Prenatal Assessment Of The Fetal Thymus: Utility Of 2D And 3D Ultrasound And The Investigation Of The Relevance Of Congenital Heart Defects And 22q11 Micro-Deletion

Background:The thymus is a lymphoepithelial organ, providing the environment for T-lymphocyte differentiation and selection, in which T-lymphocytes develop during fetal life. The thymus is believed to grow throughout the fetal life. Thymic hypoplasia or aplasia has been reported as an associated finding in various diseases, such as 22q11 micro-deletion syndrome, DiGeorge syndrome, Ellis-van Creveld syndrome, severe combined immunodeficiency, HIV infection, intrauterine growth retardation, acute illness, exposure to ethanol and chorioamnionitis ect.Assessment of thymic hypoplasia or aplasia requires normal data for thymic size at each gestational age. In previous studies, Felker et al measured the thymic anterior-posterior diameter (APD), Jeppesen and Cho et al measured the thymic maximum transverse diameter (MTD), Zalel et al measured the thymic circumference (TC) to assess the size of the fetal thymus. However, in anatomy, the thymus occupies anterior-superior mediastinum, behind the sternum, in front of and ventral to the pericardium and great vessels of the heart (pulmonary artery, aorta and superior vena cava), between the lungs, which is asymmetric lobulated parenchymatous organ. Utility of 2DUS (two-dimensional Ultrasound) to assess the size of the fetal thymus might get limitation. With the development and application of 3DUS (three-dimensional Ultrasound) and 4DUS (four-dimensional Ultrasound) in medical field, especially in prenatal diagnosis, VOCAL (Virtual Organ Computer-Aided Analysis) from 3DUS, could globally analyze and measure the whole fetal thymus and reconstruct 3D model from multiple 2D plans, which conquers the limitation of single plan information from 2DUS.During the embryo development, the pharyngeal arches, mesenchymal cells which derived from neural crest give rise to smooth muscles of the conotruncal vessels and connective tissue of the thymus and the parathyroid gland. The development of the derivatives of the pharyngeal apparatus is highly sensitive to environmental and genetic insults. Any cause affects pharyngeal apparatus fail to develop, which could result in abnormal thymus growth and congenital heart defects. The 22q11 micro-deletion (del22q11.2) is the most common micro-deletion syndrome, associate with a markedly variable phenotypic expression, more than 180 clinical findings, in which congenital heart defects and thymic hypoplasia or aplasia are the most common clinical expression.Moreover, a great deal of studies show that micro-deletion at the 22q11 position is strongly associated with congenital heart defects (CHD). The 22q11 micro-deletion is the second most common chromosomal cause of congenital heart defects after trisomy 21. However, prenatal frequency of the micro-deletion in the fetuses with increased risk for congenital heart defects has not been completely elucidated. Aim:1. Establishing the normative data of the 2DUS and 3DUS measurements of the developing fetal thymus and comparing the 2DUS and 3DUS measurements of the fetal thymus.2. Discussing the relevance between congenital heart defects and thymic hypoplasia or aplasia3. Discussing the relevance between congenital heart defects and 22q11 micro-deletion.Material & Methods:Between June 2006 and November 2007, applying GE Voluson 730 high-resolution color Doppler ultrasound diagnose system,4-6 MHz transabdominal probe, measured the fetal thymic circumference (TC) in 347 normal singletons (TC group) and 28 singletons with CHD and proved by autopsy (CHD I group).Between December 2007 and February 2010, applying Philips IU22 high-resolution color Doppler ultrasound diagnose system,6 MHz transabdominal probe, measured the fetal thymic maximum transverse diameter (MTD group), anterior-posterior diameter (APD group), superior-inferior diameter (SID group) and maximum transverse area (MTA group), meantime utilizing 3DUS VOCAL technique to measure the thymic volume (TV group) in 567 normal singletons. During the same period, the thymic volumes of 20 singletons with CHD (CHD II group) were measured.The predicted mean and 90% confidence interval of 2DUS and 3DUS measurements were calculated at each gestational week, compared the correlation of thymic MTD, APD, SID, MTA measurements and GA with that of TV and GA. Between TC group and CHDⅠgroup, fetal thymus circumferences were compared, and between TV group and CHDⅡgroup, fetal thymus volumes were also compared.Then, a retrospective cohort study of 59 consecutive patients undergoing fetal echocardiogram and evaluation for 22q11 micro-deletion at the department of Maternal-Fetal Medicine of Yale University Medical School from June 1998 to June 2008, was done to discuss the relevance between CHD and 22q11 micro-deletion.Linear regression analysis, correlation coefficients comparison after Fisher's Z-transformation and large sample t test were used where appropriate. A p value<0.05 was considered statistically significant. Institutional review board approval was obtained from Yale University, School of Medicine, Maternal-Fetal-Medicine and Central South University, The Second Xiangya Hospital prior to the study.Results:2DUS,3DUS assessments of the fetal thymic MTD, APD, SID, MTA and TV were possible in 95.8% of 567 normal singletons and 2DUS assessment of the fetal circumference was possible in 92.2% of 347 normal singletons. The fetal thymic 2D diameters/area and 3D volume grow with the GA in linear correlation, regression equations are:TC (cm) =-4.147+0.443×GA (week), r=0.980; MTD (week)=-0.8031+0.1393×GA (week), r=0.9114; APD (cm)=-0.4808+0.0597×GA (week), r=00.8559; SID (cm)=-0.2741+0.0826×GA (week), r=0.8420; MTA (cm2)=-5.3551+0.3282×GA (week), r=0.9381; TV (ml)=-7.5098+0.4538×GA (week), r=0.9907, (all p<0.01). After Fisher's Z-transformation the correlation between the 3D-US thymus volume measurements and GA was significantly higher than that of any individual 2D-US measurements and GA (p<0.05).Thymus circumference of CHDⅠgroup was significantly lower than that of TC group (p< 0.05).28 cases of CHDⅠgroup,13 cases of them were lower than 5th percentile of normal range. The fetal thymus significantly decreased in 12 cases, and no significant decrease in 1 case, which were proved by autopsy. Thymus circumference was in normal range in another 15 cases,14 cases of them were no significant decrease, and 1 case was one lobe of thymus aplasia. Thymus volume of CHDⅡgroup was significantly lower than that of TV group (p< 0.05).20 cases of CHDⅡgroup,11 cases of them were lower than 5th percentile of normal rang, another 9 cases were in normal range. Between June 1998 and June 2008, of 8220 fetal echocardiograms performed,59 singleton fetuses were identified as being high risk for 22q11 micro-deletion.43 fetal karyotypes and FISH (Fluorescence In Situ Hybridization) tests were obtained. Sixteen mothers declined amniocentesis.5 of 43 fetuses were discovered to have the 22q11 micro-deletion. Fetuses diagnosed with 22q11 micro-deletion,2 of them had tetralogy of Fallot,2 of them had aorta arch abnormality with ventricular septal defects, and one case had positive family history.Conclusion:①This study presents the normative data of the 2DUS and 3DUS measurements of the developing fetal thymus.3DUS fetal thymus volume is more significantly correlated to GA than the other 2DUS measurements, which indicates 3DUS measurement of the fetal thymus is more accurate than that of 2DUS.②Thymic aplasia or hypoplasia is associated with congenital heart defect. Therefore, when detecting thymic aplasia or hypoplasia in fetus, the detail fetal echocardiogram is really necessary.③Congenital heart defect is associated with 22q11 micro-deletion. The relevance among the fetal thymic hypoplasia or aplasia, congenital heart defect and 22q11 micro-deletion should further study, because of the limitation of sample quantity.