Endocrine And Metabolic Manifestations And Application Of Genetic Evaluation Methods In 31 Children Born Small For Gestational Age

Background and objective:Children born small for gestational age(SGA)represents a statistical grouping of infants whose birth weight and/or length is at least 2 SD below the mean(?-2 SD)for gestational age,which is approximately the third percentile for gestational age.For the mechanism and the development of long-term risk among individuals with a low birthweight,The current explanation that has gained more recognition is the "fetal insulin" hypothesis.The potential mechanism of children born SGA is diverse and may affect the prognosis and treatment of children born SGA.Genetic testing in children born SGA has not been extensively developed in the domestic and foreign clinical work,many kinds of disease,especially the Monogenic diseases have not yet been diagnosed,and the background of the Monogenic diseases in children born SGA is a lack of large-scale population studies.The purpose of this study is to analyze endocrine metabolism and clinical features,applying a variety of molecular genetic methods to carry out diagnosis of etiology in children born SGA,to discuss the mechanism and the value of genetic methods applied in the diagnosis of children born SGA,in order to provide references for Clinicians.Subjects and methods:31 children born SGA were selected between September 2015 and October 2017 from Department of Pediatric Endocrinology,Shandong Provincial Hospital affiliated to Shandong University,recording detailed clinical data,testing metabolic index,endocrine hormone levels,endocrine tests,performing MRI examination to evaluate the hypothalamus and pituitary gland,left anteroposterior X radiography to assess bone age for all selected children born SGA.Data and related metabolic indexes were analyzed on methods including K-S test and Pearson correlation analysis or Spearman correlation analysis.30 children born SGA were sequenced parallel by combination of targeted genomic enrichments and next-generation sequencing(NGS).Other specimens were tested mainly as follows,one by karyotype analysis,one by microarray-comparative genomic hybridization(microarray-CGH),one by gene sequencing of methylmalonate,one by genetic linkage analysis using fluorescent microsatellite markers.Results:There were 27 short children born SGA(9 male,18 female),4 children born SGA with precocious puberty(1 male,3 female).The height standard deviationscore(HtSDS)of 27 short children born SGA was(-3.20± 1.09)and the body mass index was(14.70 ± 2.48)kg/m2.a portion of mothers were elderly parturient women,some with a history of miscarriage or intercurrent diseases during pregnancy.Other abnormalities during pregnancy included:intrauterine hypoxia,amniotic fluid,abnormal fetal irritability,placenta or umbilical cord abnormality,etc.23 short children born SGA measured the bone age:4 cases of bone age in advance,19 cases of retardation of bone age.4 precocious children born SGA measured the bone age:3 cases of bone age in advance,1 cases of retardation of bone age.Some children had exceptions such as mental retardation,growth retardation and multiple deformities.7 cases diagnosed with other disease before,3 cases with hypothyroidism.Results of the stimulation test of GnRHa in 4 precocious children born SGA showed central precocious puberty in 3 patients,peripheral precocious puberty in 1 patients.Results of growth hormone stimulation test in 20 short children born SGA showed complete growth hormone deficiency in 5 patients,partial growth hormone deficiency in 7 patients.19 short children born SGA had magnetic resonance imaging to evaluate the hypothalamus and pituitary gland.MRI analysis showed that the pituitary height was(3.10±0.79)mm,9 cases with small size or height reduction of adenohypophysis,4 cases with pituitary dysplasia,3 cases with pituitary upper margin sag,1 case with subsidence of lower sellar region,2 cases with Rathke's cyst.IGF-1 levels were positively correlated with age;the anterior pituitary height and IGF-1 levels also positively correlated.1 specimen of chromosome abnormal karyotype is with cri-du-chat syndrome,and 1 specimen of a autosomal deletion with 15q26 deletion syndrome,1 specimen of maternal uniparental disomy with Prader-Willi syndrome.7 patients had genetic abnormality respectively with Noonan syndrome,distal arthrogryposis type 2B,Short stature and advanced bone age,with or without early-onset osteoarthritis and/or osteochondritis dissecans,Floating-Harbor syndrome,microcephaly-5,Ehlers-Danlos syndrome classic type 2,mthylmalonic acidemia(MMA)accompanied by homocysteinemia(cb1C).30 children born SGA were sequenced parallel by combination of targeted genomic enrichments and NGS.6 gene variants of 6 patients were identified in 26 children born SGA(23.08%).7 gene mutated sites(c.794G>A?c.259G>A?c.7196C>T?c.7330C>T?c.7296dupA/c.2469G>A?c.2707G>C)was found in these6 mutant gene(PTPN11?TNNT3?ACAN?SRCAP?ASPM?COL5A2),3 mutations reported before(c.794G>A?c.7330C>T?c.7296dupA)and 4 mutations not reported yet.Conclusion:The metabolic mechanism of children born SGA is complex.Impaired fetal growth is influenced by abnormalities of the fetal genetics and maternal factors.Children born SGA showed disorders of endocrine metabolism and hypothalamic-pituitary function.The method of combination of targeted genomic enrichments and NGS is accurate,reliable,fast,efficient,and suitable for gene mutation detection of SGA.Genetic evaluation methods for Children born SGA are diverse.Clinicians should make pointed choices based on clinical phenotype of patients.