Pregnancy and pregnancy outcomes after hematopoietic stem cell transplantation in childhood: a cross-sectional survey of the EBMT Pediatric Diseases Working Party.

STUDY QUESTION: What are the characteristics of patients with conceptions transplanted in childhood and adolescence? SUMMARY ANSWER: Insemination and conception after hematopoietic stem cell transplantation (HCT) in childhood or adolescence was possible, even after myeloablative conditioning regimes, although some patients required reproductive medicine support. WHAT IS KNOWN ALREADY: Preparative regimens of HCT are highly gonadotoxic, which leads to gonadal failure and pubertal development disorders. There are few population-based studies assessing the risk of future infertility in children after HCT. STUDY DESIGN, SIZE, DURATION: We conducted a retrospective study to investigate natural or assisted conceptions and their outcomes in patients <18 years old before their first transplantation who received HCT between 1995 and 2016 and were in the European Society for Blood and Marrow Transplantation (EBMT) registry. Adoptions were excluded from the analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Detailed information concerning pregnancy occurrences and outcomes were obtained by a separate questionnaire. Quantitative variables were presented as medians with their interquartile range (IQR) or range, and categorical variables were presented as frequencies and percentages. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 62 988 pediatric patients received a first HCT in EBMT centers between 1995 and 2016. Pregnancy was reported in 406 patients in the database. The median age at transplantation was 15.7 (range: 0.7-18) years, and the median age at declared conception was 25.0 (range: 16.3-38.8) years. Details concerning the first pregnancy and pregnancy outcome were obtained from 99 patients (24%) from the returned questionnaires. The median age at delivery or pregnancy interruption of the females was 23.0 (IQR: 20.8-27) years, with a median time after transplant of 10.7 (IQR: 6.6-15.4) years. Compared with the mean age of healthy women at their first child's birth (29 years old), the transplanted women delivered 5 years earlier (mean: 24.3 years). In terms of conception modality, 13/25 (52%) females conditioned with total body irradiation (TBI) and 50/52 (96%) of those conditioned without TBI conceived naturally. All seven male patients who had been conditioned with TBI achieved fatherhood but required assisted fertilization or used their cryopreserved sperm. In the females, 63/70 (90%) of all conceptions resulted in a live birth, 49/63 (84.5%) were at term and 43/46 (93%) had normal birthweight. Cesarean delivery was performed in 9/61 (15%) especially in women who had received a myeloablative regimen. LIMITATIONS, REASONS FOR CAUTION: In the EBMT pediatric dataset, the age at last follow-up or death was <17 years for 75% of the patients, therefore a longer follow-up for all patients would be necessary to calculate the cumulative incidence of conception for patients transplanted during childhood and allow all patients to realize their reproductive willingness/potential. WIDER IMPLICATIONS OF THE FINDINGS: Reproductive health surveillance and fertility preservation counseling are important in younger transplanted patients. Our results showed that there is a window of opportunity to conceive naturally or with reproductive medicine support. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by the 'Stiftung für krebskranke Kinder Regio Basiliensis', Basel, Switzerland. All authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Cytokine kinetic profiles in children with acute lower respiratory tract infection: a post hoc descriptive analysis from a randomized control trial.

OBJECTIVES: Standard inflammatory markers and chest radiography lack the ability to discriminate bacterial from non-bacterial lower respiratory tract infection (LRTI). Cytokine profiles may serve as biomarkers for LRTI, but their applicability to identify aetiology, severity of disease and need for antibiotic prescription in children remains poorly defined. Objectives were to determine the cytokine kinetic profiles over 5 days in paediatric patients with LRTI, to investigate the relationship between cytokine patterns, and clinical and laboratory variables. METHODS: We included patients aged 1 month to 18 years, with febrile LRTI and three consecutive cytokines measurements on days 1, 3 and 5 of a randomized controlled trial (ProPAED study). We evaluated differences in cytokine concentrations between days and associations with clinical and laboratory variables. RESULTS: A total of 181 patients (median age 4.1 years) were included; 72/181 (40%) received antibiotics. Serum concentrations of interferon (IFN)-γ, interleukin (IL)-1ra, IL-6, IL-10, IFN-γ-inducible protein (IP)-10 and tumor necrosis factor-α were elevated on day 1 and decreased subsequently, with the greatest decline between day 1 and 3 (by -8 to >-94%). Procalcitonin (PCT) and C-reactive protein (CRP) values showed a protracted decrease with the most prominent reduction in concentrations between days 3 and 5. Significantly elevated IL-6 concentrations were associated with hospital admission, antibiotic treatment, and prolonged antibiotic treatment. Bacteraemic LRTI patients had higher concentrations of IL-1ra (p <0.0055) and IL-6 (p <0.0055) on day 1. CONCLUSIONS: We observed an earlier decrease of elevated cytokines compared to PCT or CRP. Both pro- and anti-inflammatory cytokines may serve as markers for severity of LRTI.

Clinical case seminar in pediatric thyroid disease.

Pediatric thyroid diseases cover a large spectrum of congenital and acquired forms, ranging from congenital primary or central hypothyroidism, autoimmune thyroid disease, iodine deficiency, rare genetic defects of thyroid hormone action, metabolism and cell membrane transport to benign nodules and malignant tumors. The previous 15 papers of the textbook Paediatric Thyroidology gave a systematic overview of the current knowledge and guidelines on all these diseases. In this final paper, the authors collected a series of patient histories from their clinics illustrating frequently encountered clinical problems and providing key learning points and references to each case. Although not fully comprehensive, it aims at providing relevant clinical knowledge on thyroid diseases of the neonate, the child, and the adolescent.

Extreme phenotypic variability of thyroid dysgenesis in six new cases of congenital hypothyroidism due to PAX8 gene loss-of-function mutations.

CONTEXT: Within the last two decades, heterozygous loss-of-function PAX8 mutations have been reported in patients with a wide degree of thyroid gland dysfunction and growth despite the presence of identical mutations. OBJECTIVES: To search for PAX8 mutations in a cohort of patients with congenital hypothyroidism (CH) and various types of thyroid gland defects. DESIGN: A cross-sectional study was conducted in a cohort of patients. SETTING: The French neonatal screening program was used for recruiting patients. PATIENTS: A total of 118 patients with CH, including 45 with familial and 73 with sporadic diseases, were included in this study. The thyroid gland was normal in 23 patients had hypoplasia, 25 had hemithyroid agenesis, 21 had athyreosis, and 21 had ectopy. RESULTS: We found four different PAX8 mutations (p.R31C, p.R31H, p.R108X, and p.I47T) in ten patients (six patients with CH and four family members), two with sporadic and eight with familial diseases. Imaging studies performed in the index cases showed ectopic thyroid gland (n=2), hypoplasia (n=2), eutopic lobar asymmetry (n=1), and eutopic gland compatible with dyshormonogenesis (n=1). The previously reported p.R31C and the novel p.I47T PAX8 mutations are devoid of activity. CONCLUSION: Four different PAX8 mutations were detected in six index patients with CH (ten total subjects). The p.R31C, p.R31H, and p.R108X mutations have been reported. The novel p.I47T PAX8 mutation presented loss of function leading to CH. Thyroid ectopy was observed in two cases of PAX8 (p.R31H) mutation, a finding that has not been reported previously. We observed a high inter-individual and intra-familial variability of the phenotype in PAX8 mutations, underlining that population genetic studies for CH should include patients with various clinical presentations.

Copeptin as a marker for arginine-vasopressin/antidiuretic hormone secretion in the diagnosis of paraneoplastic syndrome of inappropriate ADH secretion.

Direct measurement of arginine-vasopressin/antidiuretic hormone (AVP/ADH) concentrations is not included in the standard diagnostic procedures for paraneoplastic syndrome of inappropriate ADH secretion (SIADH). Here, we evaluate the potential of copeptin measurement as a surrogate marker of AVP/ADH secretion for the direct diagnosis of suspected SIADH in cancer patients. Forty-six unselected cancer patients with serum sodium concentrations permanently below 135 mmol/L were included in this study. We compared standard diagnostic criteria for SIADH to the measurement of plasma copeptin in relation to osmolality. Normative data for comparison were constructed from 24 healthy controls studied under basal conditions, experimental dehydration, and hypotonic hypervolemia as well as from 222 hospital patients with no suspicion of an altered ADH regulation. Log transformation of copeptin revealed a linear relationship to plasma osmolality in the controls (R = 0.495, p < 0.001). Compared to these normative data, copeptin levels in most cancer patients were inappropriately high for plasma osmolality and were not significantly correlated. These results, suggestive for paraneoplastic SIADH, could be confirmed by conventional diagnostic procedures for SIADH. Current strategies to diagnose SIADH are difficult to perform under outpatients conditions. Our approach allows screening from a single plasma sample for true paraneoplastic ADH oversecretion and thus rapid selection for a specific therapy with an AVP receptor antagonist.

Activation of the transcription factor carbohydrate-responsive element-binding protein by glucose leads to increased pancreatic beta cell differentiation in rats.

AIMS/HYPOTHESIS: Pancreatic cell development is a tightly controlled process. Although information is available regarding the mesodermal signals that control pancreatic development, little is known about the role of environmental factors such as nutrients, including glucose, on pancreatic development. We previously showed that glucose and its metabolism through the hexosamine biosynthesis pathway (HBP) promote pancreatic endocrine cell differentiation. Here, we analysed the role of the transcription factor carbohydrate-responsive element-binding protein (ChREBP) in this process. This transcription factor is activated by glucose, and has been recently described as a target of the HBP. METHODS: We used an in vitro bioassay in which pancreatic endocrine and exocrine cells develop from rat embryonic pancreas in a way that mimics in vivo pancreatic development. Using this model, gain-of-function and loss-of-function experiments were undertaken. RESULTS: ChREBP was produced in the endocrine lineage during pancreatic development, its abundance increasing with differentiation. When rat embryonic pancreases were cultured in the presence of glucose or xylitol, the production of ChREBP targets was induced. Concomitantly, beta cell differentiation was enhanced. On the other hand, when embryonic pancreases were cultured with inhibitors decreasing ChREBP activity or an adenovirus producing a dominant-negative ChREBP, beta cell differentiation was reduced, indicating that ChREBP activity was necessary for proper beta cell differentiation. Interestingly, adenovirus producing a dominant-negative ChREBP also reduced the positive effect of N-acetylglucosamine, a substrate of the HBP acting on beta cell differentiation. CONCLUSIONS/INTERPRETATION: Our work supports the idea that glucose, through the transcription factor ChREBP, controls beta cell differentiation from pancreatic progenitors.

Effects of changes in hydration on protein, glucose and lipid metabolism in man: impact on health.

Alterations of cell volume induced by changes of extracellular osmolality have been reported to regulate intracellular metabolic pathways. Hypo-osmotic cell swelling counteracts proteolysis and glycogen breakdown in the liver, whereas hyperosmotic cell shrinkage promotes protein breakdown, glycolysis and glycogenolysis. To investigate the effect of acute changes of extracellular osmolality on whole-body protein, glucose and lipid metabolism in vivo, we studied 10 male subjects during three conditions: (i) hyperosmolality was induced by fluid restriction and intravenous infusion of hypertonic NaCl (2-5%, wt/vol) during 17 h; (ii) hypo-osmolality was produced by intravenous administration of desmopressin, liberal water drinking and infusion of hypotonic saline (0.4%); and (iii) the iso-osmolality study comprised oral water intake ad libitum. Plasma osmolality increased from 285+/-1 to 296+/-1 mosm/kg (P<0.001 during hyperosmolality, and decreased from 286+/-1 to 265+/-1 mosm/kg during hypo-osmolality (P<0.001). Total body leucine flux ([1-(13)C]leucine infusion technique), reflecting whole-body protein breakdown, as well as whole-body leucine oxidation rate (irreversible loss of amino acids) decreased significantly during hypo-osmolality. The glucose metabolic clearance rate during hyperinsulinaemic-euglycemic clamping increased significantly less during hypo-osmolality than iso-osmolality, indicating diminished peripheral insulin sensitivity. Glycerol turnover (2-[(13)C]glycerol infusion technique), reflecting whole-body lipolysis, increased significantly during hypo-osmolar conditions. The results demonstrate that the metabolic adaptation to acute hypo-osmolality resembles that of acute fasting, that is, it results in protein sparing associated with increased lipolysis, ketogenesis and lipid oxidation and impaired insulin sensitivity of glucose metabolism.

Multiple herpetic whitlow lesions in a 4-year-old girl: case report and review of the literature.

UNLABELLED: Herpetic whitlow is a herpes simplex virus type 1 or 2 infection of the fingers characterised by erythema and painful, non-purulent vesicles. In children it typically occurs after auto-inoculation from herpes stomatitis, herpes labialis or genitalis. Occasionally, person-to-person transmission occurs from family members with herpes labialis. We report a 4-year-old girl with multiple herpetic whitlows secondary to herpetic stomatitis and present a review of the medical literature based on a systematic MEDLINE search of published paediatric patients (English, French and German language). Of 42 identified patients, 72% were younger than 2 years, most had endogenous or exogenous inoculation of herpes simplex virus type 1 and 65% were initially misdiagnosed as having "bacterial felon". Recurrences were reported in 23%. CONCLUSION: herpetic whitlow should be suspected based on clinical signs. Specific diagnosis can be made by polymerase chain reaction or culture. The high rate of misdiagnosed cases indicates that this entity is not sufficiently known. Lesions are self-limited; surgical interventions can be harmful and should be avoided. Recurrences occur as frequently as in adults.