Clinical and genetic characteristics of 9 rare cases with coexistence of dual genetic diagnoses / 中华儿科杂志

Objective: To analyze the clinical and genetic characteristics of pediatric patients with dual genetic diagnoses (DGD). Methods: Clinical and genetic data of pediatric patients with DGD from January 2021 to February 2022 in Peking University First Hospital were collected and analyzed retrospectively. Results: Among the 9 children, 6 were boys and 3 were girls. The age of last visit or follow-up was 5.0 (2.7,6.8) years. The main clinical manifestations included motor retardation, mental retardation, multiple malformations, and skeletal deformity. Cases 1-4 were all all boys, showed myopathic gait, poor running and jumping, and significantly increased level of serum creatine kinase. Disease-causing variations in Duchenne muscular dystrophy (DMD) gene were confirmed by genetic testing. The 4 children were diagnosed with DMD or Becker muscular dystrophy combined with a second genetic disease, including hypertrophic osteoarthropathy, spinal muscular atrophy, fragile X syndrome, and cerebral cavernous malformations type 3, respectively. Cases 5-9 were clinically and genetically diagnosed as COL9A1 gene-related multiple epiphyseal dysplasia type 6 combined with NF1 gene-related neurofibromatosis type 1, COL6A3 gene-related Bethlem myopathy with WNT1 gene-related osteogenesis imperfecta type XV, Turner syndrome (45, X0/46, XX chimera) with TH gene-related Segawa syndrome, Chromosome 22q11.2 microduplication syndrome with DYNC1H1 gene-related autosomal dominant lower extremity-predominant spinal muscular atrophy-1, and ANKRD11 gene-related KBG syndrome combined with IRF2BPL gene-related neurodevelopmental disorder with regression, abnormal movement, language loss and epilepsy. DMD was the most common, and there were 6 autosomal dominant diseases caused by de novo heterozygous pathogenic variations. Conclusions: Pediatric patients with coexistence of double genetic diagnoses show complex phenotypes. When the clinical manifestations and progression are not fully consistent with the diagnosed rare genetic disease, a second rare genetic disease should be considered, and autosomal dominant diseases caused by de novo heterozygous pathogenic variation should be paid attention to. Trio-based whole-exome sequencing combining a variety of molecular genetic tests would be helpful for precise diagnosis.

Research advances in the biomarkers of brain damage in preterm infants / 中国当代儿科杂志

While the survival rate of preterm infants has continually increased with the development of perinatal and neonatal monitoring techniques, the incidence of brain injury in preterm infants has been increasing, resulting in varying degrees of cognitive impairment and movement disorders. Measuring the biomarkers of brain damage is an important means to diagnose brain injury. The biomarkers can be divided into neuroglial damage markers, neuronal damage markers and other markers according to the features of injured cells. The biomarkers widely used in clinical practice include S100B protein, myelin basic protein and neuron-specific enolase. Recent studies have newly discovered a collection of markers that can suggest potential brain injury in preterm infants, such as glial fibrillary acidic protein, neurofilament light chain protein, α-II spectrin breakdown products, chemokines, melatonin and urinary metabolomics. These biomarkers can contribute to the early diagnosis and treatment of preterm brain injury, essential for improving neural development and prognosis. This article reviews the latest research advances in the biomarkers of preterm brain injury, in order to provide evidence for the early diagnosis and treatment of this condition.

Effects of pituitary adenylate cyclase activating polypeptide on CD4+/CD8+ T cell levels after traumatic brain injury in a rat model / 世界急诊医学杂志（英文）

BACKGROUND: The effect of pituitary adenylate cyclase activating polypeptide (PACAP) during traumatic brain injury (TBI) and whether it can modulate secondary injury has not been reported previously. The present study evaluated the potential protective effects of ventricular infusion of PACAP in a rat model of TBI. METHODS: Male Sprague Dawley rats were randomly divided into 3 treatment groups (n=6, each): sham-operated, vehicle (normal saline)+TBI, and PACAP+TBI. Normal saline or PACAP (1g/5L) was administered intracerebroventricularly 20 minutes before TBI. Right parietal cortical contusion was produced via a weight-dropping method. Brains were extracted 24 hours after trauma. Histological changes in brains were examined by HE staining. The numbers of CD4+ and CD8+ T cells in blood and the spleen were detected via flow cytometry. RESULTS: In injured brain regions, edema, hemorrhage, inflammatory cell infiltration, and swollen and degenerated neurons were observed under a light microscope, and the neurons were disorderly arrayed in the hippocampi. Compared to the sham group, average CD4+ CD8– lymphocyte counts in blood and the spleen were significantly decreased in rats that received TBI+vehicle, and CD4– CD8+ were increased. In rats administered PACAP prior to TBI, damage was attenuated as evidenced by significantly increased CD4+, and decreased CD8+, T lymphocytes in blood and the spleen. CONCLUSION: Pretreatment with PACAP may protect against TBI by influencing periphery T cellular immune function.

Evaluation of right ventricular function by quantitative tissue velocity imaging and tissue tracking imaging in neonates with congenital hypothyroidism / 中华儿科杂志

<p><b>OBJECTIVE</b>Although several reports documented the association of congenital hypothyroidism (CH) and left ventricular (LV) function in infants or neonates, right ventricular (RV) function in neonates with CH has not been previously studied. The aim of the present study was to assess RV function in neonates with CH before and after thyroxine substitution therapy by quantitative tissue velocity imaging (QTVI) and tissue tracking imaging (TTI).</p><p><b>METHODS</b>Fifty-two neonates aged 18-28 days (25 males and 27 females) with CH and 35 healthy neonates aged 18-28 days (16 males and 19 females) were studied by QTVI, TTI as well as conventional pulsed-wave Doppler echocardiography (PWD). The standard apical four-chamber view for long-axis motion of the right ventricle was used for echocardiographic evaluation. Peak systolic displacement (D), peak systolic velocity (Vs), peak early (Ve) and late (Va) diastolic velocity of tricuspid annule were measured, Ve/Va ratio was calculated as well. Transtricuspid flow velocity during early diastole (E) and late diastole (A) were also measured by pulsed-wave Doppler echocardiography. PWD and E/A ratio were calculated too. For each neonate, serum hormone levels of TSH, TT(3), TT(4), FT(3) and FT(4) were measured with a standard chemiluminescent immunoassay. After 1 month of levothyroxine (L-T(4)) substitution therapy in CH neonates, all the echocardiographic evaluations and biochemical tests were re-evaluated. Correlation analysis was also made between serum thyroid hormones levels and right ventricular function.</p><p><b>RESULTS</b>The indices of right ventricular diastolic function by PWD (E and E/A ratio) in CH group were (45 +/- 10) cm/s and (0.8 +/- 0.3), respectively. Compared with controls, E and E/A ratio in CH neonates were significantly lower (P < 0.001, respectively), while A did not differ between the two groups (P > 0.05). QTVI and TTI showed that right diastolic function (Ve and Ve/Va ratio) as well as right systolic function (Vs and D) in CH group were (3.69 +/- 1.38) cm/s, (0.74 +/- 0.19) cm/s, (4.38 +/- 0.63) cm/s and (0.52 +/- 0.12) cm, respectively. CH neonates had significantly lower Ve, Ve/Va ratio, Vs and D of tricuspid annular velocity (P < 0.001, respectively), whereas there was no significant difference in Va between the two groups (P > 0.05). After 1 month of substitutive therapy, CH neonates showed a significant increase of Ve, Ve/Va ratio, Vs, D, E, and E/A ratio, (6.92 +/- 1.86) cm/s, (1.13 +/- 0.22), (5.92 +/- 1.03) cm/s, (0.78 +/- 0.17) cm, (61 +/- 10) cm/s and (1.1 +/- 0.4), respectively (P < 0.001). Those parameters were positively correlated with serum TT(3), TT(4), FT(3) and FT(4) levels (P < 0.01, respectively), and were negatively correlated with serum TSH levels (P < 0.01, respectively).</p><p><b>CONCLUSIONS</b>Our findings suggest that neonates with CH are associated with right ventricular subclinical systolic and diastolic dysfunction, which can be reversed by early L-T(4) substitution therapy. QTVI and TTI are valuable methods to evaluate right ventricular function in neonates. Systolic and diastolic velocities of the tricuspid annulus measured by QTVI and TTI are useful and accurate to assess RV function in neonates.</p>

Study on the Social Adaptation of Chinese Children with Down Syndrome

PURPOSE: To evaluate social adjustment and related factors among Chinese children with Down syndrome (DS). PATIENTS AND METHODS: A structured interview and Peabody Picture Vocabulary Test (PPVT) were conducted with a group of 36 DS children with a mean age of 106.28 months, a group of 30 normally-developing children matched for mental age (MA) and a group of 40 normally-developing children matched for chronological age (CA). Mean scores of social adjustment were compared between the three groups, and partial correlations and stepwise multiple regression models were used to further explore related factors. RESULTS: There was no difference between the DS group and the MA group in terms of communication skills. However, the DS group scored much better than the MA group in self-dependence, locomotion, work skills, socialization and self-management. Children in the CA group achieved significantly higher scores in all aspects of social adjustment than the DS children. Partial correlations indicate a relationship between social adjustment and the PPVT raw score and also between social adjustment and age (significant r ranging between 0.24 and 0.92). A stepwise linear regression analysis showed that family structure was the main predictor of social adjustment. Newborn history was also a predictor of work skills, communication, socialization and self-management. Parental education was found to account for 8% of self-dependence. Maternal education explained 6% of the variation in locomotion. CONCLUSION: Although limited by the small sample size, these results indicate that Chinese DS children have better social adjustment skills when compared to their mental-age-matched normally-developing peers, but that the Chinese DS children showed aspects of adaptive development that differed from Western DS children. Analyses of factors related to social adjustment suggest that effective early intervention may improve social adaptability.

Expression of androgen receptor gene in cerebral cortex and hippocampus of rats with perinatal hypothyroidism / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To investigate the effects of perinatal thyroid hormone deficiency on the expression of androgen receptor (AR) mRNA in cerebral cortex and hippocampus of rats.</p><p><b>METHODS</b>Perinatal hypothyroidism was induced by the administration of propylthiouracil (PTU) solution to the dams by gavage (50 mg/d) beginning at embryonic d15 throughout the lactational period. In the T(4) injected group hypothyroid rats were injected intraperitoneally with levothroxine (L-T(4)) 2 microg/100 g BW daily, starting from the day of birth. Cerebral cortex and hippocampus specimen were collected from controls,hypothyroid and T(4)-injected hypothyroid rats on postnatal d1, 5, 10, 15 and 20. Quantification of ARmRNA in cerebral cortex and hippocampus was performed with competitive RT-PCR using internal and external standardization.</p><p><b>RESULT</b>Age-related increasing ARmRNA levels were observed in neonatal rats, and those in male animals were significantly higher. AR expression was higher in the hippocampus than in the cerebral cortex. ARmRNA levels in the hypothyroid pups were lower than those in age-matched controls. The mRNA levels in the T(4)-injected hypothyroid pups were significantly higher compared with the age-matched hypothyroid pups, but in hippocampus ARmRNA expression did not reach normal levels in male rats at d10 and d20, in female at d15 and d20.</p><p><b>CONCLUSION</b>The expression of ARmRNA decreases in brain of rats with perinatal hypothyroidism. Treatment with thyroid hormone can recover ARmRNA expression in cerebral cortex, but not in hippocampus.</p>

Influence of congenital hypothyroidism on left ventricular function of neonates / 中华儿科杂志

<p><b>OBJECTIVE</b>To evaluate left ventricular function in neonates with congenital hypothyroidism (CH) and its correlation with thyroid hormones serum levels.</p><p><b>METHODS</b>M-mode echocardiography [left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS)], pulse wave Doppler [the peak early diastolic mitral inflow velocity (Em), the peak late diastolic mitral inflow velocity (Am)], quantitative tissue velocity imaging (QTVI) [the systolic peak mitral annular velocity (sm), the early diastolic peak mitral annular velocity (em), the late diastolic peak mitral annular velocity (am)] and tissue tracking imaging (TTI) [the systolic mitral annular displacement (MAD)] were evaluated in 35 neonates with congenital hypothyroidism aged 15-28 days and 30 normal neonates in this study. Correlation analysis was also made between left ventricular function and serum TT3, TT4 and TSH levels.</p><p><b>RESULTS</b>Left systolic function parameters (LVEF, LVFS, sm and MAD) were 0.62 +/- 0.08, (28.21 +/- 5.31)%, (2.58 +/- 0.59) cm/s and (0.27 +/- 0.07) cm, respectively, in CH group, and 0.67 +/- 0.06, (31.16 +/- 4.13)%, (3.24 +/- 0.52) cm/s and (0.41 +/- 0.08) cm in control group (P < 0.05, P < 0.01). Left diastolic function parameters (Am, Em/Am, em/am, Em and em) were (0.59 +/- 0.10) m/s, 0.98 +/- 0.18, 0.82 +/- 0.40, (0.57 +/- 0.11) m/s and (2.83 +/- 1.48) cm/s, respectively, in CH group, and (0.65 +/- 0.10) m/s, 1.14 +/- 0.20, 1.25 +/- 0.33, (0.73 +/- 0.11) m/s and (4.46 +/- 1.29) cm/s in control group (P < 0.05, P < 0.01). MAD, sm, Em and em in CH group were greatly lower than that in control group (P < 0.001). Left systolic function (LVEF, sm, MAD) and diastolic function (Em, Am, em, em/am) were positively correlated with TT3, TT4 serum levels (P < 0.05, P < 0.01), and negatively with TT4 serum levels (P < 0.05, P < 0.01). MAD, Em and em were highly correlated with TT4, TSH serum levels (r = 0.700, r = 0.564, r = 0.593, r = 0.564, P < 0.001; r = -0.674, r = -0.521, r = -0.578, r = -0.632, P < 0.001).</p><p><b>CONCLUSIONS</b>Neonates with CH have lower left systolic and diastolic function. Left ventricular function was affected by thyroid hormones. QTVI and TTI are more sensitive parameters in evaluating left ventricular function of neonates with congenital hypothyroidism than conventional echocardiography.</p>