Human inherited CCR2 deficiency underlies progressive polycystic lung disease.

We describe a human lung disease caused by autosomal recessive, complete deficiency of the monocyte chemokine receptor C-C motif chemokine receptor 2 (CCR2). Nine children from five independent kindreds have pulmonary alveolar proteinosis (PAP), progressive polycystic lung disease, and recurrent infections, including bacillus Calmette Guérin (BCG) disease. The CCR2 variants are homozygous in six patients and compound heterozygous in three, and all are loss-of-expression and loss-of-function. They abolish CCR2-agonist chemokine C-C motif ligand 2 (CCL-2)-stimulated Ca2+ signaling in and migration of monocytic cells. All patients have high blood CCL-2 levels, providing a diagnostic test for screening children with unexplained lung or mycobacterial disease. Blood myeloid and lymphoid subsets and interferon (IFN)-γ- and granulocyte-macrophage colony-stimulating factor (GM-CSF)-mediated immunity are unaffected. CCR2-deficient monocytes and alveolar macrophage-like cells have normal gene expression profiles and functions. By contrast, alveolar macrophage counts are about half. Human complete CCR2 deficiency is a genetic etiology of PAP, polycystic lung disease, and recurrent infections caused by impaired CCL2-dependent monocyte migration to the lungs and infected tissues.

Association between the development of bronchopulmonary dysplasia and platelet transfusion: a protocol for a systematic review and meta-analysis.

Background: There is a lack of consensus on the management of thrombocytopenia in preterm infants, and the threshold for prophylactic platelet transfusion varies widely among clinicians and institutions. Reports in animal models suggested that platelets may play a relevant role in lung alveolarization and regeneration. Bronchopulmonary dysplasia (BPD) is a severe respiratory condition with a multifactorial origin that affects infants born at the early stages of lung development. Recent randomized controlled trials on the platelets count threshold for prophylactic transfusions in preterm infants with thrombocytopenia suggest that a higher exposition to platelet transfusion may increase the risk of BPD. Here, we report a protocol for a systematic review, which aims to assist evidence-based clinical practice and clarify if the administration of platelet products may be associated with the incidence of BPD and/or death in preterm infants. Methods: MEDLINE, Embase, Cochrane databases, and sources of gray literature for conference abstracts and trial registrations will be searched with no time or language restrictions. Case-control studies, cohort studies, and nonrandomized or randomized trials that evaluated the risk for BPD and/or death in preterm infants exposed to platelet transfusion will be included. Data from studies that are sufficiently similar will be pooled as appropriate. Data extraction forms will be developed a priori. Observational studies and nonrandomized and randomized clinical trials will be analyzed separately. Odds ratio with 95% confidence interval (CI) for dichotomous outcomes and the mean difference (95% CI) for continuous outcomes will be combined. The expected heterogeneity will be accounted for using a random-effects model. Subgroup analysis will be performed based on a priori-determined covariate of interest. In case of sufficient homogeneity of interventions and outcomes evaluated, results from subgroups of studies will be pooled together in a meta-analysis. Discussion: This systematic review will investigate the association of BPD/death with platelet components administration in preterm infants, and, consequently, it will provide reliable indications for the evidence-based management of premature patients with thrombocytopenia.

Exclusive breastfeeding at 6 months after assisted and spontaneous conceiving: a prospective study in Northern Italy.

Conceiving by assisted infertility treatments may influence breastfeeding duration. In one-year time, to evaluate the goal of 6 months breastfeeding, we recruited 55 consecutive mothers who conceived using assisted treatment compared to 45 mothers conceiving naturally, all giving birth to healthy, full-term, singleton infants, sharing the double-occupancy room. At birth, maternal/neonatal characteristics were obtained by medical records and interviews. Six months after, a telephonic interview was done about the exclusivity of breastfeeding, mood instability, and breastfeeding complications. All the women were supported by the same neonatal-pediatrician team, during the study period. The number of mothers who were exclusively breastfeeding at six months was not statistically different between the two groups, as well as, breastfeeding initiation, BMI, smoking habit, mood instability, co-morbidities. In the assisted group, the women were older, had fewer previous children, upper degree of education, higher rate of cesarean sections, their neonate's birthweight was lower; they reported more breastfeeding complications, but the distribution was not different between groups. The control women had higher number of previously breastfed siblings. Our experience highlights that the mode of conception may not be the defining factor influencing the goal of 6 months lactation. The support of healthcare professional team has a crucial role in maintaining breastfeeding.

SIMPSON-GOLABI-BEHMEL syndrome type 1: How placental immunohistochemistry can rapidly Predict the diagnosis.

INTRODUCTION: Glypican-3 (GPC3) is an oncofetal protein involved in cellular signaling, strongly expressed in the placenta, absent or diminished in postnatal life, but often increased in human malignancies. Germline loss-of-function variants of GPC3 gene are associated with Simpson-Golabi-Behmel syndrome type 1 (SGBS1), a rare recessive X-linked overgrowth disease characterized by typical facial features, congenital abnormalities, and an increased risk of developing childhood cancers. METHODS: A clinical suspicion of SGBS1 was postulated for a newborn with prenatal history of overgrowth and polyhydramnios, presenting with neonatal weight and length >99th percentile, coarse facies, iris and retinal coloboma, supernumerary nipples, and splenomegaly. While waiting for whole-genome sequencing (WGS) results, we investigated placental GPC3 immunohistochemical expression in the proband, in three additional cases of SGBS1, and disorders commonly associated with fetal macrosomia and/or placentomegaly. RESULTS: WGS in the proband identified a likely pathogenic maternally inherited missense variant in GPC3: c.1645A > G, (p.Ile549Val), and GPC3 immunohistochemistry demonstrated full-thickness loss of stain of the placental parenchyma. The same pattern ("null") was also present in the placentas of three additional cases of SGBS1, but not in those of unaffected controls. DISCUSSION: Immunohistochemical expression of GPC3 in the placenta is highly reproducible. Our findings showed that a "null pattern" of staining is predictive of SGBS1 and represents a valuable aid in the differential diagnosis of fetal macrosomias, allowing targeted genetic testing and earlier diagnosis.

Neurodevelopmental outcome of Italian preterm ELBW infants: an eleven years single center cohort.

BACKGROUND: Preterm extremely low birth weight infants (ELBWi) are known to be at greater risk of developing neuropsychiatric diseases. Identifying early predictors of outcome is essential to refer patients for early intervention. Few studies have investigated neurodevelopmental outcomes in Italian ELBWi. This study aims to describe neurodevelopmental outcome at 24 months of corrected age in an eleven-year single-center cohort of Italian ELBWi and to identify early risk factors for adverse neurodevelopmental outcomes. METHODS: All infants born with birth weight < 1000 g and admitted to the Neonatal Intensive Care Unit of the "Fondazione IRCCS Policlinico San Matteo" hospital in Pavia, Italy, from Jan 1, 2005 to Dec 31, 2015 were eligible for inclusion. At 24 months, Griffiths' Mental Developmental Scales Extended Revised (GMDS-ER) were administered. Neurodevelopmental outcome was classified as: normal, minor sequelae (minor neurological signs, General Quotient between 76 and 87), major sequelae (cerebral palsy; General Quotient ≤ 75; severe sensory impairment). Univariate and multivariate multinomial logistic regression models were performed to analyze the correlation between neonatal variables and neurodevelopmental outcome. RESULTS: 176 ELBWi were enrolled (mean gestational age 26.52 weeks sd2.23; mean birthweight 777.45 g sd142.89). 67% showed a normal outcome at 24 months, 17% minor sequelae and 16% major sequelae (4.6% cerebral palsy on overall sample). The most frequent major sequela was cognitive impairment (8.52%). In the entire sample the median score on the Hearing-Speech subscale was lower than the median scores recorded on the other subscales and showed a significantly weaker correlation to each of the other subscales of the GMDS-ER. Severely abnormal cUS findings (RRR 10.22 p 0.043) and bronchopulmonary dysplasia (RRR 4.36 p 0.008) were independent risk factors for major sequelae and bronchopulmonary dysplasia for minor sequelae (RRR 3.00 p 0.018) on multivariate multinomial logistic regression. CONCLUSIONS: This study showed an improvement in ELBWI survival rate without neurodevelopmental impairment at 24 months compared to previously reported international cohorts. Cognitive impairment was the most frequent major sequela. Median scores on GMDS-ER showed a peculiar developmental profile characterized by a selective deficit in the language domain. Severely abnormal cUS findings and bronchopulmonary dysplasia were confirmed as independent risk factors for major sequelae.

Optimizing fresh-frozen plasma transfusion in surgical neonates through thromboelastography: a quality improvement study.

Fresh frozen plasma (FFP) is largely misused in the neonatal setting. The aim of the study is to evaluate the impact of a Thromboelastography (TEG)-based Quality Improvement (QI) project on perioperative FFP use and neonatal outcomes. Retrospective pre-post implementation study in a level-III NICU including all neonates undergoing major non-cardiac surgery before (01-12/2017) and after (01-12/2019) the intervention. In 2018, the intervention included the following: (1) Training on TEG, (2) Implementation of TEG, and (3) Algorithm for TEG-directed FFP administration in surgical neonates. We compared pre- vs post-intervention patient characteristics, hemostasis, and clinical management. Linear and logistic regression models were used to evaluate the impact of the project on main outcomes. We analyzed 139 neonates (pre-intervention: 72/post-intervention: 67) with a mean (± SD) gestational age (GA) 34.9 (± 5) weeks and birthweight 2265 (± 980) grams which were exposed to 184 surgical procedures (pre-intervention: 91/post-intervention: 93). Baseline characteristics were similar between periods. In 2019, prothrombin time (PT) was longer (14.3 vs 13.2 s; p < 0.05) and fibrinogen was lower (229 vs 265 mg/dl; p < 0.05), if compared to 2017. In 2019, the intraoperative exposure to FFP decreased (31% vs 60%, p < 0.001), while the pre-operative FFP use did not change. The reduction of intraoperative FFP did not impact on mortality and morbidity. Intraoperative FFP use was lower in the post-intervention even after controlling for GA, American Society of Anesthesiologists score, PT, and fibrinogen (Odds ratio: 0.167; 95% CI: 0.070, 0.371).   Conclusion: The TEG-based QI project for the management of FFP during neonatal surgery reduced intraoperative FFP exposure. What is Known: • PT and aPTT are poor predictors of bleeding risk in acquired neonatal coagulopathy, leading to likely unnecessary fresh frozen plasma (FFP) transfusion in the Neonatal Intensive Care Setting.  • As neonatal hemostasis is a delicate balance between the concomitant reduction of pro- and anti-coagulants drivers, thromboelastography (TEG) is a promising alternative for coagulation monitoring. What is New: • The implementation of TEG, training, and shared protocols contributed to reduced intraoperative FFP use, which was not associated with increased mortality or bleeding events. • These findings inform future research showing that there is clinical equipoise to allow for larger studies to confirm the use of TEG in NICUs and to identify TEG cut-offs for transfusion practice.

Arterial hypertension and cystatin C during neonatal physiologic dehydration.

A reduced nephron number may play a role in the pathogenesis of arterial hypertension (AH), and it is well recognized that individual nephron endowment is widely variable. However, nephrons count is technically impossible in vivo. Based on the observation that subjects with a reduced nephron mass exhibit an increase in renal functional biomarkers during acute dehydration, we hypothesized that cystatin C concentration during neonatal physiological dehydration could identify subjects with reduced nephron endowment. This is a prospective, observational, cohort study enrolling healthy, caucasian, term neonates born after an uneventful pregnancy. Two groups of newborns were compared: neonates born to fathers on antihypertensive treatment (HF) versus those born to proven normotensive fathers older than 40 years of age (NF). Enrolled newborns underwent cystatin C determination at the time of newborn screening. Forty newborns with HF and 80 with NF were enrolled. No differences in baseline characteristics were observed between the two groups except for the number of hypertensive grandparents higher among newborns to HF (47.8% vs. 21.1%; p: 0.001). Cystatin C was significantly higher in newborns with HF (1.62 ± 0.30 mg/L vs 1.41 ± 0.27 mg/L; p < 0.001). Linear regression analysis corrected for confounders confirmed that paternal hypertension was the only variable significantly associated with high cystatin C level during post-natal dehydration. Besides offering new insights on the pathogenesis of familial hypertension, our results support the specific role of nephron endowment and suggest the possibility of identifying subjects at risk for reduced nephron endowment as early as at birth.

A maChine and deep Learning Approach to predict pulmoNary hyperteNsIon in newbornS with congenital diaphragmatic Hernia (CLANNISH): Protocol for a retrospective study.

INTRODUCTION: Outcome predictions of patients with congenital diaphragmatic hernia (CDH) still have some limitations in the prenatal estimate of postnatal pulmonary hypertension (PH). We propose applying Machine Learning (ML), and Deep Learning (DL) approaches to fetuses and newborns with CDH to develop forecasting models in prenatal epoch, based on the integrated analysis of clinical data, to provide neonatal PH as the first outcome and, possibly: favorable response to fetal endoscopic tracheal occlusion (FETO), need for Extracorporeal Membrane Oxygenation (ECMO), survival to ECMO, and death. Moreover, we plan to produce a (semi)automatic fetus lung segmentation system in Magnetic Resonance Imaging (MRI), which will be useful during project implementation but will also be an important tool itself to standardize lung volume measures for CDH fetuses. METHODS AND ANALYTICS: Patients with isolated CDH from singleton pregnancies will be enrolled, whose prenatal checks were performed at the Fetal Surgery Unit of the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (Milan, Italy) from the 30th week of gestation. A retrospective data collection of clinical and radiological variables from newborns' and mothers' clinical records will be performed for eligible patients born between 01/01/2012 and 31/12/2020. The native sequences from fetal magnetic resonance imaging (MRI) will be collected. Data from different sources will be integrated and analyzed using ML and DL, and forecasting algorithms will be developed for each outcome. Methods of data augmentation and dimensionality reduction (feature selection and extraction) will be employed to increase sample size and avoid overfitting. A software system for automatic fetal lung volume segmentation in MRI based on the DL 3D U-NET approach will also be developed. ETHICS AND DISSEMINATION: This retrospective study received approval from the local ethics committee (Milan Area 2, Italy). The development of predictive models in CDH outcomes will provide a key contribution in disease prediction, early targeted interventions, and personalized management, with an overall improvement in care quality, resource allocation, healthcare, and family savings. Our findings will be validated in a future prospective multicenter cohort study. REGISTRATION: The study was registered at ClinicalTrials.gov with the identifier NCT04609163.

The Thromboelastographic Profile at Birth in Very Preterm Newborns with Patent Ductus Arteriosus.

BACKGROUND: The role of hemostasis in the closure of patent ductus arteriosus (PDA) in preterm infants is controversial. OBJECTIVE: To assess thromboelastography (TEG) at birth in very-low-birth-weight (VLBW) infants affected by PDA. METHODS: This was an ancillary study of a prospective observational study aimed at defining the TEG profile in healthy VLBW infants in the first month of life. In this analysis, we included neonates of <33 weeks' gestational age (GA) with PDA and compared TEG traces based on (1) spontaneous closure versus the need for pharmacological treatment and (2) treatment response. We collected blood samples in the 1st day of life to perform recalcified native-blood TEG (reaction time, maximum amplitude, and lysis at 30 min [Ly30)]), standard coagulation tests, and a full blood count. RESULTS: We enrolled 151 infants with a PDA at the first echocardiogram; 111 experienced spontaneous PDA closure while 40 required treatment. Mean GA was 29.7 ± 1.7 and 27.6 ± 2.1 weeks, and birth weight was 1,158 ± 256 and 933 ± 263 g in the 2 groups, respectively (p < 0.001). The hemostatic profile was similar between groups. Median hematocrit (44.6 and 48.7%; p = 0.01) and platelet count (187 and 216 × 103/µL; p = 0.04) were lower in the treated group, although differences lost significance after controlling for GA and illness severity in the multivariate analysis. Responders to PDA treatment (n = 20) had a significantly lower median Ly30 than nonresponders (0 and 0.7%; p = 0.02). CONCLUSION: TEG at birth does not predict spontaneous PDA closure in preterm newborns. Fibrinolysis is enhanced in nonresponders to PDA treatment; this observation warrants further investigation.

Iron Homeostasis Disruption and Oxidative Stress in Preterm Newborns.

Iron is an essential micronutrient for early development, being involved in several cellular processes and playing a significant role in neurodevelopment. Prematurity may impact on iron homeostasis in different ways. On the one hand, more than half of preterm infants develop iron deficiency (ID)/ID anemia (IDA), due to the shorter duration of pregnancy, early postnatal growth, insufficient erythropoiesis, and phlebotomy losses. On the other hand, the sickest patients are exposed to erythrocytes transfusions, increasing the risk of iron overload under conditions of impaired antioxidant capacity. Prevention of iron shortage through placental transfusion, blood-sparing practices for laboratory assessments, and iron supplementation is the first frontier in the management of anemia in preterm infants. The American Academy of Pediatrics recommends the administration of 2 mg/kg/day of oral elemental iron to human milk-fed preterm infants from one month of age to prevent ID. To date, there is no consensus on the type of iron preparations, dosages, or starting time of administration to meet optimal cost-efficacy and safety measures. We will identify the main determinants of iron homeostasis in premature infants, elaborate on iron-mediated redox unbalance, and highlight areas for further research to tailor the management of iron metabolism.

Effects of Red Blood Cell Transfusions on the Risk of Developing Complications or Death: An Observational Study of a Cohort of Very Low Birth Weight Infants.

Background The aim of this study was to evaluate the association between red blood cell (RBC) transfusions on the risk of death, retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), and necrotizing enterocolitis (NEC) in very low birth weight (VLBW) infants. Study Design and Methods This is an observational study. Data were entered prospectively into the study database at the time of the first transfusion. Clinical characteristics, adverse events, and outcomes of the patients transfused in the first 28 days of life were compared with the population of VLBW infants not transfused during the same period. The association among birth weight, gestational age, comorbidities, and the number of transfusions was estimated with a Poisson regression model. The association between the composite outcome and the occurrence of death, ROP, or BPD separately considered and a set of covariates was estimated with a logistic regression model. Results We enrolled 641 VLBW infants, 42% of whom were transfused. Transfusions were associated with the risk of developing the composite outcome, independently from other conditions; this risk correlated with several transfusions ≥ 3 (odds ratio: 5.88, 95% confidence interval: 2.74-12.6). ROP and BPD were associated with several transfusions ≥ 3. Conclusion We observed an association between RBC transfusions and the composite risk of death or ROP, BPD, and NEC.

A new structural rearrangement associated to Wolfram syndrome in a child with a partial phenotype.

Wolfram syndrome (WS) is a rare autosomal recessive disorder characterized by diabetes insipidus (DI), insulin-dependent diabetes mellitus (DM), optic atrophy (OA) and deafness caused by mutations in WFS1 gene (4p16.1), which encodes an endoplasmic reticulum protein, called Wolframin. We describe the case of an infant who presented hypernatremia and severe hypoplasia of the left eyeball with alteration of visual evoked potentials. Persistent hypernatremia, iposmolar polyuria and high plasma osmolality suggested DI, confirmed by a normal urine concentration after vasopressin test. Treatment with vasopressin allowed a normalization of sodium levels and urine output. Brain magnetic resonance imaging showed absence of the neurohypophysis hyperintense signal, normal adenohypophysis and optic tracts hypoplasia. The concomitant presence of DI and OA, even in the absence of DM and deafness, prompted the suspicion of WS and complete genetic analysis was performed. Genomic DNA sequencing of WFS1 showed no inactivating mutations described to date, but suggested a structural mutation as markers genotyping revealed a segmental paternal heterodisomy involving the upstream regulatory region (promoter and 5'UTR). cDNA sequencing revealed the coexistence of the wild-type transcript and two splice variants; one variant, probably benign, is known in literature and the other one causes the loss of exon 2, containing the translation initiation site. Western blot confirmed a marked protein reduction. During the clinical follow-up child's condition remained stable and glucose metabolism is still in the standard. In conclusion, the phenotype associated with this structural rearrangement, which substantially reduces the synthesis of Wolframin, confirms a tissue-specific pattern of expression of WFS1, suggests the presence of a different protein dosage sensitivity in different tissues and could be causative of DI and OA in our patient. The "incomplete" phenotype here described, usually absent in typical WS cases, is explained by the residual Wolframin expression that would preserve other organs, i.e. pancreatic islets. A careful longitudinal clinical follow-up will assess any changes in the phenotypic penetrance in our patient.

Feasibility of peritoneal dialysis in extremely low birth weight infants.

Acute renal injury is common in extremely low birth weight (ELBW) infants with a frequency ranging from 8% to 24%. Peritoneal dialysis (PD) has been used only occasionally in ELBW. We report our experience and share the solutions used to tackle the difficulties rising from the small size of this type of patients. PD was successfully performed in three ELBW infants with acute renal failure. A neonatal, single-cuff, straight Tenckhoff catheter was placed in 2 patients, while a Broviac single cuff vascular catheter was used in another. PD was feasible and effective in all children. Leakage was observed with Tenckhoff catheters, but this did not impair the PD efficacy. The technical difficulties were related to the size and shape of the peritoneal catheters, not easily fitting with the very thin abdominal wall of the preterm infants. We conclude that PD is feasible and effective, can be considered as the rescue therapy in preterm ELBW infants with acute renal failure.

The diagnosis of children with central diabetes insipidus.

Central diabetes insipidus is the end result of a number of different diseases that affect the hypothalamic-neurohypophyseal system. In many patients, especially children and young adults, it is caused by the destruction or degeneration of neurons that originate in the supraoptic and paraventricular nuclei of the hypothalamus. The known causes of these lesions include germinoma or craniopharyngioma; Langerhans cell histiocytosis; local inflammatory, autoimmune or vascular diseases; trauma resulting from surgery or an accident; sarcoidosis; metastases; and midline cerebral and cranial malformations. In rare cases, genetic defects in AVP synthesis that are inherited as autosomal dominant, autosomal recessive or X-linked recessive traits are the underlying cause. Accurate diagnostic differentiation is essential for both safe and effective disease management. Proper etiological diagnosis can be achieved via a series of steps that start with clinical observations and then progress, as needed, to more sophisticated methods. Indeed, magnetic resonance imaging (MRI) represents the examination method of choice for evaluating hypothalamic-pituitary-related endocrine diseases due to its ability to provide strongly-contrasted high-resolution multi-planar and spatial images. Specifically, MRI allows a detailed and precise anatomical study of the pituitary gland by differentiating between the anterior and posterior pituitary lobes. MRI identification of pituitary hyperintensity in the posterior part of the sella, now considered to be a clear marker of neurohypophyseal functional integrity, together with careful analysis of pituitary stalk shape and size, have provided the most striking recent findings contributing to the diagnosis and understanding of some forms of 'idiopathic' central diabetes insipidus.

Idiopathic central diabetes insipidus in children and young adults is commonly associated with vasopressin-cell antibodies and markers of autoimmunity.

OBJECTIVES: Autoimmune targeting of hypothalamic-neurohypophyseal structures in children and young adults with posterior pituitary and anterior pituitary dysfunction, as well as pituitary stalk involvement, are not yet completely understood. DESIGN: We aimed to (1) evaluate the presence of circulating vasopressin-cell autoantibodies (AVPc-Abs) in young patients with central diabetes insipidus (CDI), (2) detect organ-specific autoantibodies as markers of autoimmunity, and (3) define the relationship between immune markers and neuroimaging findings. PATIENTS: Twenty patients were evaluated at a median age of 16.3 years. Twelve patients had idiopathic CDI, six had Langerhans cell histiocytosis (LCH) and two had germinoma. AVPc-Abs were evaluated in 40 healthy children. Magnetic resonance imaging (MRI) of the hypothalamic-pituitary region was performed longitudinally in all subjects. MEASUREMENTS: Circulating arginine vasopressin (AVP), protein tyrosine phosphatase (IA2), glutamic acid decarboxylase (GAD), 21-hydroxylase (21-OH), endomysium antibodies (EMA), parietal cell (PCA), thyroid peroxidase (TPO), thyroglobulin (TG) and TSH-receptor (TSHr) autoantibodies were evaluated. RESULTS: Circulating AVPc-Abs were found in 15 patients (75%), nine with idiopathic CDI, four with LCH and two with germinoma; the pituitary stalk was involved in most of them. Five patients with idiopathic CDI showed a persistence of AVPc-Abs during follow-up and one became positive subsequently. Serum IA2 autoantibodies were demonstrated in 14 patients (70%) and 21-OH autoantibodies in three of them. CONCLUSION: In idiopathic CDI, circulating AVPc-Abs suggest an autoimmune involvement of the neurohypophyseal system. The identification of AVPc-Abs in subjects who could have either idiopathic CDI or LCH or germinoma, however, indicates that AVPc-Abs cannot be considered a completely reliable marker of autoimmune CDI. Thus, close clinical and MRI follow-up are needed because AVPc-Abs may mask germinoma or LCH.

The pre-operative endocrine assessment of craniopharyngiomas.

Pre-operative endocrinopathies are common in patients presenting with craniopharyngiomas. Clinical features may not be obvious and careful pre-operative endocrine assessment is essential. Failure to recognise and address pre-operative diabetes insipidus and secondary hypoadrenalism is potentially fatal. We review the available published data on pre-operative endocrine dysfunction and suggest an approach to assessment and management before surgery.

Diabetes insipidus in craniopharyngioma: postoperative management of water and electrolyte disorders.

Pre-operative central diabetes insipidus has been reported in 8-35% of patients affected with craniopharyngioma, and in 70-90% after surgery. The management of postoperative polyuria and polydipsia can be challenging and fluid balance needs to be closely monitored. The classical triphasic pattern of endogenous vasopressin secretion--an initial phase of symptomatic diabetes insipidus occurring 24 hours after surgery; a second phase of inappropriate vasopressin secretion potentially causing hyponatraemia; and a third phase with a return to diabetes insipidus occurring up to 2 weeks later--is often complicated by cerebral salt wasting and thirst disorders. Inadequate adrenal replacement therapy and anticonvulsant agent treatment may increase the risk of life-threatening hyponatraemia in the course of desmopressin (DDAVP) treatment. Appropriate management, in order to avoid life-threatening or disabling electrolyte disturbances, requires a good grasp of the relevant pathophysiology. We review here the pathophysiology and management of the multiple fluid disorders encountered following surgery for craniopharyngiomas.

Current perspective on the pathogenesis of central diabetes insipidus.

Diabetes insipidus is a heterogeneous condition characterised by polyuria and polydipsia caused by a lack of secretion of vasopressin, its physiological suppression following excessive water intake, or kidney resistance to its action. The clinical and laboratory diagnosis is confirmed by standard tests, but recent advances in molecular biology and imaging techniques have shed new light on the pathophysiology of this disease. In many patients, central diabetes insipidus is caused by a germinoma or craniopharyngioma; Langerhans' cell histiocytosis and sarcoidosis of the central nervous system; local inflammatory, autoimmune or vascular diseases; trauma from surgery or accident; and, rarely, genetic defects in vasopressin biosynthesis inherited as autosomal dominant or X-linked recessive traits. Thirty to fifty percent of cases are considered idiopathic. Tumour-associated central diabetes insipidus is uncommon in children younger than 5 years old. Biopsy of enlarged pituitary stalk should be reserved for patients with hypothalamic-pituitary mass and progressive thickening of the pituitary stalk since spontaneous recovery may occur. Molecular biology in selected patients may identify those with apparently idiopathic diabetes insipidus carrying the vasopressin-neurophysin II gene mutation.