Phenylbutyrate Treatment in a Boy with MCT8 Deficiency: Improvement of Thyroid Function Tests and Possible Livertoxicity.

CONTEXT: Monocarboxylate transporter 8 (MCT8) deficiency is a rare X-chromosomal inherited disease leading to severe cognitive impairment, muscular hypotonia and symptoms of peripheral thyrotoxicosis. Experimental approaches aiming to functionally rescue mutant MCT8 activity by the chemical chaperone phenylbutyrate (PB) demonstrated promising effects in vitro for several MCT8 missense mutations. OBJECTIVE: The objective was to evaluate biochemical and clinical effects of PB in doses equivalent to those approved for the treatment of urea cycle disorders in a boy with MCT8 deficiency due to a novel MCT8 missense mutation c.703G > T (p.V235L). RESULTS: During a treatment period of 13 months, PB led to a significant decrease of elevated TSH and T3 serum concentrations, while fT4 increased. Weight z-score of the toddler remained remarkably stable during the treatment period. Neurodevelopmental assessments (BSID-III) revealed a slight increase of gross motor skills from developmental age 4 to 6 months. However, increasing liver enzyme serum activities and accumulation of phenylacetate (PAA) in urine led to treatment interruptions and dose alterations. In vitro analyses in MDCK1 cells confirmed the pathogenicity of MCT8 p.V235L. However, while PB increased expression of the mutant protein, it did not rescue T3 transport, suggesting a PB effect on thyroid function tests independent of restoring MCT8 activity. CONCLUSION: In a clinical attempt of PB treatment in MCT8 deficiency we observed a significant improvement of thyroid hormone function tests, tendencies towards body weight stabilization and slight neurodevelopmental improvement. Hepatotoxicity of PB may be a limiting factor in MCT8 deficiency and requires further investigation.

Salivary Diurnal Glucocorticoid Profiles in Monozygotic Twins With Intratwin Birthweight Differences.

CONTEXT: Low birthweight (bw) and unfavorable intrauterine conditions have been associated with metabolic sequelae in later life, but little is known about their impact on glucocorticoid metabolism. OBJECTIVE: We studied monozygotic twins with intratwin bw differences to analyze the long-term impact of bw on glucocorticoid metabolism. METHODS: 46 monozygotic twin pairs with bw differences of <1 SDS (concordant; n = 29) and ≥1 SDS (discordant; n = 17) were recruited. At 6.9 years (mean age), saliva samples were collected (at 7 hours, 13 hours, 18 hours and 21 hour) and analyzed with liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: We found significant or highly significant intratwin correlations in all twin pairs at 3 of 4 (cortisol), and 4 of 4 (cortisone) time points. Graphic evaluation of the diurnal cortisol patterns for each twin pair showed a distinct alignment in all groups. Analyses of the change of intratwin differences over the day by mixed linear modeling showed no intratwin differences in diurnal patterns. Regression analyses of intratwin differences at 7:00 hours showed a significant influence of catch-up growth, indicating lower cortisol concentrations in smaller twins with more catch-up growth (adj. R2 = 0.159, P = .014, ß = -3.71, F(1,42) = 9.15, f2 = 0.19). CONCLUSION: In monozygotic twins with intratwin bw differences, intratwin catch-up growth showed a moderate influence on intratwin differences in morning cortisol concentrations. We observed no differences regarding diurnal patterns. In contrast, in all groups, we found significant intratwin correlations for cortisol and cortisone over the day and a pronounced graphic alignment of cortisol diurnal patterns. We therefore suggest a predominant significance of the genetic background compared with bw differences on cortisol metabolism.

National survey of referrals for precocious puberty in Germany.

An unusual high number of girls were referred to our paediatric endocrine clinic with suspected precocious puberty (PP) since the beginning of the COVID-19 pandemic. We analysed our data and initiated a survey among German paediatric endocrinologists.At our centre, less than 10 patients were diagnosed of PP annually between 2015 and 2019. This increased to n=23 (2020) and n=30 (2021). A German survey confirmed this observation: Out of 44 centres which completed the questionnaire, 30/44 (68%) reported an increase of PP. Above this, 32/44 (72%) stated an increase in girls diagnosed with 'early normal puberty' since the beginning of the COVID-19 pandemic.

Diabetes and gender incongruence: frequent mental health issues but comparable metabolic control - a DPV registry study.

Context: The condition when a person's gender identity does not match the sex assigned at birth is called gender incongruence (GI). Numbers of GI people seeking medical care increased tremendously over the last decade. Diabetes mellitus is a severe and lifelong disease. GI combined with diabetes may potentiate into a burdensome package for affected people. Objective: The study aimed to characterize people with GI and diabetes from an extensive standardized registry, the Prospective Diabetes Follow-up Registry (DPV), and to identify potential metabolic and psychological burdens. Methods: We compared demographic and clinical registry data of persons with type 1 or type 2 diabetes and GI to those without GI and used propensity score matching (1:4) with age, diabetes duration and treatment year as covariates. Results: 75 persons with GI, 49 with type 1 and 26 with type 2 diabetes were identified. HbA1c values were similar in matched persons with type 1 or 2 diabetes and GI compared to those without GI. Lipid profiles showed no difference, neither in type 1 nor in type 2 diabetes. Diastolic blood pressure was higher in the type 1 and GI group than in those without, whereas systolic blood pressure showed comparable results in all groups. Depression and anxiety were significantly higher in GI people (type 1 and 2). Non-suicidal self-injurious behaviour was more common in type 1 and GI, as was suicidality in type 2 with GI. Conclusion: Mental health issues are frequent in people with diabetes and GI and need to be specially addressed in this population.

Aseptic Meningitis, Mucocutaneous Lesions and Arthritis after COVID-19 Vaccination in a 15-Year-Old Boy.

We report a 15-year-old boy who developed aseptic meningitis 10 days after administration of the second dose of the COVID-19 vaccine BNT162b2. Although accompanying aphthous mouth ulcers resembling herpetic stomatitis initially led us to suspect an underlying viral infection, broad virological and microbiological screening did not identify any causative pathogen. Gonarthritis and skin lesions, which both developed within three days after admission, extended the clinical presentation eventually resembling an acute Behçet's disease episode. This is the first description of a juvenile patient with aseptic and pathogen-negative meningitis occurring in close temporal association with vaccination against COVID-19, along with a few previously reported adult patients with isolated meningitis and a further case with meningitis and an accompanying Behçet's disease-like multisystem inflammation episode as seen in our patient. With billions of individuals being vaccinated worldwide so far and only a few cases of aseptic pathogen-negative meningitis reported in close temporal relation, causality is unclear. However, aseptic meningitis should be kept in mind in the differential diagnosis of patients with persistent or delayed onset of headache and fever following COVID-19 vaccination.

Case Report: Extended Clinical Spectrum of the Neonatal Diabetes With Congenital Hypothyroidism Syndrome.

Background: Neonatal diabetes with congenital hypothyroidism (NDH) syndrome is a rare condition caused by homozygous or compound heterozygous mutations in the GLI-similar 3 coding gene GLIS3. Almost 20 patients have been reported to date, with significant phenotypic variability. Case presentation: We describe a boy with a homozygous deletion (exons 5-9) in the GLIS3 gene, who presents novel clinical aspects not reported previously. In addition to neonatal diabetes, congenital hypothyroidism and other known multi-organ manifestations such as cholestasis and renal cysts, he suffered from hyporegenerative anemia during the first four months of life and presents megalocornea in the absence of elevated intraocular pressure. Compensation of partial exocrine pancreatic insufficiency and deficiencies in antioxidative vitamins seemed to have exerted marked beneficial impact on several disease symptoms including cholestasis and TSH resistance, although a causal relation is difficult to prove. Considering reports on persistent fetal hemoglobin detected in a few children with GLIS3 mutations, the transient anemia seen in our patient may represent a further symptom associated with either the GLIS3 defect itself or, secondarily, micronutrient deficiency related to exocrine pancreatic deficiency or cholestasis. Conclusions: Our report expands the phenotypic spectrum of patients with GLIS3 mutations and adds important information on the clinical course, highlighting the possible beneficial effects of pancreatic enzyme and antioxidative vitamin substitutions on characteristic NDH syndrome manifestations such as TSH resistance and cholestasis. We recommend to carefully screen infants with GLIS3 mutations for subtle biochemical signs of partial exocrine pancreatic deficiency or to discuss exploratory administration of pancreatic enzymes and antioxidative vitamins, even in case of good weight gain and fecal elastase concentrations in the low-to-normal range.

Cerebral MRI and Clinical Findings in Children with PTEN Hamartoma Tumor Syndrome: Can Cerebral MRI Scan Help to Establish an Earlier Diagnosis of PHTS in Children?

BACKGROUND: PTEN Hamartoma Tumor Syndrome (PHTS) is caused by germline autosomal-dominant mutations of the tumor suppressor gene PTEN. Subjects harbour an increased risk for tumor development, with thyroid carcinoma occurring in young children. Establishing a diagnosis is challenging, since not all children fulfill diagnostic criteria established for adults. Macrocephaly is a common feature in childhood, with cerebral MRI being part of its diagnostic workup. We asked whether distinct cMRI features might facilitate an earlier diagnosis. METHODS: We retrospectively studied radiological and clinical data of pediatric patients who were presented in our hospital between 2013 and 2019 in whom PTEN gene mutations were identified. RESULTS: We included 27 pediatric patients (18 male) in the analysis. All patients were macrocephalic. Of these, 19 patients had received at least one cMRI scan. In 18 subjects variations were detected: enlarged perivascular spaces (EPVS; in 18), white matter abnormalities (in seven) and less frequently additional pathologies. Intellectual ability was variable. Most patients exhibited developmental delay in motor skills, but normal intelligence. CONCLUSION: cMRI elucidates EPVS and white matter abnormalities in a high prevalence in children with PHTS and might therefore aid as a diagnostic feature to establish an earlier diagnosis of PHTS in childhood.

Influence of Prenatal Environment on Androgen Steroid Metabolism In Monozygotic Twins With Birthweight Differences.

OBJECTIVE: Although low birthweight (bw) and unfavorable intrauterine conditions have been associated with metabolic sequelae in later life, little is known about their impact on steroid metabolism. We studied genetically identical twins with intra-twin bw-differences from birth to adolescence to analyze the long-term impact of bw on steroid metabolism. METHODS: 68 monozygotic twin pairs with a bw-difference of <1 standard deviation score (SDS; concordant; n = 41) and ≥1 SDS (discordant; n = 27) were recruited. At 14.9 years (mean age), morning urine samples were collected and analyzed with gas chromatography-mass-spectrometry. RESULTS: No significant differences were detected in the concordant group. In contrast, in the smaller twins of the discordant group, we found significantly higher concentrations not only of the dehydroepiandrosterone sulfate (DHEAS) metabolite 16α-OH-DHEA (P = 0.001, 656.11 vs 465.82 µg/g creatinine) but also of cumulative dehydroepiandrosterone and downstream metabolites (P = 0.001, 1650.22 vs 1131.92 µg/g creatinine). Relative adrenal (P = 0.002, 0.25 vs 0.18) and overall androgen production (P = 0.001, 0.79 vs 0.65) were significantly higher in the formerly smaller discordant twins. All twin pairs exhibited significant intra-twin correlations for all individual steroid metabolites, sums of metabolites, indicators of androgen production, and enzyme activities. Multiple regression analyses of the smaller twins showed that individual steroid concentrations of the larger co-twin were the strongest influencing factor among nearly all parameters analyzed. CONCLUSION: In monozygotic twin pairs with greater intra-twin bw-differences (≥1 SDS), we found that bw had a long-lasting impact on steroid metabolism, with significant differences regarding DHEAS metabolites and relative androgen production. However, most parameters showed significant intra-twin correlations, suggesting a consistent interrelationship between prenatal environment, genetic background, and steroid metabolism.

IGF-I in cord blood is predictive of final height in monozygotic twins with intra-twin birth weight differences.

OBJECTIVE: Adverse prenatal conditions can exert a long-lasting impact on growth up to final height (FH). Due to different prenatal nutrient availability, monozygotic twin pairs with discordant birth weight (bw) provide an excellent model to examine the impact of genes and environment and to analyse the predictive value of bw, birth length (bl) and cord blood (cb) concentration of IGF-I on FH. PATIENTS AND METHODS: Twenty eight monozygotic twin pairs with intra-twin bw-/bl-differences were studied at birth and longitudinally until FH. Intra-twin bw difference >1 SDS was defined "discordant" (n = 10 pairs). IGF-I was analysed in cord blood in all twins. Intra-twin differences (∆) in bw, bl and cord blood IGF-I were correlated with ∆FH. RESULTS: Throughout growth and up until FH intra-twin length/height differences remained for all but two (26/28) twins and for all (10/10) discordant twins. In the discordant group, a highly significant intra-twin difference for FH-SDS was found with a mean intra-twin Δheight- SDS of 1.23 (range, 0.29-2.34). This corresponds to a mean Δintra-twin difference at FH of 7.9 cm (3.1 inch; range, 2-15 cm [0.79-5.9 inch]). Correlation coefficients were calculated to identify factors predicting FH: ∆bw (r = .678; P = .0005), ∆bl (r = .333; P = .0002) and ∆IGF-I in cb (r = .418; P = .0023). Interaction terms showed that IGF-I is an additional factor to the auxological data, leading to an improvement of the ∆FH modelling. CONCLUSION: Prenatal environment leading to bw-/bl- and cbIGF-I differences in monozygotic twins had a long-lasting impact on growth until FH. Both, anthropometric data at birth and cbIGF-I are predictive of FH.

3D flow simulations and pressure measurements for the evaluation of cavitation dynamics and flow aggressiveness in ultrasonic erosion devices with varying gap widths.

Cavitation induced wall loads at an ultrasonic horn facility are analyzed by 3D flow simulations and temporally high-resolved pressure measurements for varying gap widths between horn and stationary erosion specimen. Piezoelectric polyvinylidene fluoride (PVDF) probes are placed at different radial wall positions at the stationary specimen opposite of the oscillation horn and yield a declining flow aggressiveness with increasing radial position and gap width. The measurement results are reproduced by virtual probes in CFD simulations. Pressure measurement results yield a measure of flow aggressiveness in terms of wall load collectives that correlate well with incubation times obtained by erosion tests. A maximum aggressiveness at the specimen at 0.5mm gap width is obtained. Subharmonic frequencies associated with horn-attached void cavities increase with gap width which is well captured by the simulation. Due to the revealing of 3D flow patterns by the validated CFD results, detailed flow mechanisms associated with flow aggressiveness are discussed. The subharmonic frequency characteristics vs. gap width is associated with the shielding of the inner attached cavity region for small gaps and prevents the cavity from subharmonic collapse for several horn cycles. This shielding is less pronounced for larger gaps and leads to a shorter life time of the attached cavity and therefore to higher subharmonic frequencies.

Birthweight Differences in Adolescent Monozygotic Twins Influence Androgens, Psychological Morbidity, and Health-Related Quality of Life.

BACKGROUND: Adverse prenatal conditions can exert a long-lasting impact in later life. PATIENTS AND METHODS: Thirty-eight post-pubertal monozygotic twin pairs (16 female pairs) with divergent birthweight (bw) due to twin-to-twin transfusion syndrome were examined at a median of 15.1 years. Auxological and endocrine parameters were measured. To evaluate effects of intra-twin bw and hormone differences on mental health, adolescents and their parents completed the Strengths and Difficulties Questionnaire (SDQ), identifying psychological problems. Twins answered the questionnaire on health-related quality of life (HrQoL, KIDSCREEN-52). RESULTS: Parents attributed a higher number of psychological challenges to the formerly smaller twins, for example, total difficulties (8.8 vs. 6.5, p = 0.009). Differences in bw were associated with differences in parental evaluation of problems, for example, peer relationship problems (r = -0.57 and p = 0.0001). In contrast, bw differences did not affect subjects' self-assessment of psychological factors but on physical well-being (r = 0.42, p = 0.017). The formerly smaller discordant twins showed significantly lower HrQoL regarding psychological well-being (24.9 vs. 26.6, T1,15 = -2.2, and p = 0.043) and moods and emotions (29.8 vs. 32.0, T1,15 = -2.3, p = 0.039). Higher concentrations of androstenedione were linked to greater psychological well-being (r = 0.39 and p = 0.036) in all twin pairs. CONCLUSION: Our results show that the prenatal environment leading to bw differences exerts a long-lasting impact on diverging parental evaluation of mental health. Formerly smaller discordant twins showed significantly lower HrQoL regarding psychological well-being and moods and emotions. Higher androstenedione concentrations were linked to greater psychological well-being.

A novel mutation of the StAR gene with congenital adrenal hyperplasia and its association with heterochromia iridis: a case report.

BACKGROUND: We report a novel mutation within the StAR gene, causing congenital adrenal hyperplasia, with the so far unreported association with heterochromia iridis. CASE PRESENTATION: In a now 15-year-old girl (born at 41 + 6 weeks of gestation) adrenal failure was diagnosed in the neonatal period based on the clinical picture with spontaneous hypoglycaemia, hyponatremia and an extremely elevated concentration of ACTH (3381 pmol/l; ref. level 1,1-10,1 pmol/l), elevated renin (836 ng/l; ref. level 5-308 ng/l), and a decreased concentration of aldosterone (410 pmol/l; ref. level 886-3540 pmol/l). In addition to hyperpigmented skin the patient exhibited sectorial heterochromia iridis. Sequence analysis of the steroidogenic acute regulatory protein (StAR) gene showed a novel homozygous mutation (c.652G > A (p.Ala218Thr), which was predicted in-silico to be possibly damaging. Under daily steroid substitution her electrolyte levels are balanced while she became obese. Puberty occurred spontaneously. CONCLUSION: A novel mutation in the StAR gene was identified in a patient with severe adrenal hypoplasia and sectorial heterochromia iridis. We discuss a causal relationship between these two rare phenotypes, i.e. whether very high levels of ACTH and alpha-MSH during early development might have disturbed early differentiation and distribution of uveal melanocytes. If confirmed in additional cases, discolorization of the iris might be considered as an additional phenotypical feature in the differential diagnosis of congenital adrenal insufficiency.

Phenotype-Driven Diagnostic of PTEN Hamartoma Tumor Syndrome: Macrocephaly, But Neither Height nor Weight Development, Is the Important Trait in Children.

PTEN hamartoma tumor syndrome (PHTS) encompasses different syndromic disorders which are associated with autosomal-dominant mutations of the tumor suppressor gene PTEN. Patients are at high risk to develop benign and malignant tumors. Macrocephaly is a diagnostic feature, but there is a paucity of data on auxological development during childhood. Growth charts for height, weight and head circumference for PHTS do not exist yet. In this study, patient data for height, weight and head circumferences (HC) were collected from repeated medical exams or prevention check-up visits starting at birth. Growth charts were generated and compared to German reference data. Standard deviation scores (SDS) of HC, height and body mass index (BMI) were calculated. We included 23 pediatric patients (8 female, 15 male) with molecular proven PTEN gene mutation. Most male patients already demonstrated macrocephaly at birth (73%), whereas only one female patient had documented congenital macrocephaly. By the age of two years all patients exhibited a head circumference above the 97th percentile. Stratified for different age groups the median HC-SDSs were between +3.3 and +5.5 in male patients and between +2.9 and +4.1 in female patients. Height, weight and BMI measurements for both sexes were mostly within the normal range. We conclude that macrocephaly, but not height, weight or BMI, is useful in the identification of PHTS patients. The increased HC in PHTS patients develops early in life and is more pronounced in males than in females, which might explain the finding of a higher percentage of male PHTS patients diagnosed during childhood.

Thyroid Function in Monozygotic Twins with Intra-twin Birth Weight Differences: A Prospective Longitudinal Cohort Study.

OBJECTIVE: To analyze the long-term impact of birth weight (BW) on thyroid function in genetically identical twins with intra-twin BW differences from birth to adolescence. STUDY DESIGN: In total, 52 monozygotic twin pairs underwent at least one analysis of thyroid function at mean ages of 10.1 years (27 pairs), 15.1 years (35 pairs), and 17.4 years (36 pairs); 18 pairs donated blood at all time points. BW difference of <1 SDS was defined as concordant, BW difference ≥1 SDS as discordant. RESULTS: In concordant twins, no significant differences were observed. In the discordant group, smaller twins had higher mean thyroid-stimulating hormone (TSH) than their larger co-twins at 10.1 years (3.6 vs 2.5 µU/mL; P = .04) and 15.1 years (2.6 vs 2.2 µU/mL; P = .08). Smaller twins showed lower mean thyroxine than larger co-twins at 10.1 years (7.8 vs 8.2 µg/dL P = .05) and 17.4 years (7.7 vs 8.4 µg/dL; P = .03), and a tendency at 15.1 years (6.9 vs 7.4 µg/dL; P = .09). Calculation of TSH-thyroxine ratio revealed significant differences in the discordant group, with greater ratios in the smaller twin at 10.1 years (0.5 vs 0.3; P = .006) and 15.1 years (0.4 vs 0.3; P = .04). CONCLUSIONS: In this group of monozygotic twins with intra-twin BW differences, BW seemed to exert a long-lasting impact on thyroid function. This may be due to a delay in hypothalamic-pituitary-thyroid axis maturation, with TSH resistance during childhood and early adolescence in children with low BW.

Mecasermin in Insulin Receptor-Related Severe Insulin Resistance Syndromes: Case Report and Review of the Literature.

Mutations in the insulin receptor (INSR) gene underlie rare severe INSR-related insulin resistance syndromes (SIR), including insulin resistance type A, Rabson⁻Mendenhall syndrome and Donohue syndrome (DS), with DS representing the most severe form of insulin resistance. Treatment of these cases is challenging, with the majority of DS patients dying within the first two years of life. rhIGF-I (mecasermin) has been reported to improve metabolic control and increase lifespan in DS patients. A case report and literature review were completed. We present a case involving a male patient with DS, harbouring a homozygous mutation in the INSR gene (c.591delC). Initial rhIGF-I application via BID (twice daily) injection was unsatisfactory, but continuous subcutaneous rhIGF-I infusion via an insulin pump improved weight development and diabetes control (HbA1c decreased from 10 to 7.6%). However, our patient died at 22 months of age during the course of a respiratory infection in in Libya. Currently available data in the literature comprising more than 30 treated patients worldwide seem to support a trial of rhIGF-I in SIR. rhIGF-I represents a treatment option for challenging SIR cases, but careful consideration of the therapeutic benefits and the burden of the disease is warranted. Continuous application via pump might be advantageous compared to single injections.

Thyroid disease in children and adolescents with PTEN hamartoma tumor syndrome (PHTS).

Patients with PTEN hamartoma tumor syndrome (PHTS) are at increased risk of developing benign and malignant tumors, including thyroid carcinoma. Benign thyroid lesions and single cases of thyroid carcinoma have been reported in children with PHTS. We conducted a retrospective, single-centered study including children and adolescents with a molecularly proven diagnosis of PTEN. Our cohort consists of 16 patients, with a mean age at diagnosis PHTS of 5.7 years. Twelve of 16 cases exhibited thyroid abnormalities (75%). In seven patients, thyroid abnormalities were already present at first ultrasound screening, in five cases they occurred during follow-up. Eight patients underwent thyroidectomy. Histopathology included nodular goiter, follicular adenoma, papillary microcarcinoma in a boy of six and follicular carcinoma in a girl of 13 years. Two patients had autoimmune thyroid disease. CONCLUSION: Thyroid disease is common in children with PHTS. Physicians caring for patients with early thyroid abnormalities and additional syndromal features should be aware of PHTS as a potentially underlying disorder. Ultrasound screening should be performed immediately after diagnosis of PHTS and repeated yearly or more frequently. Because of possible early cancer development, we recommend early surgical intervention in the form of total thyroidectomy in cases of suspicious ultrasound findings. What is Known: • PHTS patients are at high risk of developing benign and malignant tumors. • Individual cases of thyroid carcinoma in children have been reported. What is New: • Thyroid disease is even more common in children with PHTS (75%) than previously expected. • Frequently thyroid disease is the first organ pathology requiring diagnostic workup and therefore children with PHTS should be examined for thyroid disease right after diagnosis and receive follow-up on a regular basis throughout life.

Developmental programming of somatic growth, behavior and endocannabinoid metabolism by variation of early postnatal nutrition in a cross-fostering mouse model.

BACKGROUND: Nutrient deprivation during early development has been associated with the predisposition to metabolic disorders in adulthood. Considering its interaction with metabolism, appetite and behavior, the endocannabinoid (eCB) system represents a promising target of developmental programming. METHODS: By cross-fostering and variation of litter size, early postnatal nutrition of CB6F1-hybrid mice was controlled during the lactation period (3, 6, or 10 pups/mother). After weaning and redistribution at P21, all pups received standard chow ad libitum. Gene expression analyses (liver, visceral fat, hypothalamus) were performed at P50, eCB concentrations were determined in liver and visceral fat. Locomotor activity and social behavior were analyzed by means of computer-assisted videotracking. RESULTS: Body growth was permanently altered, with differences for length, weight, body mass index and fat mass persisting beyond P100 (all 3>6>10,p<0.01). This was paralleled by differences in hepatic IGF-I expression (p<0.01). Distinct gene expression patterns for key enzymes of the eCB system were observed in fat (eCB-synthesis: 3>6>10 (DAGLα p<0.05; NAPE-PLD p = 0.05)) and liver (eCB-degradation: 3>6>10 (FAAH p<0.05; MGL p<0.01)). Concentrations of endocannabinoids AEA and 2-AG in liver and visceral fat were largely comparable, except for a borderline significance for higher AEA (liver, p = 0.049) in formerly overfed mice and, vice versa, tendencies (p<0.1) towards lower AEA (fat) and 2-AG (liver) in formerly underfed animals. In the arcuate nucleus, formerly underfed mice tended to express more eCB-receptor transcripts (CB1R p<0.05; CB2R p = 0.08) than their overfed fellows. Open-field social behavior testing revealed significant group differences, with formerly underfed mice turning out to be the most sociable animals (p<0.01). Locomotor activity did not differ. CONCLUSION: Our data indicate a developmental plasticity of somatic growth, behavior and parameters of the eCB system, with long-lasting impact of early postnatal nutrition. Developmental programming of the eCB system in metabolically active tissues, as shown here for liver and fat, may play a role in the formation of the adult cardiometabolic risk profile following perinatal malnutrition in humans.

Impact of Early Nutrition on Body Composition in Children Aged 9.5 Years Born with Extremely Low Birth Weight.

To evaluate body composition, metabolism and growth as well as their interaction with early nutrition in former extremely low birth weight infants (ELBW), we assessed qualitative and quantitative nutritional intake during initial hospitalization and infantile growth parameters in 61 former ELBW infants with a birth weight <1000 g. In two follow-up exams, physical and biochemical development were measured at 5.7 and at 9.5 years. At the second follow-up, in addition to biochemical reassessment, body composition was analyzed by dual-energy x-ray absorptiometry (DEXA). Protein intake between birth and discharge was associated with weight gain in the first six months of life (r = 0.51; p < 0.01). Weight catch-up preceded height catch-up. Protein intake in early infancy correlated highly significantly with abdominal fat mass (r = 0.49; p < 0.05), but not with lean body mass at 9.5 years (r = 0.30; not significant (n.s.). In contrast to nutrient intake, birth weight was associated with lean body mass (r = 0.433; p < 0.001). Early protein and carbohydrate intake were associated with high-density lipoprotein (HDL)-cholesterol, and early catch-up growth correlated with fasting insulin at follow-up. Stepwise linear regression demonstrated that protein intake predicted fat mass (p < 0.05), whereas only gender and birth weight standard deviation score (SDS) contributed significantly to lean body mass variation (p < 0.05). Our results suggest an important impact of early nutrient intake on body composition and metabolism in later childhood in ELBW children.

Glucocorticoid Receptor Gene Variants and Neonatal Outcome in Very-Low-Birth-Weight Preterm Infants.

BACKGROUND: Induction of lung maturation by prenatal steroid treatment has become the standard of care for pregnant women at risk for preterm birth. In addition to the beneficial effects on lung maturation, prenatal steroids have been shown to reduce the incidence of neonatal death, necrotizing enterocolitis, sepsis, and intraventricular hemorrhage. However, little is known about the role of interindividual differences in corticoid sensitivity arising from polymorphisms in the glucocorticoid receptor (GR) gene. OBJECTIVES: To assess the impact of GR polymorphisms N363S (rs56149945), R23K (rs6190), and BclI (rs41423247) on neonatal outcome. METHODS: The GR polymorphisms N363S, R23K, and BclI were examined in 10,490 very-low-birth-weight (VLBW) preterm infants from 49 German tertiary level neonatal units (German Neonatal Network, GNN) with respect to neonatal outcome. RESULTS: Infants carrying the BclI genotype were at higher risk to develop bronchopulmonary dysplasia (BPD) (OR 1.12 per BclI allele, 95% CI: 1.02-1.23, p = 0.013) in a logistic regression model adjusted for gestational age, mechanical ventilation, and small for gestational age status. A similar relative risk was seen in the children (89.4%) who received antenatal betamethasone treatment (OR 1.16, 95% CI: 1.05-1.27, p = 0.003), whereas no such effect was detectable in infants without antenatal steroids. N363S and R23K did not show any stable association with neonatal outcome parameters. CONCLUSION: Except for a slightly higher risk of BPD in carriers of the GRBclI variant, the GR gene polymorphisms BclI, N363S, and R23K did not affect neonatal outcome parameters in this large multicenter cohort of VLBW preterm infants.

Infancy-Onset T1DM, Short Stature, and Severe Immunodysregulation in Two Siblings With a Homozygous LRBA Mutation.

CONTEXT: Type 1 diabetes mellitus (T1DM) is caused by autoimmunity against pancreatic ß-cells. Although a significant number of T1DM patients have or will develop further autoimmune disorders during their lifetime, coexisting severe immunodysregulation is rare. OBJECTIVE: Presuming autosomal-recessive inheritance in a complex immunodysregulation disorder including T1DM and short stature in two siblings, we performed whole-exome sequencing. CASE PRESENTATION: Two Libyan siblings born to consanguineous parents were presented to our diabetology department at ages 12 and 5 years, respectively. Apart from T1DM diagnosed at age 2 years, patient 1 suffered from chronic restrictive lung disease, mild enteropathy, hypogammaglobulinemia, and GH deficiency. Fluorescence-activated cell sorting analysis revealed B-cell deficiency. In addition, CD4(+)/CD25(+) and CD25(high)/FoxP3(+) cells were diminished, whereas an unusual CD25(-)/FoxP3(+) population was detectable. The younger brother, patient 2, also developed T1DM during infancy. Although his enteropathy was more severe and electrolyte derangements repeatedly led to hospitalization, he did not have significant pulmonary problems. IgG levels and B-lymphocytes were within normal ranges. RESULTS: By whole-exome sequencing we identified a homozygous truncating mutation (c.2445_2447del(C)3ins(C)2, p.P816Lfs*4) in the lipopolysaccharide-responsive beige-like anchor (LRBA) gene in both siblings. The diagnosis of LRBA deficiency was confirmed by a fluorescence-activated cell sorting-based immunoassay showing the absence of LRBA protein in phytohemagglutinin-stimulated peripheral blood mononuclear cells. CONCLUSION: We identified a novel truncating LRBA mutation in two siblings with T1DM, short stature, and severe immunodysregulation. LRBA mutations have previously been reported to cause multiorgan autoimmunity and immunodysfunction. In light of the variable phenotypes reported so far in LRBA-mutant individuals, LRBA deficiency should be considered in all patients presenting with T1DM and signs of severe immunodysregulation.