[Clinical characteristics and prognosis of five children with maturity onset of diabetes of the young 12 subtype].

Objective: To analyze the genetic and clinical characteristics, treatment and prognosis of patients diagnosed with maturity onset of diabetes of the young (MODY) 12 subtype. Methods: This retrospective study collected and analyzed data from 5 children with MODY12 subtype caused by ABCC8 gene variants who underwent inpatient and outpatient genetic testing at Beijing Children's Hospital from January 2016 to December 2023. Their clinical and genetic features, treatment, and follow-up results were analyzed. Results: Among the 5 patients with MODY12 subtype, 4 were male and 1 was female, with an age of 13.4 (5.5, 14.6) years. Four of the patients were born large for gestational age, while one was born small for gestational age. Two patients were overweight or obese. Three patients exhibited typical symptoms of diabetes, while 2 were incidentally found to have elevated blood glucose level. One patient was found to have diabetic ketoacidosis at onset, who was diagnosed with congenital hyperinsulinism during the neonatal period and received diazoxide treatment, and experienced intellectual developmental delay. All 5 patients had autosomal dominant inherited diabetes within 3 generations. The fasting blood glucose at onset was 7.5 (6.5, 10.0) mmol/L, the haemoglobin, A1c (HbA1c) was 11.8% (7.5%, 13.5%), and the fasting C-peptide was 1.2 (1.1, 2.2)µg/L. The duration of follow-up was 15 (9, 32) months. One patient underwent lifestyle intervention, two received metformin orally, one received insulin therapy, and the other received subcutaneous injection of insulin combined with sulfonylurea orally. At the last follow-up, the median fasting blood glucose was 6.1 (5.1, 7.0) mmol/L, the HbA1c was 5.9% (5.7%, 7.1%), and the fasting C-peptide was 1.7 (0.9, 2.9)µg/L. One patient developed diabetic retinopathy. There were 4 missense variations in ABCC8 gene and one in-frame deletion, all of which were maternally inherited heterozygotes. Conclusions: MODY12 subtype is a heterogeneous disorder with the age of onset from infancy to adolescence. It can present as mild hyperglycemia or diabetic ketoacidosis, and has a high incidence of obesity. Definitive diagnosis can be achieved through genetic test, and individualized treatment is recommended based on glucose levels.

[Efficacy of recombinant human growth hormone treatment in children born small for gestational age with syndromic and non-syndromic short stature].

Objective: To analyse the efficacy of recombinant human growth hormone (rhGH) treatment in children born small for gestational age (SGA) with syndormic and non-syndormic short stature. Methods: The clinical data of 59 children born SGA who were diagnosed as short stature and admitted to the Center of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital from July 2012 to June 2021 were collected and analyzed. According to the 2019 consensus on short stature, they were divided into syndromic group and non-syndromic group. Before treatment and 6, 12, 18 and 24 months after treatment, height standard deviation score (Ht-SDS), difference of height standard deviation (∆Ht-SDS) and homeostasis model assessment-insulin resistance index (HOMA-IR) were compared between groups, while Ht-SDS and HOMA-IR were compared before and after treatment. Independent t test or Kruskal-Wallis test were used for comparison between the 2 groups, and paired t test or Mann-Whitney U test were used for the intra-group comparison. Results: Among the 59 cases, 37 were males and 22 females, aged (5.5±2.3) years. There was no significant difference in Ht-SDS after 12 months of treatment between 2 groups (0.9±0.4 vs. 1.2±0.4, t=1.68, P=0.104) or in height SDS after 24 months of treatment (1.4±0.7 vs. 1.9±0.5, t=1.52, P=0.151). After 12 months of treatment, the insulin resistance index of the non-syndromic group was significantly higher than that of the syndromic group (2.29 (1.43, 2.99) vs. 0.90 (0.55, 1.40), Z=-2.95, P=0.003). There were significant differences in Ht-SDS between 6 months and before treatment, 12 months and 6 months in syndromic type (Z=7.65, 2.83 P<0.001, P=0.020), but all were significant differences in non-syndromic type between 6 months and before treatment, 12 months and 6 months, 18 months and 12 months, 24 months and 18 months (Z=11.95, 7.54, 4.26, 3.83, all P<0.001). Conclusion: The efficacy of rhGH treatment in children born SGA is comparable between syndromic and non-syndromic short stature cases, but non-syndromic children treated with rhGH need more frequent follow-up due to the risk of insulin resistance.

[Consistency evaluation of 2 methods in detecting serum insulin-like growth factorâ in children].

Objective: To evaluate the consistency of mass spectrometry (MS) and chemiluminescence immunoassay (CLIA) in detecting serum insulin-like growth factor-1 (IGF-1) and IGF-1 standard deviation score (SDS). Methods: This cross-sectional parallel control study prospectively collected the serum samples of 115 children with short stature disorders who were admitted in the Department of Endocrinology, Beijing Children's Hospital, Capital Medical University from February 2020 to December 2021. The serum IGF-1 level was detected by CLIA and MS, and converted to SDS for consistency analysis. Pearson analysis was used to analyze the correlation between the 2 methods, and Deming regression equation was established. Bland-Altman diagram and weighted Kappa coefficient were used to evaluate the consistency of the 2 methods. Results: There were 46 boys (40.0%) and 69 girls (60.0%), aged (8±3) years. Among the 115 cases, 37 were Turner syndrome, 59 were small for gestational age (SGA) at term, 1 was growth hormone deficiency (GHD) and 18 were other diseases. Pearson correlation analysis showed a preferable correlation between IGF-1 measured by the 2 detection methods (r=0.94, P<0.01), and IGF-1 SDS was also significantly correlated (r=0.92, P<0.01). Bland-Altman analysis showed that the consistency of serum IGF-1 levels detected by the 2 methods was poor, and the mean difference between CLIA and MS was 33.38 µg/L. The result detected by CLIA was significantly higher than that by MS, with SDS of 43.51 µg/L (95%CI -51.89-118.7 µg/L). After converting the results to SDS and removing 3 outliers (including 1 GHD patient), the weighted Kappa showed acceptable consistency (κ=0.68). Conclusion: In clinical application, after converting to IGF-1 SDS, IGF-1 detected by MS and CLIA can be used for cross-reference, but too high or too low levels should be cautious about.

[Changing prevalence of overweight and obesity among Chinese children aged 6-15 from 2009-2019].

Objective: To analyze the trends of overweight and obesity prevalence in Chinese children, aged from 6 to 15 years old among 4 provinces and cities from 2009 to 2019. Methods: Reviewed the national multi-center epidemiological survey data of children from the National Key Technology R&D Program of China during the Eleventh Five-Year Plan (2009 to 2010) and the National Key Research and Development Program of China during the Thirteenth Five-Year Plan (2017 to 2019). The participants' data were selected from four provinces,municipalities and autonomous region,including Beijing, Tianjin (Northern region), Zhejiang (Eastern region), and Guangxi (Southern region). Totally 14 597 pairs of 6-15 year-old children were surveyed. According to the body mass index (BMI) and standard deviation score (SDS) of children among different genders, ages, and regions, t test or chi-square test was used to evaluate the changes in overweight and obesity over a 10-year span. Results: Totally 7 721 pairs of boys and 6 876 pairs of girls were collectted in this study, whose mean age was (10.7±2.5) years. In the past 10 years, the overall BMISDS were 0.39±1.24 and 0.36±1.31 and the overall obesity rate were 11.8% (n=1 773) anel 12.5% (n=1 813) of children in the 4 administrative regions did not have statistically significant differences (all P>0.05). However, the overall overweight rate rose from 17.1% (n=2 496) to 19.1% (n=2 781) (χ²=18.657, P<0.01), and the average annual growth rate was 0.20%. The BMISDS in the Eastern region increased from 0.10±1.07 to 0.19±1.22 (t=-4.095, P<0.01), and the overweight rate and obesity rate increased by 3.8% (n=202) and 3.1% (n=169) respectively (both P<0.01); the BMISDS in the Northern region and the obesity rate did not have statistically significant differences(all P>0.05), but the overweight rate rose from 20.5% (n=1 233) to 22.8% (n=1 365) significantly (χ²=7.431, P<0.01); BMISDS in the Southern region was significantly decreased from 0.30±1.19 to 0.09±1.25 (t=1.426, P<0.01), and the rate of obesity decreased from 9.8% (n=315) to7.9% (n=256) (χ²=6.46, P<0.05), the overweight rate was not stafistically significant (P=0.10), respectively. The obesity rate of boys had risen from 16.4% (n=1 265) to 18.2% (1 407) (χ²=8.997, P<0.01) in the past 10 years, and the overweight rate had risen from 18.0% (n=1 393) to 20.5% (n=1 579) (χ²=14.26, P<0.01). The overweight+obesity rate rose from 34.4% (n=2 658) to 38.7% (n=2 986) (χ²=29.859, P<0.01), and the weight problem in the age group of 8 to 11 years was particularly severe (all P<0.01). The obesity rate of girls dropped from 6.8% (n=468) to 5.9% (n=406) (χ²=4.546, P<0.05), the overweight rate rose from 16.0% (n=1 103) to 17.5% (n=1 202) (χ²=5.006, P<0.05), and the overall overweight+obesity rate rose from 22.8% (n=1 571) to 23.4% (n=1 608) (χ²=0.53, P>0.05). Conclusions: The growth rate of obesity among children in China had slowed down from 2009 to 2019, but the overweight rate was still on the rise. The overall base of overweight and obesity population continued to expand. The weight problem of peri-adolescent boys was particularly prominent. The current status of obesity epidemics in different regions, ages, and genders are significantly different and had their own characteristics. It is necessary to establish a personalized prevention and control strategy.

[Genetic and clinical analysis of X-linked hypophosphatemic rickets].

Objective: To investigate the clinical and genetic features, and treatment of X-linked hypophosphatemic rickets (XLH). Methods: In this retrospective study, we reviewed the medical records of 25 pediatric patients with XLH who were admitted to Department of Endocrinology Genetics and Metabolism,Beijing Children's Hospital from January 2010 to January 2020. The clinical characteristics, PHEX gene variants, as well as clinical outcome of the patients were summarized. To analyze the correlation between genotype and phenotype, the patients were divided into different subgroups according to the location of the variants, including N-terminal-located vs. C-terminal-located variant, and Zn-binding domain exon 17 or 19 variant vs. non-exon 17 or 19 variant. The age at onset, height standard deviation score (HtSDS), intercondylar or intermalleolar distance, fasting serum phosphorus, and HtSDS and intercondylar or intermalleolar distance at the final follow-up were compared by rank sum test or t text. Results: Among the 25 children with XLH, 8 were boys and 17 were girls. The median age of onset was 1.2 (1.0, 1.8) years, and the median age of diagnosis was 2.5 (1.5, 4.3) years. The main clinical manifestations were abnormal gait and lower limb deformity. The HtSDS was -2.0(-3.2, -0.8), and the intercondylar or intermalleolar distance was 4.5 (3.0, 6.0) cm. The fasting serum phosphorus level was 0.8 (0.7, 0.9) mmol/L, while the serum alkaline phosphatase level was (721±41) U/L and the serum calcium level was (2.5±0.1) mmol/L. Three patients (12%) had parathyroid hormone levels above the upper limit of the normal range. Twenty-five patients (100%) showed radiographic changes of active rickets. Nephrocalcinosis was found in 2 cases (9%). Twenty-four different PHEX variations were detected in 25 patients, among whom 11 (44%) had not been reported previously. No hot spot variation was found. No statistical differences (all P>0.05) were identified in clinical features and outcomes either in comparing patients with N-terminal (21 cases) and C-terminal (4 cases) variants, or in comparing patients with variant located in exon 17 or 19 (4 cases) or not (21 cases). Twenty-four cases (96%) were treated regularly with phosphate supplements and active vitamin D. After 2.7 (1.6, 5.0) years of follow-up, clinical symptoms were relieved in 96% (24/25) of the patients. The HtSDS after treatment had no significant difference compared to that before treatment (-2.0(-3.2, -0.8) vs.-2.0(-2.8, -1.1),Z =-0.156, P>0.05), while the intercondylar or intermalleolar distance after treatment was significantly reduced compared to that before treatment (4.5(3.0, 6.0) vs. 1.5(0, 3.3) cm, Z =-3.043, P<0.05). Bone X-rays were reexamined in 17 cases after treatment, and radiographic signs of rickets were improved. Eighteen cases had secondary hyperparathyroidism and 7 cases had nephrocalcinosis. Conclusions: The main clinical manifestations of XLH are abnormal gait, lower limb deformity and short stature. A high proportion of novel variations of PHEX gene but no hot spot variation neither genotype-phenotype correlation are found. Regular treatment with phosphate supplements and active vitamin D can significantly improve the symptoms except for the height. However, the rate of adverse events including secondary hyperparathyroidism and nephrocalcinosis seems to be high.

[Clinical and genetic analysis of Noonan syndrome in 20 children].

Objective: To explore the clinical and genetic characteristics of Noonan syndrome in children. Methods: The clinical characteristics,genetic analysis and follow-up data of 20 children diagnosed with Noonan syndrome who were admitted to Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, Capital Medical University from March 2016 to December 2020 were retrospectively analyzed. Results: Among 20 children with Noonan syndrome, 13 were males and 7 were females. The age at diagnosis was 5.9 years (1.1 years to 12.2 years). The most common clinical complaints were delayed height growth, followed by hypospadias or cryptorchidism in 2 cases, and special facial appearance in 1 case. Physical examination revealed 12 cases of Noonan syndrome with facial features, 9 cases with cryptorchidism and hypospadias, 10 cases with abnormal cardiac structure, and 10 cases with mental retardation; Twelve patients were detected with PTPN11 variations, 4 patients carried SOS2 variations, 2 cases were confirmed with variations in SHOC2 and SOS1. Six children received recombinant human growth hormone treatment, and their height increased by 4.0 (2.5-6.0) cm to varying degrees at 9 months. No adverse events occurred. Conclusions: Male Noonan syndrome is more frequently found with external genitalia. In addition to the high frequency of PTPN11 variation, the frequency of gene variation in SOS2 gene is higher than previously reported. All of the SOS2 variations are de novo. The syndrome phenotype profiles could vary with the admitted clinical departments. To understand the full picture of the syndrome, it is necessary to collect medical information from different departments.

[Clinical follow-up and genetic analysis of six cases with hypophosphatasia].

Objective: To analyze the clinical, genetic characteristics and follow-up data of Chinese patients with hypophosphatasia (HPP). Methods: A retrospective analysis was conducted on six children with HPP admitted to the Department of Endocrinology, Genetics and Metabolism in Beijing Children's Hospital from October 2010 to January 2019. Summarized the clinical and follow-up data of all six patients, as well as the pathogenic variants of five children. Results: The serum alkaline phosphatase levels of all six children (five males and one female) were significantly reduced (2-49 U/L). The 6 patients aged from 2 months to 6 years and 4 months, 4 infantile HPP, 1 childhood HIP and 1 odonto HPP. The four patients with infantile HPP presented with anorexia, slow weight gain and hypercalcemia, whereas the one patient with childhood HPP and the other patient with odonto HPP had tooth loss. The patient with childhood HPP also manifested with motor dysfunction. Genetic testing was conducted for five patients and 4 unrelated Chinese families and revealed 10 variations in ALPL gene, including 7 missense variation, 1 insertion variation, 1 frameshift variation, 1 deletion variation.Of which 3 were novel (p.Y28C, p.268, F>L, p.A176V).One of the infantile patients lost follow-up and the other three deceased. The clinical conditions were much improved with medical intervention for patients with childhood, orodonto HPP. Conclusions: While HPP patients with different ages of onset present with common features, the prognosis differ significantly. The prognosis is good for patients with childhood, orodonto HPP and poor for patients with infantile HPP. Genetic testing is the main method for definitive diagnosis.

[Diagnosis and follow-up of 2 cases of pediatric nephrogenic syndrome of inappropriate antidiuresis resulting from activating mutation in AVPR2 and literature review].

Objective: To analyze the clinical and genetic features, as well as the treatment outcomes of two boys with nephrogenic syndrome of inappropriate antidiuresis (NSIAD) caused by gain-of-function mutations in the V2 vasopressin receptor gene (AVPR2). Methods: The clinical manifestations, genetic testing, therapeutic interventions and the outcomes of two boys with NSIAD hospitalized in the Department of Endocrinology, Beijing Children's Hospital in April 2019 were reported. A literature search with "Nephrogenic syndrome of inappropriate antidiuresis" and "AVPR2 gene" as keywords was conducted at the China national knowledge infrastructure (CNKI), the Wanfang Data Knowledge Service Platform, PubMed and Springer Link up to May 2020. Relevant published articles were reviewed. Results: The two cases presented with chronic and severe hyponatremia with hypo-osmolality, inappropriately elevated urinary osmolality and urinary sodium levels. The onset age was 5.25-years and 2 months respectively. AVPR2 sequencing revealed a previously described hemizygous activating mutation (c.409C>T, p.R137C) in both of boys, each inherited the variant from their mother. Patient 1 limited fluid intake by himself in his daily life, intravenous and oral sodium supplementations showed no significant increase of serum sodium level. Oral furosemide increased the serum sodium level and maintained it within normal range. The serum sodium and potassium levels were in the normal range during the 1-year follow-up period with oral furosemide. The serum sodium level of Patient 2 increased with restricting fluid intake and with salt supplementation. However, after he experienced respiratory infection, the plasma sodium level decreased. Subsequently, oral anti-infection medicine and furosemide were applied. The serum sodium level increased two days later and remained at a normal range afterwards. The boy was 1 year old with normal growth. He stopped taking furosemide after 4 months while taking 1 gram of salt per day, the blood sodium level maintained at normal range. Literature search identified no reports in Chinese journals, whereas 50 publications were found in English journals. A total of 30 NSIAD probands were reported and 16 of those (53%) had childhood onset, most presented with seizures. The majority had a hotspot change at the nucleotide position of 409 in AVPR2. Nine cases had an amino acid change as R137C and five cases as R137L. Fluid restriction and oral urea intake were main treatment options, no report so far was found with oral furosemide treatment. Conclusions: NSIAD presented with hyponatremia without any other specific presentations. Genetic testing for variants in AVPR2 is helpful for early diagnosis and timely treatment. The first two cases of oral furosemide treatment were reported by the article which helped to maintain a normal serum sodium level after limiting fluid intake and supplementing sodium which showed limited effect.

Age-Dependent Changes in the Plasma Proteome of Healthy Adults.

OBJECTIVE: Human blood plasma is a complex that communicates with most parts of the body and reflects the changes in the state of an organism. Identifying age-related biomarkers can help predict and monitor age-related physiological decline and diseases and identify new treatments for diseases. METHODS AND PARTICIPANTS: In this study, TMT-LC-MS/MS was utilized to screen differentially expressed plasma proteins in 118 healthy adults of different ages. Participants were divided into three groups: 21-30 years of age (Young), 41-50 years of age (Middle) and ≥60 years of age (Old). RESULTS: The number of differentially expressed proteins in the comparisons of Young vs Middle, Middle vs Old and Young vs Old were 82, 22 and 99, respectively. These proteins were involved in numerous physiological processes, such as "negative regulation of smooth muscle cell proliferation" and "blood coagulation". Moreover, when Young was compared with Middle or Old, "complement and coagulation cascades" was the top enriched pathway by KEGG pathway enrichment analysis. Functional phenotyping of the proteome demonstrated that the plasma proteomic profiles of young adults were strikingly dissimilar to those of the middle-aged or older adults. CONCLUSIONS: The results of this study mapped the variation in the expression of plasma proteins and provided information about possible biomarkers/treatments for different age-related functional disorders.