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We present a case of a 25-year-old man who came to our Endocrine Clinic for evaluation of short stature. He had a history of sensorineural hearing loss, hypertrichosis and hyperpigmentation with the thickening of the skin below the hip, gynecomastia and autoimmune haemolytic anaemia. Investigations showed that he had hypergonadotropic hypogonadism. His phenotype was consistent with that of a rare autosomal recessive genodermatosis of ‘H-syndrome’. The diagnosis was confirmed by genetic analysis using next-generation sequencing which showed a homozygous mutation in the SLC29A3 gene (variant: c.1330G>T (p.Glu444Ter)) which was confirmed by Sanger sequencing. This is a rare syndrome with around 100 cases reported in world literature. Though the skin manifestations are pathognomonic of the H-syndrome, it has myriad presentations like short stature, insulin-dependent diabetes mellitus, hypogonadism, hypothyroidism, dyslipidaemia, cardiac anomalies and sensorineural hearing loss. We report this case to highlight the constellation of features of this rare syndrome and bring awareness among the physicians to be vigilant about this syndrome.

Single median maxillary central incisor (SMMCI) syndrome is rare. It is commonly associated with other midline defects. About 50% of children with SMMCI have short stature, associated with isolated growth hormone deficiency or panhypopituitarism.A 6-year-old girl presented to us with worsening convergent squint, slowing linear growth and a suspected pituitary macroadenoma on neuroimaging. The key findings on examination included a disproportionate short stature, SMMCI, congenital abduction defect and pseudohypertrophy of calf muscles with myopathy. The evaluation showed autoimmune thyroiditis with pituitary hyperplasia. Bone age corresponded to 3 years.Three months after initiation of thyroxine, her myopathy resolved, and the hormone profile and neuroimaging were normal. Autoimmune thyroiditis in association with SMMCI is not reported previously. This case study emphasises the importance of growth monitoring and the exclusion of common treatable conditions.

A substantial proportion of SGA patients present with a syndrome underlying their growth restriction. Most SGA cohorts comprise both syndromic and non-syndromic patients impeding delineation of the recombinant human growth hormone (rhGH) response. We present a detailed characterization of a SGA cohort and analyze rhGH response based on adult height (AH). Clinical and auxological data of SGA patients treated with rhGH, who had reached AH, were retrieved from BELGROW, a national database of all rhGH treated patients held by BESPEED (BElgian Society for PEdiatric Endocrinology and Diabetology). SGA patients were categorized in syndromic or non-syndromic patients. 272 patients were included, 42 classified as syndromic (most frequent diagnosis (n=6): fetal alcohol syndrome and Silver-Russell syndrome). Compared with non-syndromic patients, syndromic were younger [years (median (P10/P90)] 7.43 (4.3/12.37) vs 10.21 (5.43/14.03), p=0.0005), shorter (height SDS -3.39 (-5.6/-2.62) vs -3.07 (-3.74/-2.62), p=0.0253) and thinner (BMI -1.70 (-3.67/0.04) vs -1.14 (-2.47/0.27) SDS, p=0.0054) at start of rhGH treatment. First year rhGH response was comparable (delta height SDS +0.54 (0.24/0.94) vs +0.56 (0.26/0.92), p=0.94). Growth pattern differed with syndromic patients having a higher prepubertal (SDS +1.26 vs +0.83, p=0.0048), but a lower pubertal height gain compared to the non-syndromic group (SDS -0.28 vs 0.44, p=0.0001). Mean rhGH dose was higher in syndromic SGA patients (mg/kg body weight/day 0.047 (0.039/0.064) vs 0.043 (0.035/0.056), p=0.0042). AH SDS was lower in syndromic SGA patients (-2.59 (-4.99/-1.57) vs -2.32 (-3.3/-1.2), p=0.0107). The majority in both groups remained short (

STAT5B deficiency, a rare autosomal recessive disorder characterized by severe growth hormone insensitivity (GHI) and immunodeficiency, can manifest as fatal pulmonary complications. We describe atypical STAT5B deficiency associated with a novel homozygous frame-shift STAT5B variant [c.1453delG, p.(Asp485Thrfs*29)] identified in a young 17.6 yr old female subject who had severe postnatal growth impairment, biochemistries typical of GHI, an immune profile notable for hypergammaglobulinaemia and elevated B lymphocytes, and lack of pulmonary disease. Marked elevation of serum prolactin and pathologically diagnosed eczema were evident. In reconstitution studies, the STAT5B p.(Asp485Thrfs*29) was expressed although expression was reduced compared to wild-type STAT5B and a previously identified STAT5B p.(Gln368Profs*9) variant. Both truncated STAT5B peptides could not be activated by GH, nor mobilize to the nucleus. We conclude that an intact, functional, STAT5B is essential for normal GH-mediated growth, while expressed loss-of-function STAT5B variants may alleviate severe immune and pulmonary issues normally associated with STAT5B deficiency. © 2022 Elsevier B.V., National Institute of Child Health and Human Development, NICHD: R21 HD098417, This work was supported by the National Institute of Child health and Human Development, R21 HD098417 (to VH).

Objective To systematically describe the short stature of patients with Diamond-Blackfan anemia and to explore factors affecting the height development of patients with Diamond-Blackfan anemia. Study design This cross-sectional study was conducted at the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, and the height, weight, and clinical data of 129 patients with Diamond-Blackfan anemia were collected from June 2020 to September 2020. Results The median height-age-z score (HAZ) of children affected by Diamond-Blackfan anemia was −1.54 (−6.36-1.96). Short stature was found in 37.98% of the patients. Specific Diamond-Blackfan anemia growth curves were developed for weight, height, and body mass index, separately for male and female patients. Multivariable logistic regression models showed that female sex (aOR 4.92; 95% CI 1.29-18.71; P = .0195), underweight (aOR 10.41, 95% CI 1.41-76.98, P = .0217), cardiovascular malformations (aOR 216.65; 95% CI 3.29-14279.79; P = .0118), and RPL11(aOR 29.14; 95% CI 1.18-719.10; P = .0392) or RPS26 (aOR 53.49; 95% CI 1.40-2044.30; P = .0323) mutations were independent risk factors for short stature. In the subgroup of patients who were steroid-dependent, patients with a duration of steroid therapy over 2 years (OR 2.95; 95% CI 1.00-8.66; P = .0494) or maintenance dose of prednisone >0.1 mg/kg per day (OR 3.30; 95% CI 1.02-10.72; P = .0470) had a higher incidence of short stature. Conclusions Patients with Diamond-Blackfan anemia had a high prevalence of short stature. The risk of short stature increased with age and was associated with sex, underweight, congenital malformations, and RPL11 or RPS26 mutations. The duration of steroid therapy and maintenance dose of steroid was significantly associated with the incidence of short stature in steroid-dependent patients with Diamond-Blackfan anemia.

PURPOSE OF REVIEW Pediatric short stature poses severe concerns to the patient, parents, and physicians. Management for pediatric short stature is still widely debated due to heterogenous etiological factors and treatment options. This review will address the approach to pediatric short stature, commonly within the subset of skeletal dysplasia resulting in disproportionate short stature. The following will be discussed: the etiology, clinical, and radiological evaluations, and management for pediatric short stature. RECENT FINDINGS Early recognition of short stature and appropriate referrals is shown to benefit the patient and reduce parental concern. A multidisciplinary team, comprising an orthopedic surgeon, is fundamental to provide holistic care and ensure overall good quality of life. Advancements in clinical diagnostic tools and diversified treatment modalities today provides optimism in managing pediatric short stature. SUMMARY Skeletal dysplasia can be treated with good prognosis if diagnosed and managed early. Thorough clinical, radiological, laboratory, and even genetic investigations are important to differentiate and manage various types of skeletal dysplasia. Our review will provide a comprehensive and up-to-date approach to skeletal dysplasia for pediatric orthopedic surgeons, and indications for physicians to refer patients with suspected short stature to pediatric orthopedic surgeons.

Deletions that include the gene TAB2 and TAB2 loss-of-function variants have previously been associated with congenital heart defects and cardiomyopathy. However, other features, including short stature, facial dysmorphisms, connective tissue abnormalities and a variable degree of developmental delay, have only been mentioned occasionally in literature and thus far not linked to TAB2. In a large-scale, social media-based chromosome 6 study, we observed a shared phenotype in patients with a 6q25.1 deletion that includes TAB2. To confirm if this phenotype is caused by haploinsufficiency of TAB2 and to delineate a TAB2-related phenotype, we subsequently sequenced TAB2 in patients with matching phenotypes and recruited patients with pathogenic TAB2 variants detected by exome sequencing. This identified 11 patients with a deletion containing TAB2 (size 1.68-14.31 Mb) and 14 patients from six families with novel truncating TAB2 variants. Twenty (80%) patients had cardiac disease, often mitral valve defects and/or cardiomyopathy, 18 (72%) had short stature and 18 (72%) had hypermobility. Twenty patients (80%) had facial features suggestive for Noonan syndrome. No substantial phenotypic differences were noted between patients with deletions and those with intragenic variants. We then compared our patients to 45 patients from the literature. All literature patients had cardiac diseases, but syndromic features were reported infrequently. Our study shows that the phenotype in 6q25.1 deletions is caused by haploinsufficiency of TAB2 and that TAB2 is associated not just with cardiac disease, but also with a distinct phenotype, with features overlapping with Noonan syndrome. We propose the name "TAB2-related syndrome".

Isolated growth hormone (GH) deficiency type I A is a rare autosomal recessive disorder caused by deletion of the GH1 gene and characterized by early onset severe short stature and typical phenotype. Lack of exposure to GH during fetal life often leads to formation of anti-GH antibody following exposure to the least immunogenic recombinant human GH (rhGH). Some patients with circulating ant-GH antibodies demonstrate lack of growth response to GH while others do not. However, the clinical significance of this antibody is unclear hence not routinely recommended. Three siblings born of a consanguineous union were referred to us with severe short stature. They were evaluated and IGHD was diagnosed in all of them. Genetic analysis revealed homozygous 6.7 Kb deletions of GH1 gene in all of them while their parents displayed a pattern of heterozygous 6.7 Kb deletions. rhGH was started at 10, 6 and 17/12 years of age. Their growth and hormonal parameters were monitored throughout the course of treatment. The eldest sibling demonstrated usual growth velocity (9.5 cm/year) after start of therapy that rapidly waned after 1st year (2.5 cm/year). The youngest sibling experienced excellent growth response even after 3rd year (10.3 cm/year) while the middle one displayed sub-optimal response from beginning (6.3cm/year). Change of rhGH brand did not work in the two elder sisters. Such a different growth response with rhGH in three siblings harbouring similar genetic abnormality has not been described earlier. Keywords: Isolated growth hormone deficiency type IA, GH1 gene, Anti-GH antibody.

Background Patients with 21-hydroxylase deficiency congenital adrenal hyperplasia (21OHD-CAH) have poor health outcomes with increased mortality, short stature, impaired fertility, and increased cardiovascular risk factors such as obesity. To address this, there are therapies in development that target the clinical goal of treatment, which is to control excess androgens with an adrenal replacement dose of glucocorticoid. Methods Narrative review of publications on recent clinical developments in the pharmacotherapy of congenital adrenal hyperplasia. Summary Therapies in clinical development target different levels of the hypothalamo–pituitary–adrenal axis. Two corticotrophin-releasing factor type 1 (CRF1) receptor antagonists, Crinecerfont and Tildacerfont, have been trialled in poorly controlled 21OHD-CAH patients, and both reduced ACTH and androgen biomarkers while patients were on stable glucocorticoid replacement. Improvements in glucocorticoid replacement include replacing the circadian rhythm of cortisol that has been trialled with continuous s.c. infusion of hydrocortisone and Chronocort, a delayed-release hydrocortisone formulation. Chronocort optimally controlled 21OHD-CAH in 80% of patients on an adrenal replacement dose of hydrocortisone, which was associated with patient-reported benefits including restoration of menses and pregnancies. Adrenal-targeted therapies include the steroidogenesis-blocking drug Abiraterone acetate, which reduced adrenal androgen biomarkers in poorly controlled patients. Conclusions CRF1 receptor antagonists hold promise to avoid excess glucocorticoid replacement in patients not controlled on standard or circadian glucocorticoid replacement such as Chronocort. Gene and cell therapies are the only therapeutic approaches that could potentially correct both cortisol deficiency and androgen excess.

Objective Next generation sequencing (NGS) has expanded the diagnostic paradigm turning the focus to the growth plate. The aim of the study was to determine the prevalence of variants in genes implicated in skeletal dysplasias in probands with short stature and mild skeletal anomalies. Design Clinical and radiological data were collected from 108 probands with short stature and mild skeletal anomalies. Methods A customized skeletal dysplasia NGS panel was performed. Variants were classified using ACMG recommendations and Sherloc. Anthropometric measurements and skeletal anomalies were subsequently compared in those with or without an identified genetic defect. Results Heterozygous variants were identified in 21/108 probands (19.4%). Variants were most frequently identified in ACAN (n = 10) and IHH (n = 7) whilst one variant was detected in COL2A1, CREBBP, EXT1, and PTPN11. Statistically significant differences (P < 0.05) were observed for sitting height/height (SH/H) ratio, SH/H ratio standard deviation score (SDS), and the SH/H ratio SDS >1 in those with an identified variant compared to those without. Conclusions A molecular defect was elucidated in a fifth of patients. Thus, the prevalence of mild forms of skeletal dysplasias is relatively high in individuals with short stature and mild skeletal anomalies, with variants in ACAN and IHH accounting for 81% of the cases. An elevated SH/H ratio appears to be associated with a greater probability in detecting a variant, but no other clinical or radiological feature has been found determinant to finding a genetic cause. Currently, we cannot perform extensive molecular studies in all short stature individuals so detailed clinical and radiological phenotyping may orientate which are the candidate patients to obtain worthwhile results. In addition, detailed phenotyping of probands and family members will often aid variant classification.

Objective The diagnosis of growth hormone deficiency (GHD) in children is not always straightforward because insulin-like growth factor 1 (IGF-I) or GH stimulation tests may not be able to discriminate GHD from constitutional delay of growth and puberty (CDGP) or other causes of short stature. Design Boys and girls (n = 429, 0.7–16 years) who attended our department for short stature participated in this study. They were followed up for an average period of 9 years. At the end of follow-up after reaching the final height, a definitive diagnosis was assigned, and all the components of ternary complex (IGF-I, IGF-binding protein-3 (IGFBP-3), acid-labile subunit (ALS), and IGF-I/IGFBP-3 ratio) were evaluated as biomarkers for the respective diagnosis. Results All the components of the ternary complex were tightly correlated with each other and were positively related to age. IGF-I, IGFBP-3, ALS, and IGF-I/IGFBP-3 ratio differed significantly between GHD and normal groups. IGF-I and ALS levels were lower in GHD compared to children with familial short stature, while IGF-I and IGF-I/IGFBP-3 ratio was significantly lower in GHD compared to children with CDGP. IGF-I and IGF-I/IGFBP-3 receiver operating curve cutoff points were unable to discriminate between GHD and normal groups or between GHD and CDGP groups. Conclusion Despite the tight correlation among all the components of the ternary complex, each one shows a statistically significant diagnosis-dependent alteration. There is a superiority of IGF-I, ALS, and IGF-I/IGFBP-3 ratio in the distinction between GHD and CDGP or between GHD and normal groups but without usable discriminating power, making auxology as the primary criterion for establishing the diagnosis.

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia type 1 (MED1) are two rare skeletal disorders caused by cartilage oligomeric matrix protein (COMP) variants. This study aims to analyze the genotype and phenotype of patients with COMP variants. Clinical information for 14 probands was collected; DNA was extracted from blood for COMP variant detection. Clinical manifestations and radiology scoring systems were established to evaluate the severity of each patient's condition. Serum COMP levels in PSACH patients and healthy subjects were measured. Thirty-nine patients were included, along with 12 PSACH probands and two MED1 probands. Disproportionate short stature, waddling gait, early-onset osteoarthritis and skeletal deformities were the most common features. The height Z-score of PSACH patients correlated negatively with age at evaluation (r = - 0.603, p = 0.01) and the clinical manifestation score (r = - 0.556, p = 0.039). Over 50% of the PSACH patients were overweight/obese. The median serum COMP level in PSACH patients was 16.75 ng/ml, which was significantly lower than that in healthy controls (98.53 ng/ml; p 0.001). The condition of MED1 patients was better than that of PSACH patients. Four novel variants of COMP were detected: c.874TC, c.1123_1134del, c.1531GA, and c.1576GT. Height Z-scores and serum COMP levels were significantly lower in patients carrying mutations located in calmodulin-like domains 6, 7, and 8. As the two phenotypes overlap to different degrees, PSACH and MED1 are suggested to combine to produce "spondyloepiphyseal dysplasia, COMP type". Clinical manifestations and radiology scoring systems, serum COMP levels and genotype are important for evaluating patient condition severity.

Neurosecretory dysfunction (NSD) causes growth hormone deficiency (GHD). Data on adult height after recombinant human growth hormone (rhGH) treatment are lacking.We collected treatment data of all patients with NSD seen between 1990 and 2017 at our outpatient department (tertiary centre) and measured adult height. For comparison, patients with idiopathic GHD were used. Diagnoses were based on short stature (-2 standard deviation score [SDS]), continuously low height velocity (25th percentile), delayed bone age (by1 SD) and low serum IGF-1 concentration (-2 SDS). NSD was defined by normal GH challenge results, but subnormal spontaneous GH secretion. Exclusion criteria were no information on adult height, underweight and other short stature disorders.Out of 67 patients diagnosed with NSD, six were still growing, 31 had test results exceeding validated GH cut-offs and three had other disorders causing short stature. Out of the 25 eligible patients with NSD, 21 could be recruited. These patients reached an adult height of -0.85 SDS (mean); 0.34 SDS below midparental height. Height gain during treatment was 2.01 SDS. This outcome was not different to 32 patients with idiopathic GHD.Long-term results suggest the viability of the diagnosis of NSD and the efficacy of rhGH treatment.

The spectrum of Turner syndrome (TS) includes Turner syndrome mosaicism (TSM), which is typically a nonhereditary chromosomal abnormality. Turner syndrome mosaicism presents uncommonly to primary care providers (PCPs), who often fail to recognize the subtle signs. The average age at diagnosis for common TS and TSM karyotype is 5.4 years, averaging 7.3 years. Often genetic confirmation, management, and recommended surveillance are delayed. Oftentimes, the PCP suspects a genetic etiology of an unusual phenotype, such as pinna placement or other unusual ear configurations, webbed neck with low posterior hairline, wide-spaced nipples, or short stature among other presentations. The PCP or geneticist orders diagnostic studies to confirm the diagnosis, such as a karyotype. After diagnosis, the PCP refers to the geneticist who initiates surveillance and makes recommendations for management. There are potential neurocognitive, cardiovascular, renal, reproductive, and endocrine issues. Treatment literature is vague and parental concerns are linked to quality mental health and quality of life for the family member with TS or TSM. The purpose of this article was to use a case study to introduce the topic of TS and TSM and to assist the PCP in the identification and management of patient and family concerns.

INTRODUCTION Achondroplasia is the most common genetic cause of disproportionate short stature, affecting over 360,000 individuals. Serious complications contributing to significant morbidity in affected individuals include cranio-cervical junction compression and obstructive sleep apnoea. Current clinically available treatments are predominantly symptomatic, and associated with variable outcomes. We summarise the new precision investigational products that are currently in Phase 2 and Phase 3 clinical trials for the treatment of individuals with achondroplasia. AREAS COVERED Fibroblast growth factor receptor 3 (FGFR3), a membrane-spanning tyrosine kinase receptor, binds various fibroblast growth factors (FGF) to regulate the normal process of endochondral bone growth. Gain of FGFR3 function in individuals with achondroplasia results in inhibition of normal endochondral ossification. A greater understanding of these molecular pathways through animal models has led to the development of several targeted therapies being tested in children, which we discuss in this review. EXPERT OPINION The last decade has been game-changing in terms of new precision therapies for children with achondroplasia that have the potential to fundamentally change the natural history of this condition. The next decade will see how these therapies compare, if they might be used in combination, and evaluate the balance of their long-term benefits and harms.

Objectives Constitutional delay of growth (CDG) is usually associated with a delay in pubertal onset (CDGP) and a catch-up growth after puberty. Some individuals, however, have earlier-than-expected pubertal onset resulting in a shorter adult height. We investigated the current incidence of such individuals and that of 30 years ago. Methods The study subjects are 1,312 consecutive Japanese children referred to Osaka City General Hospital (OCGH) for short stature during 2010–2018, and a cohort of 11,256 individuals in the Ogi Growth Research (OGR, 1979–1992). Individuals with the height standard deviation score Results From the OCGH cohort, 55 children (38 boys, 17 girls) met the criteria, and earlier-than-expected onset was observed in 34.2% of boys and 29.4% of girls. In the 73 short individuals with delayed bone age in the OGR cohort, earlier-than-expected onset was less common (13.0% for boys and 14.8% for girls). There was no significant association between the timing of pubertal growth onset and the BA/CA ratio, IGF-1, and midparental height. Conclusions Earlier-than-expected pubertal growth onset is common in CDG and possibly increasing.

To evaluate the effect of nutritional supplementation on height, weight and body composition in short and lean male preadolescents.A randomised, double-blinded, placebo-controlled trial of nutritional supplementation of short and lean prepubertal 10-14.5-year-old boys. Primary outcomes included Δheight-SDS and Δweight-SDS. Secondary outcomes included changes in body composition and BMI-SDS.Of 160 boys enrolled, 126 (80%) completed 6 months' intervention. Baseline age, height-SDS, weight-SDS, BMI-SDS, body composition and dietary intake were similar in the formula and placebo groups. 'Good' formula consumers (intake of ≥50% of the recommended dose, n = 30) gained significantly more in weight-SDS, BMI-SDS, fat-free-mass and muscle mass (p 0.05) than did 'poor' consumers (n = 35) and the placebo group (n = 61). Only in the formula group, positive dose-response correlations were found between consumption of the formula and changes in the outcome parameters examined, including Δheight-SDS (r = 0.301, p = 0.015). Boys aged11.4 years who were 'good' formula consumers maintained their Δheight-SDS, while Δheight-SDS declined in 'poor' consumers and the placebo group of the same age (p = 0.033).Intervention with a multi-nutrient, protein-rich formula was effective in increasing weight-SDS, fat-free-mass, muscle mass and BMI-SDS in short and lean prepubertal male adolescents. Good consumption of the formula prevented Δheight-SDS decline in the older participants.

AIM Prediction models may be useful in accurately identifying children who will benefit from growth hormone (GH) treatment. We aimed to validate the Gothenburg prediction model for this purpose. METHODS The study included prepubertal children with GH deficiency who started treatment with GH during 2004-2016 at Queen Silvia Children's Hospital, Gothenburg, based on a first-year growth prediction of ≥0.7 SDS in height according to the Gothenburg prediction model on a GH dose of 33 μg/kg/day. Observed heights retrieved from medical charts were compared with predicted heights. RESULTS The study included 121 patients (64% boys) with at least one year of data after the start of GH treatment. The median (range) GH dose was 30 (10-43) µg/kg/day for the first year and age at start of treatment was 5.32 (3-11.8) years. The model correctly excluded poor responders resulting in 119/121 (98%) patients having a height gain of at least ≥0.5 SDS in a year. However, the model underestimated relatively low predictions and overestimated relatively high predictions, with a residual standard deviation of 0.31 SDS. CONCLUSION By using a validated prediction model for GH in a clinical context, unnecessarily treating short children with an expected poor height outcome can be avoided.

Short stature is a common presentation to pediatricians with a significant overlap between physiology and pathology. Thus, while most short children have a physiological cause, growth failure may be the only manifestation of severe underlying disease. Growth failure evaluation aims to avoid unnecessary investigations in children with a physiological cause without missing pathology. Guidelines for the evaluation of short stature allow stepwise evaluation but are limited by their resource-intense nature. An objective application of anthropometric indices and careful clinical evaluation allows rational growth failure workup. The use of height standard deviation score (SDS) for determining the need for evaluation (no evaluation above -2, follow-up between -2 to -3, and immediate workup with height below -3), corrected height SDS to identify familial short stature (above -1.5), height SDS for bone age for constitutional delay of puberty and growth (above -2), and BMI SDS for nutritional pattern growth failure (below -1) helps reduce the burden of investigations. The present review provides a framework for comprehensive growth evaluation across resource levels and settings.

Seckel syndrome is a very rare autosomal recessive disorder also known as bird headed dwarfism”. It is characterised by proportional short stature, low birth weight, dysmorphic facial appearance, and mental retardation. In addition to its dysmorphic features, skeletal, endocrine, gastrointestinal, haematologic, genitourinary, and nervous system has been involved. Cardiovascular features very rarely associate with Seckel syndrome. We report two patients with Seckel syndrome, one with dilated cardiomyopathy and the other with multiple ventricular septal defects. Dilated cardiomyopathy and isolated ventricular septal defect have not been previously reported in Seckel syndrome. Cardiovascular evaluation should be performed in all patients with Seckel syndrome. Early diagnosis of congenital and acquired heart diseases will reduce morbidity and mortality in these patients.

Context: Short stature in children is a common reason for referral to pediatric endocrinologists. The underlying cause of short stature remains unclear in many cases and patients often receive unsatisfactory, descriptive diagnoses. While textbooks underline the rarity of genetic causes of growth hormone (GH) insensitivity and the severity of its associated growth failure, increased genetic testing in patients with short stature of unclear origin has revealed gene defects in the GH/insulin-like growth factor (IGF-I) axis associated with milder phenotypes. As such, heterozygous IGF1 gene defects have been reported as a cause of mild and severe short stature. Here, we aimed to describe the clinical and hormonal profile of children with IGF1 haploinsufficiency and their short-term response to growth hormone treatment (GHT). Case descriptions: We describe five patients presenting with short stature, microcephaly, and in four out of five born small for gestational age diagnosed with IGF1 haploinsufficiency. The phenotype of these patients resembles that of previously described cases with similar gene defects. In our series, segregation of the short stature with the IGF1 deletion is evident from the pedigrees and our data suggests a modest response to GHT. Conclusions: This study is the first case series of complete heterozygous IGF1 deletions in children. The specific genetic defects provide a clear image of the phenotype of IGF1 haploinsufficiency – unbiased by heterozygous mutations with possible dominant negative effects on IGF-I function. We increase the evidence for IGF1 haploinsufficiency as a cause of short stature, microcephaly, and SGA.

Objectives Some idiopathic short stature (ISS) patients may have varying degrees of insulin-like growth factor 1 (IGFI) deficiency. Others with growth hormone deficiency (GHD) (peak GH Methods We studied the effect of GH therapy (0.035–0.06 mg/kg/day) on linear growth and weight gain per day (WGPD) in children with ISS (n=13) and those with GHD (n=10) who have low pretreatment IGFISDS (IGF SDS Results At presentation, the height standard deviation score (HtSDS) of children with ISS who had low pretreatment IGFISDS was significantly lower compared to the normal IGFI group. The age, body mass index (BMI), BMISDS, peak GH response to clonidine provocation and bone age did not differ between the two study groups. After 1 year of treatment with rhGH (0.035–0.06 mg/kg/day) IGFISDS increased significantly in both groups (p Conclusions IGFI deficiency represents a low anabolic state. Correction of IGFI level (through rhGH and/or improved nutrition) in short children (ISS and GHD) was associated with increased linear growth and WGPD denoting significant effect on bone growth and muscle protein accretion.

Multiple factors influence intrauterine growth and lead to low birth sizes. The impact of genetic alterations on both pre- and post-natal growth is still largely unknown. The aim of this study was to investigate the prevalence of CNVs in an Italian cohort of SGA children with persistent short stature and complex clinical phenotype. rhGH treatment efficacy was evaluated according to the different genotypes. Twenty-four SGA children (10F/14M) with persistent short stature associated with dysmorphic features and/or developmental delay underwent CNV evaluation. CNVs were present in 14/24 (58%) SGA children. Six patients had a microdeletion involving the following regions: 3q24q25.1, 8p21.2p12, 15q26, 19q13.11, 20q11.21q12, 22q11.2. In three females, the same microdeletion involving 17p13.3 region was identified. In two different patients, two microduplications involving 10q21.3 and Xp11.3 region were observed. A further female patient showed both an 11q12.1 and an Xq27.1 microduplication, inherited from her mother and from her father, respectively. In a boy, the presence of a 12p13.33 microdeletion and a 19q13.43 microduplication was found. GH treatment efficacy, expressed by height gain and height velocity in the first 12 months of therapy, was similar in subjects with and without CNVs. These results show that pathogenic CNVs are common in SGA children with short stature associated with additional clinical features. Interestingly, the involvement of 17p13.3 region occurs with a relative high frequency, suggesting that genes located in this region could play a key role in pre- and post-natal growth. rhGH therapy has similar efficacy in the short term whether CNVs are present or not.

Protein arginine N-methyltransferase 7 (PRMT7) encodes an arginine methyltransferase central to a number of fundamental biological processes, mutations in which result in an autosomal recessive developmental disorder characterized by short stature, brachydactyly, intellectual developmental disability and seizures (SBIDDS). To date, fewer than 15 patients with biallelic mutations in PRMT7 have been documented. Here we report brothers from a consanguineous Iraqi family presenting with a developmental disorder characterized by global developmental delay, shortened stature, facial dysmorphisms, brachydactyly, and kidney dysfunction. In both affected brothers, whole genome sequencing (WGS) identified a novel homozygous substitution in PRMT7 (ENST00000339507.5), c.1097 G > A (p.Cys366Tyr), considered to account for the majority of the phenotypic presentation. Rare compound heterozygous mutations in the dysplasia-associated perlecan-encoding HSPG2 gene (ENST00000374695.3) were also found (c.10721-2dupA, p.Ser71Asn and c.212 G > A), potentially accounting for the kidney dysfunction. In addition to expanding the known mutational spectrum of variably expressive PRMT7 mutations alongside potential digenic inheritance with HSPG2, this report underlines the diagnostic utility of a WGS-guided analysis in the detection of rare genetic disorders.

Introduction: SHORT syndrome is a rare autosomal dominant condition described by its acronym of short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger abnormality, and teething delay. Individuals have a distinct progeroid craniofacial appearance with a triangular face, frontal bossing, hypoplastic or thin alae nasi, large low-set ears, and mandibular retrognathia. Objectives: To systematically appraise the literature and update the clinical phenotype with emphasis on the dental condition. Design: A systematic literature search was carried out to update the clinical phenotype, identifying reports of individuals with SHORT syndrome published after August 2015. The same search strategy but not limited to publication date was carried out to identify reports of the dental phenotype. Two independent reviewers screened 1937 articles with 55 articles identified for full-text review. Results: Nineteen individuals from 11 families were identified. Facial dysmorphism including ocular depression, triangular shaped face, frontal bossing, large low-set ears, and micrognathia were the most consistent features followed by lipodystrophy, insulin resistance, and intrauterine growth restriction. Teething delay, microdontia, hypodontia, and enamel hypoplasia have all been reported. Conclusion: Features that comprise the SHORT acronym do not accurately or completely describe the clinical phenotype. The craniofacial appearance is one of the most consistent features. Lipodystrophy and insulin resistance may also be considered cardinal features. After teething delay, enamel hypoplasia and microdontia are the most common dental manifestations. We present recommendations for the dental and orthodontic/orthognathic management of individuals with SHORT syndrome.

Background Skeletal dysplasia is a heterogeneous group of disorders. Spondyloepiphyseal dysplasias comprise one subgroup. Deficiency of carbohydrate sulfotransferase 3 has been reported in a small number of patients with recessively inherited spondyloepiphyseal dysplasia with joint dislocation, short stature and scoliosis. We report here molecular and clinical findings of affected individuals in three consanguineous Pakistani families. Affected individuals in all three families had a uniform phenotype including severe short stature, multiple dislocated joints, progressive scoliosis and facial dysmorphism. Methods Clinical evaluation was done for three unrelated families. Radiological survey of bones was completed for patients from two of the families. Whole exome sequencing index patients from each family was performed followed by Sanger sequencing for validation of segregation of identified variants in respective families. In-silico analysis for determining pathogenicity of identified variants and conservation was done. Results Whole-exome sequencing revealed biallelic variants c.590 T > C;p.(Leu197Pro), c.603C > A;p.(Tyr201Ter) and c.661C > T;p.(Arg221Cys) in CHST3 (NM_004273.5) in the three families with eight, five and two affected individuals, respectively. Contrary to previous reports, affected individuals in none of the families exhibited a hearing loss. Conclusion We describe genotypic and phenotypic findings of three unrelated families with spondyloepiphyseal dysplasia. Our study confirms phenotypic variability and adds to the genotypic spectrum of spondyloepiphyseal dysplasia.

Purpose of review The objective of this review is to assess the most recent literature on pubertal trends in boys and girls as well as evaluate genetic, epigenetic, and environmental factors implicated in the timing of pubertal progression. Recent findings Recent studies confirm the previously described link between increased adiposity and earlier onset of puberty in girls, and more recent studies shed light onto the previously unclear situation in boys as a preponderance of recent longitudinal studies suggests that increased adiposity is linked with earlier pubertal timing also in boys. Discoveries of novel pathways highlights the complexity of pubertal development and suggest mechanistic links between nutrition, obesity, leptin, insulin resistance, and puberty. Furthermore, genetic and epigenetic variants can be linked to early puberty. Other factors, such as prenatal and postnatal environment, gut microbiota, and endocrine-disrupting chemicals have also been linked to both obesity and earlier puberty. Summary Understanding how the interactions of these factors contribute the relationship between obesity and early pubertal onset is crucial as early puberty has been linked with long-term consequences, such as short stature, earlier type 2 diabetes, cardiovascular disease, and poor psychological and behavioral outcomes.

To investigate genotype and phenotype of congenital nephrogenic diabetes insipidus caused by AVPR2 mutations, which is rare and limitedly studied in Chinese population. 88 subjects from 28 families with NDI in a department (Beijing, PUMCH) were screened for AVPR2 mutations. Medical records were retrospectively reviewed and characterized. Genotype and phenotype analysis was performed. 23 AVPR2 mutations were identified, including six novel mutations (p.Y117D, p.W208R, p.L313R, p.S127del, p.V162Sfs*30 and p.G251Pfs*96). The onset-age ranged from 1 week to 3 years. Common presentations were polydipsia and polyuria (100%) and intermittent fever (57%). 21% and 14% of patients had short stature and mental impairment. Urine SG and osmolality were decreased, while serum osmolality and sodium were high. Urological ultrasonography results showed hydronephrosis of the kidney (52%), dilation of the ureter (48%), and thickened bladder wall or increased residual urine (32%), led to intermittent urethral catheterization (7%), cystostomy (11%) and binary nephrostomy (4%). Urological defects were developed in older patients. Genotype and phenotype analysis revealed patients with non-missense mutations had higher levels of serum sodium than missense mutations. In the first and largest case series of NDI caused by AVPR2 mutations in Chinese population, we established genetic profile and characterized clinical data, reporting six novel mutations. Further, we found genotype was associated with phenotype. This knowledge broadens genotype and phenotype spectrum of rare congenital NDI caused by AVPR2 mutations, and provides basis for studying molecular biology of AVPR2.

Loss of function variants in the lysine demethylase 5C (KDM5C) gene account for approximately 0.7%-2.8% of X-linked intellectual disability (ID) cases and pose significant burdens for patients and their caregivers. To date, 45 unique variants in KDM5C have been reported in individuals with ID. As a rare disorder, its etiology and natural history remain an area of active investigation, with treatment limited to symptom management. Previous studies have found that males present with moderate to severe ID with significant syndromic comorbidities such as epilepsy, short stature, and craniofacial abnormalities. Although not as well characterized, females have been reported to predominantly display mild to moderate ID with approximately half being asymptomatic. Here, we present caregiver-reported data for 37 unrelated individuals with pathogenic variants in KDM5C, the largest cohort reported to-date. We find that up to 70% of affected females were reported to display syndromic features including gastrointestinal dysfunction and hearing impairment. Additionally, more than half of individuals reported a diagnosis of Autism Spectrum Disorder (ASD) or described features consistent with this spectrum. Our data thus provide further evidence of sexually dimorphic heterogeneity in disease presentation and suggest that pathogenic variants in KDM5C may be more common than previously assumed.

Cyclin D2 (CCND2) is a critical cell cycle regulator and key member of the cyclin D2-CDK4 (DC) complex. De novo variants of CCND2 clustering in the distal part of the protein have been identified as pathogenic causes of brain overgrowth (megalencephaly, MEG) and severe cortical malformations in children including the megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome. Megalencephaly-associated CCND2 variants are localized to the terminal exon and result in accumulation of degradation-resistant protein. We identified five individuals from three unrelated families with novel variants in the proximal region of CCND2 associated with microcephaly, mildly simplified cortical gyral pattern, symmetric short stature, and mild developmental delay. Identified variants include de novo frameshift variants and a dominantly inherited stop-gain variant segregating with the phenotype. This is the first reported association between proximal CCND2 variants and microcephaly, to our knowledge. This series expands the phenotypic spectrum of CCND2-related disorders and suggests that distinct classes of CCND2 variants are associated with reciprocal effects on human brain growth (microcephaly and megalencephaly due to possible loss or gain of protein function, respectively), adding to the growing paradigm of inverse phenotypes due to dysregulation of key brain growth genes.

Objective To investigate the incidence of pseudotumor cerebri syndrome in children treated with growth hormone in a paediatric hospital and to identify risk factors of this complication. Methods Prospective pilot study of paediatric patients treated with growth hormone, prescribed by the Paediatric Endocrinology Department, between February 2013 and September 2017. In all these patients, a fundus examination was performed before starting treatment and 3-4 months later. Results 289 patients were included: 244 had a growth hormone deficiency, 36 had short stature associated with small for gestational age, six had a mutation in the SHOX gene and three had Prader-Willi Syndrome. Five patients developed papilledema, all were asymptomatic and had a growth hormone deficiency: one had a craniopharyngioma, two a polymalformative syndrome associated with hypothalamic-pituitary axis anomalies, one patient a non-specified genetic disease with hippocampal inversion and one patient with normal magnetic resonance imaging who had developed a primary pseudotumor cerebri syndrome years before. Conclusions Growth hormone treatment is a cause of pseudotumor cerebri syndrome. In our series, at risk patients had growth hormone deficiency and hypothalamic-pituitary anatomic anomalies or genetic or chromosome diseases. Fundus examination should be systematically screened in all patients in this at-risk group irrespective of the presence or not of symptoms.

We report the clinical, biochemical and genetic findings from a Spanish boy of Caucasian origin who presented with fever-dependent RALF (recurrent acute liver failure) and osteogenesis imperfecta (OI). Whole-exome sequencing (WES) uncovered two compound heterozygous variants in NBAS (c.[1265 T > C];[1549C > T]:p.[(Leu422Pro)];[(Arg517Cys)]), and a heterozygous variant in P4HB (c.[194A > G];[194=]:p.[(Lys65Arg)];[(Lys65=)]) that was transmitted from the clinically unaffected mother who was mosaic carrier of the variant. Variants in NBAS protein have been associated with ILFS2 (infantile liver failure syndrome-2), SOPH syndrome (short stature, optic nerve atrophy, and Pelger-Huet anomaly syndrome), and multisystem diseases. Several patients showed clinical manifestations affecting the skeletal system, such as osteoporosis, pathologic fractures and OI. Experiments in the patient's fibroblasts demonstrated that mutated NBAS protein is overexpressed and thermally unstable, and reduces the expression of MGP, a regulator of bone homeostasis. Variant in PDI (protein encoded by P4HB) has been associated with CLCRP1 (Cole-Carpenter syndrome-1), a type of severe OI. An increase of COL1A2 protein retention was observed in the patient's fibroblasts. In order to study if the variant in P4HB was involved in the alteration in collagen trafficking, overexpression experiments of PDI were carried out. These experiments showed that overexpression of mutated PDI protein produces an increase in COL1A2 retention. In conclusion, these results corroborate that the variants in NBAS are responsible for the liver phenotype, and demonstrate that the variant in P4HB is involved in the bone phenotype, probably in synergy with NBAS variants.

BACKGROUND Children born small for gestational age (SGA), particularly when associated with an extremely low birthweight (ELBW), have a higher risk of renal dysfunction. Growth hormone (GH) treatment is used to treat short-statured children born SGA; however, its effects on renal function remain elusive, especially in those born SGA with ELBW. METHODS Short-statured children born SGA (N = 42) were included. Subjects were subdivided into two groups based on their birthweight: the ELBW group (N = 15) with a birthweight of

In this article, we analyze several works of art which portray individuals with short stature ("dwarfism"). We have focused on eight individuals who we believe have short stature due to growth hormone deficiency (GHD) or closely related disorders, rather than skeletal dysplasia. We discuss them individually, suggest the potential diagnosis, review the characteristics of their life and personal history, and briefly outline the artistic framework in which these works of art were created. This work is a posthumous tribute to the people with short stature portrayed in these works of art, who likely experienced harassment and inappropriate treatment by others and called by derogatory names. We have tried to acknowledge their identities with the respect they deserve.

Short stature is among the most common endocrinological disease phenotypes of childhood and may occur as an isolated finding or in conjunction with other clinical manifestations. Although the diagnostic utility of clinical genetic testing in short stature has been implicated, the genetic architecture and the utility of genomic studies such as exome sequencing (ES) in a sizable cohort of patients with short stature have not been investigated systematically. In this study, we recruited 561 individuals with short stature from two centers in China during a 4-year period. We performed ES for all patients and available parents. All patients were retrospectively divided into two groups: an isolated short stature group (group I, n = 257) and an apparently syndromic short stature group (group II, n = 304). Causal variants were identified in 135 of 561 (24.1%) patients. In group I, 29 of 257 (11.3%) of the patients were solved by variants in 24 genes. In group II, 106 of 304 (34.9%) patients were solved by variants in 57 genes. Genes involved in fundamental cellular process played an important role in the genetic architecture of syndromic short stature. Distinct genetic architectures and pathophysiological processes underlie isolated and syndromic short stature.

Objective Long-term outcomes of patients with mucopolysaccharidosis (MPS) VI treated with galsulfase enzyme replacement therapy (ERT) since infancy were evaluated. Methods The study was a multicenter, prospective evaluation using data from infants with MPS VI generated during a phase 4 study (ASB-008; Clinicaltrials.gov NCT00299000 ) and clinical data collected ≥5 years after completion of the study. Results Parents of three subjects from ASB-008 (subjects 1, 2, and 4) provided written informed consent to participate in the follow-up study. One subject was excluded as consent was not provided. Subjects 1, 2, and 4 were aged 0.7, 0.3, and 1.1 years, respectively, at initiation of galsulfase and 10.5, 7.9, and 10.5 years, respectively, at follow-up. All subjects had classical MPS VI based on pre-treatment urinary glycosaminoglycans and the early onset of clinical manifestations. At follow-up, subject 4 had normal stature for age; subjects 1 and 2 had short stature, but height remained around the 90th percentile of growth curves for untreated classical MPS VI. Six-minute walk distance was normal for age/height in subjects 1 (550 m) and 4 (506 m), and reduced for subject 2 (340 m). Subject 2 preserved normal respiratory function, while percent predicted forced vital capacity and forced expiratory volume in 1 s decreased over time in the other subjects. Skeletal dysplasia was already apparent in all subjects at baseline and continued to progress. Cardiac valve disease showed mild progression in subject 1, mild improvement in subject 4, and remained trivial in subject 2. All subjects had considerably reduced pinch and grip strength at follow-up, but functional dexterity was relatively normal for age and there was limited impact on activities of daily living. Bruininks-Oseretsky Test of Motor Proficiency (BOT-2) results showed that subjects 2 and 4 had numerous fine and gross motor competencies. Corneal clouding progressed in all subjects, while progression of hearing impairment was variable. Liver size normalized from baseline in subjects 1 and 4, and remained normal in subject 2. Conclusion Very early and continuous ERT appears to slow down the clinical course of MPS VI, as shown by preservation of endurance, functional dexterity, and several fine and gross motor competencies after 7.7–9.8 years of treatment, and less growth impairment or progression of cardiac disease than could be expected based on the patients' classical phenotype. ERT does not seem to prevent progression of skeletal or eye disease in the long term.

Prader–Willi syndrome (PWS) is a genetic disorder caused by the lack of expression of genes on the paternally inherited chromosome 15q11.2-q13 region. The three main genetic subtypes are represented by paternal 15q11-q13 deletion, maternal uniparental disomy 15, and imprinting defect. Clinical picture of PWS changes across life stages. The main clinical characteristics are represented by short stature, developmental delay, cognitive disability and behavioral diseases. Hypotonia and poor suck resulting in failure to thrive are typical of infancy. As the subjects with PWS age, clinical manifestations such as hyperphagia, temperature instability, high pain threshold, hypersomnia and multiple endocrine abnormalities including growth hormone and thyroid-stimulating hormone deficiencies, hypogonadism and central adrenal insufficiency due to hypothalamic dysfunction occur. Obesity and its complications are the most common causes of morbidity and mortality in PWS. Several mechanisms for the aetiology of obesity in PWS have been hypothesized, which include aberration in hypothalamic pathways of satiety control resulting in hyperphagia, disruption in hormones regulating appetite and satiety and reduced energy expenditure. However, despite the advancement in the research field of the genetic basis of obesity in PWS, there are contradictory data on the management. Although it is mandatory to adopt obesity strategy prevention from infancy, there is promising evidence regarding the management of obesity in adulthood with current obesity drugs along with lifestyle interventions, although the data are limited. Therefore, the current manuscript provides a review of the current evidence on obesity and PWS, covering physiopathological aspects, obesity-related complications and conservative management.

Objectives Childhood growth influences their social and psychological behavior, and abnormal growth may reflect underlying pathological etiologies. It is important to diagnose children with short stature as early as possible to be able to manage treatable causes. We aim to study etiologies and characteristics of short stature in children in Jordan. Methods This is a cross-sectional retrospective review of the medical records of children diagnosed with short stature at a referral university hospital. Clinical characteristics, auxological, laboratory, and radiological investigations were collected and analyzed. Results Among a total of 551 children diagnosed with short stature, the number of boys was significantly higher than girls, 304 (55.2%) and 247 (44.8%), respectively with a p-value of 0.015. Average age at presentation for all patients was 10.24 ± 3.23, with no significant difference between boys and girls. Pathological etiology was higher than normal variants 55.7 and 44.3%, respectively with p=0.007. Constitutional delay of growth and puberty (CDGP) was the most frequent cause in the normal variant group, 59.8%. Among the pathological group, the most common etiology was growth hormone deficiency (32.2%) with mean age of presentation of 9.40 years and was not significantly different from the age in other etiological groups, 9.44 years and p=0.931. Conclusions Growth monitoring of children should start at an early age for boys and girls. Referral to the pediatric endocrine clinic should be considered when growth problems are suspected for accurate diagnosis and etiology profiling.

Background The study aimed to delineate the genotypic features and endocrine / metabolic profiles in patients with 21-hydroxylase deficiency. Methods Subjects were diagnosed with 21-hydroxylase deficiency by direct Sanger sequencing or multiple ligation-dependent probe amplification analysis and followed up in Pusan National University Children's Hospital from July 2008 to April 2019. The genotype, phenotype, and endocrine and metabolic profiles in children and young adults with congenital adrenal hyperplasia were investigated. Results Of a total of 33 patients, 16 (48.5%) were males. Median age was 7.4 years (range, 0.1-23.8 years). Thirty (90.9%) had salt-wasting phenotypes. Eleven (33.3%) initially presented with abnormality in a neonatal screening test without other symptoms. Among the 17 girls, seven received genital surgery. Sixty-five alleles from the 33 patients were evaluated. The distribution of CYP21A2 gene mutations revealed an intron 2 splice site (c.293-13A>G or c.293-13C>G) mutation as the most common one (22, 33.8%), followed by c.518T>A (10, 15.4%) and a large deletion / conversion (7, 10.8%), in order. One novel mutation was detected, c.332del(p.G111fs). Among the 27 patients aged >2 years, fifteen (55.6%) were obese / overweight, and ten (37.0%) needed growth hormone therapy due to short stature. Among the seven subjects aged >2 years and having high-risk genotype, five had impaired fasting glucose, three had precocious puberty, and four used growth hormone. A greater proportion of the high current corticosteroid dose group had impaired fasting glucose than in the low-dose group (64.3 vs 23.1%, P = 0.031). Conclusions Early monitoring of endocrine and metabolic complications from childhood might benefit patients with congenital adrenal hyperplasia.

Noonan syndrome (NS) is an autosomal dominant disease caused by aberrant up-regulated signaling through RAS GTPase. It is characterized by facial dysmorphisms, short stature, congenital heart defects, malformations of rib cage bones, bleeding problems, learning difficulties, or mild intellectual disability. Additional intracranial findings in NS patients include tumors, midline anomalies, and malformations of cortical development. In this report, we present the case of a young female patient, with a known diagnosis of Noonan syndrome that in complete well being developed two brain lesions, in the right nucleus pallidus and in the left cerebellar hemisphere respectively, whose location and signal on MRI looked similar to neurofibromatosis type 1 unidentified bright objects (UBOs), and whose spectroscopic characteristics excluded neoplasms.

The relationship between insulin‐like growth factor‐1 (IGF‐1) and systolic blood pressure (SBP) is controversial in adults and children. The purpose of this study was to investigate the relationship between the IGF‐1 standard deviation score (IGF‐1 SDS) and SBP in children with short stature. A cross‐sectional analysis including 1315 children with short stature was conducted from March 2013 to October 2020. We estimated IGF‐1, blood pressure and other laboratory tests, and anthropometric indicators were also evaluated. Subgroup analyses of the pubertal stage, sex, growth hormone levels, thyroid hormone levels, fasting blood glucose levels, and triglyceride levels were performed. A positive association between the IGF‐1 SDS and SBP was observed by univariate analysis (p

Purpose To identify novel genes associated with intellectual disability (ID) in four unrelated families. Methods Here, through exome sequencing and international collaboration, we report eight individuals from four unrelated families of diverse geographic origin with biallelic loss-of-function variants in UBE4A. Results Eight evaluated individuals presented with syndromic intellectual disability and global developmental delay. Other clinical features included hypotonia, short stature, seizures, and behavior disorder. Characteristic features were appreciated in some individuals but not all; in some cases, features became more apparent with age. We demonstrated that UBE4A loss-of-function variants reduced RNA expression and protein levels in clinical samples. Mice generated to mimic patient-specific Ube4a loss-of-function variant exhibited muscular and neurological/behavioral abnormalities, some of which are suggestive of the clinical abnormalities seen in the affected individuals. Conclusion These data indicate that biallelic loss-of-function variants in UBE4A cause a novel intellectual disability syndrome, suggesting that UBE4A enzyme activity is required for normal development and neurological function.

Objective: To assess the BMI among children with Growth Hormone Deficiency (GHD) and Idiopathic Short Stature (ISS) and its correlation to ghrelin, Growth Hormone (GH), and Insulin-like Growth Factor-1 (IGF-1) levels. Methods: A cross-sectional descriptive study in which 42 patients attending the Pediatric endocrine clinic were enrolled, allocated into two groups: group I: GHD children; group II: ISS children. Ghrelin, IGF-1 and GH in both groups were measured. Results: Ghrelin was significantly higher among GHD group (p < 0.001). Overall, there was a strong negative correlation between IGF-1 and ghrelin (r = -0.977, p-value = < 0.001) while a moderate positive correlation between ghrelin and BMI (r = 0.419, p-value = 0.006). There was a weak positive non-significant correlation between IGF-1 and BMI (r = 0.276, p-value = 0.077). In GHD group, there was a weak positive non-significant correlation between ghrelin and GHmax measurement (r = 0.052, p-value = 0.824), while a weak negative non-significant correlation between both variables in ISS group (r = -0.243, p-value = 0.288). In GHD group, there was a moderate positive correlation between ghrelin and BMI (r = 0.500, p-value = 0.021), but weak negative non-significant correlation between both variables in ISS group (r = -0.255, p-value = 0.265). Conclusion: There was a negative feedback loop between ghrelin and IGF-1, whereas a positive feedback between ghrelin and BMI. BMI was more affected in the ISS group but was non-signifi-cantly correlated with ghrelin. There was no significant compensatory response of ghrelin suggesting its contribution to the pathogenesis of ISS.

Natriuretic peptide receptor 2 (NPR2) plays a key role in cartilage and bone morphogenesis. The NPR2 gene mutations result in acromesomelic dysplasia, Maroteaux type (AMDM), short stature with nonspecific skeletal abnormalities (SNSK), and epiphyseal chondrodysplasia, Miura type (ECDM). However, the pathogenic mechanism remains unclear. In our study, we identified one de novo (R557C) and six novel variants (G602W, V970F, R767*, R363*, F857S, and Y306S) in five independent Chinese families with familial short stature. Three patients with heterozygous mutations (G602W, V970F, and R767*) were diagnosed with SNSK (height SD score ranged from −2.25 to −5.60), while another two with compound heterozygous mutations (R363* and F857S, R557C and Y306S) were diagnosed with AMDM (height SD score ranged from −3.10 to −5.35). Among three patients with heterozygous status, two patients before puberty initiation with rhGH treatment significantly improved their growth (height velocity 7.2 cm/year, 6.0 cm/year), and one patient in puberty had a poor response to the rhGH treatment (height velocity 2.5 cm/year). Seven NPR2 gene variants were constructed and overexpressed in HEK293T and ATDC5 cells, and we found that ATDC5 cells with mutant NPR2 gene showed decreased differentiation, as evidenced by lower expression of ColII, ColX, and BMP4 and higher expression of Sox9. Moreover, the apoptosis rate was elevated in ATDC5 cells expressing the mutant NPR2 gene. N-glycosylation modification, plasma membrane localization, and ER stress resulted from the accumulation of mutant protein in ER, as shown by the higher expression of GRP78 and p-IRE1α. Overall, our results provide a novel insight into NPR2 loss of function, which could promote chondrocyte apoptosis and repress cell differentiation through ER stress and the unfolded protein response.

Objectives To assess pubertal development and its determinants in adolescents with transfusion-dependent thalassemia (TDT). Methods In this cross-sectional study from a tertiary teaching hospital in Delhi, records of adolescents aged 17-19 years with TDT on regular transfusion at thalassemia day-care centre were reviewed. Pubertal development and its determinants were assessed. Results Records of 58 (33 male) adolescents with TDT were reviewed. Among them, 42 (72.4%) had normal/delayed onset with spontaneous progression of puberty, while 16 (27.6%) had pubertal arrest/failure and received hormonal replacement therapy (HRT). Short stature was observed in all adolescents on HRT. Amongst other endocrinopathies, only hypoparathyroidism was found to be significantly higher in the HRT group. On multivariate analysis, serum ferritin (OR-1.005, 95% CI 1.002, 1.009) was observed to be the only significant determinant of pubertal arrest/failure. Conclusions A significant proportion of adolescents with TDT continue to have pubertal arrest/failure. High systemic iron load is the key determinant for this.

Objective: Short stature may reflect health in early life and be an enduring disability. How birth weight, gender, household, elementary schooling and diet play a role in associations between stature and overall school competence (OSC) have been assessed. Design: The 2001–2002 Nutrition and Health Survey in Taiwan (NAHSIT) for elementary schoolchildren (n 2274, 52·1 % boys) was linked to birth records. It provided sociodemographic, dietary quality, body compositional and school performance (as Scale for Assessing Emotional Disturbance, SAED; OSC as an SAED subscale) data. Lower birth weight was ≤15th percentile: 2850 g for boys and 2700 g for girls, and stature as z-scores for Taiwanese. Multivariable linear regression was used for relationships between OSC and stature. Trends in OSC by stature and school grade were assessed. Setting: The 2001–2002 NAHSIT for elementary schoolchildren. Participants: Totally, 2274 schoolchildren aged 6–13 years. Results: Compared to normal height (−2< height for age z-score (HAZ) v. 10·5, P < 0·05) and taller girls (HAZ ≥ 2) had a better OSC (12·3 v. 10·5, P < 0·001). Maternal education and household income each contributed more than 5 % of OSC variance. OSC and HAZ among girls were positively associated and emotional disturbance negatively associated. Shortness-associated lower OSC underwent remediation with advancing school grade. Stature and OSC were not evidently related in boys. Conclusions: Shorter stature can compromise OSC among school girls. The major determinants in shorter girls are less household income and limited parental education.