Expression of aldehyde dehydrogenase family 1, member A3 in glycogen trophoblast cells of the murine placenta.

INTRODUCTION: Retinoic acid (RA) signaling is a well known regulator of trophoblast differentiation and placental development, and maternal decidual cells are recognized as the source of much of this RA. We explored possible trophoblast-derived sources of RA by examining the expression of RA synthesis enzymes in the developing mouse placenta, as well as addressed potential sites of RA action by examining the ontogeny of gene expression for other RA metabolizing and receptor genes. Furthermore, we investigated the effects of endogenous RA production on trophoblast differentiation. METHODS: Placental tissues were examined by in situ hybridization and assayed for RARE-LacZ transgene activity to locate sites of RAR signaling. Trophoblast stem cell cultures were differentiated in the presence of ALDH1 inhibitors (DEAB and citral), and expression of labyrinth (Syna, Ctsq) and junctional zone (Tpbpa, Prl7b1, Prl7a2) marker genes were analyzed by qRT-PCR. RESULTS: We show Aldh1a3 is strongly expressed in a subset of ectoplacental cone cells and in glycogen trophoblast cells of the definitive murine placenta. Most trophoblast subtypes of the placenta express RA receptor combinations that would enable them to respond to RA signaling. Furthermore, expression of junctional zone markers decrease in differentiating trophoblast cultures when endogenous ALDH1 enzymes are inhibited. DISCUSSION: Aldh1a3 is a novel marker for glycogen trophoblast cells and their precursors and may play a role in the differentiation of junctional zone cell types via production of a local source of RA.

Ly6e expression is restricted to syncytiotrophoblast cells of the mouse placenta.

In the present study, we characterized the expression of lymphocyte antigen 6, locus E (Ly6e) in mouse placental trophoblast. We identified Ly6e mRNA expression in trophoblast stem (TS) cells by a gene expression screen. In vivo, Ly6e was first detectable by mRNA in situ hybridization in the chorion beginning at E8.5 with spatial expression similar to Syncytin a (Syna). At later stages of gestation, Ly6e was restricted to syncytiotrophoblast in the labyrinth. Northern blot confirmed that Ly6e was expressed in both undifferentiated and differentiated TS cell cultures but that its expression increased with differentiation. FACS analysis confirmed these results and allowed us to isolate LY6E⁺ cells, which we found to express Syna at a much higher level than did LY6E⁻ cells. Our findings suggest that LY6E is expressed in differentiated syncytiotrophoblast and may also be useful as an early marker, expressed in progenitors of this cell-type.

[Early onset Alzheimer's disease - diagnosis, therapy and management]. / Die Alzheimer-Demenz mit präsenilem Beginn - Besonderheiten in Diagnostik, Therapie und Management.

This work describes the characteristics of diagnosis, therapy and management of patients with presenile, early onset Alzheimer's disease on the basis of two case reports. The current state of knowledge regarding aetiological, pathophysiological and clinical characteristics is presented. The diagnostic procedures and differential diagnostic considerations are illustrated. The importance of the disclosure of the diagnosis is highlighted. Options for non-cognitive treatment, counselling and support are described.

Validation of the German revised Addenbrooke's cognitive examination for detecting mild cognitive impairment, mild dementia in alzheimer's disease and frontotemporal lobar degeneration.

BACKGROUND/AIMS: The diagnostic accuracy of the German version of the revised Addenbrooke's Cognitive Examination (ACE-R) in identifying mild cognitive impairment (MCI), mild dementia in Alzheimer's disease (AD) and mild dementia in frontotemporal lobar degeneration (FTLD) in comparison with the conventional Mini Mental State Examination (MMSE) was assessed. METHODS: The study encompasses 76 cognitively healthy elderly individuals, 75 patients with MCI, 56 with AD and 22 with FTLD. ACE-R and MMSE were validated against an expert diagnosis based on a comprehensive diagnostic procedure. Statistical analysis was performed using the receiver operating characteristic method and regression analyses. RESULTS: The optimal cut-off score for the ACE-R for detecting MCI, AD, and FTLD was 86/87, 82/83 and 83/84, respectively. ACE-R was superior to MMSE only in the detection of patients with FTLD [area under the curve (AUC): 0.97 vs. 0.92], whilst the accuracy of the two instruments did not differ in identifying MCI and AD. The ratio of the scores of the memory ACE-R subtest to verbal fluency subtest contributed significantly to the discrimination between AD and FTLD (optimal cut-off score: 2.30/2.31, AUC: 0.77), whereas the MMSE and ACE-R total scores did not. CONCLUSION: The German ACE-R is superior to the most commonly employed MMSE in detecting mild dementia in FTLD and in the differential diagnosis between AD and FTLD. Thus it might serve as a valuable instrument as part of a comprehensive diagnostic workup in specialist centres/clinics contributing to the diagnosis and differential diagnosis of the cause of dementia.

[A case of Listeria monocytogenes meningitis in an immunocompetent infant]. / Un caso clinico di meningite da Listeria Monocytogenes in un bambino immunocompetente.

Listeria Monocytogenes meningitis is a rare affection after the neonatal period, but in immunocompromised patients. Listeria Monocytogenes is a Gram-positive, facultative intracellular bacterium frequently causing infection in pregnant women, in patients with cell-mediated immunity deficit and in the early and late stages of life. We present a case of Listeria Monocytogenes meningitis in an immunocompetent nomad 8-month-child, preceded by gastroenteritis. Although gastrointestinal symptoms may be due to intestinal infection by Listeria, the concomitant presence of other bacteric or viral enteric pathogens may have promoted bacterium intestinal translocation and generated disseminated disease. The main transmission route of infection after the neonatal period is ingestion of contaminated food. A diet history was taken after isolation of the bacterium in liquor and showed that the child was an eater of undercooked hot-dogs. Despite the frequency of clinical complication in such affection, the outcome in this patient was a complete recovery. Although the infection is extremely infrequent in healthy children, physicians should always consider Listeria as a possible etiologic agent of meningitis in pediatric patients, regardless of their age or immunological status, especially in patients living in precarious sanitary conditions, where weaning times and conditions are not respected and a suitable food cooking is not assured.

Highly active antiretroviral-treated HIV-infected children show fat distribution changes even in absence of lipodystrophy.

BACKGROUND: Combined use of dual-energy X-ray absorptiometry (DXA) and magnetic resonance imaging (MRI) allows a precise estimate of regional body composition and intra-abdominal adipose tissue (IAT). Data on body composition in HIV-infected children (HIV+) receiving highly active antiretroviral therapy (HAART) with (LD+) and without (LD-) lipodystrophy are lacking. METHODS: DXA scans were performed in 34 HIV+: six LD+, 28 LD- and 34 pair-matched (age, sex and body mass index) healthy controls (HC): six for LD+ (HC+) and 28 for LD- (HC-). MRI scans were performed in 16 HIV+: six LD+, 10 LD- and 16 pair-matched (age and sex) HC. Data were analysed by analysis of variance, post hoc Fisher test and Mann-Whitney test. RESULTS: LD+ and LD- were similar for: previous exposure to zidovudine/zidovudine + didanosine, months on HAART (stavudine + lamuvidine + one protease inhibitor), CD4+ cells, patients with HIV-RNA < 50 copies/ml. In HIV+ and HC, fat mass and distribution were significantly different, whereas lean mass was comparable. Thus, LD+ and LD- as compared to HC+ and HC- respectively showed: (1) reduced fat amount and percentage; (2) lower truncal fat mass; (3) markedly reduced limbs fat mass. Within the HIV+ group, (4) LD+ showed higher fat trunk/fat total (P = 0.04) and lower fat limbs/ fat total ratios (P = 0.009) than LD-; (5) LD+ showed larger IAT areas than LD- and HC (P < 0.0003). CONCLUSIONS: Increased central fat and peripheral lipoatrophy are distinctive features of all HAART-treated children. Changes in body fat composition are detectable by DXA even in the absence of signs of Lipodystrophy. Only LD+ show true central obesity.

Electroretinogram B-wave amplitude in panic disorder.

Abnormal light-related behaviors have been described for patients with panic disorder (PD). The present study was undertaken to investigate the retinal light response in PD using electroretinography (ERG). The authors conducted b-wave ERG measurements with a bright light (after dark adaptation) in 28 patients with PD and 28 control subjects. There were no significant differences in the mean b-wave amplitude between the two groups, but the retinal response to light in PD patients was generally lower than in healthy subjects. A large interindividual variability was found; also noted was a significant difference in the mean b-wave amplitude between the right and left eyes in the control group. The data indicate subtle variation of retinal photosensitivity in a subgroup of patients with PD. Because dopaminergic retinal activity affects b-ERG amplitude, the authors hypothesize that the dopaminergic system is involved in the response to light in PD patients.

Vasopressin and thirst in patients with posterior pituitary ectopia and hypopituitarism.

OBJECTIVE: Partial diabetes insipidus has been documented in patients with congenital hypopituitarism and posterior pituitary ectopia, some cases being clinically silent except for enuresis. The objective of our study was to evaluate vasopressin (AVP) secretion and thirst appreciation in hypopituitary patients with posterior pituitary ectopia. PATIENTS: Twelve males and three females, aged between 13 and 38 years (median 19 years). Eleven had multiple pituitary deficiencies, adequately replaced at the time of the study, and four were only growth hormone deficient. None of the patients suffered from polyuria, polydipsia or nocturnal enuresis. We tested the patients with a 5% NaCl infusion. Five patients with abnormal vasopressin production were also tested with nitroprusside, which affects baroceptor vasopressin secretion. RESULTS: We found that only two out of 12 patients had normal AVP secretion. Thirst assessment showed severe hypodipsia in one patient, hyperdipsia in three out of 15 and more subtle abnormalities in two out of 15 patients. Concordance was found between osmotically and baroceptor-stimulated vasopressin. CONCLUSIONS: Patients with posterior pituitary ectopia showed a high prevalence of subclinical subnormal vasopressin response to the osmolar stimulus and moreover an impairment of thirst appreciation. Our data on nonosmotically stimulated AVP release suggest the existence of a damage in the hypothalamic vasopressin secreting centres.

Nuclear localization of the type 1 PTH/PTHrP receptor in rat tissues.

The localization of PTH/PTH-related peptide (PTHrP) receptor (PTHR) has traditionally been performed by autoradiography. Specific polyclonal antibodies to peptides unique to the PTHR are now available, which allow a more precise localization of the receptor in cells and tissues. We optimized the IHC procedure for the rat PTHR using 5-microm sections of paraffin-embedded rat kidney, liver, small intestine, uterus, and ovary. Adjacent sections were analyzed for the presence of PTHR mRNA (by in situ hybridization) and PTHrP peptide. A typical pattern of staining for both receptor protein and mRNA was observed in kidney in cells lining the proximal tubules and collecting ducts. In uterus and gut, the receptor and its mRNA are present in smooth muscle layers (PTHrP target) and in glandular cuboidal cells and surface columnar epithelium. This suggests that PTH, or more likely PTHrP, plays a role in surface/secretory epithelia that is as yet undefined. In the ovary, PTHR was readily detectable in the thecal layer of large antral follicles and oocytes, and was present in the cytoplasm and/or nucleus of granulosa cells, regions that also contained receptor transcripts. PTHR protein and mRNA were found in the liver in large hepatocytes radiating outward from central veins. Immunoreactive cells were also present around the periphery of the liver but not within two or three cell layers of the surface. Clear nuclear localization of the receptor protein was present in liver cells in addition to the expected cytoplasmic/peripheral staining. PTHR immunoreactivity was present in the nucleus of some cells in every tissue examined. RT-PCR confirmed the presence of PTHR transcripts in these same tissues. Examination of the hindlimbs of PTHR gene-ablated mice showed no reaction to this antibody, whereas hindlimbs from their wild-type littermates stained positively. The results emphasize that the PTHR is highly expressed in diverse tissues and, in addition, show that the receptor protein itself can be localized to the cell nucleus. Nuclear localization of the receptor suggests that there is a role for PTH and/or PTHrP in the regulation of nuclear events, either on the physical environment (nucleoskeleton) or directly on gene expression.

Nuclear localization of the type 1 parathyroid hormone/parathyroid hormone-related peptide receptor in MC3T3-E1 cells: association with serum-induced cell proliferation.

We have recently demonstrated that the receptor for parathyroid hormone (PTH) and PTH-related peptide (PTHrP), PTHR, can be localized to the nucleus of cells within the liver, kidney, uterus, gut, and ovary of the rat. We set out to determine the localization of the PTHR in cultured osteoblast-like cells. MC3T3-E1, ROS 17/2.8, UMR106, and SaOS-2 cells were cultured in alpha-modified eagle medium containing 15% fetal calf serum under standard conditions. Untreated cells were grown on glass coverslips to 75-95% confluence and fixed in 1% paraformaldehyde. For experiments designed to examine cells synchronized by serum starvation, cells were grown on glass coverslips, starved of serum for 46 h, and then fixed at 2-h intervals for a total of 26 h after the addition of serum to the medium. Parallel sets of cells were pulsed with [3H]thymidine to track the DNA duplication interval. The PTHR was localized by immunocytochemistry using a primary antibody raised against a portion of the N-terminal extracellular domain of the PTHR. The results presented herein indicate that the PTHR attains a nuclear localization in each cell line examined. In UMR106 cells, PTHR immunoreactivity was restricted to the nucleolus. After cell synchronization, MC3T3-E1 cells double approximately 24 h after the addition of serum. Immunocytochemistry for the PTHR in these cells showed that the receptor staining is initially diffuse for the first 6 h, then becomes more perinuclear in distribution by 12-16 h. Nuclear localization of the receptor is achieved approximately 16-20 h after the addition of serum and remains there throughout the mitotic phase. Intense staining of mitotic and postmitotic cells was observed. No change in cell proliferation kinetics was observed in MC3T3-E1 cells cultured in the presence of 25 nM PTH(1-34). These data suggest an important role for the PTHR in the nucleus of MC3T3-E1 cells at the time of DNA synthesis and mitosis.

Dexamethasone in the diagnostic work-up of growth hormone deficiency.

OBJECTIVE: Acute administration of dexamethasone (dexa) has recently been shown to induce growth hormone (GH) release. To ascertain the efficacy of this stimulus in assessing GH secretory status in children, we tested it in a large group of patients with short stature. METHODS: We administered dexamethasone at the dose of 2 mg/m2 to 44 short normal children and 19 GH deficient (GHD) children, either orally or intravenously and compared the results of the dexa-test to the more classical clonidine test. RESULTS: The oral dexa-test induced a GH peak similar to the clonidine test (clo) (controls clo: 23.8 +/- 7.8 mU/l, median 22.8, range 15.2-45.4 vs. control dexa: 20.6 +/- 10.8, median 16.8, range 8-47, P = 0.2. GHD clo: 9.8 +/- 2.6, median 9.2, range 6.4-13.4 vs. GHD dexa: 9.4 +/- 3.4, median 10.2, range 4.6-14, P = 0.8). Its sensitivity and specificity with respect to the clonidine test were 91% (10/11 GHD) and 65% (15/23 controls), respectively. The GH peak after i.v. dexa was smaller than that after clonidine (control clo: 30.6 +/- 14 micrograms/l, median 24.8, range 14.2-62.4 vs. control dexa: 21.6 +/- 5.4, median 21.6, range 11.2-33, P = 0.01. GHD clo: 7.4 +/- 4.2, median 8.8, range 0.4-11.8 vs. GHD dexa: 6.4 +/- 5.6, median 5.8, range 0.4-16.2, P = 0.17) with sensitivity and specificity of 87% (7/8 GHD) and 90% (19/21 controls), respectively. The lower potency of dexamethasone could account for these figures, since when a different cut-off was used (12 mU/l and 11 mU/l for the oral and i.v. route) both sensitivity and specificity were improved. More data are needed to support these findings and establish a clear cut-off. In the control group, no difference was found between GH peak after oral or i.v. dexa but GH-area under the curve (AUC) was larger for i.v. than for oral dexa. No side effects were noted. CONCLUSIONS: Intravenous dexamethasone appears to be a promising stimulus for the detection of GH deficiency in children, particularly for use in outpatients.

Pseudodiastrophic dysplasia type Burgio in a newborn.

Pseudodiastrophic dysplasia is a distinct disorder that differs from diastrophic dysplasia on the basis of elbow and proximal interphalangeal joint dislocations, platyspondyly, and scoliosis. We report on a new patient with this rare skeletal dysplasia and two previously undescribed major malformations: omphalocele and complex heart defect.

Glucose turnover and insulin clearance after growth hormone treatment in girls with Turner's syndrome.

The study was performed to elucidate, by means of a euglycemic-hyperinsulinemic clamp, whether insulin sensitivity, lipid levels, posthepatic insulin delivery, and insulin clearance are impaired in girls with Turner's syndrome in the absence of previous treatment (T0) and after 6 (T6) and 12 (T12) months of growth hormone (GH) therapy (GHT). The study was performed in six girls with Turner's syndrome and eight healthy girls. We found that previously untreated girls with Turner's syndrome had a normal insulin activity on glucose metabolism. GHT progressively and significantly decreased hepatic insulin sensitivity. In fact, residual hepatic glucose release (HGR), which was 19.6 +/- 4.7 mg/m2. min at T0, doubled at T6 (39.3 +/- 5.1 mg/m2.min) and showed a threefold increase at T12 (68.7 +/- 10.8 mg/m2.min, P < .05 v T0). On the contrary, GHT did not show an appreciable influence on peripheral insulin sensitivity. Insulin clearance was higher in girls with Turner's syndrome than in control girls at T0 (30.0 +/- 2.8 v 20.2 +/- 1.1 mL.kg-1.min-1). It decreased to normal values at T6 (18.2 +/- 2.0 mL.kg-1.min-1, P < .05 v T0) and remained at normal levels at T12 (23.8 +/- 2.9 mL.kg-1. min-1). The posthepatic insulin delivery rate significantly increased at T6 and T12, suggesting increased insulin secretion. In conclusion, we found that insulin-stimulated glucose turnover was normal in girls with Turner's syndrome before therapy. One year of GHT was successful in stimulating the growth rate, but significantly decreased the insulin suppressibility on HGR with only slight changes in peripheral insulin sensitivity. In addition, an increase in the insulin posthepatic delivery rate and a normalization of insulin clearance were present, probably to counteract hepatic insulin resistance.

Biliary malformation with renal tubular insufficiency in two male infants: third family report.

We report two male sibs, born to non-consanguineous healthy parents, who showed arthrogryposis, cholestatic jaundice and tubular renal insufficiency. The liver biopsy of the first case showed scanty hypoplastic biliary ducts. This association, first reported by Lutz and Richner in 1973, is a distinct syndrome, characterized by intra-extrahepatic biliary hypoplasia, and described in McKusick's catalogue under the number 210550. All reported cases were males and consanguinity was found in two families. For these reasons, the possibility of an autosomal recessive or of an X-linked transmission should be considered. A similar association, in reports by Nezelof, Di Rocco, and Saraiva, without intra-extrahepatic atresia but with a cholestatic pigmentary liver disease was considered as another condition (no. 301820) by McKusick in 1992.

Bone mineral metabolism and thyroid replacement therapy in congenital hypothyroid infants and young children.

Impairment of calcium metabolism and low bone density have been found in hypothyroid adults. We investigated the effect of thyroid replacement therapy on calcium metabolism and bone mineralization in congenital hypothyroid (CH) infants and children. One hundred and 16 Caucasian CH consecutive patients were studied and were grouped according to their age: 23 patients at diagnosis, 20 at 3 mo, 24 at 6 mo, 25 at 12 mo and 24 at 36 mo. Thyroid replacement therapy was started at an initial dose of 6-8 micrograms/kg/day of L-thyroxine, and then decreased progressively. Calcium, phosphorus, magnesium, alkaline phosphatase (AP), parathyroid hormone (PTH) and osteocalcin (BGP) were measured as calcium metabolism indices. Bone mineral content (BMC) was measured at the mid-portion of the right radius AP, PTH and BGP concentrations were significantly higher in subjects at 3 mo of age (p < 0.05). This rise coincided with the end of the period of maximum dosage of L-thyroxine. Mild asymptomatic hypercalcemia was observed in 20 patients. All the other indices did not differ between age groups. BMC values and BMC annual increment were not different from those calculated for age-matched controls. We found that L-thyroxine replacement therapy does not alter bone mineralization of CH infants and children. Only a transitory increase of osteoblastic function was observed after the first few months of therapy.

Role of magnetic resonance imaging in hypothalamic-pituitary disorders.

Improvement of MRI diagnostic accuracy in the study of the hypothalamic-pituitary region provides precise anatomic details. In pituitary dwarfism, MRI reveals severe sella/pituitary gland and stalk hypoplasia with or without posterior pituitary ectopia, and empty sella, and this more frequently in patients with multiple pituitary hormone deficiency. Two main hypotheses have been proposed to explain these findings: traumatic stalk transection during breech delivery, and abnormal embryonic development of the pituitary gland. The association between neuroradiological findings and type/severity of endocrine alteration has not yet been clarified. In diabetes insipidus, MRI findings are normal picture, posterior lobe not visible, and thickened stalk (as expression of preclinical/initial histocytosis). Patients with central precocious puberty or hypogonadotropic hypogonadism rarely show morphologic abnormalities (hamartoma of the tuber cinereum, partially empty sella). So far, MRI permits one to identify morphologic pictures in diseases previously considered 'idiopathic'.

Peripheral and abdominal adiposity in childhood obesity.

The aim of this work was to evaluate peripheral and abdominal adipose tissue (AT) content detected by MRI in normal weight and obese children, to compare MRI data with simple anthropometric indexes and to estimate intrabdominal adipose tissue (IAT) influence on cardiovascular risk factors. The subjects were 23 obese and 21 normal weight children aged 10 to 15 years. The following measurements were carried out: MRI analysis at lumbar level with definition of subcutaneous adipose tissue (SAT) area and IAT area; arm fat area (AFA); thigh fat area (TFA) and waist/hip ratio from anthropometry. SAT (353 +/- 94 cm2) was predominant compared with IAT (49 +/- 21 cm2) in obese as well as in controls (SAT: 79 +/- 61 cm2; IAT: 22 +/- 11 cm2). No differences in SAT/IAT ratio were found for sex and puberty, either in obese subjects or in controls. SAT and IAT were significantly related in controls (r = 0.77, P < 0.0001), but not in obese subjects (r = 0.12, P = 0.59). IAT was related to total and LDL cholesterol and triglycerides levels (r = 0.54, P < 0.02, r = 0.60, P < 0.01, r = 0.46, P < 0.04, respectively) in obese children. AFA and TFA from anthropometry significantly underestimated AT compared with MRI in both groups. Methods agreement analysis showed unacceptable results for anthropometry. It was concluded that childhood obesity has a subcutaneous adipose pattern with no differences between the sexes. IAT already begins to have clinical significance since it has a relationship to some cardiovascular risk factors.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence of a congenital midline brain anomaly in pituitary dwarfs: a magnetic resonance imaging study in 101 patients.

BACKGROUND: Magnetic resonance imaging (MRI) of the brain in pituitary dwarfs has revealed a previously unknown entity: ectopia of the posterior pituitary (PPE), absence or hypoplasia of the pituitary stalk and hypoplasia of the anterior pituitary. The pathogenesis of these findings was explained originally by a traumatic transection of the pituitary stalk during delivery. A high incidence of breech delivery has been reported in these groups, but the traumatic hypothesis cannot explain the findings in the relatively high percentage of patients with normal delivery, nor account for a different feature also found in other pituitary dwarfs consisting of pituitary hypoplasia with normal posterior pituitary. A second hypothesis could then been proposed, based on dysgenesis or abnormal embryonic development of both adenohypophysis and neurohypophysis. OBJECTIVE: To review the value and significance of these two different etiopathogenetic hypotheses by analyzing clinical, endocrinological, and MRI findings in a large population of pituitary dwarfs. METHODS: One hundred and one consecutive patients with congenital idiopathic growth hormone deficiency (CIGHD) were studied by MRI; they were compared with a control group of 46 healthy short children. A complete clinico-endocrinological evaluation was obtained in both patients and controls to assess the perinatal history, the pituitary-hypothalamic function, and the neurological status. MRI studies were evaluated both qualitatively and quantitatively and the pituitary volume (PV) was calculated in both patients and controls. Quantitative data were statistically analyzed to compare the mean PV of the patients with the mean PV of controls, the hormonal therapy, the single or multiple pituitary hormone deficiency, and the presence of breech delivery. RESULTS: MRI revealed PPE in 59 patients and a normal posterior pituitary (NPP) in 42. PV was extremely small in patients with PPE and in patients with NPP associated with a severely narrowed pituitary stalk; mean PV was significantly lower in CIGHD patients when compared with that of healthy short children. PV was not influenced by hormonal therapy and did not differ between patients with single and multiple pituitary hormone deficiency and between patients with normal and breech delivery. PPE patients differed from NPP patients for a higher male/female ratio (3:1 vs 1:1) and for a greater frequency of multiple pituitary hormone deficiency (49% vs 12%), breech delivery (32% vs 7%), and associated congenital brain anomalies (12% vs 7%). In PPE patients breech delivery was strongly associated with multiple pituitary hormone deficiency. CONCLUSION: On the basis of this study the traumatic hypothesis could theoretically explain the pathogenesis of PPE only in 32% of the patients with this condition. On the basis of modern understanding of embryogenesis of anterior and posterior pituitary, it is then justified to propose that a defective induction of mediobasal structure of the brain in the early embryo could account for both the complex morphological MRI abnormality and the clinico-endocrinological features encountered in all PPE patients. The close contiguity between the future pituitary and hypothalamus, the peculiar association with congenital midline brain anomalies, and the recent data about a possible role of Pit-1 gene, all support the hypothesis of a congenital defect. Finally, breech delivery can be considered not as a cause of PPE, but as an effect of the embryonic pituitary-hypothalamic abnormalities.