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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: 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]

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]

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]

Skeletal dysplasias are a heterogeneous group of disorders presenting mild to lethal defects. Several factors, such as genetic, prenatal, and postnatal environmental may contribute to reduced growth. Fourteen families of Pakistani origin, presenting the syndromic form of short stature either in the autosomal recessive or autosomal dominant manner were clinically and genetically investigated to uncover the underlying genetic etiology. Homozygosity mapping, whole exome sequencing, and Sanger sequencing were used to search for the disease‐causing gene variants. In total, we have identified 13 sequence variants in 10 different genes. The variants in the HSPG2 and XRCC4 genes were not reported previously in the Pakistani population. This study will expand the mutation spectrum of the identified genes and will help in improved diagnosis of the syndromic form of short stature in the local population. [ABSTRACT FROM AUTHOR]

Biallelic variants in PISD cause a phenotypic spectrum ranging from short stature with spondyloepimetaphyseal dysplasia (SEMD) to a multisystem disorder affecting eyes, ears, bones, and brain. PISD encodes the mitochondrial‐localized enzyme phosphatidylserine decarboxylase. The PISD precursor is self‐cleaved to generate a heteromeric mature enzyme that converts phosphatidylserine to the phospholipid phosphatidylethanolamine. We describe a 17‐year‐old male patient, born to unrelated healthy parents, with disproportionate short stature and SEMD, featuring platyspondyly, prominent epiphyses, and metaphyseal dysplasia. Trio genome sequencing revealed compound heterozygous PISD variants c.569C>T; p.(Ser190Leu) and c.799C>T; p.(His267Tyr) in the patient. Investigation of fibroblasts showed similar levels of the PISD precursor protein in both patient and control cells. However, patient cells had a significantly higher proportion of fragmented mitochondria compared to control cells cultured under basal condition and after treatment with 2‐deoxyglucose that represses glycolysis and stimulates respiration. Structural data from the PISD orthologue in Escherichia coli suggest that the amino acid substitutions Ser190Leu and His267Tyr likely impair PISD's autoprocessing activity and/or phosphatidylethanolamine biosynthesis. Based on the data, we propose that the novel PISD p.(Ser190Leu) and p.(His267Tyr) variants likely act as hypomorphs and underlie the pure skeletal phenotype in the patient. [ABSTRACT FROM AUTHOR]

Meier–Gorlin syndrome (MGORS) is an autosomal recessive disorder characterized by short stature, microtia, and patellar hypoplasia, and is caused by pathogenic variants of cellular factors involved in the initiation of DNA replication. We previously reported that biallelic variants in GINS3 leading to amino acid changes at position 24 (p.Asp24) cause MGORS. Here, we describe the phenotype of a new individual homozygous for the Asp24Asn variant. We also report the clinical characteristics of an individual harboring a novel homozygous GINS3 variant (Ile25Phe) and features suggestive of MGORS. Modification of the corresponding residue in yeast Psf3 (Val9Phe) compromised S phase progression compared to a humanized Psf3 Val9Ile variant. Expression of Psf3 Val9Phe in yeast also caused sensitivity to elevated temperature and the replicative stress‐inducing drug hydroxyurea, confirming partial loss of function of this variant in vivo and allowing us to upgrade the classification of this variant. Taken together, these data validate the critical importance of the GINS DNA replication complex in the molecular etiology of MGORS. [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]

Objective: To determine if there is a correlation between maternal short stature and neonatal birth weight among women with adverse outcomes related to labor dystocia. Methods: The medical records of singleton deliveries with adverse obstetric outcomes related to labor dystocia during 2014–2020, in a single tertiary center, were reviewed. Outcomes included at least one of the following: cesarean delivery (CD) due to cephalopelvic disproportion (CPD), prolonged second stage, shoulder dystocia, third‐ or fourth‐degree perineal tear. Maternal short stature was defined as height below the 10th centile (short stature group) and normal stature was defined as maternal height between the 10th and 90th centiles (normal stature group). Maternal and neonatal characteristics were compared between the groups. Results: A total of 3295 women were included, among them, 307 in the short stature group (9.3%, height 1.52 ± 0.02 m) and 2988 in the normal stature group (90.7%, height 1.63 ± 0.04 m). Evaluating the entire cohort revealed similar neonatal birth weights comparing the short and normal stature groups. A subgroup analysis of women after CD due to CPD (n = 296) revealed lower neonatal birth weights in the short stature group (n = 31) compared with the normal stature group (n = 265) (3215 ± 411 vs 3484 ± 427 g, P = 0.001, respectively). Multivariable linear regression was performed for women who underwent CD due to CPD. After adjusting for obesity and diabetes mellitus, short stature and nulliparity were found to be independently associated with decreased neonatal birth weight (266 g less for short stature, P = 0.001, and 294 g less for nulliparity, P = 0.001). Conclusions: Among women with short stature, CD due to CPD occurs at lower neonatal birth weights. Synopsis: Cesarean deliveries due to cephalopelvic disproportion occur in lower neonatal birth weights among short‐statured women compared with women with normal stature. [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]

Background: Kagami–Ogata syndrome (KOS) and Temple syndrome (TS) are two imprinting disorders characterized by the absence or reduced expression of maternal or paternal genes in the chromosome 14q32 region, respectively. We present a rare prenatally diagnosed case of recurrent KOS inherited from a mother affected by TS. Case presentation: The woman's two affected pregnancies exhibited recurrent manifestations of prenatal overgrowth, polyhydramnios, and omphalocele, as well as a small bell-shaped thorax with coat-hanger ribs postnatally. Prenatal genetic testing using a single-nucleotide polymorphism array detected a 268.2-kb deletion in the chromosome 14q32 imprinted region inherited from the mother, leading to the diagnosis of KOS. Additionally, the woman carried a de novo deletion in the paternal chromosome 14q32 imprinted region and presented with short stature and small hands and feet, indicating a diagnosis of TS. Conclusions: Given the rarity of KOS as an imprinting disorder, accurate prenatal diagnosis of this rare imprinting disorder depends on two factors: (1) increasing clinician recognition of the clinical phenotype and related genetic mechanism, and (2) emphasizing the importance of imprinted regions in the CMA workflow for laboratory analysis. [ABSTRACT FROM AUTHOR]

Ankyrin repeat domain containing-protein 11 (ANKRD11), a transcriptional factor predominantly localized in the cell nucleus, plays a crucial role in the expression regulation of key genes by recruiting chromatin remodelers and interacting with specific transcriptional repressors or activators during numerous biological processes. Its pathogenic variants are strongly linked to the pathogenesis and progression of multisystem disorder known as KBG syndrome. With the widespread application of high-throughput DNA sequencing technologies in clinical medicine, numerous pathogenic variants in the ANKRD11 gene have been reported. Patients with KBG syndrome usually exhibit a broad phenotypic spectrum with a variable degree of severity, even if having identical variants. In addition to distinctive dental, craniofacial and neurodevelopmental abnormalities, patients often present with skeletal anomalies, particularly postnatal short stature. The relationship between ANKRD11 variants and short stature is not well-understood, with limited knowledge regarding its occurrence rate or underlying biological mechanism involved. This review aims to provide an updated analysis of the molecular spectrum associated with ANKRD11 variants, investigate the prevalence of the short stature among patients harboring these variants, evaluate the efficacy of recombinant human growth hormone in treating children with short stature and ANKRD11 variants, and explore the biological mechanisms underlying short stature from both scientific and clinical perspectives. Our investigation indicated that frameshift and nonsense were the most frequent types in 583 pathogenic or likely pathogenic variants identified in the ANKRD11 gene. Among the 245 KBGS patients with height data, approximately 50% displayed short stature. Most patients showed a positive response to rhGH therapy, although the number of patients receiving treatment was limited. ANKRD11 deficiency potentially disrupts longitudinal bone growth by affecting the orderly differentiation of growth plate chondrocytes. Our review offers crucial insights into the association between ANKRD11 variants and short stature and provides valuable guidance for precise clinical diagnosis and treatment of patients with KBG syndrome. [ABSTRACT FROM AUTHOR]

The assessment of growth during infancy and childhood is an essential component of paediatric medicine, as atypical growth may point to the existence of an underlying health condition. To reduce morbidity, it is vital that treatment for growth disorders is provided in a timely fashion. However, although there are guidelines regarding referral criteria for short stature in Europe and the USA, there are no such guidelines in Canada. To address this, a series of consultations and workshops with paediatricians, paediatric endocrinologists, family physicians and nurses were held, with the aim of developing a consensus-based set of recommendations for children in Canada showing atypical growth and to identify red flags for children who might benefit from early referral. To achieve this, a referral algorithm and referral form for primary care providers were developed to ensure timely and appropriate referrals, and transmission of the most relevant details to the secondary care consultant. [ABSTRACT FROM AUTHOR]

CTNND2 encodes δ‐catenin, a component of an adherens junction complex, and plays an important role in neuronal structure and function. To date, only heterozygous loss‐of‐function CTNND2 variants have been associated with mild neurodevelopmental delay and behavioral anomalies, a condition, which we named Rauch‐Azzarello syndrome. Here, we report three siblings of a consanguineous family of Syrian descent with a homozygous deletion encompassing the last 19 exons of CTNND2 predicted to disrupt the transcript. All presented with severe neurodevelopmental delay with absent speech, profound motor delay, stereotypic behavior, microcephaly, short stature, muscular hypotonia with lower limb hypertonia, and variable eye anomalies. The parents and the fourth sibling were heterozygous carriers of the deletion and exhibited mild neurodevelopmental impairment resembling that of the previously described heterozygous individuals. The present study unveils a severe manifestation of CTNND2‐associated Rauch‐Azzarello syndrome attributed to biallelic loss‐of‐function aberrations, clinically distinct from the already described mild presentation of heterozygous individuals. Furthermore, we demonstrate novel clinical features in homozygous individuals that have not been reported in heterozygous cases to date. [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]

The increasing density of woody plants threatens the integrity of grassy ecosystems. It remains unclear if such encroachment can be explained mostly by direct effects of resources on woody plant growth or by indirect effects of disturbances imposing tree recruitment limitation. Here, we investigate whether woody plant functional traits provide a mechanistic understanding of the complex relationships between these resource and disturbance effects. We first assess the role of rainfall, soil fertility, texture, and geomorphology to explain variation in woody plant encroachment (WPE) following livestock grazing and consequent fire suppression across the Serengeti ecosystem. Second, we explore trait‐environment relationships and how these mediate vegetation response to fire suppression. We find that WPE is strongest in areas with high soil fertility, high rainfall, and intermediate catena positions. These conditions also promote woody plant communities characterized by small stature and seed sizes smaller relative to a comparative baseline within the Serengeti ecosystem, alongside high recruit densities (linked to a recruitment‐stature trade‐off). The positioning of species along this "recruitment‐stature axis" predicted woody stem density increase in livestock sites. Structural equation modeling suggested a causal pathway where environmental factors shape the community trait composition, subsequently influencing woody recruit numbers. These numbers, in turn, predicted an area's vulnerability to WPE. Our study underscores the importance of trait‐environment relationships in predicting the impact of human alterations on local vegetation change. Understanding how environmental factors directly (resources) and indirectly (legacy effects and plant traits) determine WPE supports the development of process‐based ecosystem structure and function models. [ABSTRACT FROM AUTHOR]

Objective: We aimed to investigate the presence of monogenic causes of systemic lupus erythematosus (SLE) in our early-onset SLE patients. Methods: Fifteen pediatric SLE cases who had early disease onset (≤6 years) were enrolled in this study. All patients fulfilled the Systemic Lupus International Collaborating Clinics (SLICC) criteria. Genomic DNA was used for whole exome sequencing (WES). Pathogenic variants were confirmed by Sanger sequencing. Results: The median age at diagnosis of 15 early-onset SLE patients included in the study was 4 (2-6) years (F/M = 12/3). Significant gene mutations were detected in five of these patients (33.3%). Patients 1 and 2 with homozygous DNASE1L3 mutations [ c.320+4_320+7del and G188 A (c.563 G>C) variants] had skin involvement and oral ulcers. One of them (patient 1) had arthritis and nephritis, and another (patient 2) had nonscarring alopecia and thrombocytopenia. They are currently clinically inactive but have positive serological findings. Patient 3 with homozygous pathogenic ACP5 mutation [ G109 R (c.325 G>A) variant] had arthritis, nephritis, short stature, and skeletal dysplasia. Patient 4 with a heterozygote novel IFIH1 mutation [ L809 F (c.2425 C>T) variant] had skin findings and leukopenia. Patient 5 with novel C1S variant [homozygous C147 W (c.441 C>G) variant] had marked skin findings, oral ulcers, nonscarring alopecia, pancytopenia, and low total hemolytic complement CH50 level. All patients have responded to the treatments and have low Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores, on therapy. Conclusion: Genetic causes should be investigated in early-onset SLE, for better management and genetic counseling. On the other hand, multicenter studies may help to further define genotype-phenotype associations. [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]

Objective: To investigate the relationships of sleep patterns and respiratory disturbance index (RDI) with key physiological parameters (height, body mass index (BMI), bone age (BA), and IGF-1 levels) in children aged 6 to 16 years with self-perceived short stature. Methods: For this cross-sectional study, conducted from October 2019 to November 2021, 238 children aged 6 to 16 years with self-perceived short stature were enrolled. The primary outcomes of sleep patterns and the RDI were non-invasively collected at home using the LARGAN Health AI-Tech Sleep Apnea and Sleep Quality Examination System, which operates based on polygraphy. Additionally, various physiological parameters, including height, BMI, bone age, and IGF-1 levels, were measured to assess their associations with sleep patterns and RDI. Results: Significant age-related reductions were observed in both the total and deep sleep durations. Children aged 6–9 years averaged 8.5 ± 1.0 h of total sleep, which decreased to 8.1 ± 1.1 h in ages 10–11 and further to 7.5 ± 0.9 h in ages 12–16 (p < 0.0001). Deep sleep followed a similar pattern, decreasing from 4.4 ± 1.1 h in the youngest group to 3.3 ± 1.0 h in the oldest (p < 0.0001). Notably, girls experienced significantly longer deep sleep than boys, averaging 4.0 ± 1.2 h compared to 3.6 ± 1.2 h (p = 0.0153). In a multivariable regression analysis, age (beta = 4.89, p < 0.0001) and RDI (beta = −0.54, p = 0.0022) were significantly associated with body height. Age and deep sleep duration (beta = −0.02, p = 0.0371) were significantly associated with BMI. Conclusions: The results demonstrate significant age-related decreases in the total and deep sleep duration among children with self-perceived short stature, along with a notable association between RDI and body height and an association between deep sleep duration and BMI. These findings suggest that sleep disturbances in pediatric endocrine patients are intricately linked with physiological growth parameters. The identified correlations underline the importance of monitoring sleep patterns in this demographic to better understand the impact of endocrine disorders on developmental health. Further research is needed to explore interventions that could alleviate these sleep disturbances, thereby potentially improving outcomes for the affected children. [ABSTRACT FROM AUTHOR]

Key Clinical Message: A comprehensive diagnostic approach is crucial for patients with primary amenorrhea and short stature. Karyotyping and imaging studies help to detect hidden chromosomal abnormalities and anatomical differences, emphasizing their value in this context. A 16‐year‐old girl with absent menstruation and short stature. Further examination revealed constitutional stunting and primary amenorrhea. Karyotyping revealed a 46, XY chromosomal abnormality, whereas pelvic ultrasonography showed uterine hypoplasia and a unicornuate uterus with a rudimentary horn. After 11 months of therapy, she experienced menarche and improved secondary sexual characteristics. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Pituitary stalk interruption syndrome is a rare, congenital abnormality. Early identification and treatment can improve patient prognosis and quality of life and prevent adverse effect on growth and development. The patient described is an 8‐year‐old child with a history of short stature. [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]

Growth hormone therapy (GHT) can improve growth velocity and final height, but can also accelerate the process of bone growth, which is related to structural bone modeling in both formation and resorption. This study evaluated the capacity of bone turnover markers to predict early growth response to one year of GHT in short stature children born small for gestational age (SGA). This study included 25 prepubertal children born SGA. We estimated P1NP (N-terminal procollagen type 1), CTX (C-terminal telopeptide of collagen type 1), P3NP (N-terminal procollagen type 3), NT-pro-CNP (amino-terminal C-type natriuretic peptide) and Ca-P metabolism using standard ECLIA (electrochemiluminescence), RIA (radioimmunoassay), and ELISA (enzyme-linked immunosorbent assay) methods. A statistically significant increase in bone resorption markers (CTX) was found at both 6 and 12 months. P1NP bone markers were increased at 6 months and after 12 months of therapy. The P3NP marker for collagen synthesis also increased after 12 months of therapy. We obtained significant increases in phosphorus levels at 6 and 12 months, and similar ALP (alkaline phosphatase) increases. We found a significant correlation between height (cm) and CTX after 6–12 months, as well as a P1NP/height (SD) correlation after 12 months. Calcium levels significantly correlated with height (SD) after 12 months. We found strong reactions of bone resorption and bone formation markers during growth hormone therapy, which may determine their selection as predictors of GHT outcome in children born SGA. However, the issue requires further research. [ABSTRACT FROM AUTHOR]

Short stature affects approximately 2.5% of children. Some of them, when diagnosed with growth hormone deficiency (GHD), benefit from recombinant human growth hormone (rhGH) therapy; in others, this treatment is controversial. We aimed to present the clinical characteristics of Polish short stature children in the context of current GHD diagnostic standards, as obtaining more data gives a broader foundation for the potential modifications of diagnostic and therapeutic recommendations. This retrospective analysis was based on a cohort of 277 short stature children divided into two subgroups depending on their peak growth hormone (GH) cutoff level, set at 10 ng/mL: 138 had growth hormone deficiency (GHD) and 137 had normal growth hormone secretion (GHN). These subgroups were then compared based on the extracted clinical data. In the obtained result, no significant differences between the GHD and GHN subgroups were found in any of the variables, including the following: gender distribution, birth weight, bone age delay, height SDS, IGF-1 SDS, vitamin D levels, celiac disease indices, prevalence of hypothyroidism or anemia. As our results point to major clinical similarities between the GHD and GHN children, it seems that distinguishing patients with normal GH secretion from those with deficient GH secretion based on a 10 ng/mL cutoff value might not be clinically relevant. [ABSTRACT FROM AUTHOR]

BackgroundMethods and ResultsConclusionsGeleophysic 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.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.Mounting evidence suggests that GD and WMS may be allelic diseases of the ADAMTSL2 gene. [ABSTRACT FROM AUTHOR]

Background: The history of rare diseases is largely unknown. Research on this topic has focused on individual cases of prominent (historical) individuals and artistic (e.g., iconographic) representations. Medical collections include large numbers of specimens that exhibit signs of rare diseases, but most of them date to relatively recent periods. However, cases of rare diseases detected in mummies and skeletal remains derived from archaeological excavations have also been recorded. Nevertheless, this direct evidence from historical and archaeological contexts is mainly absent from academic discourse and generally not consulted in medical research on rare diseases. Results: This desideratum is addressed by the Digital Atlas of Ancient Rare Diseases (DAARD: https://daard.dainst.org), which is an open access/open data database and web-based mapping tool that collects evidence of different rare diseases found in skeletons and mummies globally and throughout all historic and prehistoric time periods. This easily searchable database allows queries by diagnosis, the preservation level of human remains, research methodology, place of curation and publications. In this manuscript, the design and functionality of the DAARD are illustrated using examples of achondroplasia and other types of stunted growth. Conclusions: As an open, collaborative repository for collecting, mapping and querying well-structured medical data on individuals from ancient times, the DAARD opens new avenues of research. Over time, the number of rare diseases will increase through the addition of new cases from varied backgrounds such as museum collections and archaeological excavations. Depending on the research question, phenotypic or genetic information can be retrieved, as well as information on the general occurrence of a rare disease in selected space–time intervals. Furthermore, for individuals diagnosed with a rare disease, this approach can help them to build identity and reveal an aspect of their condition they might not have been aware of. Thus, the DAARD contributes to the understanding of rare diseases from a long-term perspective and adds to the latest medical research. [ABSTRACT FROM AUTHOR]

Background: Idiopathic short stature (ISS) is characterized by short stature with unknown causes. Recent studies showed different gut microbiota flora and reduced fecal short-chain fatty acids in ISS children. However, the roles of the microbiome and metabolites in the pathogenesis of ISS remains largely unknown. Methods: We recruited 51 Chinese subjects, comprising 26 ISS children and 25 normal-height control individuals. Untargeted metabolomics was performed to explore the fecal metabolic profiles between groups. A shotgun metagenomic sequencing approach was used to investigate the microbiome at the strains level. Mediation analyses were done to reveal correlations between the height standard deviation (SD) value, the gut microbiome and metabolites. Results: We detected marked differences in the composition of fecal metabolites in the ISS group, particularly a significant increase in erucic acid and a decrease in spermidine, adenosine and L-5-Hydroxytryptophan, when compared to those of controls. We further identified specific groups of bacterial strains to be associated with the different metabolic profile. Through mediation analysis, 50 linkages were established. KEGG pathway analysis of microbiota and metabolites indicated nutritional disturbances. 13 selected features were able to accurately distinguish the ISS children from the controls (AUC = 0.933 [95%CI, 79.9–100%]) by receiver operating characteristic (ROC) analysis. Conclusion: Our study suggests that the microbiome and the microbial-derived metabolites play certain roles in children's growth. These findings provide a new research direction for better understanding the mechanism(s) underlying ISS. [ABSTRACT FROM AUTHOR]

Background: TCF4 acts as a transcription factor that binds to the immunoglobulin enhancer Mu-E5/KE5 motif. Dominant variants in TCF4 are associated with the manifestation of Pitt-Hopkins syndrome, a rare disease characterized by severe mental retardation, certain features of facial dysmorphism and, in many cases, with abnormalities in respiratory rhythm (episodes of paroxysmal tachypnea and hyperventilation, followed by apnea and cyanosis). Frequently, patients also develop epilepsy, microcephaly, and postnatal short stature. Although TCF4 is expressed in skeletal muscle and TCF4 seems to play a role in myogenesis as demonstrated in mice, potential myopathological findings taking place upon the presence of dominant TCF4 variants are thus far not described in human skeletal muscle. Method: To address the pathological effect of a novel deletion affecting exons 15 and 16 of TCF4 on skeletal muscle, histological and immunofluorescence studies were carried out on a quadriceps biopsy in addition to targeted transcript studies and global proteomic profiling. Results: We report on muscle biopsy findings from a Pitt-Hopkins patient with a novel heterozygous deletion spanning exon 15 and 16 presenting with neuromuscular symptoms. Microscopic characterization of the muscle biopsy revealed moderate fiber type I predominance, imbalance in the proportion of fibroblasts co-expressing Vimentin and CD90, and indicate activation of the complement cascade in TCF4-mutant muscle. Protein dysregulations were unraveled by proteomic profiling. Transcript studies confirmed a mitochondrial vulnerability in muscle and confirmed reduced TCF4 expression. Conclusion: Our combined findings, for the first time, unveil myopathological changes as phenotypical association of Pitt-Hopkins syndrome and thus expand the current clinical knowledge of the disease as well as support data obtained on skeletal muscle of a mouse model. [ABSTRACT FROM AUTHOR]

Background/Objectives: Develop a clinical and genetic characterization, in a group of small-for-gestational-age (SGA) patients who did not experience catch-up growth Methods: In an ambispective cohort study with (SGA) patients. These patients received one treatment with growth hormone (GH) over 14 years. This study analyzes their response to treatment and conducts a genetic analysis in order to identify cases with specific phenotypic and auxological characteristics, defined as presenting two or more dysmorphic traits and/or a stature below −3 SDS (standard deviation score). Whole-exome sequencing (WES) was performed on selected patients. Results: Forty-four SGA patients were examined, with an average age of 6.4 (2.49) years and an initial size of −3.3 SDS. The pubertal growth was 24.1 (5.2) cm in boys and 14.7 (4.3) cm in girls. WES in 11 SGA patients revealed conclusive genetic variants in eight, including two pathogenic ACAN variants, one 15q26.2-q26.3 deletion, and four variants of uncertain significance in other genes. Conclusions: Treatment with GH in SGA patients was shown to be effective, with a similar response in the group with positive genetic results and in the group who did not undergo a genetic study. Genetic testing based on auxological and clinical criteria proved highly cost-effective. [ABSTRACT FROM AUTHOR]

Hypophosphatasia (HPP) is a rare, inherited, and systemic disorder characterized by impaired skeletal mineralization and low tissue nonspecific serum alkaline phosphatase (TNSALP) activity. It is caused by either autosomal recessive or dominant‐negative mutations in the gene that encodes TNSALP. The phenotype of HPP is very broad including abnormal bone mineralization, disturbances of calcium and phosphate metabolism, pain, recurrent fracture, short stature, respiratory impairment, developmental delay, tooth loss, seizures, and premature death. Other than supportive care, there has been no disease‐specific treatment available for those with HPP. Asfotase alfa is a fully humanized, recombinant enzyme replacement therapy for the management of HPP. It is available in several countries for the treatment of the more severe forms of HPP, namely perinatal and infantile HPP. This review will summarize the preclinical data on asfotase alfa and highlight the data from clinical trials and case reports. These data show the transformative nature of asfotase alfa when administered as part of an interdisciplinary treatment model. [ABSTRACT FROM AUTHOR]

Worldwide, the implementation of forest management guidelines has tried to mimic natural forest dynamics. The Oliver forest stand dynamics model has been successful in bridging natural forest dynamics associated with the disturbances of various spatial scales and silviculture also related to various spatial scales of management. However, the application of this model (and others) is restricted to tall forests.We claim here that the general research and commercial interest bias towards tall tree species has permeated silviculture and forest management, and that both the stand dynamics of short‐stature tree species and their treatment have remained largely unexplored and unknown.Using one short‐stature tree species, Nothofagus antarctica, as a model system, we show that this species indeed follows a stand dynamic different from other tall Nothofagus‐dominated forests in southern South America. This species forms short, mature, even‐aged stands without large canopy gaps that promote tree regeneration. With this in mind, we propose a conceptual ecology‐based silvicultural guideline focusing on the creation of strip cuts or gaps along with topsoil scarification to ensure regeneration and forest reorganization after disturbances.Policy implications. The acknowledgement that short‐stature tree species follow a stand dynamic different from tall tree species necessarily implies that they must be managed differently. This recognition, along with the implementation of ecology‐based silvicultural recommendations, represents strong arguments to make modifications to forest legislation that, together, must be aimed at conservation and sustainable forest management. [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 Heterozygous Indian Hedgehog gene (IHH) variants are associated with brachydactyly type A1 (BDA1). However, in recent years, numerous variants have been identified in patients with short stature and more variable forms of brachydactyly. Many are located in the C-terminal domain of IHH (IHH-C), which lacks signaling activity but is critical for auto-cleavage and activation of the N-terminal (IHH-N) peptide. The absence of functional studies of IHH variants, particularly for those located in IHH-C, has led to these variants being classified as variants of uncertain significance (VUS). Objective To establish a simple functional assay to determine the pathogenicity of IHH VUS and confirm that variants in the C-terminal domain affect protein function. Design/Methods In vitro studies were performed for 9 IHH heterozygous variants, to test their effect on secretion and IHH intracellular processing by western blot of cells expressing each variant. Results IHH secretion was significantly reduced in all mutants, regardless of the location. Similarly, intracellular levels of N-terminal and C-terminal IHH peptides were severely reduced in comparison with the control. Two variants present at a relatively high frequency in the general population also reduced secretion but to a lesser degree in the heterozygous state. Conclusions These studies provide the first evidence that variants in the C-terminal domain affect the secretion capacity of IHH and thus, reduce availability of IHH ligand, resulting in short stature and mild skeletal defects. The secretion assay permits a relatively easy test to determine the pathogenicity of IHH variants. All studied variants affected secretion and interestingly, more frequent population variants appear to have a deleterious effect and thus contribute to height variation. [ABSTRACT FROM AUTHOR]

Background: The rates of labor induction and cesarean delivery is rising worldwide. With the confluence of these trends, the labor induction rate in trials of labor after cesarean can be as high as 27-32.7%. Induction of labor after one previous cesarean (IOLAC) is a high-risk procedure mainly due to the higher risk of uterine rupture. Nevertheless, the American College of Obstetricians and Gynecologists considers IOLAC as an option in motivated and informed women in the appropriate care setting. We sought to identify predictors of a composite of maternal and newborn adverse outcomes following IOLAC. Methods: The electronic medical records of women who delivered between January 2018 to September 2022 in a Malaysian university hospital were screened to identify cases of IOLAC. A case is classified as a composite adverse outcome if at least one of these 11 adverse outcomes of delivery blood loss ≥ 1000 ml, uterine scar complications, cord prolapse or presentation, placenta abruption, maternal fever (≥ 38 0C), chorioamnionitis, intensive care unit (ICU) admission, Apgar score < 7 at 5 min, umbilical artery cord artery blood pH < 7.1 or base excess ≤-12 mmol/l, and neonatal ICU admission was present. An unplanned cesarean delivery was not considered an adverse outcome as the practical management alternative for a clinically indicated IOLAC was a planned cesarean. Bivariate analysis of participants' characteristics was performed to identify predictors of their association with composite adverse outcome. Characteristics with crude p < 0.10 on bivariate analysis were incorporated into a multivariable binary logistic regression analysis model. Results: Electronic medical records of 19,064 women were screened. 819 IOLAC cases and 98 cases with composite adverse outcomes were identified. Maternal height, ethnicity, previous vaginal delivery, indication of previous cesarean, indication for IOLAC, and method of IOLAC had p < 0.10 on bivariate analysis and were incorporated into a multivariable binary logistic regression analysis. After adjustment, only maternal height and IOLAC by vaginal dinoprostone compared to Foley balloon remained significant at p < 0.05. Post hoc adjusted analysis that included all unplanned cesarean as an added qualifier for composite adverse outcome showed higher body mass index, short stature (< 157 cm), not of Chinese ethnicity, no prior vaginal delivery, prior cesarean indicated by labor dystocia, and less favorable Bishop score (< 6) were independent predictors of the expanded composite adverse outcome. Conclusion: Shorter women and IOLAC by vaginal dinoprostone compared to Foley balloon were independently predictive of composite of adverse outcome. Synopsis: Shorter stature and dinoprostone labor induction are independent predictors of a composite maternal-newborn adverse outcome excluding unplanned cesarean delivery. [ABSTRACT FROM AUTHOR]

Introduction: 2p15p16.1 microdeletion syndrome was described for the first time in 2007. The size of the microdeletion is variable and encompasses several genes, like XPO1, USP34, BCL11A, REL, PAPOLG, PEX13, COMMD1, B3GNT2, and EHBP1. Features of the syndrome include short stature, microcephaly, hypotonia, psychomotor developmental delay, anomalies of the fingers of the upper and lower limbs, dysmorphic features like receding forehead, broad nasal bridge, telecanthus, ptosis, flat philtrum, small mouth with a high, narrow palate and everted lower lip. The precise genotype–phenotype correlation in 2p15 deletion syndrome is not understood. The aim of the study is to present the patient's medical history and the diagnostic process. Case Presentation: A boy aged 9 was admitted to the Genetic Outpatient Clinic due to dysmorphic features and mild mental retardation. Full lips, broad nasal root, very light hair, excessively developed subcutaneous tissue, joint laxity, postural defect, flat-valgus foot with sandal gap, brachydactyly, and problems with concentration, memory, and counting were found. Diagnosis was based on microarray testing, and copy-number variation analysis was performed using CytoScan 750K array. Genetic imbalance in the form of a deletion within the short arm of chromosome 2 in the 2p15 region (containing 50 kbp) was shown. The microdeletion covers 2 genes: USP34 and XPO1. Parents were not carriers of that mutation. Conclusion: The phenotypic features presented by the patient were reflected in the genetic test. 2p15 microdeletion syndrome is genetically heterogeneous with possible de novo occurrence, as in the presented case. The precise genotype–phenotype correlation in 2p15 deletion syndrome should be widely studied because in the literature there is mainly mentioned 2p15p16.1 syndrome. Even though 2p15 microdeletion syndrome is a rare discovery and its features are mainly mild, it is necessary to pay special attention to them to refer patients to genetic counseling to make an accurate diagnosis. [ABSTRACT FROM AUTHOR]

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Context The assessment and treatment of children with growth retardation is increasingly complex, and due to availability of targeted genetic sequencing, an ever-expanding number of conditions impeding growth are being identified. Among endocrine-related etiologies of short stature amenable to hormonal treatment, defects in the growth hormone (GH)–insulin-like growth factor I axis remain pre-eminent, with a multiplicity of disorders causing decreased secretion or insensitivity to GH action. Sex steroids in puberty increase epiphyseal senescence and eventual growth plate closure. This is mediated mostly via estrogen receptor (ER)α in males and females, effects that can greatly limit time available for growth. Evidence Acquisition Extensive literature review through PubMed and other search engines. Evidence Synthesis Therapeutic strategies to be considered in peripubertal and pubertal children with disordered growth are here discussed, including daily and weekly GH, low-dose sex steroids, gonadotropin hormone releasing hormone (GnRH) analogues in combination with GH, aromatase inhibitors (AIs) alone and in combination with GH in boys. When used for at least 2 to 3 years, GnRH analogues combined with GH can result in meaningful increases in height. AIs used with GH permit puberty to progress in boys without hindrance, selectively decreasing estrogen, and resulting in taller height. With more than 20 years of cumulative experience in clinical use of these medications, we discuss the safety profile of these treatments. Conclusion The approach of growth retardation in the peripubertal and pubertal years must consider the sex steroid milieu and the tempo of bone acceleration. Treatment of affected children in this period must be individualized. [ABSTRACT FROM AUTHOR]