Regional variation in lifestyle patterns and BMI in young children: the GECKO Drenthe cohort.

BACKGROUND: A better understanding of lifestyle behaviours of children < 7 years and the relation with childhood overweight is needed. The aim of our prospective study was to examine how lifestyle patterns in young children are associated with the development of childhood overweight. As ecological models suggest focusing on not only the child as an individual, but also their environment, we also considered the role of socio-economic status (SES) and spatial clustering of lifestyle and body mass index (BMI). METHODS: In 1792 children (aged 3-6 years) participating in the GECKO Drenthe cohort, diet, screen time, outdoor play and sleep were assessed by questionnaires and moderate-to-vigorous physical activity and sedentary time by accelerometry (Actigraph GT3X). At 10-11 years, height and weight were measured to calculate age- and sex-specific standardized BMI z-scores (zBMI). Lifestyle patterns were identified using principal component analysis. To assess spatial clustering for the lifestyle patterns and zBMI, we calculated the Global Moran's I statistic. Linear- and logistic regression models, taking into account SES, were performed to examine the association between the lifestyle patterns and the development of overweight. For the spatial analyses, we added spatial terms for the determinants, the outcome, and the error term. RESULTS: Three lifestyle patterns were identified: (1) 'high activity', (2) 'low screen time, high sleep and healthy diet', and (3) 'high outdoor play'. No associations were observed between the 'high activity' or 'high outdoor play' patterns at young age with the development of childhood overweight (all p > 0.05). In contrast, children who adhered to the 'low screen time, high sleep and healthy diet' pattern had lower odds to become overweight and a lower zBMI at 10-11 years (odds ratio [95% CI] = 0.766 [0.65; 0.90]). These findings remained similar after taking SES into account. Regarding the spatial analyses, we found spatial clustering of zBMI, but no spatial clustering of the lifestyle patterns. CONCLUSIONS: Low screen time, high sleep duration and a healthy diet cluster into a pattern that seems favourable in the prevention of childhood overweight, independent of individual SES. The spatial analyses suggest that there are likely other neighbourhood factors that contribute to the spatial clustering of childhood overweight.

Prevalence of growth hormone (GH) deficiency in previously GH-treated young adults with Prader-Willi syndrome.

OBJECTIVE: Some features of subjects with Prader-Willi syndrome (PWS) resemble those seen in growth hormone deficiency (GHD). Children with PWS are treated with growth hormone (GH), which has substantially changed their phenotype. Currently, young adults with PWS must discontinue GH after attainment of adult height when they do not fulfil the criteria of adult GHD. Limited information is available about the prevalence of GHD in adults with PWS. This study aimed to investigate the GH/insulin-like growth factor (IGF-I) axis and the prevalence of GHD in previously GH-treated young adults with PWS. DESIGN: Cross-sectional study in 60 young adults with PWS. MEASUREMENTS: Serum IGF-I and IGFBP-3 levels, GH peak during combined growth hormone-releasing hormone (GHRH)-arginine stimulation test. RESULTS: Serum IGF-I was <-2 standard deviation scores (SDS) in 2 (3%) patients, and IGFBP-3 was within the normal range in all but one patient. Median (IQR) GH peak was 17.8 µg/L (12.2; 29.7) [~53.4 mU/L] and below 9 µg/L in 9 (15%) patients. Not one patient fulfilled the criteria for adult GHD (GH peak < 9 µg/L and IGF-I < -2 SDS), also when BMI-dependent criteria were used. A higher BMI and a higher fat mass percentage were significantly associated with a lower GH peak. There was no significant difference in GH peak between patients with a deletion or a maternal uniparental disomy (mUPD). CONCLUSIONS: In a large group of previously GH-treated young adults with PWS, approximately 1 in 7 exhibited a GH peak <9 µg/L during a GHRH-arginine test. However, none of the patients fulfilled the consensus criteria for adult GHD.

An analysis of body proportions in children with CHARGE syndrome using photogrammetric anthropometry.

BACKGROUND: Growth retardation is one of the main hallmarks of CHARGE syndrome (CS), yet little is known about the body proportions of these children. Knowledge of body proportions in CS may contribute to a better characterization of this syndrome. This knowledge is important when considering starting growth-stimulating therapy. METHODS: For this cross-sectional study, we selected 32 children with CS and a CHD7 mutation at the Dutch CHARGE Family Day in 2016 or 2017 and the International CHARGE conference in Orlando, Florida, in 2017. We used photogrammetric anthropometry-a measurement method based on digital photographs-to determine various body proportions. We compared these to measurements in 21 normally proportioned children with growth hormone deficiency, using independent-samples t test, Mann-Whitney U test, or chi-square test as appropriate. RESULTS: Children with CS appear to have a shorter trunk in proportion to their height, head length, and arm length. Children with CS also had smaller feet proportional to tibia length compared to controls. The change of body proportions with age was similar in children with CS and controls. CONCLUSION: Body proportions in children with CS are significantly different from those of normally proportioned controls, but a similar change of body proportions with age was noted for both groups.

Maternal use of prednisolone is unlikely to be associated with neonatal adrenal suppression-a single-center study of 16 cases.

The use of supra-physiological, exogenous corticosteroids in pregnancy may lead to neonatal adrenal suppression. We report on a single-center, case series study carried out between 2006 and 2014, which included all newborns (n = 16) of mothers using prednisolone ≥10 mg/day during pregnancy. Newborns were routinely assessed according to hospital protocol, with follow-up until 6 weeks after birth. We investigated the clinical symptoms and biochemical findings of adrenal suppression occurring in the newborns. Mean dose of maternal prednisolone was 29.7 ± 16.1 mg/day with a mean duration of 18.4 ± 15.4 weeks. Five newborns showed hypoglycemia with normal serum cortisol concentrations and urinary steroid profiles. Two newborns had abnormal urinary steroid profiles, probably the result of prematurity, but with adequate adrenal stress response during clinical sepsis. CONCLUSION: In this retrospective case series, we found no evidence of prolonged effects of maternal prednisolone use during pregnancy on the neonatal hypothalamic-pituitary-adrenal axis. What is known: • The use of prednisolone during pregnancy may cause increased steroid levels in the fetus by partially passing through the placenta. • So far, there was very limited data available on the occurrence of adrenal suppression in the newborn of mothers using prednisolone during pregnancy. What is new: • The use of high-dosage prednisolone during pregnancy for ≥1 week (mean duration of 18.4 ± 15.4 weeks), prior to delivery, appears to have little influence on the neonatal hypothalamic-pituitary-adrenal axis.

Central Adrenal Insufficiency Is Not a Common Feature in CHARGE Syndrome: A Cross-Sectional Study in 2 Cohorts.

OBJECTIVE: To evaluate whether central adrenal insufficiency (CAI) is present in CHARGE (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital hypoplasia, and Ear abnormalities, including deafness) syndrome, a complex malformation disorder that includes central endocrine dysfunction. STUDY DESIGN: Two cross-sectional studies were performed in Dutch (September 2013-February 2015) and Australian (January 2012-January 2014) CHARGE syndrome clinics. Twenty-seven Dutch and 19 Australian patients (aged 16 months-18 years) with genetically confirmed CHARGE syndrome were included. The low-dose adrenocorticotropin (ACTH) test was used to assess CAI in the Dutch cohort. A peak cortisol response less than 18.1 µg/dL (500 nmol/L) was suspected for CAI, and a glucagon stimulation test was performed for confirmation. Australian patients were screened by single measurements of ACTH and cortisol levels. If adrenal dysfunction was suspected, a standard-dose ACTH test was performed. RESULTS: The low-dose ACTH test was performed in 23 patients (median age 8.4 [1.9-16.9] years). Seven patients showed an insufficient maximum cortisol level (10.3-17.6 µg/dL, 285-485 nmol/L), but CAI was confirmed by glucagon stimulation test in only 1 patient (maximum cortisol level 15.0 µg/dL, 415 nmol/L). In the Australian cohort, 15 patients (median age 9.1 [1.3-17.8] years) were screened, and none had CAI. CONCLUSIONS: CAI was not common in our cohorts, and routine testing of adrenal function in children with CHARGE syndrome is not indicated.

Dutch healthcare professionals inadequately perceived if three- and four-year-old preschool children were overweight.

AIM: We studied whether healthcare professionals adequately perceived if preschool children were overweight and whether this was influenced by their own body mass index (BMI). METHODS: We sent 716 Dutch healthcare professionals questionnaires containing seven pictures and seven sketches of three- and four-year-old children showing body weights from underweight to morbidly obese. The professionals rated the pictures on a five-point scale from too heavy to too light and chose the sketch that they felt best depicted the child's body shape. They also reported their own height and weight and their BMI was calculated. RESULTS: Of the 716 questionnaires, 346 (48.3%) were returned with complete information and analysed. Healthcare professionals mostly chose sketches that showed children as being lighter than they really were. Depending on their own BMI group, the overweight child was perceived as having a normal weight by 74-79% of the healthcare professionals. The obese children were rated correctly by 44-52% of the professionals, but 14-15% said their weight was normal. The morbidly obese child was adequately assessed by 93-98% of the professionals. CONCLUSION: Healthcare professionals inadequately perceived whether three- and four-year-old children were overweight and this may have hindered early interventions, leading to overweight children becoming overweight adolescents.

Effect of obesity intervention programs on adipokines, insulin resistance, lipid profile, and low-grade inflammation in 3- to 5-y-old children.

BACKGROUND: Childhood obesity can cause the development of cardiovascular risk factors. We assessed the effect of a multidisciplinary intervention program on cardiovascular risk factors and compared this effect with a usual-care program in 3- to 5-y-old overweight or obese children. METHODS: Seventy-five children were randomly assigned to a multidisciplinary intervention or a usual-care program. Anthropometry, body composition, and abdominal adipose tissue were assessed at the start and end of a 16-wk program. Concurrently, fasting concentrations of serum lipids, glucose, insulin, HbA1c, leptin, adiponectin, high-sensitive C-reactive protein (hsCRP), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 were determined. RESULTS: In both groups, insulin sensitivity improved, demonstrated by decreased insulin concentrations and a decreased HOMA2-IR. In the multidisciplinary intervention group, there was also a decrease of HbA1c and TNF-α. In the usual-care group, an increase in glucose concentrations was found. Comparing both groups, changes over time were not different, besides trends in the decrease in total cholesterol and TNF-α, in favor of the multidisciplinary intervention group. Combining the results of both groups, a correlation was found between the decrease in body fat percentage (BF%), and both HOMA2-IR and triglyceride (TG) concentrations. CONCLUSION: In 3- to 5-y-old children, both obesity intervention programs improved insulin sensitivity, in parallel with a reduced BF%.

Children with asthma have significantly lower long-term cortisol levels in their scalp hair than healthy children.

AIM: Noninvasive measurement of long-term cortisol levels is a useful way of evaluating the effect of chronic disease on the hypothalamic-pituitary-adrenal axis in children. The aim of this pilot study was to compare hair cortisol levels in children using inhaled corticosteroids for asthma and healthy children and to determine the association with short-term salivary cortisol levels. METHODS: Cortisol levels were measured in the scalp hair and saliva of prepubertal children with asthma (n = 10) and without asthma (n = 10). Asthma control was assessed using an asthma questionnaire and pulmonary function tests. RESULTS: The median (95% CI) cortisol level in the scalp hair of the children with asthma (2.0 pg/mg; 1.4-4.1) was significantly lower than the healthy children (4.3 pg/mg; 1.8-5.9). Morning salivary cortisol levels were significantly lower for the children with asthma (5.9 nmol/L; 3.2-11.1) than the healthy children (9.0 nmol/L; 4.4-31.6). There was no significant association between cortisol levels in hair and saliva. CONCLUSION: Long-term cortisol levels were significantly lower in children with asthma than healthy children. Measuring long-term cortisol levels in scalp hair is an attractive, noninvasive tool that can evaluate the effect of asthma and its treatment on the hypothalamic-pituitary-adrenal axis.

Puberty progression in girls with Turner syndrome after ovarian tissue cryopreservation.

OBJECTIVE: To study the impact of unilateral ovariectomy for ovarian tissue cryopreservation (OTC) on the function of the remaining ovary in girls with Turner syndrome. DESIGN: A prospective cohort study as follow up of OTC in a research setting (The TurnerFertility trial, NCT03381300). SETTING: University hospital in Nijmegen, the Netherlands. SUBJECTS: A total of 28 girls with Turner syndrome with follicles in their cryopreserved ovarian cortex tissue, aged 5-19 years. Of the 28 girls, 21 girls had a 45,X/46,XX mosaic karyotype, five had structural aberrations of the X-chromosome, one girl had a 45,X monosomy, and one girl had a 45,X/47,XXX karyotype. INTERVENTIONS: Girls were monitored annually after OTC for pubertal development and levels of anti-Müllerian hormone (AMH), Follicle Stimulating Hormone, Luteinizing Hormone, Estradiol, and Inhibin B. MAIN OUTCOME MEASURES: Thelarche, menarche and onset of premature ovarian insufficiency. RESULTS: The girls were monitored for a median duration of 3.4 years (maximum 6.6 years). The pubertal development of five prepubertal girls is still unknown, all were under the age of 10 and had low gonadotropins and estradiol levels at the end of the follow-up. Seven of the eight girls around pubertal age (10-12 years) experienced spontaneous thelarche, while one received medication to induce puberty. Eleven of the fourteen girls between the age of 14-17 years experienced spontaneous menarche, three other girls with thelarche still had ongoing puberty at the end of follow-up with normal gonadotropins and AMH levels above the detection limit. Around six to twelve months after OTC, a decline in AMH concentration was observed in 57% of girls (16/28 girls), followed by an increase in AMH concentration in the following years. Six of the total 28 girls started hormone replacement therapy due to symptoms of premature ovarian insufficiency, and all had AMH levels below 0.50 µg/L before OTC. CONCLUSION: Pubertal development progressed after unilateral ovariectomy for OTC in most girls with Turner syndrome. Hormone replacement therapy was required within a few years for girls with unfavorable parameters before OTC, such as AMH below 0.50 µg/L. Decisions regarding OTC should be personalized, considering the girl's preferences and specific characteristics.

IGF1 Haploinsufficiency: Phenotype and Response to Growth Hormone Treatment in 9 Patients.

INTRODUCTION: The clinical features of bi-allelic IGF1 defects are well established, i.e., severe growth failure and microcephaly, delayed psychomotor development, and sensorineural deafness. However, information on clinical and endocrine consequences of heterozygous IGF1 variants and treatment options is scarce. We aimed at extending the knowledge base of the clinical presentation and growth response to recombinant human growth hormone (rhGH) of patients carrying such variants. METHODS: Retrospective case series of patients with pathogenic heterozygous IGF1 variants. RESULTS: Nine patients from six families were included, harbouring five whole or partial gene deletions and one frameshift variant resulting in a premature stop codon (three de novo, one unknown inheritance). In the other two families, variants segregated with short stature. Mean (SD) birth length was -1.9 (1.3) SDS (n = 7), height -3.8 (0.6) SDS, head circumference -2.5 (0.6) SDS, serum IGF-I -1.9 (0.7) SDS, serum IGFBP-3 1.1 (0.4) SDS (n = 7), and GH peak range 5-31 µg/L (n = 4). Five patients showed feeding problems in infancy. Average height increased after 1 and 2 years of rhGH treatment by 0.8 SDS (range 0.3-1.3 SDS) and 1.3 SDS (range 0.5-2.0 SDS), respectively. Adult height in 2 patients was -2.8 and -1.3 SDS, which was, respectively, 1.3 and 2.9 SDS taller than predicted before start of treatment. CONCLUSION: Haploinsufficiency of IGF1 causes a variable phenotype of prenatal and postnatal growth failure, microcephaly, feeding difficulties, low/low-normal serum IGF-I values in contrast to serum IGFBP-3 in the upper-normal range. Treatment with rhGH increased growth in the first 2 years of treatment, and in 2 patients adult height after treatment was higher than predicted at treatment initiation.

Vaginal bleeding in a 4-month-old preterm girl: extreme minipuberty mimicking central precocious puberty.

We present a 4-month-old girl who showed vaginal bleeding and breast development. She was born preterm at 25 weeks and 4 days of gestation. Luteinizing hormone and follicle-stimulating hormone levels were extremely elevated. Magnetic resonance imaging showed a lesion of unknown nature in the pituitary gland, most likely a Rathke's cleft cyst. Because central precocious puberty (CPP) was suspected, a gonadotropin-releasing hormone analogue was started. At the age of 18 months, the treatment was stopped. Thereafter, no signs of puberty developed. The pituitary lesion remained unchanged. Therefore, the initial diagnosis of CPP was incorrect, and instead, an extreme minipuberty had occurred. If treatment for idiopathic CPP in girls younger than 2 years is started, we recommend the treatment be stopped after a certain period, for reevaluation of the diagnosis of CPP.

Non-invasive measurement of adrenal response after standardized exercise tests in prepubertal children.

OBJECTIVE: To determine the feasibility of non-invasive evaluation of adrenal response in healthy prepubertal children by standardized exercise tests. METHODS: On separate occasions, healthy prepubertal children performed a submaximal cycling test, a maximal cycling test, and a 20-m shuttle-run test. Salivary cortisol levels were determined before exercise, and 1 and 15 min after exercise. RESULTS: Immediately after cessation of the cycling and shuttle-run tests, salivary cortisol levels remained unchanged or decreased. Fifteen minutes after the shuttle-run test, salivary cortisol levels increased significantly. This increase in salivary cortisol levels was not observed 15 min after the cessation of the cycling tests. CONCLUSION: The results of this study demonstrate a different response in salivary cortisol levels after standardized cycling and running tests in prepubertal children. The increase in salivary cortisol levels found after a short standardized running test suggests that this may be a practical non-invasive method for evaluating adrenal response in healthy prepubertal children.

Prenatal Environmental Exposure to Persistent Organic Pollutants and Indices of Overweight and Cardiovascular Risk in Dutch Adolescents.

Persistent organic pollutants (POPs) may have obesogenic effects. Knowledge about the effects of prenatal exposure to POPs on anthropometric measurements and metabolic parameters into adolescence is limited. Therefore, the aim of the current study was to determine whether prenatal environmental exposure to several POPs is associated with indices of overweight and cardiovascular risk in 13-15-year-old children. In this Dutch observational cohort study, 194 mother-infant pairs were included (1998-2002). Maternal pregnancy serum levels of PCBs, OH-PCBs, PBDEs, and other POPs were measured. At follow-up (2014-2016), levels of cholesterol, HDL-C, LDL-C, triglycerides, fasting insulin, fasting glucose, leptin, and adiponectin were measured in their children. The children's height, weight, waist circumference, hip circumference, and blood pressure were measured. In total, 101 adolescents (14.4 ± 0.8 years; 53.7% of invited) participated of which 55 were boys. Mean BMI was 19.1 ± 3.6 kg/m2 and mean BMI z-score 0.13 ± 1.14. Higher prenatal levels of PCBs were associated with lower levels of HDL-C and adiponectin in boys and higher levels of PBDEs with higher triglycerides in girls. We found significant differences by sex in the associations with OH-PCBs, with lower HDL-C and adiponectin, higher LDL-C/HDL-C ratio, fasting glucose, HOMA2-IR, height, and weight for boys. Our study indicates that higher prenatal exposure to PCBs, OH-PCBs, and PBDEs was associated with adolescent levels of some metabolic cardiovascular risk markers and hormones associated with the development of obesity and cardiovascular disease.

Prenatal Environmental Exposure to Persistent Organic Pollutants and Reproductive Hormone Profile and Pubertal Development in Dutch Adolescents.

Persistent organic pollutants (POPs), such as polychlorinated biphenyls (PCBs), may interfere with hormonal processes. Knowledge about the effects of prenatal exposure to PCBs and their hydroxylated metabolites (OH-PCBs) on pubertal development is limited. Therefore, the aim of the current study was to determine whether prenatal environmental PCB and OH-PCB exposure are associated with reproductive hormone levels and pubertal characteristics in 13- to 15-year-old children. In this Dutch observational cohort study, 194 mother-infant pairs were included (1998-2002). Maternal pregnancy serum levels of PCBs, OH-PCBs, and other POPs were measured. At follow-up (2014-2016), we measured serum or plasma levels of reproductive hormones in their children. We assessed Tanner stages and testicular volume (by clinician or standardized self-assessment), and participants completed questionnaires on pubertal onset. In total, 101 adolescents (14.4 ± 0.8 years; 53.7% of invited) participated, and 55 were boys. In boys, higher prenatal PCB levels were associated with higher testosterone levels, higher pubic hair stage, larger testicular volume, and younger age at onset of growth spurt and voice break. In girls, higher prenatal PCB levels were associated with higher stages for breast development. In conclusion, higher prenatal PCB exposure could be associated with more advanced pubertal development in 13- to 15-year-old children.

Optimizing the Timing of Highest Hydrocortisone Dose in Children and Adolescents With 21-Hydroxylase Deficiency.

CONTEXT: Hydrocortisone treatment of young patients with 21-hydroxylase deficiency (21OHD) is given thrice daily, but there is debate about the optimal timing of the highest hydrocortisone dose, either mimicking the physiological diurnal rhythm (morning), or optimally suppressing androgen activity (evening). OBJECTIVE: We aimed to compare 2 standard hydrocortisone timing strategies, either highest dosage in the morning or evening, with respect to hormonal status throughout the day, nocturnal blood pressure (BP), and sleep and activity scores. METHODS: This 6-week crossover study included 39 patients (aged 4-19 years) with 21OHD. Patients were treated for 3 weeks with the highest hydrocortisone dose in the morning, followed by 3 weeks with the highest dose in the evening (n = 21), or vice versa (n = 18). Androstenedione (A4) and 17-hydroxyprogesterone (17OHP) levels were quantified in saliva collected at 5 am; 7 am; 3 pm; and 11 pm during the last 2 days of each treatment period. The main outcome measure was comparison of saliva 17OHP and A4 levels between the 2 treatment strategies. RESULTS: Administration of the highest dose in the evening resulted in significantly lower 17OHP levels at 5 am, whereas the highest dose in the morning resulted in significantly lower 17OHP and A4 levels in the afternoon. The 2 treatment dose regimens were comparable with respect to averaged daily hormone levels, nocturnal BP, and activity and sleep scores. CONCLUSION: No clear benefit for either treatment schedule was established. Given the variation in individual responses, we recommend individually optimizing dose distribution and monitoring disease control at multiple time points.

Progressive diastolic dysfunction in survivors of pediatric differentiated thyroid carcinoma.

Background: Pediatric differentiated thyroid cancer (DTC) has an excellent prognosis but unknown late effects of treatment. The initial cardiac evaluation showed subclinical diastolic dysfunction in 20% of adult survivors. The objective of this follow-up study was to determine the clinical course of this finding. Methods: This multicenter study, conducted between 2018 and 2020, re-evaluated survivors after 5 years. The primary endpoint was echocardiographic diastolic cardiac function (depicted by the mean of the early diastolic septal and early diastolic lateral tissue velocity (e' mean)). Secondary endpoints were other echocardiographic parameters and plasma biomarkers. Results: Follow-up evaluation was completed in 47 (71.2%) of 66 survivors who had completed their initial evaluation. Of these 47 survivors, 87.2% were women. The median age was 39.8 years (range: 18.8-60.3), and the median follow-up after the initial diagnosis was 23.4 years (range: 10.2-48.8). Between the first and second evaluation, the e' mean significantly decreased by 2.1 cm/s (s.d. 2.3 cm/s, P < 0.001). The median left ventricular ejection fraction did not significantly change (58.0% vs 59.0%, P= NS). In the best explanatory model of e' mean, multivariate linear regression analysis showed that BMI and age were significantly associated with e' mean (ß coefficient: -0.169, 95% CI: -0.292; -0.047, P = 0.008 and ß coefficient: -0.177, 95% CI: -0.240; -0.113, P < 0.001, respectively). Conclusions and relevance: In these relatively young survivors of pediatric DTC, diastolic function decreased significantly during 5-year follow-up and is possibly more pronounced than in normal aging. This finding requires further follow-up to assess clinical consequences.

Anosmia predicts hypogonadotropic hypogonadism in CHARGE syndrome.

OBJECTIVE: To test the hypothesis that a smell test could predict the occurrence of hypogonadotropic hypogonadism (HH) in patients with CHARGE syndrome, which is a variable combination of ocular coloboma, heart defects, choanal atresia, retardation of growth/development, genital hypoplasia, and ear anomalies or hearing loss caused by mutations in the CHD7 (chromodomain helicase DNA binding protein 7) gene. STUDY DESIGN: We performed endocrine studies and smell testing (University of Pennsylvania Smell Identification Test) in 35 adolescent patients with molecularly confirmed CHARGE syndrome. RESULTS: Complete data on smell and puberty were available for 15 patients; 11 patients had both anosmia and HH, whereas 4 patients had normosmia/hyposmia and spontaneous puberty. In addition, 7 boys were highly suspected of having HH (they were too young for definite HH diagnosis, but all had cryptorchidism, micropenis, or both) and had anosmia. The type of CHD7 mutation could not predict HH because a father and daughter with the same CHD7 mutation were discordant for HH and anosmia. CONCLUSION: Anosmia and HH were highly correlated in our cohort, and therefore smell testing seems to be an attractive method for predicting the occurrence of HH in patients with CHARGE syndrome. The use of this test could prevent delay of hormonal pubertal induction, resulting in an age-appropriate puberty.

Second-tier Testing for 21-Hydroxylase Deficiency in the Netherlands: A Newborn Screening Pilot Study.

CONTEXT: Newborn screening (NBS) for classic congenital adrenal hyperplasia (CAH) consists of 17-hydroxyprogesterone (17-OHP) measurement with gestational age-adjusted cutoffs. A second heel puncture (HP) is performed in newborns with inconclusive results to reduce false positives. OBJECTIVE: We assessed the accuracy and turnaround time of the current CAH NBS algorithm in comparison with alternative algorithms by performing a second-tier 21-deoxycortisol (21-DF) pilot study. METHODS: Dried blood spots (DBS) of newborns with inconclusive and positive 17-OHP (immunoassay) first HP results were sent from regional NBS laboratories to the Amsterdam UMC Endocrine Laboratory. In 2017-2019, 21-DF concentrations were analyzed by LC-MS/MS in parallel with routine NBS. Diagnoses were confirmed by mutation analysis. RESULTS: A total of 328 DBS were analyzed; 37 newborns had confirmed classic CAH, 33 were false-positive and 258 were categorized as negative in the second HP following the current algorithm. With second-tier testing, all 37 confirmed CAH had elevated 21-DF, while all 33 false positives and 253/258 second-HP negatives had undetectable 21-DF. The elevated 21-DF of the other 5 newborns may be NBS false negatives or second-tier false positives. Adding the second-tier results to inconclusive first HPs reduced the number of false positives to 11 and prevented all 286 second HPs. Adding the second tier to both positive and inconclusive first HPs eliminated all false positives but delayed referral for 31 CAH patients (1-4 days). CONCLUSION: Application of the second-tier 21-DF measurement to inconclusive first HPs improved our CAH NBS by reducing false positives, abolishing the second HP, and thereby shortening referral time.

Bone Mineral Density in Adult Survivors of Pediatric Differentiated Thyroid Carcinoma: A Longitudinal Follow-Up Study.

Background: Survivors of pediatric differentiated thyroid carcinoma (DTC) receive thyrotropin-suppressive therapy to minimize disease recurrence. However, knowledge about long-term effects of subclinical hyperthyroidism on bone mineral density (BMD) in pediatric DTC survivors is scarce, as is the information regarding long-term consequences of permanent hypoparathyroidism on BMD. We evaluated BMD in pediatric DTC survivors and investigated if BMD was affected by subclinical hyperthyroidism and/or permanent hypoparathyroidism during long-term follow-up. Methods: In this nationwide longitudinal study, we determined BMD in the lumbar spine and femur by dual energy X-ray absorptiometry in 65 pediatric DTC survivors. Measurements were repeated after minimal 5 years of follow-up in 46 pediatric DTC survivors. BMD results were evaluated according to the recommendations of the International Society for Clinical Densitometry (ISCD) and WHO. At both visits, we determined biochemical parameters and markers of bone resorption (C-terminal telopeptide of type I collagen [ß-CTX]) and formation (N-propeptide of type I collagen [PINP] and osteocalcin). Results: First and second BMD measurements were done after a median follow-up of 17.0 (interquartile range [IQR] 8.0-25.0) and 23.5 (IQR 14.0-30.0) years after diagnosis, respectively. Median age at diagnosis was 15 years (IQR 13.0-17.0). Twenty-nine percent of the survivors had subclinical hyperthyroidism. In most survivors, BMD T- and Z-scores were within the reference range during both BMD evaluations. However, after 23.5 years of follow-up, a low BMD was found in 13.0%. In the 13 survivors with permanent hypoparathyroidism, BMD values did not differ after 5 years of follow-up compared with baseline values or in comparison with the 33 survivors without permanent hypoparathyroidism. During follow-up, turnover markers ß-CTX and PINP remained stable. Conclusions: This longitudinal study of pediatric DTC survivors demonstrated normal and stable median lumbar spine and femur BMD values after a median time of 17 and 23.5 years after diagnosis. However, compared with controls, a lower BMD was still found in 13.0% after prolonged follow-up despite intensive follow-up. Based on the studied follow-up period, these data do not provide convincing evidence in support of standard monitoring of bone mass among DTC survivors, but may be restricted to individual cases at low frequency. Trial Registration: This follow-up study was registered in The Netherlands Trial Register under no. NL3280 (www.trialregister.nl/trial/3280).

Long-Term Effects of Radioiodine Treatment on Female Fertility in Survivors of Childhood Differentiated Thyroid Carcinoma.

Background: Differentiated thyroid carcinoma (DTC) during childhood is a rare disease. Its excellent survival rate requires a focus on possible long-term adverse effects. This study aimed to evaluate fertility in female survivors of childhood DTC by assessing various reproductive characteristics combined with anti-Müllerian hormone (AMH) levels (a marker of ovarian reserve). Methods: Female survivors of childhood DTC, diagnosed at ≤18 years of age between 1970 and 2013, were included. Survivors were excluded when follow-up time was less than five years or if they developed other malignancies before or after diagnosis of DTC. Survivors filled out a questionnaire regarding reproductive characteristics (e.g., age at menarche and menopause, pregnancies, pregnancy outcomes, need for assisted reproductive therapy). Survivors aged <18 years during evaluation received an altered questionnaire without questions regarding pregnancy and pregnancy outcomes. These data were combined with information from medical records. AMH levels were measured in serum samples and were compared with AMH levels from 420 women not treated for cancer. Results: Fifty-six survivors with a median age of 31.0 (interquartile range, IQR, 25.1-39.6) years were evaluated after a median follow-up of 15.4 (IQR 8.3-24.7) years. The median cumulative dose of 131I administered was 7.4 (IQR 3.7-13.0) GBq/200.0 (IQR 100.0-350.0) mCi. Twenty-five of the 55 survivors aged 18 years or older during evaluation reported 64 pregnancies, 45 of which resulted in live birth. Of these 55, 10.9% visited a fertility clinic. None of the survivors reported premature menopause. Age at AMH evaluation did not differ between DTC survivors and the comparison group (p = 0.268). Median AMH levels did not differ between DTC survivors and the comparison group [2.0 (IQR 1.0-3.7) µg/L vs. 1.6 (IQR 0.6-3.1) µg/L, respectively, p = 0.244]. The cumulative dose of 131I was not associated with AMH levels in DTC survivors (rs = 0.210, p = 0.130). Conclusions: Female survivors of DTC who received 131I treatment during childhood do not appear to have major abnormalities in reproductive characteristics nor in predictors of ovarian failure.