve this objective, an experiment was conducted in the Pescado watershed (La Plata, Buenos Aires, Argentina), where the colonization process of artificial glass substrates by diatoms was followed for 75 days in two streams with different intensities of agricultural land use. The results show that the Pampean Diatom Index and diversity reflect water quality in agricultural sites, and there is an increase in diversity and richness during the colonization process, which stabilizes after 20 days. Considering the ecological guilds, the motile guild (fast-moving species) dominated the assemblages, while the low-profile guild (species of short stature, including prostate, adnate, and erect diatoms resistant to physical disturbance and low tolerance to nutrient enrichment) was more abundant in the most impacted stream. However, the variations in the size classes did not produce a consistent trend representing environmental quality. The nuclear alterations were sensitive enough to show the differences in water quality, while the deformed frustules were not significantly different between the studied sites. These results show that measuring the impact of human activities on freshwater bodies under multiple-stressor scenarios has to consider multiple endpoints of the assemblage rather than a single structural or functional metric. [ABSTRACT FROM AUTHOR]

Biallelic IGFALS variants lead to acid‒labile subunit (ALS) deficiency characterized by growth hormone resistance with or without delayed puberty. Here, we report a prepubertal boy with a homozygous 2-amino acid deletion within the fourth N-glycosylation motif (c.1103_1108del, p.N368_S370delinsT) associated with parental consanguinity. He showed short stature consistent with ALS deficiency. This case expands the mutation spectrum of IGFALS to include the elimination of only one N-glycosylation motif of ALS. [ABSTRACT FROM AUTHOR]

Mendelian disorders of the epigenetic machinery (MDEMs) are caused by genetic mutations, a considerable fraction of which are associated with epigenetic modification. These MDEMs exhibit phenotypic overlap broadly characterized by multiorgan abnormalities. The variant detected in genes associated with epigenetic modification can lead to short stature accompanied with multiple system abnormalities. This study is aimed at presenting and summarizing the diagnostic rate, clinical, and genetic profile of MDEMs-associated short stature. Two hundred and fourteen short-stature patients with multiorgan abnormalities were enrolled. Clinical information and whole exome sequence (WES) were analyzed for these patients. WES identified 33 pathogenic/likely pathogenic variants in 19 epigenetic modulation genes (KMT2A, KMT2D, KDM6A, SETD5, KDM5C, HUWE1, UBE2A, NIPBL, SMC1A, RAD21, CREBBP, CUL4B, BPTF, ANKRD11, CHD7, SRCAP, CTCF, MECP2, UBE3A) in 33 patients (15.4%). Of note, 19 variants had never been reported previously. Furthermore, these 33 variants were associated with 16 different disorders with overlapping clinical features characterized by development delay/intelligence disability (31/33; 93.9%), small hands (14/33; 42.4%), clinodactyly of the 5th finger (14/33; 42.4%), long eyelashes (13/33; 39.4%), and hearing impairment (9/33; 27.3%). Additionally, several associated phenotypes are reported for the first time: clubbing with KMT2A variant, webbed neck with SETD5 variant, retinal detachment with CREBBP variant, sparse lateral eyebrow with HUWE1 variant, and long palpebral fissure with eversion of the lateral third of the low eyelid with SRCAP variant. Conclusions: Our study provided a new conceptual framework for further understanding short stature. Specific clinical findings may indicate that a short-stature patient may have an epigenetic modified gene variant. [ABSTRACT FROM AUTHOR]

As we continue to understand more about the complex mechanism of growth, a plethora of novel therapies have recently been developed that aim to address barriers and optimize efficacy. This review aims to explore these novel therapies and provide a succinct review based on the latest clinical studies in order to introduce clinicians to therapies that will soon constitute the future in the field of short stature. Conclusion: The review focuses on long-acting growth hormone formulations, a novel growth hormone oral secretagogue, novel treatments for children with achondroplasia, and targeted therapies for rare forms of skeletal dysplasias. What is Known: • Recombinant human growth hormone has been the mainstay of treatment for children with short stature for years. • Such therapy is not always effective based on the underlying diagnosis (e.g achondroplasia, Turner syndrome). Compliance with daily injections is challenging and can directly affect efficacy. What is New: • Recent development of long-acting growth hormone regimens and oral secretagogues can overcome some of these barriers, however several limitations need to be taken into consideration. • Newer therapies for achondroplasia, and other rare forms of skeletal dysplasias introduce us to a new era of targeted therapies for children with short stature. Clinicians ought to be aware of pitfalls and caveats before introducing these novel therapies to every day practice. [ABSTRACT FROM AUTHOR]

Objective: To analyse the clinical and radiological characteristics of pituitary stalk interruption syndrome (PSIS). Methods: A retrospective analysis of confirmed cases of PSIS was performed. The development of new pituitary hormonal deficiencies and response to recombinant human growth hormone (rhGH) therapy were assessed during follow-up. Results: This study included 14 children (10 boys) of PSIS with median (range) age of 12.15 years (2 months–18 years). Short stature was the most common presentation (n = 13), and micropenis (n = 4), cleft lip (n = 1) and single central incisor (n = 1) were other midline defects. Growth hormone (GH) deficiency was present in 14 children and 7 of them also had multiple pituitary hormone deficiencies at baseline. Central hypothyroidism (n = 5), secondary adrenal deficiency (n = 4) and gonadotropin deficiencies (n = 2) were also seen. All children received rhGH. The mean height gain on follow-up was 12.78 cm in first year (n = 14), 6.5 cm in second year (n = 8) and 4.07 cm in third year (n = 7) of rhGH therapy. Four children developed additional pituitary hormone deficiency on follow-up. Conclusion: Short stature with isolated GH deficiency was the most common presentation of PSIS that showed good response to rhGH therapy. [ABSTRACT FROM AUTHOR]

GJA1 is the causative gene for oculodentodigital dysplasia (ODDD). A novel de novo GJA1 variant, NM 000165:c263C > T [p.P88L], was identified in a mosaic state in a patient with short stature, seizures, delayed myelination, mild hearing loss, and tooth enamel hypoplasia. Although the patient exhibited severe neurodevelopmental delay, other clinical features of ODDD, including limb anomalies, were mild. This may be due to differences in the mosaic ratios in different organs. [ABSTRACT FROM AUTHOR]

Autosomal dominantly inherited neurofibromatosis type I (NF1) is a systemic disorder caused by a mutation of a gene on chromosome 17q11.2 and characterized by multiple café-au-lait spots, lentiginous macules, Lisch nodules of the iris, and tumors of the nervous system. Bony manifestations such as scoliosis, dysplasia of the greater sphenoidal wing, tibial pseudoarthrosis, short stature, and macrocephaly have been reported in approximately 50% of patients. However, calvarial bone defects are rare. After screening 324 articles, 23 cases (12 adult and 11 pediatric patients) of occipital bone defects in NF1 patients were selected. All patients had a single/multiple bone defect over the lambdoid suture. Adjacent benign plexiform neurofibromas were observed in 14 patients (60.8%, 7 adults and 7 children); one adult patient was diagnosed with neurofibrosarcoma. Meningoencephalocele over the occipital defect was noted in 8 cases (34.78%, all adults). Cranioplasty was performed in only 17.39% of patients. Histologic examination was performed in 7 of the 15 patients with associated neurofibromas/neurofibrosarcomas. Biopsy of the bone margins surrounding the defect was performed in only one case. Pathologic examination of the herniated parieto-occipital or cerebellar tissue was not performed in any of the patients studied. We report the case of a 9-year-old girl with NF1 and a significant occipital bone defect and performed a systematic review of the relevant literature to highlight the challenges in treating this condition and to investigate the underlying mechanisms contributing to bone defects or dysplasia in NF1. [ABSTRACT FROM AUTHOR]

In-vivo bone microstructure measured by high-resolution peripheral quantitative computed tomography (HR-pQCT) is gaining importance in research and clinical practice. Second-generation HR-pQCT (XCT2) shows improved image quality and shorter measurement duration compared to the first generation (XCT1). Predicting and understanding the occurrence of motion artifacts is crucial for clinical practice. We retrospectively analyzed data from HR-pQCT measurements at the distal radius and tibia of 1,000 patients (aged 20 to 89) evenly distributed between both generations of HR-pQCT. Motion artifacts were graded between 1 (no motion) and 5 (severe motion), with grades greater 3 considered unusable. Additionally, baseline characteristics and patients' muscle performance and balance were measured. Various group comparisons between the two generations of HR-pQCT and regression analyses between patient characteristics and motion grading were performed. The study groups of XCT1 and XCT2 did not differ by age (XCT1: 64.9 vs. XCT2: 63.8 years, p = 0.136), sex (both 74.5% females, p > 0.999), or BMI (both 24.2 kg/m2, p = 0.911) after propensity score matching. XCT2 scans exhibited significantly lower motion grading in both extremities compared to XCT1 (Radius: p < 0.001; Tibia: p = 0.002). In XCT2 motion-corrupted scans were more than halved at the radius (XCT1: 35.3% vs. XCT2: 15.5%, p < 0.001), and at the tibia the frequency of best image quality scans was increased (XCT1: 50.2% vs. XCT2: 63.7%, p < 0.001). The strongest independent predictor for motion-corrupted images is the occurrence of high motion grading at the other scanning site during the same consultation. The association between high motion grading in one scan and a corresponding high motion grading in another scan within the same session suggests a non-resting patient. Additionally, aged, female, and patients with smaller stature tend towards higher motion grading, requiring special attention to a correct extremity fixation. [ABSTRACT FROM AUTHOR]

Purpose: Doses of spinal bupivacaine adjusted to patient height or height/weight have been shown to provide hemodynamic stability during cesarean section. However, their effects in short stature parturients are unknown. Methods: In this double-blind, randomized clinical trial, we randomly assigned short parturients (height < 150 cm) undergoing elective cesarean section, to receive doses of intrathecal hyperbaric bupivacaine either height or height/weight-adjusted, in a 1:1 ratio. The primary outcome was post-spinal hypotension (defined as systolic blood pressure [SBP] < 90% of baseline between spinal administration and delivery of the baby). Secondary outcomes included severe post-spinal hypotension (SBP < 80% of baseline), post-delivery hypotension (SBP < 90% and < 80% of baseline), intraoperative bradycardia, nausea and vomiting, shivering, rescue analgesic needed, and spinal block characteristics. Results: A total of 112 patients underwent randomization. Post-spinal hypotension (SBP < 90% of baseline) occurred in 52% of the patients in the height/weight group and in 55% in the height group (difference − 3.5%: 95% confidence interval [CI] − 22 to 14.8, P = 0.705). There was no significant difference between the two groups in the occurrences of post-spinal severe hypotension (SBP < 80% of baseline), post-delivery hypotension, and spinal block characteristics. Six patients (11%) in the height/weight group needed intraoperative rescue analgesic compared to none in the height group (P = 0.027). Conclusion: We found that height-based dosing in short parturients provides the optimal trade-off between intraoperative hemodynamic instability and provision of pain-free anesthesia. Trial registration: clinicaltrial.gov-NCT04082676. https://clinicaltrials.gov/ct2/show/NCT04082676. [ABSTRACT FROM AUTHOR]

The aim of this study was to explore the relationship between serum uric acid (SUA) and the triglyceride-glucose (TyG) index, which is a more effective indicator of insulin resistance. The study participants included 1700 children and adolescents with short stature who were recruited at the Affiliated Hospital of Jining Medical University in China between March 2013 and April 2021. A positive association between SUA levels and the TyG index was detected by univariate analysis (p < 0.001). Furthermore, a nonlinear relationship was detected between SUA and the TyG index, whose point was 6.55 mg/dL. There was a positive association between SUA and the TyG index when the SUA level was greater than 6.55 mg/dL (β 0.17, 95% CI: 0.07, 0.27; P < 0.001). However, we did not observe a significant relationship between SUA and the TyG index when the SUA level was less than 6.55 mg/dL (β 0.02, 95% CI: − 0.01, 0.05; P = 0.091). In addition, a stratified analysis was performed to appraise changes in this relationship for different sexes. The relationship between SUA and the TyG index in males and females is consistent with that in the general population, showing a nonlinear relationship. However, the inflection points of SUA level were significantly higher in males than in females, and the inflection points were approximately 6.72 and 5.88 mg/dL, respectively. This study revealed a nonlinear relationship between SUA and the TyG index in children with short stature. The nonlinear relationship remained in gender stratification analysis, but the inflection point of SUA level was higher in men. Further studies are needed to establish a causal relationship between SUA levels and the TyG index in children with short stature. [ABSTRACT FROM AUTHOR]

Matrix Gla protein (MGP) is a vitamin K-dependent post-translationally modified protein, highly expressed in vascular and cartilaginous tissues. It is a potent inhibitor of extracellular matrix mineralization. Biallelic loss-of-function variants in the MGP gene cause Keutel syndrome, an autosomal recessive disorder characterized by widespread calcification of various cartilaginous tissues and skeletal and vascular anomalies. In this study, we report four individuals from two unrelated families with two heterozygous variants in MGP, both altering the cysteine 19 residue to phenylalanine or tyrosine. These individuals present with a spondyloepiphyseal skeletal dysplasia characterized by short stature with a short trunk, diffuse platyspondyly, midface retrusion, progressive epiphyseal anomalies and brachytelephalangism. We investigated the cellular and molecular effects of one of the heterozygous deleterious variants (C19F) using both cell and genetically modified mouse models. Heterozygous 'knock-in' mice expressing C19F MGP recapitulate most of the skeletal anomalies observed in the affected individuals. Our results suggest that the main underlying mechanism leading to the observed skeletal dysplasia is endoplasmic reticulum stress-induced apoptosis of the growth plate chondrocytes. Overall, our findings support that heterozygous variants in MGP altering the Cys19 residue cause autosomal dominant spondyloepiphyseal dysplasia, a condition distinct from Keutel syndrome both clinically and molecularly. Biallelic loss-of-function variants in the gene encoding Matrix Gla Protein (MGP) are known to cause a recessive disorder called Keutel syndrome. Here, the authors report that heterozygous missense variants affecting one particular cysteine residue of MGP can cause a clinically distinct, dominant disorder, likely via impaired signal peptide processing leading to cellular stress and apoptosis. [ABSTRACT FROM AUTHOR]

Background: Hypogonadism is a significant late complication in childhood cancer survivors (CCS). The aim of this study was to elucidate the advantages and limitations of estrogen replacement therapy (ERT) for CCS with hypogonadism. Methods: Seventeen CCS were divided into two groups: gonadal hypogonadism (GH) group (n = 8) and central hypogonadism (CH) group (n = 9). Pearson correlation coefficients were used to investigate the impact of cancer management on final height, bone density, and uterine development. Results: Seven of GH group had hematologic malignancies, and all of them underwent total body irradiation before bone marrow transplantation. The GH group showed significant positive correlations between the onset age of disease treatment and final height (p < 0.05, R = 0.712) and uterine size following ERT (p < 0.05, R = 0.775). All CCS in the CH group had brain tumors, and seven of them received chemotherapy. There were trends towards positive and negative correlations between the onset age of disease treatment and final height (p = 0.09, R = 0.598) or uterine size (p = 0.07, R = − 0.669), respectively. A negative correlation trend was observed between the age at ERT initiation and final height (p = 0.07, R = − 0.769) or bone density (p = 0.18, R = − 0.626) in six CH patients who received growth hormone therapy. Five CCS in both groups experienced osteoporosis, despite receiving ERT. Conclusion: Individualized management strategies beyond ERT are essential to reduce long-term complications in CCS with hypogonadism, considering the type and timing of cancer treatment. [ABSTRACT FROM AUTHOR]

Global change drivers that modify the quality and quantity of litter inputs to soil affect greenhouse gas fluxes, and thereby constitute a feedback to climate change. Carbon cycling in the Yukon–Kuskokwim (Y–K) River Delta, a subarctic wetland system, is influenced by landscape variations in litter quality and quantity generated by herbivores (migratory birds) that create 'grazing lawns' of short stature, nitrogen-rich vegetation. To identify the mechanisms by which these changes in litter inputs affect soil carbon balance, we independently manipulated qualities and quantities of litter representative of levels found in the Y–K Delta in a fully factorial microcosm experiment. We measured CO2 fluxes from these microcosms weekly. To help us identify how litter inputs influenced greenhouse gas fluxes, we sequenced soil fungal and bacterial communities, and measured soil microbial biomass carbon, dissolved carbon, inorganic nitrogen, and enzyme activity. We found that positive correlations between litter input quantity and CO2 flux were dependent upon litter type, due to differences in litter stoichiometry and changes to the structure of decomposer communities, especially the soil fungi. These community shifts were particularly pronounced when litter was added in the form of herbivore feces, and in litter input treatments that induced nitrogen limitation (i.e., senesced litter). The sensitivity of carbon cycling to litter quality and quantity in this system demonstrates that herbivores can strongly impact greenhouse gas fluxes through their influence on plant growth and tissue chemistry. [ABSTRACT FROM AUTHOR]

Idiopathic short stature (ISS) accounts for more than 70% of childhood short stature cases, with an undefined etiology and pathogenesis, leading to limited treatment. However, recent studies have shown that intestinal microbiota may be associated with ISS. This study aimed to characterize the intestinal microbiota in children with ISS, effect of treatment with growth hormones, and association between specific bacterial species and ISS. This study enrolled 55 children, comprising 40 diagnosed with ISS at Jinhua Hospital, Zhejiang University, and 15 healthy controls. The subjects with ISS were divided into the untreated ISS group (UISS group, 22 children who had not been treated with recombinant human growth hormone [rhGH]), treated ISS group (TISS group, 18 children treated with rhGH for 1 year), and control group (NC group, 15 healthy children). High-throughput sequencing was used to determine the intestinal microbiota characteristics. Higher abundances of Bacteroides, Prevotella, Alistipes, Parabacteroides, Agathobacter and Roseburia were found in the UISS and TISS groups than in the control group, whereas Bifidobacterium, Subdoligranulum, and Romboutsia were less abundant. The composition of intestinal microbiota in the UISS and TISS groups was almost identical, except for Prevotella. The TISS group had significantly lower levels of Prevotella than did the UISS group, which were closer to those of the NC group. Receiver operating characteristic curve analysis revealed that the abundances of Prevotella, Bifidobacterium, Bacteroides, and Subdoligranulum were effective in differentiating between the UISS and NC groups. Conclusion: Alterations in intestinal microbiota may be associated with ISS. Specific bacterial species, such as Prevotella, may be potential diagnostic markers for ISS. What is Known: • ISS is associated with the GH-IGF-1 axis. • Recent studies indicated an association between the GH-IGF-1 axis and intestinal microbiota. What is New: • Children with ISS showed alterations in intestinal microbiota, with a relative increase in the abundance of gut inflammation-related bacteria. • The relative abundances of Prevotella, Bacteroides, Bifidobacterium, and Subdoligranulum may serve as potential diagnostic markers. [ABSTRACT FROM AUTHOR]

Objectives: To determine the prevalence of impaired growth parameters (height and BMI z scores) among adolescents aged 10–19 years, with onset of idiopathic nephrotic syndrome between the age of 1 and 6 years. Methods: A cross-sectional study was conducted among adolescents aged 10–19 years with onset of idiopathic nephrotic syndrome between the age of 1–6 years, and under regular follow-up at our center. The data were retrieved for a 10-year period (2012–2022). The current weight, height and body mass index (BMI) were recorded and interpreted as per world Health Organization (WHO) growth standards. Results: 116 adolescents [60 Frequently relapsing nephrotic syndrome (FRNS)/Steroid dependent nephrotic syndrome (SDNS), and 56 Steroid resistant nephrotic syndrome (SRNS)] patients were enrolled with median (IQR) age of 133 (120,168) months and age at disease onset of 48 (26,68) months. The proportion of children with overweight (BMI for age >1 z and cushingoid features), obesity (BMI for age >2z), stunting (height for age (HFA) <2z), and severe stunting (HFA <3z) were 29 (25%), 3 (2.6%), 31 (26.7%), and 7 (6%), respectively. The median (IQR) cumulative steroid dose for FRNS/SDNS and SRNS group was 19986.96 (14597.1, 26181.96) mg/m2 and 14385 (10758.82, 21355.95) mg/m2, respectively (P=0.003). Conclusions: The proportion of short stature and overweight was high among adolescents with nephrotic syndrome, emphasizing the need for measures to reduce steroid use and other measures to support growth. [ABSTRACT FROM AUTHOR]

Purpose: To analyze the clinical, hormonal, and radiological characteristics of Pituitary stalk interruption syndrome (PSIS) in children with growth hormone deficiency (GHD). Methods: This is a prospective cross-sectional study, conducted over a period of three years in a short stature clinic of tertiary care referral hospital. 57 severe short stature children with proven GHD were included in the study. Results: Among 57 children with GHD, 14 (24%) were diagnosed as PSIS. The mean age at diagnosis was 11.8 ± 2.6years. The male to female ratio was 2.5:1. Nine (64%) children had multiple pituitary hormone deficiency (MPHD) and 5 (36%) had isolated growth hormone deficiency (IGHD). In spite of absent or ectopic posterior pituitary (EPP)in Magnetic Resonance Imaging (MRI) of PSIS cohorts, only one had Arginine vasopressin (AVP) deficiency. EPP was seen near median eminence in 6 (44%), elsewhere in 4 (28%), and absent in 4 (28%)children. The height gain following growth hormone therapy was better in PSIS cohorts as compared to non-PSIS. Conclusion: Male gender, breech presentation, external congenital anomalies like cryptorchidism, midline defects and nystagmus were more common in children with PSIS. MPHD were more frequently seen in PSIS whereas IGHD in non-PSIS cohort. AVP deficiency is very rare in PSIS despite of absent or ectopic posterior pituitary in MRI. High index of clinical suspicion in all severe short stature may lead to early diagnosis and prompt initiation of growth hormone treatment for better outcome. [ABSTRACT FROM AUTHOR]

Rare genetic skeletal disorders (GSDs) remain the major problem in orthopedics and result in significant morbidity in patients, but the causes are highly diverse. Precise molecular diagnosis will benefit management and genetic counseling. This study aims to share the diagnostic experience on a three-generation Chinese family with co-occurrence of spondyloepiphyseal dysplasia (SED) and X-linked hypophosphatemia (XLH), and evaluate the therapeutic effects of two third-generation siblings. The proband, his younger brother, and mother presented with short stature, skeletal problems, and hypophosphatemia. His father, paternal grandfather, and aunt also manifested short stature and skeletal deformities. Whole exome sequencing (WES) of proband–brother–parents initially only found the proband and his younger brother had a pathogenic c.2833G > A(p.G945S) variant in the COL2A1 gene inherited from their father. Re-analysis of WES uncovered the proband and his younger brother also harbored a pathogenic ex.12 del variant in the PHEX gene transmitted from their mother. Sanger sequencing, agarose gel electrophoresis, and quantitative polymerase chain reaction proved these results. The proband and his younger brother were confirmed to have a paternally inherited SED and a maternally inherited XLH. During a 2.8-year follow-up, these two siblings remained short stature and hypophosphatemia, but their radiographic signs and serum bone alkaline phosphatase levels were improved with treatment of oral phosphate and calcitriol. Our study presents the first report of co-occurrence of SED and XLH, shows the possibility that two different rare GSDs co-exist in a single patient, and alerts clinicians and geneticists to be cautious about this condition. Our study also suggests that next-generation sequencing has limit in detecting exon-level large deletions. [ABSTRACT FROM AUTHOR]

Background: Achondroplasia is the most common form of skeletal dysplasia. Recent advances in therapeutic options have highlighted the need for understanding the burden and treatment landscape of the condition. This systematic literature review (SLR) aimed to identify health-related quality of life (HRQoL)/utilities, healthcare resource use (HCRU), costs, efficacy, safety and economic evaluation data in achondroplasia and to identify gaps in the research. Methods: Searches of MEDLINE, Embase, the University of York Centre for Reviews and Dissemination (CRD), the Cochrane Library and grey literature were performed. Articles were screened against pre-specified eligibility criteria by two individuals and study quality was assessed using published checklists. Additional targeted searches were conducted to identify management guidelines. Results: Fifty-nine unique studies were included. Results demonstrated a substantial HRQoL and HCRU/cost-related burden of achondroplasia on affected individuals and their families throughout their lifetimes, particularly in emotional wellbeing and hospitalisation costs and resource use. Vosoritide, growth hormone (GH) and limb lengthening all conferred benefits for height or growth velocity; however, the long-term effects of GH therapy were unclear, data for vosoritide were from a limited number of studies, and limb lengthening was associated with complications. Included management guidelines varied widely in their scope, with the first global effort to standardise achondroplasia management represented by the International Achondroplasia Consensus Statement published at the end of 2021. Current evidence gaps include a lack of utility and cost-effectiveness data for achondroplasia and its treatments. Conclusions: This SLR provides a comprehensive overview of the current burden and treatment landscape for achondroplasia, along with areas where evidence is lacking. This review should be updated as new evidence becomes available on emerging therapies. [ABSTRACT FROM AUTHOR]

Objective: To study the clinico-hematological profile, complications, and management of children with non-transfusion dependent thalassemia (NTDT) in northern India. Method: We retrieved and analyzed the data of 69 children with NTDT diagnosed between January, 2006 to December, 2018, aged under 18 years from our unit's records. Result: The participants mean (SD) age was 4.4 (3.1) years, and they presented with anemia (29%), jaundice (13%), hemolytic facies (13%), splenomegaly (87%), thromboembolism (2.9%) and pathological short stature (28.5%). The most common cause of NTDT was β-thalassemia (45%), followed by either compound-heterozygous or homozygous for Eβ-thalassemia mutation. The most frequent single genotype observed was compound heterozygous for IVS1–5 (G>nd codon 26 (G>A). The mean (SD) follow-up duration was 3.5 (2.4) years. On follow-up, 27 children (%) remained transfusion free, and 30 (%) needed occasional transfusions. 63% of patients initially presenting with pathological short stature showed improvement in growth. Amongst children older than 10 years (n=20), subclinical hypothyroidism was detected in 6 children and impaired glucose tolerance test in 1 child. Conclusion: Eß-thalassemia was the commonest cause of NTDT in this population. [ABSTRACT FROM AUTHOR]

Kelch-like (KLHL) 15, localized on chromosome Xp22.11, was recently identified as an X-linked intellectual disability gene. Herein, we report a case of a male patient with a novel nonsense variant, c.736 C > T p.(Arg246*), in KLHL15, who presented with impaired intelligence, short stature, frequent hypoglycemia, and periodic fever. Patients with nonsense variants in KLHL15 may develop intellectual disabilities, minor skeletal anomalies, and facial dysmorphisms. [ABSTRACT FROM AUTHOR]

This document is a correspondence published in the journal Indian Pediatrics. It discusses the clinical features of seven children who presented with hematemesis (vomiting blood) and respiratory symptoms, and later tested positive for adenovirus infection. The children did not have a significant drop in hemoglobin or require intensive care, and there was no history of excessive NSAID usage or comorbidity. Upper gastrointestinal endoscopy showed severe erosive pan-gastritis, but no abnormalities were found in biopsies or viral testing. The authors suggest a possible association between adenovirus infection and hematemesis, but further studies are needed for confirmation. [Extracted from the article]

Recent studies reported an impact of the melanocortin 3 receptor (MC3R) on the regulation of body weight, linear growth and puberty timing. Previously, allele p.44Ile of a frequent non-synonymous variant (NSV) p.Val44Ile was reported to be associated with decreased lean body mass (LBM) and later puberty in both sexes. We Sanger sequenced the coding region of MC3R in 185 children or adolescents with short normal stature (SNS) or 258 individuals with severe obesity, and 192 healthy-lean individuals. Eleven variants (six NSVs) were identified. In-silico analyses ensued. Three rare loss-of-function (LoF) variants (p.Phe45Ser, p.Arg220Ser and p.Ile298Ser) were only found in severely obese individuals. One novel highly conserved NSV (p.Ala214Val), predicted to increase protein stability, was detected in a single lean female. In the individuals with SNS, we observed deviation from Hardy–Weinberg Equilibrium (HWE) (p = 0.012) for p.Val44Ile (MAF = 11.62%). Homozygous p.44Ile carriers with SNS had an increased BMI, but this effect did not remain significant after Bonferroni correction. In line with previous findings, the detected LoF NSVs may suggest that dysfunction in MC3R is associated with decreased body height, obesity and delayed puberty. [ABSTRACT FROM AUTHOR]

Turner syndrome is the most common chromosomal anomaly in females. The typical features include short stature, amenorrhoea, short webbed neck, shielded chest and many comorbidities like osteoporosis, cardiac anomalies, diabetes and hypothyroidism. Primary hyperparathyroidism caused by parathyroid adenoma is rarely reported in patients of turner syndrome. The exact cause is not known at present. We report a case of a 21 years old patient of Turner syndrome who had symptoms of renal stones and hypercalcemia. USG neck and sestamibi scans revealed left inferior parathyroid adenoma. Surgical excision of the involved gland was done which led to normalization of S. calcium and PTH levels. Although hyperparathyroidism is extremely rare in patients of Turner syndrome, any symptoms of renal stones, pathological fractures and hypercalcemia should raise the suspicion of parathyroid adenoma. Surgical management should be planned as early as possible. [ABSTRACT FROM AUTHOR]

Artificial-intelligence (AI) allows large-scale analyses of long-leg-radiographs (LLRs). We used this technology to derive an update for the classical regression formulae by Trotter and Gleser, which are frequently used to infer stature based on long-bone measurements. We analyzed calibrated, standing LLRs from 4200 participants taken between 2015 and 2020. Automated landmark placement was conducted using the AI-algorithm LAMA™ and the measurements were used to determine femoral, tibial and total leg-length. Linear regression equations were subsequently derived for stature estimation. The estimated regression equations have a shallower slope and larger intercept in males and females (Femur-male: slope = 2.08, intercept = 77.49; Femur-female: slope = 1.9, intercept = 79.81) compared to the formulae previously derived by Trotter and Gleser 1952 (Femur-male: slope = 2.38, intercept = 61.41; Femur-female: slope = 2.47, intercept = 54.13) and Trotter and Gleser 1958 (Femur-male: slope = 2.32, intercept = 65.53). All long-bone measurements showed a high correlation (r ≥ 0.76) with stature. The linear equations we derived tended to overestimate stature in short persons and underestimate stature in tall persons. The differences in slopes and intercepts from those published by Trotter and Gleser (1952, 1958) may result from an ongoing secular increase in stature. Our study illustrates that AI-algorithms are a promising new tool enabling large-scale measurements. [ABSTRACT FROM AUTHOR]

Blood pressure (BP) control is a global health issue with an increase in BP beyond the normal BP leading to different stages of hypertension in humans and hence the need to identify risk factors of BP for efficient and effective control. Multiple BP measurement have proven to provide BP readings close to the true BP status of the individual. In this study, we used multiple BP measurement data on 3809 Ghanaians to determine risk factors associated with BP. The data were obtained from World Health Organization study on Global AGEing and Adult Health. We defined high blood pressure (HBP) as ≥ 130/80 mmHg or normal as ≤ 130/80 mmHg. We provide summary statistics and also used the Chi-Square test to assess significance of association between HBP versus risk factors of HBP. The aim of this study is to identify risk factors of BP using the mixed effects logistic regression model. Data were analyzed using R version 4.2.2. The results showed that the risk of high blood pressure (HBP) decreases across the three measurement periods. There is reduced risk (OR = 0.274, 95% CI = 0.2008, 0.405) of HBP among male participants relative to female participants. The risk (OR = 2.771, 95% CI = 1.8658, 4.1145) of HBP increased by 2.771-folds among those who are 60 years and above relative to those below the age of 60 years. Those whose work involves/requires vigorous exercise has 1.631-fold increase in the risk (OR = 1.631, 95% CI = 1.1151, 2.3854) of HBP relative to those whose work does not involve vigorous exercise. There is approximately 5-folds increased in the risk (OR = 4.896, 95% CI = 1.9535, 12.2268) of among those who have ever been diagnosed with diabetes. The results also revealed high risk (OR = 1.649, 95%CI = 1.1108, 2.4486) of HBP among those who have formal education. The risk (OR = 1.009, 95% CI = 1.0044, 1.0137) of HBP increases with increasing weight and a reduced risk (OR = 0.996, 95% CI = 0.9921, 0.9993) of HBP with increasing height. We found that sad experience, either mild, moderate or severe, is associated with a reduced risk of HBP. Those who have vegetable servings at least 2 cups per day have increased risk of HBP and those who have fruits servings at least 2 cups per day is associated with a reduced risk of HBP, however this is not statistically significant. To achieve success in BP control, programs should be designed with the aim of reducing weight, educate those with formal eduction on issues relating to HBP. Those whose work requires vigorous exercise are recommended to have regular check-ups to ensure that pressure build-up in the lungs is cleared. SBP is lower for women at young age but continue to increase after menopause as their BP increase becomes salt-sensitive. Hence there is need to give more attention to menopausal women so as to improve BP. Both young and old individuals are recommended to practice regular exercise since this has shown to reduce risk of being overweight or becoming diabetic and reduces the risk of HBP at yong age and old age. Also, to improve blood pressure control, programs for management of blood pressure or hypertension should focus more short stature individuals since such people are more likely to experience HBP. [ABSTRACT FROM AUTHOR]

KDM3B is located on chromosome 5q31 and encodes KDM3B, which is involved in histone demethylation and epigenetic regulation. Pathogenic KDM3B variants cause a dominantly inherited disorder presenting with intellectual disability (ID), short stature, and facial dysmorphism, named Diets–Jongmans syndrome. We describe two patients with KDM3B variants presenting with Diets–Jongmans syndrome. Genetic testing was performed because of the clinical data and a lack of a clear diagnosis in both patients. Candidate variants were verified by Sanger sequencing. After KDM3B variants were detected, in silico tools were used to predict the pathogenicity of the missense variants. A minigene assay was performed to evaluate the splicing effects of the c.5070 + 1G > A variant on KDM3B. Patient 1 mainly presented with repetitive upper respiratory tract infection and patient 2 presented with palpitation, shortness of breath, and pitting edema; both had ID. Whole exome sequencing identified variants of KDM3B. Patient 1 had the de novo KDM3B c.5070 + 1G > A variant, whereas patient 2 had the c.2828G > A (p.R943Q) variant. Transcriptional experiments of the splicing variant c.5070 + 1G > A revealed aberrant transcripts leading to truncated protein products. We found two pathogenic variants in KDM3B, one of which is novel. Both patients had additional clinical presentations, and patient 1 had transient neutropenia. KDM3B c.5070 + 1G > A is the first KDM3B splice-site variant and was identified as a germline variant. Neutropenia and cardiomyopathy are newly found presentations of Diets–Jongmans syndrome. Our report enriches our knowledge of the genotypic spectrum of the KDM3B variants and phenotypic diversity of Diets–Jongmans syndrome. [ABSTRACT FROM AUTHOR]

Background: Pituitary stalk interruption syndrome is a rare congenital pituitary anatomical defect manifested with wide and various clinical presentations. Short stature and delayed puberty are present in most cases and may be combined with extra pituitary malformations. Magnetic resonance imaging is considered the key factor for reaching the definite diagnosis as it reveals the different radiological presentations of this syndrome. Case presentation: A 17-year-old male patient from Jordan was presented to the radiology department for pituitary MRI. The patient presents with multiple pituitary hormonal deficiency, short stature, and under-developed secondary sexual characteristics. The bone age of the patient was significantly less than the chronological age. MRI pituitary gland showed hypoplasia of the anterior pituitary, absence of the pituitary stalk and ectopic posterior pituitary gland located posterior to the optic chiasm. These findings were consistent with pituitary stalk interruption syndrome. Conclusions: Considering uncommon incidence of pituitary stalk interruption syndrome, magnetic resonance imaging of the pituitary should be considered while examining a patient with pituitary deficiency for prompt diagnosis and treatment. Hormone replacement medication is the primary treatment for pituitary stalk interruption syndrome and should be started as soon as feasible. Thus, early diagnosis and monitoring of individuals are crucial. [ABSTRACT FROM AUTHOR]

Key message: Using map-based cloning and transgenic transformation, we revealed that glycogen kinase synthase 3-like kinase, BnaC01.BIN2, modulates plant height and yield in rapeseed. The modification of plant height is one of the most important goals in rapeseed breeding. Although several genes that regulate rapeseed plant height have been identified, the genetics mechanisms underlying rapeseed plant height regulation remain poorly understood, and desirable genetic resources for rapeseed ideotype breeding are scarce. Here, we map-based cloned and functionally verified that the rapeseed semi-dominant gene, BnDF4, greatly affects rapeseed plant height. Specifically, BnDF4 encodes brassinosteroid (BR)-insensitive 2, a glycogen synthase kinase 3 primarily expressed in the lower internodes to modulate rapeseed plant height by blocking basal internode-cell elongation. Transcriptome data showed that several cell expansion-related genes involving auxin and BRs pathways were significantly downregulated in the semi-dwarf mutant. Heterozygosity in the BnDF4 allele results in small stature with no marked differences in other agronomic traits. Using BnDF4 in the heterozygous condition, the hybrid displayed strong yield heterosis through optimum intermediate plant height. Our results provide a desirable genetic resource for breeding semi-dwarf rapeseed phenotypes and support an effective strategy for breeding rapeseed hybrid varieties with strong yield heterosis. [ABSTRACT FROM AUTHOR]

Pathway involving insulin-like growth factor 1 (IGF-1) plays significant role in growth and development. Crucial role of IGF-1 was discovered inter alia through studies involving deficient patients with short stature, including Laron syndrome individuals. Noteworthy, despite disturbances in proper growth, elevated values for selected stem cell populations were found in IGF-1 deficient patients. Therefore, here we focused on investigating role of these cells—very small embryonic-like (VSEL) and hematopoietic stem cells (HSC), in the pathology. For the first time we performed long-term observation of these populations in response to rhIGF-1 (mecasermin) therapy. Enrolled pediatric subjects with IGF-1 deficiency syndrome were monitored for 4–5 years of rhIGF-1 treatment. Selected stem cells were analyzed in peripheral blood flow cytometrically, together with chemoattractant SDF-1 using immunoenzymatic method. Patients' data were collected for correlation of experimental results with clinical outcome. IGF-1 deficient patients were found to demonstrate initially higher levels of VSEL and HSC compared to healthy controls, with their gradual decrease in response to therapy. These changes were significantly associated with SDF-1 plasma levels. Correlations of VSEL and HSC were also reported in reference to growth-related parameters, and IGF-1 and IGFBP3 values. Noteworthy, rhIGF-1 was shown to efficiently induce development of Laron patients achieving at least proper rate of growth (compared to healthy group) in 80% of subjects. In conclusion, here we provided novel insight into stem cells participation in IGF-1 deficiency in patients. Thus, we demonstrated basis for future studies in context of stem cells and IGF-1 role in growth disturbances. [ABSTRACT FROM AUTHOR]

Purpose: According to the American College of Medical Genetics (ACMG) classification, variants of uncertain significance (VUS) are gene variations whose impact on the disease risk is not yet known. VUS, therefore, represent an unmet need for genetic counselling. Aim of the study is the use the AlphaFold artificial intelligence algorithm to predict the impact of novel mutations of the IGFALS gene, detected in a subject with short stature and initially classified as VUS according to the ACMG classification. Methods: A short-stature girl and her parents have been investigated. IGFALS mutations have been detected through clinical exome and confirmed by Sanger sequencing. The potential presence of co-occurring gene alterations was investigated in the proband by whole exome and CGH array. Structure of the ALS protein (encoded by the IGFALS gene) was evaluated through the AlphaFold artificial intelligence algorithm. Results: Two IGFALS variants were found in the proband: c.1349T > C (p.Leu450Pro) and c.1363_1365delCTC (p.Leu455del), both classified as VUS, according to ACMG. Parents' analysis highlighted the in trans position of the two variants. AlphaFold showed that the mutated positions were found the concave side a horseshoe structure of the ALS protein, likely interfering with protein-protein interactions. According to a loss of function (LoF) effect of the two variants, reduced levels of the IGF1 and IGFBP-3 proteins, as well as a growth hormone (GH) excess were detected in the proband's serum. Conclusions: By using the AlphaFold structure we were able to predict two IGFALS gene mutations initially classified as VUS, as potentially pathogenetic. Our proof-of-concept showed a potential application of AlphaFold as tool to a better inform VUS interpretation of genetic tests. [ABSTRACT FROM AUTHOR]

Data on the clinical validity of DNA copy number variants (CNVs) in spermatogenic failure (SPGF) is limited. This study analyzed the genome-wide CNV profile in 215 men with idiopathic SPGF and 62 normozoospermic fertile men, recruited at the Andrology Clinic, Tartu University Hospital, Estonia. A two-fold higher representation of > 1 Mb CNVs was observed in men with SPGF (13%, n = 28) compared to controls (6.5%, n = 4). Seven patients with SPGF were identified as carriers of microdeletions (1q21.1; 2.4 Mb) or microduplications (3p26.3, 1.1 Mb; 7p22.3-p22.2, 1.56 Mb; 10q11.22, 1.42 Mb, three cases; Xp22.33; 2.3 Mb) linked to severe congenital conditions. Large autosomal CNV carriers had oligozoospermia, reduced or low-normal bitesticular volume (22–28 ml). The 7p22.3-p22.2 microduplication carrier presented mild intellectual disability, neuropsychiatric problems, and short stature. The Xp22.33 duplication at the PAR1/non-PAR boundary, previously linked to uterine agenesis, was detected in a patient with non-obstructive azoospermia. A novel recurrent intragenic deletion in testis-specific LRRC69 was significantly overrepresented in patients with SPGF compared to the general population (3.3% vs. 0.85%; χ2 test, OR = 3.9 [95% CI 1.8–8.4], P = 0.0001). Assessment of clinically valid CNVs in patients with SPGF will improve their management and counselling for general and reproductive health, including risk of miscarriage and congenital disorders in future offspring. [ABSTRACT FROM AUTHOR]

Rothmund-Thomson syndrome, a heterogeneous genodermatosis with autosomal recessive hereditary pattern, is an uncommon cancer susceptibility genetic syndrome. To date, only 400 cases have been reported in the literature, and the severity of the features varies among individuals with the condition. Here, we describe a 55-year-old male who had been diagnosed with Bloom Syndrome during childhood due to the suggestive physical features such as short stature, chronic facial erythema, poikiloderma in face and extremities, microtia and microcephaly. However, the genetic test demonstrated that the patient carried two pathogenic variants resulting in compound heterozygous in the RECQL4 gene (c.2269C>T and c.2547_2548delGT). He subsequently developed a calcaneal osteosarcoma, which was successfully treated, and has currently been oncologic disease-free for 3 years. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to detect metabolic bone disease and endocrinopathies in a cohort of patients with transfusion-dependent thalassemia (TDT). Methods: This prospective study was conducted between March 2020–August 2021. Children with TDT older than 5 years, receiving regular blood transfusion, underwent comprehensive endocrine and metabolic bone disease evaluation, which included screening for short stature, delayed puberty, diabetes mellitus, hypothyroidism, adrenal insufficiency and hypoparathyroidism. Children older than 10 years also underwent. X-ray of thoracolumbar spine, and dual energy X-ray absorptiometry (DXA) scanning. Results: Out of 37 patients (19 males), with mean (SD) age 15 (6) years, hypogonadism was the commonest endocrine deficiency seen in 15 (62%), followed by short stature, abnormal glucose metabolism, subclinical adrenal insufficiency, hypothyroidism, and hypoparathyroidism. Vitamin D insufficiency/deficiency was seen in 12 (60%) and hypocalcemia in 2 patients. Low bone mass was seen in 8, and osteoporosis, as evidenced by vertebral fractures, in 4 patients. Of the four patients with vertebral fracture, three were aged ≤18 years, one was symptomatic, two each had grade 1 and grade 2 fractures, one had multiple vertebral fractures, and all four had hypogonadism and multiple endocrine deficiencies. Conclusion: Vertebral fractures occur even in the second decade among patients with TDT, and are often associated with endocrinopathies, most commonly hypogonadism. Early screening and prevention of vertebral fractures is necessary. [ABSTRACT FROM AUTHOR]

Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability. The SMC5/6 complex is critical for genome stability. Here, the authors identify mutations in SLF2 and SMC5 as cause of Atelís Syndrome characterized by microcephaly, short stature, anemia, segmented chromosomes and mosaic variegated hyperploidy. [ABSTRACT FROM AUTHOR]

Oryza nivara is considered one of the wild progenitors of cultivated Asian rice (O. sativa). An O. nivara (IRGC104443) accession, previously identified as being moderately resistant to rice sheath blight disease, was used as the donor parent to develop an advanced backcross population with the U.S. rice (O. sativa) cultivar, LaGrue, as the recurrent parent. The population was genotyped with 210 DNA markers and a linkage map constructed that spanned 1488.9 cM. Sheath blight (ShB) disease was evaluated in both greenhouse and field conditions. Days to heading (DTHD), plant height (PTHT) and culm (angle) habit (CULMHAB) were recorded because they can confound sheath blight disease ratings under field conditions. Multiple interval mapping identified qShB9 as the ShB-QTL being the source of resistance and the resistance was attributed to the O. nivara allele. The single CULMHAB QTL, qCULMHAB9, was also located in this region but had a different peak suggesting the more open tillering was most likely due to the TILLER ANGLE CONTROL-1 gene which was fine-mapped near the chromosome 9 ShB resistance in other O. sativa populations. The ShB QTL, qShB3-2-mc, identified in the greenhouse study was not verified in the field studies. None of the three DTHD QTL were colocalized with ShB QTL, while the single PTHT QTL was mapped to the region of the semi-dwarf-1 gene for short stature on chromosome 1. Further studies will be undertaken to fine map the qShB9 region and identify linked markers for use in cultivar development. [ABSTRACT FROM AUTHOR]