Joachim Woelfle

Fibroblast Growth Factor 21 (FGF-21) and Its Relation to Obesity, Metabolic Syndrome, and Nonalcoholic Fatty Liver in Children: A Longitudinal Analysis

CONTEXT Fibroblast growth factor 21 (FGF-21), a potent activator of glucose uptake, has been proposed to be related to insulin resistance, metabolic syndrome (MetS), nonalcoholic fatty liver disease (NAFLD), and weight status. OBJECTIVE Our objective was to study the relationships between FGF-21, parameters of MetS, and NAFLD before and after weight loss in obese children. DESIGN AND SETTING This was a cross-sectional comparison between obese and normal-weight children and longitudinal 1-yr follow-up study in obese children participating in a lifestyle intervention in a primary care setting. PATIENTS Patients included 60 obese and 40 lean children of same age, gender, and pubertal stage. INTERVENTION The outpatient 1-yr intervention program was based on exercise, behavior, and nutrition therapy. MAIN OUTCOMES MEASURES We evaluated fasting serum FGF-21, weight status [body mass index (BMI) expressed as sd score (SDS)], body fat, insulin resistance index (homeostasis model assessment), leptin, transaminases, free fatty acids (FFA), waist circumference, blood pressure, and lipids. RESULTS Compared with the normal-weight children, obese children demonstrated significantly (P < 0.001) increased FGF-21, leptin, and homeostasis model assessment levels. FGF-21 was significantly (P < 0.05) correlated to BMI, SDS-BMI, FFA, and leptin both in cross-sectional and longitudinal analyses but not to any additional analyzed parameter. Children with and without MetS or NAFLD did not differ significantly with respect to their FGF-21 concentrations. A decrease of SDS-BMI was associated with a significant (P = 0.038) decrease of FGF-21 levels (mean -34%). CONCLUSIONS FGF-21 concentrations are reversibly increased in obese children and are related to leptin and FFA. However, our data do not support a significant relationship between FGF-21, insulin resistance, and features of MetS or NAFLD in children.

Growth and puberty in German children: is there still a positive secular trend?

BACKGROUND Since the mid-19th century, growth in German children has accelerated and final height increased. Possible causes of this secular trend include improvements in nutrition, hygiene, and health care. While the upward secular trend still continues in some parts of the world, it seems to be slowing in industrialized countries. METHODS Selective literature review. RESULTS Reliable data on growth that have been published since the middle of the 19th century reveal an increase in final height by 1 to 2 cm per decade in most European countries. Recent epidemiological studies, however, suggest that human height may be nearing an upper limit, beyond which it cannot increase even with further improvements in nutrition and health care. In Germany and other northern European countries, the upward trend in final height has slowed significantly over the last 30 years; in Germany, it now stands at less than 1 cm/decade. In the same interval, the age at menarche has remained constant at just under 13 years (currently 12.8). CONCLUSIONS In Germany, as elsewhere in northern Europe, the upward secular trend in height is slowing (ca. 2 cm/decade up to the mid-20th century, currently less than 1 cm/decade), and the age at menarche has stabilized at just under 13 years. It remains an open question whether the observed slowing will merely be temporary, or whether it indeed represents the near-attainment of an endpoint owing to relatively stable environmental conditions.

Subdural hemorrhage as an initial sign of glutaric aciduria type 1: a diagnostic pitfall

The case of a 9-month-old girl with glutaric aciduria type 1 (GA 1) is reported. On initial presentation at 6 months of age, the patient demonstrated bilateral subdural hemorrhages and widening of the basal cisterns. After neurosurgical intervention the subdural effusions regressed; their etiology remained unclear. At the age of 9 months the patient presented again because of progressive loss of psychomotor abilities and a dystonic movement disorder. Cerebral MRI revealed regressive subdural hematoma, but marked frontotemporal atrophy as well. Because of a suspected metabolic disorder, urinary analysis of organic acids was performed. This repeatedly showed marked excretion of glutaric acid, 3-hydroxyglutaric acid and glutaconic acid, indicating a diagnosis of GA 1. Considering our patients history, we recommend the inclusion of GA 1 in the differential diagnosis of patients with unexplained subdural hematoma and neurological deficits.

Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting

Turner syndrome affects 25-50 per 100,000 females and can involve multiple organs through all stages of life, necessitating multidisciplinary approach to care. Previous guidelines have highlighted this, but numerous important advances have been noted recently. These advances cover all specialty fields involved in the care of girls and women with TS. This paper is based on an international effort that started with exploratory meetings in 2014 in both Europe and the USA, and culminated with a Consensus Meeting held in Cincinnati, Ohio, USA in July 2016. Prior to this meeting, five groups each addressed important areas in TS care: 1) diagnostic and genetic issues, 2) growth and development during childhood and adolescence, 3) congenital and acquired cardiovascular disease, 4) transition and adult care, and 5) other comorbidities and neurocognitive issues. These groups produced proposals for the present guidelines. Additionally, four pertinent questions were submitted for formal GRADE (Grading of Recommendations, Assessment, Development and Evaluation) evaluation with a separate systematic review of the literature. These four questions related to the efficacy and most optimal treatment of short stature, infertility, hypertension, and hormonal replacement therapy. The guidelines project was initiated by the European Society for Endocrinology and the Pediatric Endocrine Society, in collaboration with The European Society for Pediatric Endocrinology, The Endocrine Society, European Society of Human Reproduction and Embryology, The American Heart Association, The Society for Endocrinology, and the European Society of Cardiology. The guideline has been formally endorsed by the European Society for Endocrinology, the Pediatric Endocrine Society, the European Society for Pediatric Endocrinology, the European Society of Human Reproduction and Embryology and the Endocrine Society. Advocacy groups appointed representatives who participated in pre-meeting discussions and in the consensus meeting.

Cantu syndrome resulting from activating mutation in the KCNJ8 gene.

ATP‐sensitive potassium (KATP) channels, composed of inward‐rectifying potassium channel subunits (Kir6.1 and Kir6.2, encoded by KCNJ8 and KCNJ11, respectively) and regulatory sulfonylurea receptor (SUR1 and SUR2, encoded by ABCC8 and ABCC9, respectively), couple metabolism to excitability in multiple tissues. Mutations in ABCC9 cause Cantú syndrome (CS), a distinct multiorgan disease, potentially via enhanced KATP channel activity. We screened KCNJ8 in an ABCC9 mutation‐negative patient who also exhibited clinical hallmarks of CS (hypertrichosis, macrosomia, macrocephaly, coarse facial appearance, cardiomegaly, and skeletal abnormalities). We identified a de novo missense mutation encoding Kir6.1[p.Cys176Ser] in the patient. Kir6.1[p.Cys176Ser] channels exhibited markedly higher activity than wild‐type channels, as a result of reduced ATP sensitivity, whether coexpressed with SUR1 or SUR2A subunits. Our results identify a novel causal gene in CS, but also demonstrate that the cardinal features of the disease result from gain of KATP channel function, not from a Kir6‐independent SUR2 function.

Lack of association between apelin, insulin resistance, cardiovascular risk factors, and obesity in children: a longitudinal analysis.

Apelin has been proposed as a novel beneficial adipokine that is related to insulin resistance, cardiovascular risk factors, and obesity. However, findings in humans are controversial; and longitudinal analyses in childhood are still missing. We compared apelin levels between 80 obese and 40 lean children of the same age, sex, and pubertal stage. In addition, we analyzed the relationships between apelin levels and weight status (as standard deviation of body mass index [SDS-BMI]), body fat, insulin resistance (homeostasis model assessment [HOMA]), leptin, and cardiovascular risk factors associated with obesity (waist circumference, blood pressure, lipids, and adiponectin) in 80 obese children before and after participating in a 1-year lifestyle intervention. Apelin levels did not differ significantly (P = .061) between obese (1.50 ± 0.47 ng/mL, mean ± SD) and lean children (1.67 ± 0.49 ng/mL). Apelin concentrations were not significantly related to age, pubertal stage, SDS-BMI, body fat, leptin, or any cardiovascular risk factor. In longitudinal analyses, no significant correlations were found between changes of apelin and changes of SDS-BMI, body fat, leptin, HOMA, or any cardiovascular risk factor. Adiponectin, HOMA, blood pressure, waist circumference, and triglycerides improved significantly in 39 obese children with SDS-BMI reduction, whereas leptin decreased significantly and apelin did not change significantly in these children. In 41 children with increase of SDS-BMI, no significant changes were observed in 1-year follow-up period. This is the first study demonstrating that weight loss in obese children was not associated with a change of apelin concentrations. Our data do not support a significant relationship in childhood between apelin on one hand and leptin, HOMA, cardiovascular risk factors, or weight status on the other.

MKRN3 Mutations in Familial Central Precocious Puberty

Loss-of-function mutations in the gene encoding the makorin RING finger protein 3 (MKRN3) have recently been reported to underlie familial cases of central precocious puberty (CPP). The imprinted MKRN3 gene is expressed only from the paternal allele, and mutations inherited from the father affect boys and girls equally, which is in contrast to the known female preponderance in idiopathic CPP. By screening a series of 6 families and 1 male patient with idiopathic CPP, we identified 2 further families carrying loss-of-function mutations in MKRN3, the previously reported variant c.475_476insC (p.Ala162Glyfs*14) and a novel one, c.331G>T (p.Glu111*). We conclude that MKRN3 mutations appear to be a frequent cause of familial CPP and, considering the imprinted mode of inheritance, may also account for a certain proportion of isolated CPP cases. Remarkably, four out of six MKRN3 mutations described so far encode either a stop codon or a frameshift followed by a premature stop codon. Consequently, there may be less severe mutations that possibly associate with more subtle phenotypes, which could even explain variation within the physiological range. Mutation screening in larger cohorts is necessary in order to estimate the real prevalence of MKRN3 mutations in idiopathic CPP.

Methylation of L1Hs promoters is lower on the inactive X, has a tendency of being higher on autosomes in smaller genomes and shows inter-individual variability at some loci

LINE-1 repeats account for ∼17% of the human genome. Little is known about their individual methylation patterns, because their repetitive, almost identical sequences make them difficult to be individually targeted. Here, we used bisulfite conversion to study methylation at individual LINE-1 repeats. The loci studied included 39 X-linked loci and 5 autosomal loci. On the X chromosome in women, we found statistically significant less methylation at almost all L1Hs compared with men. Methylation at L1P and L1M did not correlate with the inactivation status of the host DNA, while the majority of L1Hs that were possible to be studied lie in inactivated regions. To investigate whether the male–female differences at L1Hs on the X are linked to the inactivation process itself rather than to a mere influence of gender, we analyzed six of the L1Hs loci on the X chromosome in Turners and Klinefelters which have female and male phenotype, respectively, but with reversed number of X chromosomes. We could confirm that all samples with two X chromosomes are hypomethylated at the L1Hs loci. Therefore, the inactive X is hypomethylated at L1Hs; the latter could play an exclusive role in the X chromosome inactivation process. At autosomal L1Hs, methylation levels showed a correlation tendency between methylation level and genome size, with higher methylation observed at most loci in individuals with one X chromosome and the lowest in XXY individuals. In summary, loci-specific LINE-1 methylation levels show considerable plasticity and depend on genomic position and constitution.

False negative 17-hydroxyprogesterone screening in children with classical congenital adrenal hyperplasia

We report 5 out of 214 children with classical congenital adrenal hyperplasia (CAH) that was not detected by neonatal 17-Hydroxyprogesterone screening. Therefore, diagnosis was only based on a suspect clinical picture and subsequent re-evaluation. In addition to 3 patients suffering from the simple virilizing form of CAH and not reported so far, the remaining 2 children whose CAH was missed by the screening suffered from the severe salt-wasting form. This report underlines the importance of a careful clinical investigation of newborns to detect signs of genital virilization. The differential diagnosis of classical CAH should be kept in mind even if neonatal screening is reported to be normal.

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 β-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.