Are Ethnic and Gender Specific Equations Needed to Derive Fat Free Mass from Bioelectrical Impedance in Children of South Asian, Black African-Caribbean and White European Origin? Results of the Assessment of Body Composition in Children Study

Background Bioelectrical impedance analysis (BIA) is a potentially valuable method for assessing lean mass and body fat levels in children from different ethnic groups. We examined the need for ethnic- and gender-specific equations for estimating fat free mass (FFM) from BIA in children from different ethnic groups and examined their effects on the assessment of ethnic differences in body fat. Methods Cross-sectional study of children aged 8–10 years in London Primary schools including 325 South Asians, 250 black African-Caribbeans and 289 white Europeans with measurements of height, weight and arm-leg impedance (Z; Bodystat 1500). Total body water was estimated from deuterium dilution and converted to FFM. Multilevel models were used to derive three types of equation {A: FFM = linear combination(height+weight+Z); B: FFM = linear combination(height2/Z); C: FFM = linear combination(height2/Z+weight)}. Results Ethnicity and gender were important predictors of FFM and improved model fit in all equations. The models of best fit were ethnicity and gender specific versions of equation A, followed by equation C; these provided accurate assessments of ethnic differences in FFM and FM. In contrast, the use of generic equations led to underestimation of both the negative South Asian-white European FFM difference and the positive black African-Caribbean-white European FFM difference (by 0.53 kg and by 0.73 kg respectively for equation A). The use of generic equations underestimated the positive South Asian-white European difference in fat mass (FM) and overestimated the positive black African-Caribbean-white European difference in FM (by 4.7% and 10.1% respectively for equation A). Consistent results were observed when the equations were applied to a large external data set. Conclusions Ethnic- and gender-specific equations for predicting FFM from BIA provide better estimates of ethnic differences in FFM and FM in children, while generic equations can misrepresent these ethnic differences

Pathological and Incidental Findings on Brain MRI in a Single-Center Study of 229 Consecutive Girls with Early or Precocious Puberty

Central precocious puberty may result from organic brain lesions, but is most frequently of idiopathic origin. Clinical or biochemical factors which could predict a pathological brain MRI in girls with CPP have been searched for. With the recent decline in age at pubertal onset among US and European girls, it has been suggested that only girls with CPP below 6 years of age should have brain MRI performed

Serum AMH concentration as a marker evaluating gonadal function in boys operated on for unilateral cryptorchidism between 1st and 4th year of life

The aim of this study was to measure the serum AMH (anti-Mullerian hormone) concentrations in a group of boys with or without cryptorchidism, evaluation of karyotypes, testicular position, morphology, and major length of the undescended testes. Fifty boys who were 1–4 years old (median = 2.4 years) with unilateral cryptorchidism were evaluated. All of them underwent orchidopexy in 2010. Prior to the procedure, all of the subjects had undergone karyotyping to exclude chromosomal abnormalities. Fifty healthy boys within the same age range (median = 2.1 years) admitted for planned inguinal hernia repair in 2010, served as controls. Blood samples were collected, while obtaining blood for standard laboratory tests routinely performed before the surgeries. Medians of AMH in boys with cryptorchidism were lower than in boys with inguinal hernia and differed significantly between two groups. Undescended testes were generally found in superficial inguinal pouch (n = 46), in two cases were noted to be in the external ring of the inguinal canal, and in another two instances, in the abdominal cavity. The major lengths of the undescended testes were smaller in comparison to the testes positioned normally (mean of 1 cm vs. a mean of 1.5 cm, respectively). In nine of the cases, the testes had turgor deficit, a drop shape, with epididymides that were small, dysplastic, and separated from the testis. The authors found that AMH was lower in boys with unilateral cryptorchidism (also found to have smaller testis) when compared with the control group

The Stature of Boys Is Inversely Correlated to the Levels of Their Sertoli Cell Hormones: Do the Testes Restrain the Maturation of Boys?

The testes of preadolescent boys appear to be dormant, as they produce only trace levels of testosterone [1]. However, they release supra-adult levels of Müllerian Inhibiting Substance (MIS, anti-Müllerian hormone) and lesser levels of inhibin B (InhB), for unknown reasons [2], [3]. Boys have a variable rate of maturation, which on average is slower than girls. The height of children relative to their parents is an index of their maturity [4], [5]. We report here that a boy's level of MIS and InhB is stable over time and negatively correlates with his height and his height relative to his parent's height. This suggests that boy's with high levels of MIS and InhB are short because they are immature, rather than because they are destined to be short men. The levels of MIS and InhB in the boys did not correlate with known hormonal modulators of growth, and were additive with age and the growth hormone/IGF1 axis as predictors of a boy's height. If MIS and InhB were causal regulators of maturity, then the inter-boy differences in the levels of these hormone produces variation in maturation equivalent to 18-months of development. MIS and InhB may thus account for most of the variation in the rate of male development. If boys lacked these hormones, then an average 5-year-old boy would be over 5 cm taller than age-matched girls, making boys almost as dimorphic as men, for height. This indicates that boys have a high growth potential that is initially suppressed by their testes. The concept of the childhood testes suppressing an adult male feature appears paradoxical. However, the growth of children requires intergenerational transfer of nutrients. Consequently, the MIS/InhB slowing of male growth may have been historically advantageous, as it would minimizes any sex bias in the maternal cost of early child rearing

Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging.

Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3 alpha (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G > A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father, and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated as genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. These findings were most marked in a carrier of the AML-associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype-related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders: NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamental new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance, and determinants of biological aging in these growth disorders

EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF); Scientific Opinion on Flavouring Group Evaluation 96 (FGE.96): Consideration of 88 flavouring substances considered by EFSA for which EU production volumes / anticipated production volumes have been submitted on request by DG SANCO. Addendum to FGE. 51, 52, 53, 54, 56, 58, 61, 62, 63, 64, 68, 69, 70, 71, 73, 76, 77, 79, 80, 83, 84, 85 and 87

Overgrowth disorders are a heterogeneous group of conditions characterized by increased growth parameters and other variable clinical features such as intellectual disability and facial dysmorphism1. To identify new causes of human overgrowth, we performed exome sequencing in ten proband-parent trios and detected two de novo DNMT3A mutations. We identified 11 additional de novo mutations by sequencing DNMT3A in a further 142 individuals with overgrowth. The mutations alter residues in functional DNMT3A domains, and protein modeling suggests that they interfere with domain-domain interactions and histone binding. Similar mutations were not present in 1,000 UK population controls (13/152 cases versus 0/1,000 controls; P < 0.0001). Mutation carriers had a distinctive facial appearance, intellectual disability and greater height. DNMT3A encodes a DNA methyltransferase essential for establishing methylation during embryogenesis and is commonly somatically mutated in acute myeloid leukemia2, 3, 4. Thus, DNMT3A joins an emerging group of epigenetic DNA- and histone-modifying genes associated with both developmental growth disorders and hematological malignancie

The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants.

Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as the DNMT3A-overgrowth syndrome, is an overgrowth intellectual disability syndrome first described in 2014 with a report of 13 individuals with constitutive heterozygous DNMT3A variants. Here we have undertaken a detailed clinical study of 55 individuals with de novoDNMT3A variants, including the 13 previously reported individuals. An intellectual disability and overgrowth were reported in >80% of individuals with TBRS and were designated major clinical associations. Additional frequent clinical associations (reported in 20-80% individuals) included an evolving facial appearance with low-set, heavy, horizontal eyebrows and prominent upper central incisors; joint hypermobility (74%); obesity (weight ³2SD, 67%); hypotonia (54%); behavioural/psychiatric issues (most frequently autistic spectrum disorder, 51%); kyphoscoliosis (33%) and afebrile seizures (22%). One individual was diagnosed with acute myeloid leukaemia in teenage years. Based upon the results from this study, we present our current management for individuals with TBRS

Prenatal Stress Exposure Related to Maternal Bereavement and Risk of Childhood Overweight

BACKGROUND: It has been suggested that prenatal stress contributes to the risk of obesity later in life. In a population-based cohort study, we examined whether prenatal stress related to maternal bereavement during pregnancy was associated with the risk of overweight in offspring during school age. METHODOLOGY/PRINCIPAL FINDINGS: We followed 65,212 children born in Denmark from 1970-1989 who underwent health examinations from 7 to 13 years of age in public or private schools in Copenhagen. We identified 459 children as exposed to prenatal stress, defined by being born to mothers who were bereaved by death of a close family member from one year before pregnancy until birth of the child. We compared the prevalence of overweight between the exposed and the unexposed. Body mass index (BMI) values and prevalence of overweight were higher in the exposed children, but not significantly so until from 10 years of age and onwards, as compared with the unexposed children. For example, the adjusted odds ratio (OR) for overweight was 1.68 (95% confidence interval [CI] 1.08-2.61) at 12 years of age and 1.63 (95% CI 1.00-2.61) at 13 years of age. The highest ORs were observed when the death occurred in the period from 6 to 0 month before pregnancy (OR 3.31, 95% CI 1.71-6.42 at age 12, and OR 2.31, 95% CI 1.08-4.97 at age 13). CONCLUSIONS/SIGNIFICANCE: Our results suggest that severe pre-pregnancy stress is associated with an increased risk of overweight in the offspring in later childhood