Immunoendocrine interrelationship--effect of ovariectomy on spleen and thymus in mouse.

Increase in the weights of spleen were observed 15 days after ovariectomy in adult as well as immature mice. However, no corresponding change was recorded in the splenocyte count. Morphological alterations in the shape of germinal centres was noted after ovariectomy in adult and immature mice. Increase in weight of the thymus could be demonstrated in adult mice only, with a concomitant enlargement of cortical and medullary region.     

Ontogeny and organization of the stationary non-lymphoid cells in the human thymus

Summary Ontogenetic differentiation of the human thymus was investigated in 50 embryos by means of light and electron microscopic methods in an attempt to clarify the morphogenesis of the complicated microecology of thymic tissue. At the 8th gestational week (g.w.), the primordium of the thymus contains almost exclusively undifferentiated epithelial cells. At the 10th g.w., the epithelial cells in the central part are spindle-shaped. During the subsequent weeks the cortical region of the thymus becomes separated into lobes by mesenchymal septa containing hemopoietic precursor cells and large electronlucent cells with irregularly shaped nuclei. The latter cells are also found in the deeper presumptive medullary regions of the thymus; they differentiate into interdigitating reticulum cells (IDC). The permeation of the medulla of the thymus by non-epithelial IDC occurs concurrently with the formation of cortical and medullary epithelial cells. Between the 12th and 14th g.w. the cortical and medullary differentiation is completed. At this time-stage cortical small lymphocytes differ in morphological shape from medullary lymphocytes, the latter acquiring the appearance of immunocompetent T cells and establishing intimate contact with the IDC.These findings indicate that the thymic cortex and medulla contain different epithelial cells. In addition, the thymic medulla displays cells characterized by the morphology of typical interdigitating reticulum cells of peripheral lymphoid tissue. The structural pattern of the thymus is correlated to morphologically differing lymphoid cell populations in the cortical and medullary regions.This investigation was supported by grants from the Deutsche Forschungsgemeinschaft and by the Sonderforschungsbereich 111The authors dedicate this paper to Professor Helmut Leonhardt on the occasion of his 60th birthday. The authors also appreciate the excellent technical assistance of Mrs. I. Knauer, Mrs. H. Waluk and Mrs. H. Siebke     

A homing receptor-bearing cortical thymocyte subset: implications for thymus cell migration and the nature of cortisone-resistant thymocytes

The thymus exports a selected subset of virgin T lymphocytes to the peripheral lymphoid organs. The mature phenotype of these thymus emigrants is similar to that of medullary thymocytes and has been cited as supporting a medullary rather than cortical exit site. Using the monoclonal antibody MEL-14, we identify a 1%-3% subpopulation of thymocytes that expresses high levels of a receptor molecule involved in lymphocyte homing to peripheral lymph nodes. We present evidence that these rare MEL-14hi thymocytes are predominantly of mature phenotype and represent the major source of thymus emigrants. Surprisingly, MEL-14hi thymocytes are exclusively cortical in location, although their mature phenotype may allow them to masquerade as medullary cells in conventional studies. We also demonstrate that unlike medullary thymocytes, many cortisone-resistant thymocytes (CRT) are MEL-14hi. Thus, in contrast to current dogma, CRT do not represent a sample of medullary thymocytes as they are found in situ and their level of immunocompetence does not necessarily reflect that of the medullary population. Our findings refute the hypothesis that phenotypically and functionally mature cells are restricted to the medulla, and support our proposition that most thymus emigrants are derived from the MEL-14hi cortical subset.     

Cytoarchitecture of the Xenopus thymus following gamma-irradiation

This paper describes in vitro and in vivo attempts to deplete the 4- to 8-month-old Xenopus laevis (J strain) thymus of its lymphocyte compartment. Gamma irradiation (2-3000 rad) of the excised thymus, followed by two weeks in organ culture, is effective in removing lymphocytes, but causes drastic reduction in size and loss of normal architecture. In contrast, in vivo whole-body irradiation (3000 rad) and subsequent in situ residence for 8-14 days proves successful in providing a lymphocyte-depleted froglet thymus without loss of cortical and medullary zones. In vivo-irradiated thymuses are about half normal size, lack cortical lymphocytes, but still retain some medullary thymocytes; they show no signs of lymphocyte regeneration when subsequently organ cultured for 2 weeks. Light microscopy of 1 micron, plastic-embedded sections and electron microscopy reveal that a range of thymic stromal cell types are retained and that increased numbers of cysts, mucous and myoid cells are found in the thymus following whole-body irradiation. In vivo-irradiated thymuses are therefore suitable for implantation studies exploring the role of thymic stromal cells in tolerance induction of differentiating T lymphocytes.     

Morphometrical analysis of the thymus from mice submitted to low temperature

Thymic involution is a slow physiological process than can be accelerated by some pathological or experimental conditions. In this work we kept male mice under low temperatures in order to observe whether or not thymic involution would be promoted. For this purpose, we carried out a histometrical analysis of the thymus and observed that there was a decrease in both cortical and medullary regions of the thymic lobules. These changes paralleled a loss in the absolute and relative weights of the thymus. It was concluded that low temperatures induce thymic involution even in nonhibernating animals.     

Distribution of thymocytes expressing gamma delta receptors in the murine thymus during development

We have examined the appearance of thymocytes expressing gamma delta TCR within the developing thymus by using immunohistochemical techniques and flow cytometry in conjunction with the mAb 3A10, which recognizes a determinant associated with the constant region of the delta-chain. gamma delta+ Cells were first detected at day 16 of gestation, attained maximal levels at day 17 of gestation, and declined thereafter. By using the Ulex europeus agglutinin to identify medullary epithelial cells in situ, we observed a striking colocalization of gamma delta+ thymocytes and U. europeus agglutinin-positive medullary epithelial cells during late fetal and neonatal periods of development. In the thymuses of adult mice, gamma delta+ thymocytes were scattered throughout cortical and medullary areas of the thymus and most concentrated in the subcapsular areas of the thymus. Ultrastructural immunohistochemistry confirmed the close association between medullary thymic epithelial cells and gamma delta+ thymocytes in the neonatal thymus and also showed that some TCR-gamma delta molecules were patched to areas of contact with medullary epithelial cells. In contrast to the cellular distribution of either CD3 molecules or the TCR-alpha beta, where extensive intracellular labeling of thymocytes has been observed, cytoplasmic accumulation of delta-chain was not detected.     

Immunohistochemical and histometrical studies of the human thymus with special emphasis on age-related changes in medullary epithelial and dendritic cells

Age-related changes in medullary epithelial and dendritic cells in the human thymus were examined quantitatively using immunohistochemistry and histometry. The material used was thymic biopsy specimens obtained from 105 patients during cardiac surgery, none of whom had immunological abnormalities. By using keratin and tissue polypeptide antigen markers to identify epithelial cells and S-100 protein and LN-2 markers to identify dendritic cells, the numbers of these cells in the medulla were counted morphometrically. The relative proportions of the cortex, medulla, Hassall's bodies, perivascular space, connective tissue and fatty tissue were evaluated using a computer image-analysis system and the respective relative volumes were calculated. Our results indicate that the number of medullary dendritic cells/mm2 and the relative volume of cortical thymocytes decrease steadily up to the age of 40 years, whereas no major change was found in the number of medullary epithelial cells/mm2.     

Differentiation of human T lymphocytes. I. Acquisition of a novel human cell surface protein (p80) during normal intrathymic T cell maturation

The thymus is thought to be the primary central lymphoid organ in which T cells mature. Although thymic cortical and medullary compartments are distinct histologically, few antigens have been described that are absolutely acquired during the presumed intrathymic maturation pathway from cortical to medullary thymocytes. In this paper, we describe the acquisition during human intrathymic T cell maturation of a novel protein (p80) defined by a monoclonal antibody (A1G3). Although the p80-A1G3 antigen is distributed throughout the body and is not T cell specific, our study demonstrates that expression of p80-A1G3 antigen in normal human thymus is associated with thymocyte functional maturity and location in the thymus medulla. Moreover, in contrast to other markers of mature human T cells, the p80-A1G3 cell surface protein is not expressed on T6+ cortical thymocytes, and, therefore, is absolutely acquired by medullary thymocytes during T cell maturation. Thus, the p80-A1G3 antigen and the A1G3 antibody provide a heretofore unavailable system for the study of molecular events that transpire during the maturation of thymocytes.     

Total lymphoid irradiation leads to transient depletion of the mouse thymic medulla and persistent abnormalities among medullary stromal cells

Mice given multiple doses of sublethal irradiation to both the thymus and the peripheral lymphoid tissues showed major transient, and some persistent disruptions in general thymic architecture and in thymic stromal components. At 2 wk after total lymphoid irradiation (TLI), the thymus lacked identifiable medullary regions by immunohistochemical analyses. Medullary stromal cells expression MHC Ag or a medullary epithelial cell Ag, as well as medullary macrophages, were undetectable. Instead, the processes of cortical epithelial cells were observed throughout the entire thymus. Strikingly, thymocyte subsets with mature phenotypes (CD4+CD8- and CD4-CD8+) were present in the apparent absence of a medulla. This early, gross effect was rapidly reversed such that by 1 to 2 mo after TLI, medullary areas with MHC Ag-positive cells were evident. However, abnormalities in a subset of medullary stromal cells appeared to be more persistent. Medullary epithelial cells, identified by the MD1 mAb, were greatly reduced in number and abnormally organized for at least 4 mo after TLI. In addition, macrophages containing endogenous peroxidase activity, normally abundant in medullary regions, were undetectable at all times examined after TLI. Therefore, this irradiation regimen induced both transient and long term effects in the thymus, primarily in medullary regions. These results suggest that TLI may be used as an experimental tool for studying the impact of selective depletion of medullary stromal cells on the development of specific T cell functions.     

Histological distribution of the 35-KD protein substrate of the epidermal growth factor receptor/kinase in thymus

Rat thymus has been identified as a tissue comparatively enriched in a 35-KD substrate of the epidermal growth factor receptor/kinase (lipocortin-1) (J Biol Chem 261:13784, 1986). A polyclonal antiserum prepared against the 35-KD protein was used to determine histological distribution of the protein in thymus. Frozen sections of rat thymus were examined after indirect labeling of the 35-KD protein with a rhodamine conjugate of secondary antibody. The antigen was localized primarily in the reticular network of the thymic epithelium, with no detectable labeling of resident thymocytes. Immunoblotting (Western blots) of cytosol extracts also demonstrated that thymocytes did not contain detectable amounts of the antigen. Cultured thymic epithelial cells (TEC), however, contained an abundance of two immunologically related protein bands with molecular weights similar but not identical to the antigen from the parental cell line (human A-431 carcinoma). Paraffin sections of rat and human thymus were subjected to an immunoperoxidase staining procedure, and it was observed that Hassall's corpuscles (keratinized epithelial cells) and other cortical and medullary TECs were intensely stained. The demonstration that the antigen is primarily associated with TEC in thymus, in conjunction with its distribution in other tissues, will aid in deducing its physiological role.     

Heterogeneity of Thymic Lymphocytes, as Assessed by the Effects of Treatment with Cortisol, both in vivo and in vitro

The response of thymus to repeated injections of cortisol was complex and proceeded in at least four phases. During the first 2 days, there was a selective loss of cortical lymphocytes. Between the 2nd and 6th days, some medullary lymphocytes were lost and there was a rise in the collagen concentration, to stabilize the weight of the thymus at about 12% of its original weight. During the next 2 days, the density of medullary lymphocytes increased, with a corresponding drop in collagen concentration. Between days 8 and 12, some of the medullary lymphocytes were replaced by collagen.
This series of events is interpreted in terms of a differential sensitivity of cortical and medullary lymphocytes to cortisol with the operation of a mechanism for compensatory proliferation of resistant medullary lymphocytes.
Thymic cortical explants were characterized by a high rate of cellular death of lymphocytes, with no significant change in their mitotic index. Cellular death in explants was further increased by cortisol; and from the dose-response relationship, there were at least three types of lymphocyte which differed with regard to cortisol sensitivity.
The implications of these findings are briefly discussed in relation to the possibility of clonal selection of thymic lymphocytes occurring in response to environmental influences.     

Immunohistochemical and histometrical studies of the human thymus with special emphasis on age-related changes in medullary epithelial and dendritic cells

Age-related changes in medullary epithelial and dendritic cells in the human thymus were examined quantitatively using immunohistochemistry and histometry. The material used was thymic biopsy specimens obtained from 105 patients during cardiac surgery, none of whom had immunological abnormalities. By using keratin and tissue polypeptide antigen markers to identify epithelial cells and S-100 protein and LN-2 markers to identify dendritic cells, the numbers of these cells in the medulla were counted morphometrically. The relative proportions of the cortex, medulla, Hassall’s bodies, perivascular space, connective tissue and fatty tissue were evaluated using a computer image-analysis system and the respective relative volumes were calculated. Our results indicate that the number of medullary dendritic cells/mm² and the relative volume of cortical thymocytes decrease steadily up to the age of 40 years, whereas no major change was found in the number of medullary epithelial cells/mm². Supported in part by a Grant-in-Aid (No. 61570664) for Scientific Research from the Japanese Ministry of Education     

Embryologic development of rat adrenal medulla in transplants to the anterior chamber of the eye

The morphological development and plasticity of embryonic and postnatal rat adrenal medullary cells were studied in homologous adrenal grafts to the anterior chamber of the eye. The eyes of recipient rats were adrenergically denervated 10 days prior to grafting by extirpation of the superior cervical ganglion in order to increase levels of NGF and NGF-like activities in the iris. Grafts taken at the 15th day of embryonic development (E15), i.e., at the beginning of immigration of medullary progenitor cells into the adrenal cortical anlagen, contained no cortical or mature medullary cells after 2 weeks in oculo. Numerous sympathoblastic cells, however, were located at the anterior surface of the iris. E 16 and E 17 transplants showed abundant mature cortical tissue after 2 weeks. Small groups of medullary cells with the ultrastructural characteristics of mature pheochromoblasts or young chromaffin cells were interspersed among cortical cells without forming a discrete medulla. Neuronal cells were exclusively found outside the cortical cell mass. Sympathoblasts grew at the surface of the iris, while young sympathetic nerve cells, which were invested by Schwann cells and received synaptic axon terminals, were embedded into the stroma of the iris. Grafting of E 21 adrenals yielded very similar results except that, in a few instances, young chromaffin cells were located outside the cortex and sympathetic nerve cells were seen to be in close contact with cortical cells. In transplants of adult medullary cells typical mature adrenaline and noradrenaline cells were clearly distinguishable after 8 weeks even in the absence of cortical cells. The only indication of phenotypical changes in these cells was the formation by some of them, of neuritic processes which could be visualized in glyoxylic acid-treated whole mounts of irises. These results are compatible with the idea that embryonic adrenal medullary cells have the environmentally controlled potential to develop along the neuronal or endocrine line, but could also be interpreted in terms of a selection of a specific subpopulation with predetermined potentialities by a specific microenvironment. Moreover, these results suggest that increasing differentiation of medullary cells is accompanied by progressive restrictions in their genetic program, which eventually prevent full transdifferentiation of mature chromaffin into neuronal cells.     

Effect of thermal environment upon transplanted tumors and growth of mice.

Ehrlich ascites tumor cells were inoculated subcutaneously in the dorsal, interscapular region of three groups of mice that were subsequently maintained in normo-, hypo- or hyperthermic environments. The controls, mice that had homologous whole spleens or thymic glands implanted in the same location, were maintained in a normothermic environment. Number of tumors established, their weights and volumes, and weights of animals were compared as well as tumor temperature, which was compared to brown fat and core temperatures.(1) The percentage of animals developing tumors was independent of environment. (2) Mice with tumors, and mice in which tumors did not take, gained more weight at the normothermic temperatures (21 °C) than at either 31 or 5 °C. (3). When the weight and volume of tumors are expressed per gram of mouse body weight, there is no difference between the hypo- and normothermic environments, but the weights and volume of tumors in a hyperthermic environment are only 36 and 58% respectively of the tumors in normothermic animals. (4) Tumor temperatures are about 1 °C cooler than the underlying brown fat regardless of environment, and brown fat was 0.5 °C cooler than the core temperature. (5) Transplanted thymus glands and spleens become encysted after 31 days; they proved to be cooler than the malignant tumors.     

Identification of subsets of proliferating low Thy 1 cells in thymus cortex and medulla

Subsets of proliferating thymocytes were identified in the normal mouse thymus by in vivo labeling with [³H]TdR and by cell separation according to relative amounts of Thy 1 antigen. In order to resolve apparent discrepancies in the literature, parenteral and topical application of [³H]TdR were compared as labeling methods for dividing thymocytes, and limited complement lysis and fluorescence-activated cell sorting were compared as separation principles for high Thy 1 and low Thy 1 thymocyte subsets. The separated cells were further characterized by immunofluorescence for terminal deoxynucleotidyltransferase (TdT), which normally is restricted to cortical thymocytes, and for H2 alloantigens, which are preponderant on medullary thymocytes. Four subsets of proliferating cortical thymocytes were identified after application of [³H]TdR to the thymus capsule. The major subset, which comprised about 92% of dividing cortical thymocytes, had a high Thy 1, low H2 phenotype. Most were also TdT + ve. The three minor subsets of proliferating cortical thymocytes each had a low Thy 1 phenotype, but differed according to H2 and TdT markers. Systemic injection of [³H]TdR also labeled the above subsets of dividing cortical thymocytes, but in addition it detected a subset of proliferating low Thy 1, low H2, TdT — ve cells in the thymus medulla. The latter subset comprised about one-third of the pool of proliferating low Thy 1 cells. In their aggregate the four subsets of low Thy 1 cells constituted approximately 13% of total proliferating thymocytes and 1.1% of total thymocytes. The identification of discrete subsets of proliferating low Thy 1 cells in the thymus cortex as well as in the thymus medulla is compatible with the hypotheses that all thymocytes are descended from low Thy 1 precursors and that separate precursor cell subsets exist for cortical and medullary thymocytes.     

Enzymatic and morphological response of the thymus to drugs in normal and zinc-deficient pregnant rats and their fetuses

In the thymus of normally fed pregnant rats the plasma membrane enzymes dipeptidyl peptidase IV (DPP IV) and alkaline phosphatase (alP) were found in cortical and medullary lymphocytes (thymocytes). Plasma membrane aminopeptidase A (APA) and adenosine monophosphate hydrolysing phosphatase (AMPP) were present in cortical reticular cells. In medullary reticular cells, aminopeptidase M (APM), gamma-glutamyl transferase (GGT), adenosine triphosphate (ATPP) and thiamine pyrophosphate (TPPP) cleaving phosphatases were detected. Medullary reticular cells did not contain APA. Lysosomal DPP I and II, acid phosphatase, acid beta-D-galactosidase, beta-D-N-acetyl-glucosaminidase, beta-D-glucuronidase and non-specific esterases occurred especially in macrophages at the corticomedullary junction. The 21-day-old fetal thymus showed a similar reaction pattern as the maternal organ except for APA which was absent before birth. After treatment of the pregnant rats with valproic acid (VPA), salicylic acid (SA), streptozotocin (ST) and retinoic acid (RA) APA showed an increase in activity in the thymic cortex. In addition, ST and RA induced AMPP, ATPP and TPPP activity in cortical reticular cells up to the same pattern as in medullary reticular cells. After ethanol (ET) administration severe damages occurred. The thymic cortex was free of DPP IV-positive lymphocytes; the medullary reticular cells showed reduced or no GGT and occasionally an increased APM activity. Dexamethasone (DEXA) given to normal or zinc-deficient rats produced the most severe lesions; thymocytes with DPP IV activity were completely absent in the cortex and medulla. In Zn-deficient pregnant rats similar alterations were observed as after ET.(ABSTRACT TRUNCATED AT 250 WORDS)     

Are any functionally mature cells of medullary phenotype located in the thymus cortex?

Experiments were undertaken to test if thymocytes of "mature" or "medullary" phenotype were restricted to the medullary area of the thymus. A calculation based on direct cell counts on serial sections indicated that 11.5% of adult male CBA thymic lymphoid cells were within the medullary zone. Since only 3-4% of thymocytes were cortisone resistant, the majority of thymocytes within the medulla were, like cortical thymocytes, cortisone sensitive. A series of cell surface antigenic markers, used alone or in pairs, suggested that 13-15% of thymocytes were of medullary phenotype, somewhat more than the number of thymocytes actually present in the medulla. However, much of this discrepancy could be explained by differential death of cortical cells during isolation and staining, and by the existence in the cortex of a subpopulation of early blast cells which shared some, but not all markers with medullary thymocytes. A direct test for mature or medullary phenotype cells in the cortex involved selective transcapsular labeling of outer-cortical cells with fluorescent dyes, followed by multiparameter immunofluorescent analysis of the 10% labeled population. Outer-cortical thymocytes included some cells (mainly early blasts) sharing some markers with medullary thymocytes, but very few (less than 1%) of these cells expressed all the characteristic "mature" markers. Limit-dilution precursor frequency studies showed the level of functional cells in the outer cortex was extremely low. The overall conclusion was that the vast majority of cells of complete "mature" phenotype are confined to the thymic medulla. These findings favor the view that thymus migrants originate from the thymic medulla, but do not exclude a cortical origin. The results also illustrate the need for multiparameter analysis to distinguish medullary thymocytes from early blast cells.     

Fine structure of the thymus in the adult cling fish Sicyases sanguineus (Pisces, Gobiesocidae)

The structure of the thumus in adult specimens of a marine teleost, the cling fish Sicyases sanguineus, has been studied by light and transmission electron microscopy. Most cling fishes have an outer thymus located beneath the opercular epithelium. A few of them, however, have a large inner thymus besides a poorly developed outer thymus. In the well-developed outer thymus of cling fish there are three different zones: outer cortex, inner cortex, and medulla. The inner cortex is similar to the cortical region of the thumus in other vertebrates, whereas the outer cortex is a specialized lympho-epithelial zone containing cystic cells (also present in medullary region) and true Hassall's corpuscles. In accordance with the development of the thymic parenchyma, the medullary or basal region may appear either like a true thymic medulla or like a subcapsular region. In the inner thymus, a subcapsular or peripheral "medullary" region and a central area (inverted cortex) show structural features like those of the medullary (basal) and deep cortical regions of the outer thymus, respectively. In addition to the above regions, sometimes there is a lymphomyeloid perithymic infiltration that often extends along connective tissue septa into the perivascular spaces of the gland. Reticuloepithelial, mesenchymal, and unidentified types of stromal cells within the thymus are described. Some erythrocytes, granulocytes, and monocytoid cells are found, but no plasma cells nor erythropoietic foci are evident. The probable significance of these findings is discussed.     

Changes in the argyrophil carcass of the lobules of the thymus gland during its age-related involution

Fibrillar components of the thymus lobules have been studied in persons 9-73 years of age and in 11-30 month-old noninbred white rats. Beginning from 9-10 years of age, i. e. before the onset of age involution, in the medullary substance of the lobules argyrophil carcass is formed; it includes numerous microvessels. At the age of 30-40 years a part of argyrophil fibers is subjected to destruction. At the same time in the medullary substance adipocytes appear. Their increasing amount is accompanied with substitution of the medullary substance for adipose substance, while a part of the cortical substance is preserved. These data are confirmed, when the thymus in old animals is studied. Ultrastructural manifestations of extra- and intracellular destruction of fibers are noted in them, too. The dynamics of the fibrillar component changes in the thymus in different animal individuals is not the same and can serve as one of the criteria of its age involution.     

Reviewing old concepts at the start of a new millenium: growth restriction,adrenal hypoplasia,and thymomegaly in human anencephaly

BACKGROUND: Anencephaly has been associated frequently with intrauterine growth retardation (IUGR), consistently with adrenal hypoplasia, and occasionally with an enlarged thymus. Few studies have analyzed the relationship between gestational age (GA), IUGR, associated anomalies and thymomegaly in anencephaly. The aims of our study were to evaluate this relationship and to highlight the usefulness of anencephaly as a model when investigating immune-endocrine interactions. METHODS: Fifty-two anencephalics' autopsies were reviewed retrospectively. Body weight, adrenal, and thymus weights were compared to prenatal, postnatal, and stillborn control values, and between associated and isolated anencephalic cases (presenting with and without other unrelated anomalies). Comparisons of adrenal and thymus weights were done by GA and by body weight. Thymus weight:body weight (TW:BW) ratios were compared to expected values. RESULTS: Anencephalics' body and adrenal weights were lower than their control values, whereas thymus weights did not differ. Body and thymus weights were twice as high in isolated than in associated anencephaly, whereas adrenal weights did not differ. Anencephalics TW:BW ratios were higher than their control values, higher in cases with IUGR, and higher in isolated rather than associated cases. When distributed by GA, thymus weights in anencephaly increased at a higher-than-expected rate. CONCLUSIONS: Our results suggest that adrenal hypoplasia is invariably present in anencephaly, and depending on an underdeveloped pituitary gland, seems to be independent of its etiology. On the contrary, IUGR mainly exists in associated cases and thymus enlargement mainly exists in isolated cases, suggesting a relationship with the underlying cause.