Bettina Gohlke

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.

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.

Fetal Adiponectin and Resistin in Correlation with Birth Weight Difference in Monozygotic Twins with Discordant Growth

Background: Various studies have demonstrated an increased risk for adult diseases in newborns born small-for-gestational-age (SGA). Adiponectin and resistin can be detected in cord blood and are suggested to affect insulin resistance (IR). This might represent a link between metabolic syndrome and SGA birth. Study Design: We investigated the relationship between the adipocytokines and inter-twin birth weight (BW) difference of 31 monozygotic twins with twin-twin transfusion syndrome; in 14 twin pairs BW difference was >15% (1 SGA twin, 1 appropriate-for-gestational-age, AGA, twin). Results: BW and length of all patients were positively related to adiponectin (r = 0.57; p < 0.0001; r = 0.47; p < 0.0001) and to resistin (r = 0.31; p < 0.01; r = 0.35; p < 0.01). In 71% (10/14), the SGA twins showed lower adiponectin concentrations than their AGA co-twins (only 6/14 for resistin). To correct for gestational age we calculated the relationship between the intrapair differences (Δ) of BW and Δ of the hormones. We found ΔBW positively correlated with adiponectin (r = 0.55; p < 0.001) but not with resistin (r = 0.22; p = 0.2). Δadiponectin was positively correlated with Δresistin (r = 0.45; p < 0.01). Conclusion: These data demonstrate that adiponectin and resistin levels are associated with BW with only adiponectin levels being reduced in SGA children independently of gestational age. Prenatally different metabolic status between the twins might predispose the SGA twin to develop IR later in life.

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.

Cystic fibrosis-related diabetes compared with type 1 and type 2 diabetes in adults

With increasing life expectancy of patients with cystic fibrosis (CF), secondary diabetes becomes more prevalent. It appears to be the most common co‐morbidity in persons with cystic fibrosis. Therefore, the objective of our study was to describe characteristics of cystic fibrosis‐related diabetes compared with type 1 and 2 diabetes (T1DM/T2DM) in adults.

Changes in dynamic insulin and gastrointestinal hormone secretion in obese children.

ABSTRACT Background: Disturbed satiety and hunger perception in obese individuals has been reported, however data on the dynamic changes of hormonal mediators are sparse. Objective: To evaluate the secretion pattern of insulin, ghrelin, peptide-YY (PYY), and amylin via 0 to 180 min oral glucose tolerance testing in obese and lean children. Subjects and Methods: A prospective clinical study was conducted on lean (n=9) and obese (n=20) Caucasian children of comparable age, gender, and pubertal stage. Serial blood samples were collected. Results: Compared to baseline, levels of acylated ghrelin showed a significant decrease in lean (p<0.05) but not in obese children. PYY increase was blunted and of shorter duration (60 min) in obese children. Amylin levels increased in both groups, and attained significantly higher levels in obese children (p<0.05). Conclusion: Glucose stimulated gut hormone secretion differed between obese and lean children, and may explain the disturbed satiety observed in obese children.

Cord blood leptin and IGF-I in relation to birth weight differences and head circumference in monozygotic twins

OBJECTIVES To investigate a potential role of leptin and insulin-like growth factor (IGF)-I on fetal growth and metabolic function we determined plasma leptin and IGF-I concentrations in twins in relation to discordant fetal growth. STUDY DESIGN In studying monochorionic twins with inter-twin birth weight difference, we investigated the relative contribution of genetic (fetus) versus environmental (maternal/placental) factors on growth. Thirty-six sets of twins (14 with discordant growth, birth weight difference >15%) who had been treated for severe twin-to-twin transfusion syndrome (TTTS) by laser coagulation were studied. Cord blood samples were collected at birth and analyzed for IGF-I and leptin. Inter-twin differences (delta) of birth weight and head circumference were correlated to delta hormone levels. RESULTS An inter-twin correlation for leptin (r = 0.69; p <0.0001) and delta IGF-I (r = 0.49; p <0.0001) was found. delta birth weight correlated significantly with delta IGF-I (r = 0.67; p <0.0001) but not with delta leptin (r = 0.23; p = 0.19). delta IGF-I concentrations did not correlate with delta leptin (r = 0.18). delta head circumference correlated significantly with delta leptin (r = 0.47; p <0.01) and with delta IGF-I (r = 0.46; p <0.01). Using a multiple regression model with head circumference as dependent variable, adjusted for gestational age, head circumference remained significantly associated with higher leptin concentrations in all patients (p = 0.03). CONCLUSION IGF-I is a good indicator for fetal growth and brain development. Leptin seems to be mainly genetically determined but may play a role in fetal brain development and is not only an index for fetal fat mass.

Longitudinal Data for Intrauterine Levels of Fetal IGF-I and IGF-II

Objective: An increasing body of evidence supports a major role for the insulin-like growth factors (IGFs) in the control of human fetal growth. Individual data at various times of pregnancy suggest that IGF-I and IGF-II levels remain stable up to the 33rd week of pregnancy. Thereafter, both increase to reach values 2–3 times higher at term. In order to provide an accurate reflection of fetal IGFs in utero, we sampled fetal blood from the umbilical cord by cordocentesis. Methods: We measured IGF-I and IGF-II in 12 fetuses longitudinally for up to 5 times between the 21st week of gestation and delivery. Results: All patients showed a progressive increase in IGF-I and IGF-II levels. Data determined during different time intervals (before 29th, 29th to 32nd, after 32nd week) were compared and the main increase was found after the 32nd week. The median for IGF-I before the 29th week was 33.5 ng/ml (range 19–40.5) and increased to 41 ng/ml (32–59) between the 29th to 32nd and further to 54.1 ng/ml (range 17–70) thereafter. During the same time interval, the median for IGF-II increased from 217 ng/ml (86–326) to 349 ng/ml (227–467). In 7 patients, cord blood after delivery was available. For IGF-II a further increase was consistently found after birth (from 282 ng/ml (175–511) to 393 ng/ml (297–513)), whereas only 2 fetuses showed an increase in IGF-I. Conclusion: We conclude that in human fetuses, IGF-I and IGF-II levels increase longitudinally throughout pregnancy. Therefore, they may become important markers of healthy fetal development.

Insulin-Like Growth Factor-I in Cord Blood Is Predictive of Catch-Up Growth in Monozygotic Twins with Discordant Growth

OBJECTIVE The aim was to investigate the growth of monozygotic twins with discordant birth weights and the predictive value of birth-weight, birth-length, and cord-blood concentration of growth factors on their catch-up growth up to the age of 4 yr. PATIENTS AND METHODS Twenty-five monozygotic twin-pairs [14 with an intertwin birth-weight sd score (SDS) difference>1] were studied at birth and at 4 yr of age. In all pairs, several parameters including IGF-I were analyzed in cord blood, and in 20 pairs parameters were analyzed again at 4 yr of age. Intertwin differences (Δ) in birth weight, birth length, and growth at 3, 6, 12, 24, and 48 months were correlated with Δ of the parameters analyzed. RESULTS We found a reduction of Δ height SDS from birth to 4 yr, with the main catch-up occurring during the first year, but only a slight, statistically insignificant reduction of Δ body mass index SDS during the observation period. Correlation coefficients were used to identify factors predicting postnatal catch-up growth. Both birth-weight difference (r=0.653; P=0.001) and Δ IGF-I in cord blood (r=0.613; P=0.007) were of similar predictive value. Variance analysis showed no significant difference in individual impact between these two parameters, although both correlated strongly with actual height. CONCLUSION We observed a gradual convergence in height but not body mass index up to the age of 4 yr between genetically identical twins with discordant birth weights. Both birth-weight and cord-blood IGF-I are predictive of subsequent catch-up growth.