Clinical characteristics of sitosterolemic children with xanthomas as the first manifestation.

BACKGROUND: Sitosterolemia (STSL) is an extremely rare genetic disease. Xanthomas as the first symptom are frequently misinterpreted as familial hypercholesterolemia (FH) in children. Inappropriate treatment may deteriorate the condition of STSL. OBJECTIVES: To present the clinical and laboratory characteristics of xanthomatous children diagnosed with sitosterolemia in comparison with childhood FH with xanthomas. METHODS: We summarized and compared the clinical characteristics of STSL and FH patients with xanthomas as the first manifestations and investigated the different indicators between the STSL and FH groups, as well as their diagnostic values for STSL. RESULTS: Two tertiary pediatric endocrinology departments contributed ten STSL cases. Five of the STSL patients (50%) experienced mild anemia, whereas two (20%) had vascular complications. The xanthomas of the STSL group displayed morphologies comparable to those of the FH group. There were ten cases of homozygous FH (HoFH) with xanthomas as the predominant symptom of the control group who had no anemia. The serum cholesterol (Chol) levels of the STSL and FH groups were 12.57 (9.55 ~ 14.62) mmol/L and 17.45 (16.04 ~ 21.47) mmol/L, respectively (p value 0.002). The serum low-density lipoprotein cholesterol (LDL-c) levels of the STSL and FH groups were 9.26 ± 2.71 mmol/L and 14.58 ± 4.08 mmol/L, respectively (p value 0.003). Meanwhile, the mean platelet volume (MPV) levels of the STSL and FH groups were 11.00 (9.79 ~ 12.53) fl. and 8.95 (8.88 ~ 12.28) fl., respectively (p value 0.009). The anemia proportions of the STSL and FH groups were 50% and 0%, respectively (p value 0.033). The AUC values of Chol, LDL-c, MPV, hemoglobin (Hb) for the diagnosis of STSL were 0.910, 0.886, 0.869, 0.879, respectively. Chol ≤ 15.41 mmol/L, LDL-c ≤ 13.22 mmol/L, MPV ≥ 9.05 fl., or Hb≤120 g/L were the best thresholds for diagnosing STSL with childhood xanthomas. CONCLUSION: The xanthoma morphology of STSL patients resembles that of FH patients. Xanthomas as the initial symptom of a child with Chol ≤ 15.41 mmol/L, LDL-c≤13.22 mmol/L, MPV ≥ 9.05 fl., or Hb≤120 g/L, he was most likely to have STSL.

Aldosterone signaling defect in young infants: single-center report and review.

BACKGROUND: Aldosterone (Ald) is a crucial factor in maintaining electrolyte and water homeostasis. Defect in either its synthesis or function causes salt wasting (SW) manifestation. This disease group is rare, while most reported cases are sporadic. This study aimed to obtain an overview of the etiology and clinical picture of patients with the above condition and report our rare cases. METHODS: A combination of retrospective review and case studies was conducted at the Pediatric Endocrine unit of The First Affiliated Hospital Sun Yat Sen University from September 1989 to June 2020. RESULTS: A total of 187 patients with SW were enrolled, of which 90.4% (n = 169) were diagnosed with congenital adrenal hyperplasia (CAH). SW type 21-hydroxylase deficiency accounted for 98.8% (n = 167) of CAH diagnosis, while 1.2% (n = 2) was of lipoid CAH. Non-CAH comprised 9.6% (n = 18) of the total patients whose etiologies included SF-1 gene mutation (n = 1), X-linked adrenal hypoplasia congenita (n = 9), aldosterone synthase deficiency (ASD, n = 4), and pseudo-hypoaldosteronism type 1 (PHA1, n = 1). Etiologies were not identified in three patients. All of patients with ASD and PHA1 exhibited SW syndrome in their early neonatal period. DNA sequencing showed mutations of CYP11B2 for P1-P4 and NR3C2 for P5. P1 and P2 were sibling brothers affected by compound heterozygous mutations of c.1121G > A (p.R374Q) and c.1486delC p.(L496fs); likewise, P4 was identified with compound heterozygous mutations of c.1200 + 1G > A and c.240-1 G > T; meanwhile P3 demonstrated c.1303G > A p.(G435S) homozygous mutation in CYP11B2 gene. Lastly, P5 showed c.1768 C > T p.(R590*) heterozygous mutation in the NR3C2 gene. CONCLUSION: Etiology of infant with aldosterone defect was mostly congenital. Renal and adrenal imaging are recommended to exclude renal causes. If clinical picture is suggestive, normal plasma Ald in early infancy cannot rule out aldosterone insufficiency.

[Efficacy of letrozole in treatment of male adolescents with idiopathic short stature].

ObjectiveTo evaluate the efficacy and safety of aromatase inhibitor letrozole in treatment of male adolescents with idiopathic short stature (ISS). MethodSeventy five boys with height less than 2 standard deviation (SD) below the mean who had entered puberty were enrolled in our study from 2004 to 2017, in the Pediatric Department of the First Affiliated Hospital, Sun Yat-Sen University. Among 75 patients, 28 in letrozole group received letrozole and spironolactone, 30 in gonadotrophin releasing hormone analogue (GnRHa) group received GnRHa injection and 17 had no intervention. Height velocity (HV), increment of bone age/chronological age (ΔBA/ΔCA), the final adult height (FAH) were compared among groups and the safety of letrozole treatment was evaluated. ResultsHV maintained faster during letrozole treatment when compared with other groups. HV during GnRHa treatment showed slightly decline in the first 6 months, but decreased remarkably after 6 months, and was significantly lower than that in letrozole group ( P < 0.05). The maturation of BA slowed down in both letrozole and GnRHa groups. But the ΔBA/ΔCA in letrozole group during the first and the second year of treatment were significantly higher (0.67±0.09, 0.50±0.15, respectively) when compared with GnRHa group (0.59±0.16, 0.44±0.13, respectively) ( t=2.78 and 2.20, all P < 0.05). FAH in letrozole group and GnRHa group were (170±4) cm and (170±6)cm, there was no significant differences between the two groups ( P>0.05), and both were higher than that in no intervention group (162±4 cm, P < 0.01). After 6 months of letrozole treatment, testicular volumes and serum testerone levels increased; 39.2% (11/28) boys had clinical manifestations of hyperandrogenemia, and 82.1% (23/28) boys had decreased serum high-density lipoprotein (HDL) levels. Serum levels of HDL and testerone returned normal and the hyperandrogenemia disappeared after the cessation of letrozole treatment. No significant changes in serum triglyceride, serum low-density lipoprotein (LDL), fating serum levels of insulin and glucose, HOMA-IR were observed. No abnormal liver function, myalgia, scoliosis or aggravations of scoliosis was found. ConclusionsLong term letrozole therapy during puberty in boys with ISS can delay bone maturation without significant decrease of linear growth, and thus can improve the final adult height. No severe adverse reactions were found.

The pubertal development mode of Chinese girls with turner syndrome undergoing hormone replacement therapy.

BACKGROUND: Further knowledge about the pubertal development mode of girls with Turner syndrome (TS) who have undergone hormone replacement therapy (HRT) is beneficial to the proposal of an optimal HRT regimen. This study examined the pubertal development mode of girls with TS who underwent HRT and evaluated the characteristics of optimal sex induction therapy in girls with TS. METHOD: We conducted a retrospective, longitudinal study over the past two decades at The First Affiliated Hospital, Sun Yat-sen University. PATIENTS: Seventy-one patients with TS and two groups of normal Chinese girls. RESULTS: The total investigation time was 3.00 (2.00, 4.66) years. The interval of each stage was significantly longer (P < 0.001) in the girls with TS than that in the normal Chinese girls, except for B2-3 (P = 0.011). The uterine volumes of the girls with TS in stages B2 and 3 were greater than those of the control group (P = 0.046), whereas the uterine volume of the control group was inversely greater than that of the TS group among those who reached stages B4 and 5 (P = 0.034). During HRT, the uterine volume grew significantly from all previous stages except for breast stage 5 (B3 vs.2: Z = - 2.031; P = 0.042; B4 vs. 3: Z = - 2.273; P = 0.023; B5 vs. 4: Z = - 1.368; P = 0.171). The paired data of 27 girls with TS showed that the uterine volume (17.93 ± 9.31 ml vs. 13.75 ± 6.67 ml) and width (2.54 ± 0.66 cm vs. 2.22 ± 0.36 cm) increased significantly during artificial cycles compared with before artificial cycles (t = - 2.79 and - 2.51, P = 0.01 and 0.018). CONCLUSION: HRT led to normal breast development in girls with TS; half of the girls with TS in our study reached Tanner stage B5, although the uterus ultimately developed suboptimally. The girls' breasts and uteruses grew quickly at the beginning of HRT (stages B2-4). An optimal HRT regimen for girls with TS may specifically focus on Tanner stages B2-4 and artificial cycles.

Low serum adiponectin levels are associated with reduced insulin sensitivity and lipid disturbances in short children born small for gestational age.

BACKGROUND: Being born as small for gestational age (SGA) has an increased risk of developing metabolic/cardiovascular disturbances in later life. The role of adiponectin in the metabolic disturbance in SGA children remained undefined. OBJECTIVE: The aim of this study was to investigate the association between serum levels of adiponectin and insulin sensitivity as well as lipid profile in short children born SGA at prepubertal ages. PATIENTS AND METHODS: Serum levels of adiponectin, fasting glucose, insulin, IGF-I, IGFBP-1, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), apolipoprotein A-I (ApoA-I) and Apo B were measured in 30 prepubertal short children born SGA. Insulin resistance (IR) and ß-cell function were assessed using the method of homeostatic model (HOMA). Data were compared to those of 30 short appropriate for gestational age (AGA) children matched for age, gender, height and body mass index, and correlation analysis was performed. RESULTS: Short SGA children had significantly higher levels of fasting insulin, HOMA-IR and HOMA-ß but lower levels of adiponectin than short AGA controls. No significant differences in the level of IGFBP-1 and IGF-I were found between the two groups. Serum levels of TC, TG, Apo B and Apo B/ApoA-I ratio were significantly higher in SGA, with 33% of hypercholesteraemia and 23% of hyperglyceridaemia. Stepwise multiple regression analysis revealed that serum adiponectin level was negatively correlated with HOMA-IR and TG and was positively correlated with birthweight SDS in SGA children. CONCLUSIONS: These findings suggest that low serum adiponectin levels are associated with reduced insulin sensitivity and unfavourable lipid profiles in short children born SGA at prepubertal ages.

Therapeutic effects of growth hormone combined with low-dose stanozolol on growth velocity and final height of girls with Turner syndrome.

OBJECTIVE: Turner syndrome (TS), which is characterized by short stature and gonadal dysfunction, is managed by pharmacotherapy. This study aimed to investigate the therapeutic effects of recombinant human growth hormone (rhGH) combined with low-dose stanozolol on the growth and final adult height (FAH) of girls with Turner syndrome (TS). DESIGN: Prospective study. PATIENTS: A total of 44 girls with TS were treated with rhGH (47·6-52·4 µg/kg/day) and low-dose stanozolol (20-35 µg/kg/day), starting at a mean age of 12·65 ± 1·99 year. The control group consisted of 22 girls with TS, who did not receive treatment. MEASUREMENTS: Subjects' growth velocity (GV) was investigated. Height standard deviation score (HtSDS) was calculated relative to healthy Chinese girls (HtSDSN or ) as well as untreated Chinese girls with TS (HtSDSTS ). Post-treatment follow-up was performed until the subjects achieved FAH or near FAH. RESULTS: FAH was significantly higher in subjects receiving treatment compared to the untreated controls (151·42 vs 137·75 cm, P < 0·001). GV was significantly higher in the first to fourth years of treatment compared to baseline values (P < 0·001); it was significantly lower in the second to fourth years of treatment compared to the first year (P < 0·001). CONCLUSIONS: In girls with TS, 9-12 years of age, rhGH combined with low-dose stanozolol may effectively increase growth. At least a 2-year course of this treatment may effectively improve FAH with proper delay of oestrogen-induced development.

Complete androgen insensitivity syndrome coexisting with müllerian duct remnants: a case report and literature review.

This study represents the first documentation of the coexistence of complete androgen insensitivity syndrome (CAIS) with Müllerian duct remnants (MDRs) in mainland China. Additionally, we provide a comprehensive review of the existing literature concerning CAIS with MDRs resulting from androgen receptor (AR) gene mutations. This study broadens the clinical spectrum of CAIS and offer novel insights for further exploration into Müllerian duct regression. A 14-year-old patient, initially raised as female, presented to the clinic with complaints of "primary amenorrhea." Physical examination revealed the following: armpit hair (Tanner stage 2), breast development (Tanner stage 4 with bilateral breast nodule diameter of 7 cm), sparse pubic hair (Tanner stage 3), clitoris measuring 0.8 cm × 0.4 cm, separate urethral and vaginal openings, and absence of palpable masses in the bilateral groin or labia majora. The external genital virilization score was 0 points. Serum follicle-stimulating hormone level was 13.43 IU/L, serum luteinizing hormone level was 31.24 IU/L, and serum testosterone level was 14.95 nmol/L. Pelvic magnetic resonance imaging (MRI) did not reveal a uterus or bilateral fallopian tubes, but nodules on both sides of the pelvic wall indicated cryptorchidism. The karyotype was 46,XY. Genetic testing identified a maternal-derived hemizygous variation c.2359C > T (p.Arg787*) in the AR gene. During abdominal exploration, dysplastic testicles and a dysplastic uterus were discovered. Histopathological analysis revealed the presence of fallopian tube-like structures adjacent to the testicles. The CAIS patient documented in this study exhibited concurrent MDRs, thus expanding the spectrum of clinical manifestations of AIS. A review of prior literature suggests that the incidence of CAIS combined with histologically MDRs is not uncommon. Consequently, the identification of MDRs in AIS cases may represent an integral aspect of clinical diagnosis for this condition.

Long-term Pegylated GH for Children With GH Deficiency: A Large, Prospective, Real-world Study.

CONTEXT: The evidence of long-term polyethylene glycol recombinant human GH (PEG-rhGH) in pediatric GH deficiency (GHD) is limited. OBJECTIVE: This study aimed to examine the effectiveness and safety of long-term PEG-rhGH in children with GHD in the real world, as well as to examine the effects of dose on patient outcomes. DESIGN: A prospective, observational, posttrial study (NCT03290235). SETTING, PARTICIPANTS AND INTERVENTION: Children with GHD were enrolled from 81 centers in China in 4 individual clinical trials and received weekly 0.2 mg/kg/wk (high-dose) or 0.1 to <0.2 mg/kg/wk (low-dose) PEG-rhGH for 30 months. MAIN OUTCOMES MEASURES: Height SD score (Ht SDS) at 12, 24, and 36 months. RESULTS: A total of 1170 children were enrolled in this posttrial study, with 642 patients in the high-dose subgroup and 528 in the low-dose subgroup. The Ht SDS improved significantly after treatment in the total population (P < 0.0001), with a mean change of 0.53 ± 0.30, 0.89 ± 0.48, 1.35 ± 0.63, 1.63 ± 0.75 at 6 months, 12 months, 24 months, and 36 months, respectively. In addition, the changes in Ht SDS from baseline were significantly improved in the high-dose subgroup compared with the low-dose subgroup at 6, 12, 24, and 36 months after treatment (all P < 0.05). A total of 12 (1.03%) patients developed serious adverse events. There was no serious adverse event related to the treatment, and no AEs leading to treatment discontinuation or death occurred. CONCLUSIONS: PEG-rhGH showed long-term effectiveness and safety in treating children with GHD. Both dose subgroups showed promising outcomes, whereas PEG-rhGH 0.2 mg/kg/wk might show additional benefit.

[Rapid prenatal genetic diagnosis of a fetus with a high risk for Morquio A syndrome].

OBJECTIVE: To provide rapid and accurate prenatal genetic diagnosis for a fetus with high risk of Morquio A syndrome. METHODS: Based on ascertained etiology of the proband and genotypes of the parents, particular mutations of the GALNS gene were screened at 10th gestational week with amplification refractory mutation system (ARMS), denaturing high performance liquid chromatography (DHPLC), and direct DNA sequencing. RESULTS: DHPLC screening has identified abnormal double peaks in the PCR products of exons 1 and 10, whilst only a single peak was detected in normal controls. Amplification of ARMS specific primers derived a specific product for the fetus's gene, whilst no similar product was detected in normal controls. Sequencing of PCR products confirmed that exons 1 and 10 of the GALNS gene from the fetus contained a heterozygous paternal c.106-111 del (p.L36-L37 del) deletion and a heterozygous maternal c.1097 T>C (p.L366P) missense mutation, which resulted in a compound heterozygote status. CONCLUSION: The fetus was diagnosed with Morquio A syndrome and a genotype similar to the proband. Termination of the pregnancy was recommended. Combined ARMS, DHPLC and DNA sequencing are effective for rapid and accurate prenatal diagnosis for fetus with a high risk for Morquio A syndrome. Such methods are particularly suitable for early diagnosis when pathogenesis is clear. Furthermore, combined ARMS and DHPLC are suitable for rapid processing of large numbers of samples for the identification of new mutations.

Pleomorphism of the HPG axis with NR0B1 gene mutation - a case report of longitudinal follow-up of a proband with central precocious puberty.

OBJECTIVES: X-linked adrenal hypoplasia congenita (AHC) is characterized by adrenal insufficiency and hypogonadotropic hypogonadism. Herein, we report a rare case of X-linked AHC with central precocious puberty (CPP). CASE PRESENTATION: An 11-month-old male patient was found to have premature pubarche, enlargement of the penis, and frequent erection. LH and FSH levels after the GnRHa test were in the pubertal range. Direct sequencing revealed a heterozygous variant of the NR0B1 gene. The proband was treated with hydrocortisone and 9-alpha fludrocortisone because of the significantly elevated ACTH and renin activity. The secondary sexual characteristics relieved gradually. The serum testosterone and LH subsequently returned to the prepubertal range. The basal serum FSH values have been between 1.0 and 2.0 IU/L since the age of 2.25 years, with extremely low AMH levels beginning at 3 years. CONCLUSIONS: The clinical course of CPP with NR0B1 variant may be temporary. HPG axis status of X-linked AHC may probably be pleomorphic during the longitudinal follow-up.

Gonadal Y-chromosome mosaicism with 45, X Turner syndrome complicated with bilateral HCG-secreting gonadoblastoma.

We report a rare case of bilateral HCG-secreting gonadoblastomas (Gb) in a 5.25-year-old girl of 45, X Turner syndrome (TS) with gonadal Y chromosome mosaicism. The clinical data were summarized, and the literatures were reviewed. The patient had enlarged breasts for 2 years and 3 months, with elevated ß-HCG of blood found for 8 months. The level of ß-HCG of cerebrospinal fluid, cranial MRI, chest and abdominal CT, and pelvic MRI were normal. After surgical gonad exploration, biopsy and excision, gonad venous blood hormone examination and SRY gene detection of gonad tissue, the diagnosis was confirmed as HCG-secreting Gb (bilateral) and TS (45, X) with gonad Y chromosome mosaicism. The patient received 4 courses of chemotherapy, and regular outpatient follow-up. At 9 months after gonadectomy, there was no clinical, laboratory, or radiological evidence of recurrence. We reported a nonclassical case of 45, X Turner syndrome (TS) with gonadal Y chromosome mosaicism, who presented with breast development as the first manifestation and then virilization due to bilateral HCG-secreting gonadoblastomas. Detection of serum ß-HCG and AFP is requisite for the diagnosis of precocious puberty, karyotyping is important for virilizing phenotypic female, and virilization in Turner syndrome implies the existence of Y chromosome(substance) (peripheral blood or tissue mosaicism) and the occurrence of gonadal tumors.

Association between height and weight catch-up growth with insulin resistance in pre-pubertal Chinese children born small for gestational age at two different ages.

This study was performed to test whether children born small for gestational age (SGA) with catch-up growth (CUG) could be associated with the early development of insulin resistance and the ß-cell dysfunction and to explore the impacts of height CUG and weight CUG on the insulin resistance in a Chinese population. A total of 30 children born SGA with CUG, 37 non-CUG (NCUG), and 42 born appropriate for gestational age (AGA) with normal height were recruited. Their fasting serum insulin, fasting glucose, insulin-like growth factor-1 (IGF-1) concentrations, and the homeostasis assessment model for insulin resistance (HOMA-IR) and ß-cell function (HOMA%) were evaluated. The values of HOMA-IR in CUG SGA were significantly higher than that in NCUG SGA (P = 0.002) and AGA children (P = 0.036), respectively. Correlation analysis revealed that the concentrations of fasting serum insulin were positively correlated with IGF-1 (r = 0.443, P = 0.001) and Δheight standard deviation score (SDS; r = 0.500, P = 0.002) in ≤ 6-year-old SGA children, but only with Δweight SDS (r = 0.496, P = 0.030) in >6-year-old children. In conclusion, SGA children with CUG in height and a higher body mass index are prone to the development of insulin resistance. Higher levels of insulin were closely correlated with the postnatal height CUG in young SGA children and with the weight CUG in old children.

Epidermal growth factor receptor signalling mediates growth hormone-induced growth of chondrocytes from sex hormone-inhibited adolescent rats.

1. Growth hormone (GH) has been demonstrated to overcome the inappropriate deceleration of growth rate in children with central precocious puberty treated with gonadotropin-releasing hormone analogue (GnRHa). However, the underlying mechanisms remain largely unclear. In the present study, we investigated the potential involvement of the epidermal growth factor receptor (EGFR) pathway in the growth promotion by GH using in vitro cultured growth plate chondrocytes isolated from adolescent rats treated with GnRHa. 2. Chondrocytes were stimulated with GH in the presence or absence of the Janus tyrosine kinase (JAK) 2 inhibitor AG490 (1, 10 and 100 nmol/L), the EGFR kinase inhibitor AG1478 (0.1, 1 and 10 nmol/L), U0126 (an inhibitor of extracellular signal-regulated kinase (Erk) activation; 10 µmol/L) or a neutralizing antibody against epidermal growth factor (EGF Ab; 0.1, 1 and 10 µg/mL). The proliferation of chondrocytes was assessed by the 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide assay and immunostaining for proliferating cell nuclear antigen (PCNA). Phosphorylation of Erk1/2 and EGFR was detected by western-blotting. Intracellular mRNA and extracellular protein levels of EGF were detected using reverse transcription-polymerase chain reaction and ELISA, respectively. 3. Growth hormone promoted the proliferation of chondrocytes, which was correlated with increased phosphorylation of Erk1/2 and EGFR and enhanced expression of EGF. Pretreatment with AG490, AG1478, U0126 or EGF Ab completely or partially inhibited the proliferation of chondrocytes and activation of Erk1/2 and EGFR. Pretreatment with AG490, AG1478, or U0126 partially inhibited the expression of EGF. 4. The findings indicate that GH promotes chondrocyte proliferation by activating EGFR signalling.

Clinical characteristics of adrenocortical tumors in children.

BACKGROUND: Adrenocortical tumors (ACTs) are rare in children. Because of the rarity and various manifestations of ACTs, patients of ACTs are not easily diagnosed. Some patients were misdiagnosed before surgery. OBJECTIVE: Identify the clinical, laboratorial, imaging and histopathological characteristics of adrenocortical tumors in children. Compare adrenalcortical adenoma with carcinoma. METHODS: A retrospective review of 34 identified patients who were younger than 15 years old with histologic confirmation of adrenocortical carcinoma (ACC) or adenomas from 1991 to 2010. RESULTS: In these 34 patients, 19 were adrenocortical adenoma (ACA) and 15 were ACC. The median age at diagnosis was 3.33 years (range, 0-16 years), and 70.6% of the patients were younger than five years. Girls slightly predominated over boys (1.4:1). For endocrine abnormality, 14 patients had isolated precocious puberty, five patients had isolated Cushing syndrome, 10 patients had precocious puberty plus Cushing syndrome, and five patients did not have any symptoms. The most frequent findings in laboratory tests were disturbance of the normal circadian rhythm of cortisol secretion (93.8%), followed by elevated serum level of testosterone (89.7%). Only 3.8% of ultrasound diagnosis and 12.1% of computed tomography (CT) diagnosis were consistent with pathologic diagnosis. CONCLUSION: Different from those in adult, the most frequent presentation in children with ACTs is peripheral precocious puberty with or without Cushing syndrome, and isolated Cushing syndrome. Few present with non-functional local mass. Laboratory tests usually reveal the discordantly elevated serum levels of sexual corticosteroid hormones, change of diurnal rhythm of cortisol or increase of morning cortisol. The differentiation of malignant from benign tumor cannot merely depend on imaging. Final diagnosis relies on comprehensive evaluation of clinical manifestations, laboratory data, imaging and pathology.

Stanozolol regulates proliferation of growth plate chondrocytes via activation of ERalpha in GnRHa-treated adolescent rats.

Improving the final adult height is one of the most important aims for treatment of central precocious puberty. Stanozolol (ST) is a synthetic derivative of androgen. In this study, we investigated the effects and the mechanisms of ST on the proliferation of growth plate chondrocytes isolated from adolescent rats treated with gonadotropin-releasing hormone analogue (GnRHa). Treatment with ST resulted in time- and concentration-dependent effects on proliferation as determined by MTT and proliferating cell nuclear antigen (PCNA) assays. Western blotting showed that ST increased the phosphorylation level of the estrogen receptor alpha (ERalpha), but not the androgen receptor (AR). Pharmacological inhibition of ERalpha and mitogen-activated protein kinase (MAPK) attenuated the effects of ST on the proliferation of growth plate chondrocytes. A molecular dynamics simulation showed hydrophobic interactions between ST and ERalpha. These results suggested that ERalpha, but not AR, partially mediates the ST-driven proliferation of growth plate chondrocytes, and that multiple pathways may be involved in the mechanism of action of ST.

A Multicenter Survey of Type I Diabetes Mellitus in Chinese Children.

Purpose: To investigate the features and treatment status of children with type 1 diabetes mellitus (T1DM) in China. Methods: We recruited patients <14 years of age with T1DM from 33 medical centers in 25 major cities of China between January 2012 and March 2015. All patients completed a questionnaire that was conducted by their pediatric endocrinologists at all centers. Results: A total of 1,603 children (755 males and 848 females) with T1DM participated in this survey. Of these, 834 (52.03%) of the patients exhibited diabetic ketoacidosis (DKA) at onset, while 769 patients (47.97%) did not exhibit DKA (non-DKA) at onset. There was a higher proportion of females (55.71%) in the cohort of patients exhibiting DKA at onset than in the non-DKA cohort (49.33%). The mean age of patients exhibiting DKA at presentation was 7.12 ± 0.14 years; this was significantly younger than that in non-DKA group (7.79 ± 0.15 years; P < 0.005). The frequency of DKA in 3 years old, 3-7 years old, and 7 years old or more was 77.21%, 26.17%, and 37.62%, respectively. Upon initial diagnosis, 29.4%, 15.2% and 11.8% of patients showed positivity for glutamic acid decarboxylase antibody (GADA), Insulin autoantibodies (IAA), or islet cell antibody (ICA), respectively. During six months follow-up, 244 patients (15.21%) reported receiving insulin pump therapy, and more than 60% of patients monitored their blood glucose levels less than 35 times per week. Although the majority of patients had no problems with obtaining insulin, 4.74% of the children surveyed were not able to receive insulin due to financial reasons, a shortage of insulin preparations, or the failure of the parents or guardians to acquire the appropriate medicine. Conclusion: DKA is more common in very young children. Treatment and follow-up of T1DM in China still face very serious challenges.

Novel genotypes and phenotypes among Chinese patients with Floating-Harbor syndrome.

BACKGROUND: Floating-Harbor syndrome (FHS) is a rare syndromic short stature disorder caused by truncating variants in SRCAP. Few Chinese FHS patients had been reported so far and limited knowledge regarding the benefit of growth hormone treatment existed. METHODS: We ascertained 12 short stature patients with molecularly confirmed diagnosis of FHS by whole exome sequencing. We performed a comprehensive clinical evaluation for all patients and assessed the responsiveness of growth hormone treatment in a subset of the patients. RESULTS: Five distinct pathogenic/likely pathogenic variants were identified in 12 independent FHS patients including two previously reported variants (c.7303C > T/p.Arg2435Ter and c.7330C > T/p.Arg2444Ter) and three novel variants (c.7189G > T/p.Glu2397Ter, c.7245_7246delAT/p.Ser2416ArgfsTer26 and c.7466C > G/p.Ser2489Ter). The c.7303C > T/p.Arg2435Ter mutation appears more common in Chinese FHS patients. The clinical presentations of Chinese FHS patients are very similar to those of previously reported patients of different ethnicities. Yet we noticed micropenis and ear abnormalities in multiple patients, suggesting that these may be novel phenotypes of Floating-Harbor syndrome. Eight patients (one with GH deficiency, one with undetermined GH level, six without GH deficiency) underwent growth hormone treatment, 3 patients had good responses, one with modest and two with poor responses. CONCLUSION: We described novel genotypes and phenotypes in a Chinese FHS patient cohort. We showed that about half of FHS patients exhibited modest to good response to GH treatment regardless of their respective GH deficiency status. We didn't find any correlation between different mutations and response to GH treatment.

Postreceptor crosstalk on PI3K/Akt between GH and insulin in non-catch-up growth rats born small for gestational age.

BACKGROUND/AIMS: Children born small for gestational age (SGA) are at increased risk for short stature and type 2 diabetes mellitus as a result of growth hormone (GH) resistance and insulin resistance. The mechanisms of multiple hormone resistance remain unclear. This study was designed to investigate the relationship between GH resistance and insulin resistance in non-catch-up growth (NCU-SGA) rats, and how their signaling pathways are related based on their crosstalk on the insulin receptor substrate-1 phosphatidylinositol 3'-kinase (IRS-1-PI3K) pathway. METHODS: NCU-SGA rat model was developed by restricting prenatal food intake in pregnant dams. Activated levels of IRS-1 and Akt in liver protein extracts were compared between NCU-SGA and age- and sex-matched controls born appropriate for gestational age rats at baseline, after insulin stimulation, and after pretreatment with AG490 (GH-JAK2 pathway inhibitor) followed by insulin stimulation. RESULTS: GH secretion was positively related to markedly increased insulin levels in NCU-SGA rats. There was no difference of IRS-1 phosphorylation in response to insulin between two groups, however, insulin-stimulated Akt phosphorylation was attenuated in NCU-SGA rats compared to appropriate for gestational age rats. Pretreatment with AG490 restored the Akt response to insulin demonstrated by significantly increased Akt phosphorylation. CONCLUSION: GH plays a role in inducing insulin resistance via signaling crosstalk with insulin at the level of PI3K/Akt in NCU-SGA rats.

[Correlation between growth hormone/insulin-like growth factor-1 resistance and insulin resistance in non catch-up growth rats born small for gestational age].

OBJECTIVE: To investigate the post-receptor signaling mechanism responsible for insulin resistance-induced growth hormone (GH) resistance in non-catch-up (NCU) growth rats born small for gestational age (SGA). METHODS: Twenty pregnant female SD rats were fed with restricted food (40% of normal intake, 9 g/d) throughout the pregnancy so as to develop NCU-SGA rats. The rats with their length and body weight < or = -2SD were out into the NCU-SGA group, and those with their length and body weight > -2SD were out into the catch-up (CU) growth group. Rats born to normally-fed pregnant rats were set as normal control (control Group, C Group, n = 17). The body weight and length were measured every 2 weeks. At the age of 4 weeks, 24 h urine was collected to measure the urine GH (U-GH). Then blood samples were collected to measure the serum insulin-like growth factor-1 (IGF-1), fasting insulin (FINS), and glucose levels, and the liver was taken out to detect the expression of STAT5 signal. Twelve 3-week NCU-SGA rats were divided into 2 equal groups: P13K blocking group, undergoing intraperitoneal injection of LY294002, blocker of P13K twice every 3 days, and solvent control group, undergoing intraperitoneal injection of DMSO. At the age of 4 weeks, blood samples were collected and then the liver was taken out to detect the IGF-1 mRNA and STAT5 signal. RESULTS: (1) The body weight and length at birth of the NCU-SGA group were (4.4 +/- 0.5) g and (4.5 +/- 0.2) cm, both significantly lower than those of Group C [(6.8 +/- 0.6) g and (5.3 +/- 0.2) cm respectively], and the body weight and length at 4 weeks of age of the NCU-SGA group were (63 +/- 12) g and (13.2 +/- 1.0) cm respectively, both significantly lower than those of the C group [(88 +/- 12) g and (15.3 +/- 0.5) cm respectively, all P < 0.01]. The serum IGF-1 level, IGF-1 mRNA expression, and total and phosphate STAT5 level in liver of the NCU-SGA group were (248 +/- 58) ng/ml, (6.1 +/- 0.3) copies, and (61 +/- 22)% respectively, all significantly lower than those of the C group [(383 +/- 62) ng/ml, (6.6 +/- 0.4) copies, and (91 +/- 29)%, all P < 0.01]. There was no statistic difference in 24 h U-GH between the NCU-SGA and C groups (P > 0.05). The FINS and glucose level of the NCU-SGA group were (24.7 +/- 9.6) mU/ml and (5.4 +/- 0.3) mmol/L respectively, both significantly higher than those of the C group [(9.8 +/- 2.8) mU/ml and (4.5 +/- 1.7) mmol/L respectively, both P < 0.05]. The level of 24 h U-GH was positively correlated with FINS (r = 0.680, P = 0.000). No correlation was found between IGF-1 and fasting insulin level. (2) After the PI3K pathway was chronically blocked, the NCU-SGA rats lost weight and developed a more severe insulin resistance, decreased serum IGF-1 level and the IGF-1 mRNA expression level of the PI3K inhibitor group were (218 +/- 60) ng/ml and (6.1 +/- 0.3) copies respectively, both significantly lower than those of the solvent control group [(286 +/- 45) ng/ml and (6.3 +/- 0.3) copies, both P < 0.05]. No statistically significant difference in total and phosphate STAT5 levels in liver between the P13K blocker and solvent groups. CONCLUSION: GH resistance is closely associated with insulin resistance in the NCU-SGA rats. GH resistance-induced failure of catch-up growth is related to the impairment of JAK2-STAT5 pathway. Insulin resistance exacerbates growth axis resistance and growth retardation in NCU-SGA rats via a non-STAT5 dependent pathway.

[Estrogen stimulates cell proliferation and regulates the expression of proteins in C-type natriuretic peptide signaling pathway during chondrogenesis in ATDC5 cells].

OBJECTIVE: To investigate the effect of estrogen on cell proliferation and expression of proteins of C-type natriuretic peptide (CNP), natriuretic peptides B receptor (NPR-B) and natriuretic peptides C receptor (NPR-C) in ATDC5 cells during chondrogenesis. METHOD: ATDC5 cells were induced for differentiation with insulin 10 µg/ml (day 0), and were started to be investigated on day 6. They were incubated with: (1) Estradiol (E2) at different concentrations (10(-11)-10(-5) mol/L) for 24 hours (for studying cell proliferation), or for 48 hours (for studying CNP, NPR-B and NPR-C protein expression); (2) E2 (10(-8) mol/L) for 24, 48, 72, 96 and 120 h (for studying cell proliferation), or for 24, 48, 72 and 96 hours (for studying CNP, NPR-B and NPR-C protein expression); (3) E2 (10(-8) mol/L) , and/or ICI 182782 (estrogen receptor antagonist ) (10(-7) mol/L) for 24 hours (for studying cell proliferation). ATDC5 cells proliferation were determined by MTT (OD value). Western-blotting was performed to identify the protein levels of CNP, NPR-B and NPR-C. RESULT: (1) After incubation with E2 (10(-11)-10(-5) mol/L) for 24 h, ATD5 cell number increased with the increasing E2 concentration, peak in E2 concentrations of 10(-9) and 10(-8) mol/L (0.56 ± 0.06 and 0.52 ± 0.02, P < 0.05 and <0.01, respectively) , while significantly decreased in E2 (10(-5) mol/L) (0.30 ± 0.02) compared with DMSO-control (0.38 ± 0.02) (P < 0.05). After incubation with E2 (10(-11)-10(-5) mol/L) for 48 h, the protein level of CNP, NPR-B and NPR-C increased significantly, with the greatest effect seen at a concentration of 10(-10) mol/L E2 for CNP and NPR-B, 10(-9) mol/L E2 for NPR-C (P < 0.05). (2) After incubation with E2 (10(-8) mol/L) for 24 to 96 hours: (1) The cell number in each of the four time points was significantly increased compared with DMSO-control, with the greatest effect in 48 h (0.030 ± 0.003) (P < 0.05 or <0.01, respectively). While the cell number at 120 h was similar to that in DMSO-control. (2) The protein level of CNP increased significantly at 24 h (P < 0.05), seemed to be increased at 48 h and 72 h and decreased at 96 h. Both NPR-B and NPR-C level seemed to be increased at 24 h (P = 0.060 and 0.055, respectively) and seemed to decrease at 48 h, with decreasing significantly at both 72 h and 96 h (P < 0.05). (3) After incubation for 24 h, there was significant difference among the cell number of the four groups (P < 0.05). Cell number of group E2 (0.470 ± 0.032) was increased compared with group (E2+ICI) (0.410 ± 0.018), both being increased compared with group DMSO-control (0.370 ± 0.011, P < 0.05, respectively). There was no difference in cell number between group ICI 182782(0.360 ± 0.035) and group DMSO-control. CONCLUSION: E2 promotes the proliferation of ATDC5 cells i.e. chondrogenesis via estrogen receptor mediated mechanism, in both concentration-dependent and time-dependent manner. E2 (10(-11)-10(-8) mol/L) up-regulates protein expression of CNP, NPR-B and NPR-C of ATDC5 cells during chondrogenesis, and regulate the expression of the three proteins mentioned above positively or negatively at different time point, which implied that estrogen is one of the regulators of CNP signaling pathway.