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Background: Raising a child with type 1 diabetes (T1D) means combining the demands of the disease management with everyday parenting, which is associated with increased levels of distress. A Web-based patient portal, Sugarsquare, was developed to support parents, by providing online parent-professional communication, online peer support and online disease information., Objective: The first aim of this study was to assess the feasibility of conducting a multicenter, randomized controlled trial in Dutch parents of a child with T1D. The second aim was to assess the feasibility of implementing Sugarsquare in clinical practice., Methods: The parents of 105 children (N=105) with T1D below the age of 13 participated in a 6-month multicenter randomized controlled feasibility trial. They were randomly assigned to an experimental (n=54, usual care and Sugarsquare) or a control group (n=51, usual care). Attrition rates and user statistics were gathered to evaluate feasibility of the trial and implementation. To determine potential efficacy, the parenting stress index (PSI-SF) was assessed at baseline (T0) and after 6 months (T1)., Results: Of a potential population of parents of 445 children, 189 were willing to participate (enrollment refusal=57.5%, n=256), 142 filled in the baseline questionnaire (baseline attrition rate=25%, n=47), and 105 also filled in the questionnaire at T1 (post randomization attrition rate during follow-up=26%, n=32). As such, 24% of the potential population participated. Analysis in the experimental group (n=54) revealed a total of 32 (59%) unique users, divided into 12 (38%) frequent users, 9 (28%) incidental users, and 11 (34%) low-frequent users. Of the total of 44 professionals, 34 (77%) logged in, and 32 (73%) logged in repeatedly. Analysis of the user statistics in the experimental group further showed high practicability and integration in all users, moderate acceptability and demand in parents, and high acceptability and demand in health care professionals. Baseline parenting stress index scores were related to the parents' frequency of logging on (ρ=.282, P=.03) and page-views (ρ=.304, P=.01). No significant differences in change in parenting stress between experimental and control group were found (F 3,101 =.49, P=.49)., Conclusions: The trial can be considered feasible, considering the average enrollment refusal rate, baseline attrition rate and postrandomization attrition rate, compared to other eHealth studies, although lower than hypothesized. Implementing Sugarsquare in clinical practice was partly feasible, given moderate demand and acceptability in parent users and lack of potential efficacy. Parents who reported higher levels of parenting stress used Sugarsquare more often than other parents, although Sugarsquare did not reduce parenting stress. These results indicate that Web-based interventions are a suitable way of providing parents of children with T1D with additional support. Future studies should determine how Sugarsquare could reduce parenting stress, for instance by adding targeted interventions. Factors potentially contributing to successful implementation are suggested., Trial Registration: Nederlands Trial Register Number: NTR3643; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3643 (Archived by WebCite at http://www.webcitation.org/6qihOVCi6)., (©Emiel Boogerd, Nienke M Maas-Van Schaaijk, Theo C Sas, Agnes Clement-de Boers, Mischa Smallenbroek, Roos Nuboer, Cees Noordam, Chris M Verhaak. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 22.08.2017.)

Neonatal encephalitis caused by herpes simplex virus (HSV) is a familiar disease with a high mortality and morbidity rate. Isolated skin-eye-mouth infection is less familiar among professionals. In this article we present two neonates with an isolated skin lesion caused by an HSV infection. Of the neonates infected with HSV, 40-45% show isolated skin-eye-mouth disease. With correct treatment, the risk of spread to the central nervous system will decrease from 50-60% to 5-10%. Typical HSV skin lesions may present at a late stage of the disease or may be masked by a secondary bacterial infection. When a neonate presents with atypical skin lesions starting 7-12 days after the birth, immediate testing for HSV and immediate treatment are required, to decrease the risk of further progression of the disease.

Turner syndrome (TS) is the result of (partial) absence of one X-chromosome. Besides short stature, gonadal dysgenesis and other physical aspects, TS women have typical psychological features. Since psychological effects of androgen exposure in childhood probably are long-lasting, we explored long-term psychological functioning after oxandrolone (Ox) therapy during childhood in adults with TS in terms of neurocognition, quality of life and social-emotional functioning. During the initial study, girls were treated with growth hormone (GH) combined with placebo (Pl), Ox 0.03 mg/kg/day, or Ox 0.06 mg/kg/day from the age of eight, and estrogen from the age of twelve. Sixty-eight women participated in the current double-blinded follow-up study (mean age 24.0 years, mean time since stopping GH/Ox 8.7 years). We found no effects on neurocognition. Concerning quality of life women treated with Ox had higher anxiety levels (STAI 37.4 ± 8.4 vs 31.8 ± 5.0, p=0.002) and higher scores on the depression subscale of the SCL-90-R (25.7 ± 10.7 vs 20.5 ± 4.7, p=0.01). Regarding social-emotional functioning, emotion perception for fearful faces was lower in the Ox-treated patients, without effect on interpersonal behavior. Our exploratory study is the first to suggest that androgen treatment in adolescence possibly has long-term effects on adult quality of life and social-emotional functioning. However, differences are small and clinical implications of our results seem limited. Therefore we would not recommend against the use of Ox in light of psychological consequences., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To evaluate karyotype-specific ear and hearing problems in young-adult patients with Turner syndrome (TS) and assess the effects of previous treatment with oxandrolone (Ox)., Study Design: Double-blind follow-up study., Setting: University hospital., Patients: Sixty-five TS patients (mean age, 24.3 yr) previously treated with growth hormone combined with placebo, Ox 0.03 mg/kg per day, or Ox 0.06 mg/kg per day from the age of 8 years and estrogen from the age of 12 years., Intervention: Ear examination was performed according to standard clinical practice. Air- and bone conduction thresholds were measured in decibel hearing level., Main Outcome Measures: We compared patients with total monosomy of the short arm of the X chromosome (Xp), monosomy 45,X and isochromosome 46,X,i(Xq), with patients with a partial monosomy Xp, mosaicism or other structural X chromosomal anomalies. We assessed the effect of previous Ox treatment., Results: Sixty-six percent of the patients had a history of recurrent otitis media. We found hearing loss in 66% of the ears, including pure sensorineural hearing loss in 32%. Hearing thresholds in patients with a complete monosomy Xp were about 10 dB worse compared with those in patients with a partial monosomy Xp. Air- and bone conduction thresholds were not different between the placebo and Ox treatment groups., Conclusion: Young-adult TS individuals frequently have structural ear pathology, and many suffer from hearing loss. This indicates that careful follow-up to detect ear and hearing problems is necessary, especially for those with a monosomy 45,X or isochromosome 46,X,i(Xq). Ox does not seem to have an effect on hearing.

The ZAC1 gene, mapped to the 6q24 region, is part of a network of co-regulated imprinted genes involved in the control of embryonic growth. Loss of methylation at the ZAC1 differentially methylated region (DMR) is associated with transient neonatal diabetes mellitus, a developmental disorder involving growth retardation and diabetes in the first weeks of post-natal life. We assessed whether the degree of methylation of the ZAC1 DMR in leukocytes DNA extracted from cord blood is associated with fetal, birth and post-natal anthropometric measures or with C-peptide concentrations in cord serum. We also searched for an influence of dietary intake and maternal parameters on ZAC1 DMR methylation. We found positive correlations between the ZAC1 DMR methylation index (MI) and estimated fetal weight (EFW) at 32 weeks of gestation, weight at birth and weight at one year of age (respectively, r = 0.15, 0.09, 0.14; P values = 0.01, 0.15, 0.03). However, there were no significant correlations between the ZAC1 DMR MI and cord blood C-peptide levels. Maternal intakes of alcohol and of vitamins B2 were positively correlated with ZAC1 DMR methylation (respectively, r = 0.2 and 0.14; P = 0.004 and 0.04). The influence of ZAC1 seems to start in the second half of pregnancy and continue at least until the first year of life. The maternal environment also appears to contribute to the regulation of DNA methylation.

Background/aims: Growth Hormone (GH) dosage in childhood is adjusted for body size, but there is no consensus whether body weight (BW) or body surface area (BSA) should be used. We aimed at comparing the biological effect and cost-effectiveness of GH treatment dosed per m2 BSA in comparison with dosing per kg BW in girls with Turner syndrome (TS)., Methods: Serum IGF-I, GH dose, and adult height gain (AHG) from girls participating in two Dutch and five Swedish studies on the efficacy of GH were analyzed, and the cumulative GH dose and costs were calculated for both dose adjustment methods. Additional medication included estrogens (if no spontaneous puberty occurred) and oxandrolone in some studies., Results: At each GH dose, the serum IGF-I standard deviation score remained stable over time after an initial increase after the start of treatment. On a high dose (at 1 m2 equivalent to 0.056-0.067 mg/kg/day), AHG was at least equal on GH dosed per m2 BSA compared with dosing per kg BW. The cumulative dose and cost were significantly lower if the GH dose was adjusted for m2 BSA., Conclusion: Dosing GH per m2 BSA is at least as efficacious as dosing per kg BW, and is more cost-effective., (© 2014 S. Karger AG, Basel.)

There has been no consensus regarding the efficacy and safety of oxandrolone (Ox) in addition to growth hormone (GH) in girls with Turner syndrome (TS), the optimal age of starting this treatment, or the optimal dose. This collaborative venture between Dutch, UK and US centers is intended to give a summary of the data from three recently published randomized, placebo-controlled, double-blind studies on the effects of Ox. The published papers from these studies were reviewed within the group of authors to reach consensus about the recommendations. The addition of Ox to GH treatment leads to an increase in adult height, on average 2.3–4.6 cm. If Ox dosages<0.06 mg/kg/day are used, side effects are modest. The most relevant safety concerns are virilization(including clitoromegaly and voice deepening) and a transient delay of breast development. We advise monitoring signs of virilization breast development and possibly blood lipids during Ox treatment, in addition to regular follow-up assessments for TS. In girls with TS who are severely short for age, in whom very short adult stature is anticipated,or in whom the growth rate is modest despite good compliance with GH, adjunctive treatment with Ox at a dosage of 0.03–0.05 mg/kg/day starting from the age of 8–10 years onward scan be considered., (© 2014 S. Karger AG, Basel.)

Objective: Short stature is a prominent feature of Turner syndrome (TS), which is partially overcome by GH treatment. We have previously reported the results of a trial on the effect of oxandrolone (Ox) in girls with TS. Ox in a dose of 0.03 mg/kg per day (Ox 0.03) significantly increased adult height gain, whereas Ox mg/kg per day (0.06) did not, at the cost of deceleration of breast development and mild virilization. The aim of this follow-up study in adult participants of the pediatric trial was to investigate the long-term effects of previous Ox treatment., Design and Methods: During the previous randomized controlled trial, 133 girls were treated with GH combined with placebo (Pl), Ox 0.03, or Ox 0.06 from 8 years of age and estrogen from 12 years. Sixty-eight women (Pl, n=23; Ox 0.03, n=27; and Ox 0.06, n=18) participated in the double-blind follow-up study (mean age, 24.0 years; mean time since stopping GH, 8.7 years; and mean time of Ox/Pl use, 4.9 years). We assessed height, body proportions, breast size, virilization, and body composition., Results: Height gain (final minus predicted adult height) was maintained at follow-up (Ox 0.03 10.2±4.9 cm, Ox 0.06 9.7±4.4 cm vs Pl 8.0±4.6 cm). Breast size, Tanner breast stage, and body composition were not different between groups. Ox-treated women reported more subjective virilization and had a lower voice frequency., Conclusion: Ox 0.03 mg/kg per day has a beneficial effect on adult height gain in TS patients. Despite previously reported deceleration of breast development during Ox 0.03 treatment, adult breast size is not affected. Mild virilization persists in only a small minority of patients. The long-term evaluation indicates that Ox 0.03 treatment is effective and safe.

The treatment of children with type 1 diabetes mellitus has improved dramatically over the last few decades. The maintenance of acceptable metabolic control, nevertheless, remains challenging because the success of treatment is so dependent on patient compliance. Children with type 1 diabetes and poor metabolic control are at risk of developing Mauriac syndrome, a condition characterised by hepatomegaly, growth retardation and cushingoid features. A similar complication may occur in type-1 or type-2 adult diabetics; namely, glycogenic hepatopathy. We describe two children, a 12-year-old girl and a 16-year-old boy, who presented with classic symptoms of Mauriac syndrome. After metabolic control was achieved, reduction of hepatomegaly and the disappearance of cushingoid features were observed, proving the reversibility of the syndrome. Awareness that this syndrome still exists despite improved insulin therapy is crucial for earlier recognition and treatment.

Objectives/hypothesis: Oxandrolone (Ox) increases height gain but may also cause voice deepening in growth hormone (GH)-treated girls with Turner syndrome (TS). We assessed the effect of Ox on objective and subjective speaking voice frequency in GH-treated girls with TS., Study Design: A multicenter, randomized, placebo (Pl)-controlled, double-blind study was conducted., Methods: One hundred thirty-three patients were included and treated with GH (1.33 mg/m2/d) from baseline, combined with Pl or Ox in a low (0.03 mg/kg/d) or conventional (0.06 mg/kg/d) dose from the age of 8 years and estrogens from the age of 12 years. Yearly from starting Ox/Pl until 6 months after discontinuing GH+Ox/Pl, voices were recorded and questionnaires were completed., Results: At start, mean (±standard deviation [SD]) voice frequency SD score (SDS) was high for age (1.0±1.2, P<0.001) but normal for height. Compared with GH+Pl, voices tended to lower on GH+Ox 0.03 (P=0.09) and significantly lowered on GH+Ox 0.06 (P=0.007). At the last measurement, voice frequency SDS was still relatively high in GH+Pl group (0.6±0.7, P=0.002) but similar to healthy girls in both GH+Ox groups. Voice frequency became lower than -2 SDS in one patient (3%) on GH+Ox 0.03 and three patients (11%) on GH+Ox 0.06. The percentage of patients reporting subjective voice deepening was similar between the dosage groups., Conclusions: Untreated girls with TS have relatively high-pitched voices. The addition of Ox to GH decreases voice frequency in a dose-dependent way. Although most voice frequencies remain within the normal range, they may occasionally become lower than -2 SDS, especially on GH+Ox 0.06 mg/kg/d., (Copyright © 2011 The Voice Foundation. Published by Mosby, Inc. All rights reserved.)

Background: The weak androgen oxandrolone (Ox) may increase height but may also affect glucose metabolism in girls with Turner syndrome (TS)., Methods: In a randomized, placebo-controlled, double-blind study, we assessed the effect of Ox at a dosage of either 0.06 or 0.03 mg/kg/day on glucose metabolism in 133 growth hormone (GH)-treated girls with TS. Patients were treated with GH (1.33 mg/m(2)/day) from baseline, combined with placebo (Pl) or Ox from the age of 8, and estrogens from the age of 12. Oral glucose tolerance tests (OGTT) were performed, and HbA1c levels were measured before, during, and after discontinuing Ox/Pl therapy., Results: Insulin sensitivity, assessed by the whole-body insulin sensitivity index (WBISI) decreased during GH+Ox/Pl (p = 0.003) without significant differences between the dosage groups. Values returned to pre-treatment levels after discontinuing GH+Ox/Pl. On GH+Ox, fasting glucose was less frequently impaired (Ox 0.03, p = 0.001; Ox 0.06, p = 0.02) and HbA1c levels decreased more (p = 0.03 and p = 0.001, respectively) than on GH+Pl., Conclusions: We conclude that in GH-treated girls with TS, Ox at a dosage of 0.03 or 0.06 mg/kg/day does not significantly affect insulin sensitivity. Insulin sensitivity decreases during GH therapy, to return to a pre-treatment level after discontinuing therapy., (Copyright © 2010 S. Karger AG, Basel.)

Introduction: McArdle disease is a hereditary myopathy caused by muscle phosphorylase deficiency. Patients experience painful muscle cramps after strenuous exercise; the condition is sometimes associated with rhabdomyolysis, myoglobinuria and resulting acute renal failure., Case Description: A 12-year-old boy visited the Paediatric and Neurology outpatients' departments with symptoms of leg myalgia, occurring during the warming-up phase of soccer practice, which disappeared after a short rest. Detailed history-taking revealed that he already experienced pain while walking during early childhood. An elevated serum creatine kinase concentration in combination with the typical presentation led to the presumptive diagnosis 'McArdle disease', which was confirmed by molecular genetic analysis., Conclusion: There is no effective gene therapy; a multidisciplinary approach by a neurologist, paediatrician, physiotherapist and nutritionist is advised.

Objective: Untreated girls with Turner syndrome (TS) have short stature, relatively broad shoulders, a broad pelvis, short legs, a high fat mass and low muscle mass. Our objective was to assess the effect of the weak androgen oxandrolone (Ox) on body proportions and composition in growth hormone (GH)-treated girls with TS., Design/patients: 133 patients were included in a randomized, placebo-controlled, double-blind study., Methods: Patients were treated with GH (1.33 mg/m(2) per day) from baseline, combined with placebo (Pl) or Ox in a low (0.03 mg/kg per day) or previously conventional (0.06 mg/kg per day) dose from the age of eight, and oestrogens from the age of twelve. Sitting height, biacromial and biiliacal distances compared with height (i.e. shape values), BMI, waist circumference, sum of 4 skinfolds (sum4skin) and upper arm muscle area (UAMA) SD scores (SDS) were assessed half-yearly., Results: Compared with GH + Pl, adult shape values on GH + Ox tended to be higher for sitting height (Ox 0.03, P = 0.2; Ox 0.06, P = 0.02) and biacromial distance (Ox 0.03, P = 0.2; Ox 0.06, P = 0.07) and lower for biiliacal distance (Ox 0.03, P = 0.004; Ox 0.06, P = 0.08). Sum4skin SDS tended to decrease more (Ox 0.03, P = 0.2; Ox 0.06, P = 0.005) while UAMA SDS increased more (Ox 0.03, P < 0.001; Ox 0.06, P < 0.001) than on GH + Pl. The increase in BMI and waist circumference SDS was comparable between the dosage groups., Conclusions: In GH-treated girls with TS, Ox 0.06 increases sitting height and tends to increase biacromial distance and decrease biiliacal distance, while Ox 0.03 significantly decreases biiliacal distance compared with height. Furthermore, Ox 0.06 reduces subcutaneous fat mass, and both Ox dosages increase muscle mass.

The weak androgen oxandrolone (Ox) increases height gain in growth-hormone (GH) treated girls with Turner syndrome (TS), but may also give rise to virilizing side effects. To assess the effect of Ox, at a conventional and low dosage, on behavior, aggression, romantic and sexual interest, mood, and gender role in GH-treated girls with TS, a randomized, placebo-controlled, double-blind study was conducted. 133 patients were treated with GH (1.33 mg/m(2)/d) from baseline, combined with placebo (Pl), Ox 0.03 mg/kg/d, or Ox 0.06 mg/kg/d from the age of eight, and with estrogens from the age of 12. The child behavior checklist (CBCL), Junior Dutch Personality Questionnaire (DPQ-J), State-subscale of the Spielberger's State-Trait Anger Scale, Romantic and Sexual Interest Questionnaire, Mood Questionnaire, and Gender Role Questionnaire were filled out before, during, and after discontinuing Ox/Pl. The changes during Ox/Pl therapy were not significantly different between the dosage groups. In untreated patients, the mean CBCL total (P=0.002) and internalizing (P=0.003) T scores, as well as the mean DPQ-J social inadequacy SD score (SDS) (P=0.004) were higher than in reference girls, but decreased during GH+Ox/Pl therapy (P<0.001, P=0.05, P<0.001, respectively). Whereas the mean total (P=0.01) and internalizing (P<0.001) T score remained relatively high, the mean social inadequacy SDS became comparable with reference values. We conclude that in GH-treated girls with TS, Ox 0.03 mg/kg/d or 0.06 mg/kg/d does not cause evident psychological virilizing side effects. Problem behavior, frequently present in untreated girls with TS, decreases during therapy, but total and internalizing problem behavior remain increased., (Copyright 2009 Elsevier Inc. All rights reserved.)

Context and Objective: GH therapy increases growth and adult height in Turner syndrome (TS). The benefit to risk ratio of adding the weak androgen oxandrolone (Ox) to GH is unclear., Design and Participants: A randomized, placebo-controlled, double-blind, dose-response study was performed in 10 centers in The Netherlands. One hundred thirty-three patients with TS were included in age group 1 (2-7.99 yr), 2 (8-11.99 yr), or 3 (12-15.99 yr). Patients were treated with GH (1.33 mg/m(2) . d) from baseline, combined with placebo (Pl) or Ox in low (0.03 mg/kg . d) or conventional (0.06 mg/kg . d) dose from the age of 8 yr and estrogens from the age of 12 yr. Adult height gain (adult height minus predicted adult height) and safety parameters were systematically assessed., Results: Compared with GH+Pl, GH+Ox 0.03 increased adult height gain in the intention-to-treat analysis (mean +/- sd, 9.5 +/- 4.7 vs. 7.2 +/- 4.0 cm, P = 0.02) and per-protocol analysis (9.8 +/- 4.9 vs. 6.8 +/- 4.4 cm, P = 0.02). Partly due to accelerated bone maturation (P < 0.001), adult height gain on GH+Ox 0.06 was not significantly different from that on GH+Pl (8.3 +/- 4.7 vs. 7.2 +/- 4.0 cm, P = 0.3). Breast development was slower on GH+Ox (GH+Ox 0.03, P = 0.02; GH+Ox 0.06, P = 0.05), and more girls reported virilization on GH+Ox 0.06 than on GH+Pl (P < 0.001)., Conclusions: In GH-treated girls with TS, we discourage the use of the conventional Ox dosage (0.06 mg/kg . d) because of its low benefit to risk ratio. The addition of Ox 0.03 mg/kg . d modestly increases adult height gain and has a fairly good safety profile, except for some deceleration of breast development.

Aim: To investigate the effect of 2 growth hormone (GH) doses on adult height (AH) in GH deficiency (GHD)., Methods: A multicenter, randomized, controlled dose-response trial compared attained AH minus target height (TH) between children receiving 0.7 mg/m(2)/day biosynthetic GH (approx. 0.025 mg/kg/day) or 1.4 mg/m(2)/day (approx. 0.050 mg/kg/day). The patients enrolled in the trial were 20 'naïve' GHD children (had not received GH before) and 15 'transfer' GHD children (already on GH for at least 1 year)., Results: In the naïve group, the mean +/- SD AH minus TH was -5.3 +/- 6.1 and -2.2 +/- 6.9 cm in patients on 0.7 and 1.4 mg/m(2)/day, respectively (mean +/- SE difference 3.1 +/- 2.9; p = 0.3). In the transfer group, the mean +/- SD AH minus TH was -4.4 +/- 6.4 and +0.6 +/- 7.0 cm in patients on 0.7 and 1.4 mg/m(2)/day, respectively (mean +/- SE difference 5.0 +/- 3.5; p = 0.17). Spontaneous puberty started 1.1 years earlier in children on 1.4 compared to 0.7 mg/m(2)/day. Induction of puberty was more often delayed in transfer children on 0.7 than on 1.4 mg/m(2)/day., Conclusion: In our GHD patients, AH was 4-5 cm less than TH in patients on 0.7 mg/m(2)/day GH, while it was 0-2 cm less in patients on 1.4 mg/m(2)/day GH, but this difference did not reach statistical significance, probably due to limited numbers of patients, considerable variability in the growth response and earlier spontaneous puberty and pubertal induction in the children on 1.4 mg/m(2)/day., (2010 S. Karger AG, Basel.)

An 8-year-old girl presented with cramp and tingling of the hands due to hypocalcaemia caused by pseudohypoparathyroidism.

Several studies have demonstrated an association between low birth weight and impaired insulin sensitivity or even type 2 diabetes mellitus (DM2) in later life. Growth hormone (GH) is known to increase fasting and postprandial insulin levels. For that reason concern has been expressed regarding possible detrimental effects of GH therapy in children born SGA. In a Dutch trial the possible side effects of GH therapy on carbohydrate metabolism were assessed in short children born SGA after 6 years and at 6 months after discontinuation of GH therapy. This study included 79 prepubertal short children born SGA, participating in a multicenter double-blind, randomized, dose-response GH trial. Inclusion criteria were: 1) birth length SDS below -1.88, 2) age 3-11 years in boys and 3-9 years in girls, 3) height SDS < -1.88, 4) no spontaneous catch-up growth, and 5) an uncomplicated neonatal period. Mean (SD) value for age was 7.3 (2.1) years, birth length SDS -3.6, height SDS -3.0 (0.7) and BMI SDS -1.2 (1.3). All children were randomly assigned to either group A (n = 41) using 1 mg GH/m2/day or group B (n = 38) using 2 mg/m2/ d/ay (approximately 0.1 or 0.2 IU/kg/d, respectively). Standard oral glucose tolerance tests (OGTTs) were performed before and during 6 years of GH therapy and 6 months after discontinuation of GH therapy. Before GH therapy 8% of the children had impaired glucose tolerance (IGT) according to criteria of the WHO. After 6 years of GH therapy, IGT was found in 4% and after stopping GH in 10%. Mean fasting glucose increased significantly with 0.5 mMol/l after 1 year of GH therapy, without a further increase thereafter. GH therapy induced considerably higher fasting and glucose-stimulated insulin levels. None of the observed changes were different between the GH dosage groups. Children who remained prepubertal had similar glucose and insulin levels compared to children who entered puberty. HbA1c levels were always in the normal range and none of the children developed diabetes mellitus. After discontinuation of GH therapy the mean serum glucose levels remained normal and the mean serum insulin levels decreased significantly, to normal age reference values. Before the start of GH the mean systolic blood pressure was significantly higher compared to age-matched peers, whereas during GH therapy a significant decline in mean systolic blood pressure occurred, which remained similar after discontinuation of GH treatment. In conclusion, continuous, long-term GH therapy in short children born SGA has no adverse effects on glucose levels, even with GH dosages up to 2 mg/m2/day. However, as has been reported in other patient groups, GH induced higher fasting and glucose-stimulated insulin levels, indicating insulin resistance. After discontinuation of GH, serum insulin levels declined to normal age-matched reference levels. Since impaired insulin sensitivity and DM2 have been demonstrated in relatively young patients born SGA, long-term follow-up of children born SGA is advised, also after discontinuation of GH therapy.

Although GH treatment for short stature in Turner syndrome is an accepted treatment in many countries, which GH dosage to use and which age to start puberty induction are issues of debate. This study shows final height (FH) in 60 girls with Turner syndrome treated in a randomized dose-response trial, combining GH treatment with low dose estrogens at a relatively young age. Girls were randomly assigned to group A (4 IU/m(2).d; approximately 0.045 mg/kg/d), group B (first year, 4 IU/m(2).d; thereafter 6 IU/m(2).d), or group C (first year, 4 IU/m(2).d; second year, 6 IU/m(2).d; thereafter, 8 IU/m(2).d). After a minimum of 4 yr of GH treatment, at a mean age of 12.7 +/- 0.7 yr, low dose micronized 17beta-estradiol was given orally. After a mean duration of GH treatment of 8.6 +/- 1.9 yr, FH was reached at a mean age of 15.8 +/- 0.9 yr. FH, expressed in centimeters or SD score, was 157.6 +/- 6.5 or -1.6 +/- 1.0 in group A, 162.9 +/- 6.1 or -0.7 +/- 1.0 in group B, and 163.6 +/- 6.0 or -0.6 +/- 1.0 in group C. The difference in FH in centimeters, corrected for height SD score and age at start of treatment, was significant between groups A and B [regression coefficient, 4.1; 95% confidence interval (CI), 1.4, 6.9; P < 0.01], and groups A and C (coefficient, 5.0; 95% CI, 2.3, 7.7; P < 0.001), but not between groups B and C (coefficient, 0.9; 95% CI, -1.8, 3.6). Fifty of the 60 girls (83%) had reached a normal FH (FH SD score, more than -2). After starting estrogen treatment, the decrease in height velocity (HV) changed significantly to a stable HV, without affecting bone maturation (change in bone age/change in chronological age). The following variables contributed significantly to predicting FH SD score: GH dose, height SD score (ref. normal girls), chronological age at start of treatment, and HV in the first year of GH treatment. GH treatment was well tolerated. In conclusion, GH treatment leads to a normalization of FH in most girls, even when puberty is induced at a normal pubertal age. The optimal GH dosage depends on height and age at the start of treatment and first year HV.

GH treatment increases insulin levels in girls with Turner syndrome (TS), who are already predisposed to develop diabetes mellitus and other risk factors for developing cardiovascular disease. Therefore, in the present study, we investigated carbohydrate metabolism and several other risk factors that may predict development of cardiovascular disease in girls with TS after discontinuation of long-term GH treatment. Fifty-six girls, participating in a randomized dose-response study, were examined before, during, and 6 months after discontinuing long-term GH treatment with doses of 4 IU/m(2).d ( approximately 0.045 mg/kg.d), 6 IU/m(2).d, or 8 IU/m(2).d. After a minimum of 4 yr of GH treatment, low-dose micronized 17beta-estradiol was given orally. Mean (SD) age at 6 months after discontinuation of GH treatment was 15.8 (0.9) yr. Mean duration of GH treatment was 8.8 (1.7) yr. Six months after discontinuation of GH treatment, fasting glucose levels decreased and returned to pretreatment levels. The area under the curve for glucose decreased to levels even lower than pretreatment level (P < 0.001). Fasting insulin levels and the area under the curve for insulin decreased to levels just above pretreatment level (P < 0.001 for both), although being not significantly different from the control group. No dose-dependent differences among GH dosage groups were found. At 6 months after discontinuation, impaired glucose tolerance was present in 1 of 53 girls (2%), and none of the girls developed diabetes mellitus type 1 or 2. Compared with pretreatment, the body mass index SD-score had increased (P < 0.001), and the systolic and diastolic blood pressure SD-score had decreased significantly at 6 months after discontinuation of GH treatment (P < 0.001 for both) although remaining above zero (P < 0.001, P < 0.05, and P < 0.005, respectively). Compared with pretreatment, total cholesterol (TC) did not change after discontinuation of GH treatment, whereas the atherogenic index [AI = TC/high-density lipoprotein cholesterol (TC/HDL-c)] and low-density lipoprotein cholesterol (LDL-c) had decreased; and both HDL-c and triglyceride levels increased (P < 0.001 for AI, LDL-c, and HDL-c; P < 0.05 for triglyceride). Compared with the control group, AI, serum TC, and LDL-c levels were significantly lower (P < 0.001 for all), whereas HDL-c levels were significantly higher (P < 0.05). In conclusion, after discontinuation of long-term GH treatment in girls with TS, the GH-induced insulin resistance disappeared, blood pressure decreased but remained higher than in the normal population, and lipid levels and the AI changed to more cardio-protective values.

To assess bone mineral density (BMD) in girls with Turner's syndrome before and during long-term treatment with GH, longitudinal measurements using phalangeal radiographic absorptiometry were performed in 68 girls with Turner's syndrome. These previously untreated girls, age 2-11 y, participating in a randomized, dose-response trial, were randomly assigned to one of three GH dosage groups: group A, 4 IU/m(2)/d ( approximately 0.045 mg/kg/d); group B, first year 4 IU/m(2)/d, thereafter 6 IU/m(2)/d ( approximately 0.0675 mg/kg/d); or group C, first year 4 IU/m(2)/d, second year 6 IU/m(2)/d, thereafter 8 IU/m(2)/d ( approximately 0.090 mg/kg/d). In the first 4 y of GH treatment, no estrogens for pubertal induction were prescribed to the girls. Thereafter, girls started with 17beta-estradiol (5 microg/kg body weight/d, orally) when they had reached the age of 12 y. BMD results were adjusted for bone age and sex, and expressed as SD scores using reference values of healthy Dutch girls. At baseline, almost every individual BMD value of bone consisting predominantly of cortical bone, as well as that of bone consisting predominantly of trabecular bone, was within the normal range of healthy girls and the SD scores were not significantly different from zero [mean (SE) 0.38 (0.22) and -0.04 (0.13)]. During 7 y of GH treatment, BMD SD scores showed a significant increase to values significantly higher than zero [mean (SE) 0.87 (0.15) and 0.95 (0.14)]. The increment in BMD SD score of bone consisting predominantly of cortical bone was significantly higher in group C compared with that of the other two GH dosage groups. The pretreatment bone age was significantly negatively related to the increment in BMD SD score. We found no significant influence of spontaneous puberty or the use of low-dose estrogens in the last 3 y of the study period on the increment in BMD SD score during 7 y of GH treatment. In conclusion, most untreated young girls with Turner's syndrome have a normal volumetric BMD. During 7 y of GH treatment with 4, 6, or 8 IU/m(2)/d, the BMD SD score increased significantly.

In childhood the symptoms with the greatest impact on girls with Turner's syndrome are: (1) congenital cardiac abnormalities (which can be corrected by surgical intervention); (2) short stature (mean adult height between 142 and 147 cm); and (3) ovarian failure (absent spontaneous puberty). Recent studies have shown that growth hormone (GH) treatment in young girls (8 years of age or younger) with Turner's syndrome results in normalization of adult height in most of the girls when using the 'standard' GH dose of about 4 IU/m(2) per day ( approximately 0.045 mg/kg per day). Higher GH doses (6 or 8 IU/m(2) per day) or the use of oxandrolone may be more effective, but their efficacy on adult height and safety in the very long term still have to be proven. If GH treatment is started early, low-dose oestrogens for induction of puberty can be given at 12 years of age without interfering with the capability of the GH treatment to normalize adult height. GH does not seem to have negative side effects on body proportions, cardiac dimensions, blood pressure, carbohydrate metabolism or bone mineral density., (Copyright 2001 S. Karger AG, Basel)

Prenatal exposure to polychlorinated biphenyls (PCBs) and dioxins is associated with changes in the T-cell lymphocyte population in healthy Dutch infants. We investigated whether these changes persist into later childhood and whether background exposure to PCBs and dioxins is associated with the prevalence of infectious or allergic diseases and humoral immunity at preschool age. The total study group consisted of 207 healthy mother-infant pairs. We estimated prenatal exposure to PCBs and dioxins by the sum of PCBs 118, 138, 153, and 180 (sigmaPCB) in maternal and cord plasma and in breast-fed infants by the dioxin, planar, and mono-ortho PCB toxic equivalent (TEQ) levels in human milk. At 42 months of age, current body burden was estimated by the PCB in plasma. We assessed the prevalence of infectious and allergic diseases by parent questionnaire, and measured humoral immunity by antibody levels for mumps, measles, and rubella after primary vaccination. We performed immunologic marker analyses of lymphocytes in a subgroup of 85 children. Prenatal PCB exposure was associated with an increased number of lymphocytes, T-cells, and CD3CD8(+) (cytotoxic), CD4(+)CD45RO(+) (memory), T-cell receptor (TcR) [alpha]ss(+), and CD3(+)HLA-DR(+) (activated) T cells and lower antibody levels to mumps and measles at preschool age. Adjusted for confounders, prenatal PCB exposure was associated with less shortness of breath with wheeze, and current PCB body burden was associated with a higher prevalence of recurrent middle-ear infections and of chicken pox and a lower prevalence of allergic reactions. A higher dioxin TEQ was associated with a higher prevalence of coughing, chest congestion, and phlegm. We conclude that in Dutch preschool children the effects of perinatal background exposure to PCBs and dioxins persist into childhood and might be associated with a greater susceptibility to infectious diseases. Common infections acquired early in life may prevent the development of allergy, so PCB exposure might be associated with a lower prevalence of allergic diseases.

The aim of this study was to assess body proportions in children with short stature born small for gestational age (SGA) before and during 6 years of growth hormone (GH) treatment. A prospective randomised double-blind dose-response study comparing the effects of 3 vs. 6 IU GH/m2/day. Seventy-nine children with short stature (height SD-score < -1.88) born small for gestational age (birth length SD-score < -1.88). Before and during GH treatment, height, sitting height (SH), hand (Hand) and foot length (Foot), biacromial (Biac) and biiliacal diameter (Biil) were measured. All results were adjusted for age and sex, and expressed as SD-scores (SDS) using reference values for healthy Dutch children. To describe the size of SH, Hand, Foot, Biac, and Biil in relation to height, these values were adjusted for the SDS of height. At baseline, these short children had small hands and feet and narrow shoulders and pelvis compared to healthy peers. Height and SH, were, however, even more affected. Consequently, on average, these children had relatively large hands and feet, and relatively broad shoulders and pelvis compared to their height, but a normal sitting height in proportion to height. In most of the individuals, the values for body proportions were, however, within the normal range. During 6 years of GH treatment the SD-scores of all measurements increased significantly towards values more close to zero. The mean size of Hand, Foot, and Biil decreased in proportion to height. The mean SH increased relatively more than height, however, to values well within the normal range. The mean Biac in relation to height had not changed after 6 years of GH treatment. No differences in the 6-year changes in body proportions were found between the two GH dosage groups. Untreated short children born small for gestational age have, on average, relatively large hands and feet, and broad shoulders and pelvis, but a normal sitting height compared to height. The increase in height during 6 years of GH treatment is accompanied by an improvement of the proportions of the size of hands, feet, and biiliacal diameter, in relation to height. The increase in height appeared to be the result of the increase in sitting height as well as leg length, but the sitting height SD-score increased slightly more than that of leg length. The changes in body proportion during GH treatment were dose-independent. Thus, 6-year continuous GH treatment with either 3 or 6 IU/m2/day in children with short stature born small for gestational age does not negatively influence body proportions.

To assess possible side-effects of GH treatment with supraphysiological doses on carbohydrate (CH) metabolism in girls with Turner syndrome (TS) during long term GH treatment and after discontinuation of GH treatment, the results of oral glucose tolerance tests and hemoglobin A1c measurements were analyzed in 68 girls with TS participating in a randomized dose-response trial. These previously untreated girls, aged 2-11 yr, were randomly assigned to 1 of 3 GH dosage groups: group A, 4 IU/m2 x day (-0.045 mg/kg x day); group B, first year ,4 IU/m2 day; thereafter, 6 IU/m2 x day (approximately 0.0675 mg/kg x day); group C, first year, 4 IU/m2 x day; second year, 6 IU/m2 x day; thereafter, 8 IU/m2 x day (approximately 0.090 mg/kg x day). After the first 4 yr, girls 12 yr of age or older started with 5 microg/kg BW-day 17beta-estradiol for induction of puberty. To assess the effects of long term high dose GH treatment on CH metabolism, the 7-yr data from the oral glucose tolerance tests in 9 girls of group C were evaluated (group C1). To determine whether the changes in CH metabolism during GH treatment would persist after discontinuation of GH treatment, the data for 28 girls who had reached adult height (group A, n = 9; group B, n = 10; group C, n = 9) were evaluated at baseline, after 4 yr of GH treatment, and 6 months after discontinuation of GH. Seven-year data for group C1 showed that glucose levels did not significantly change during GH treatment, whereas fasting insulin levels as well as glucose-induced insulin levels increased significantly. The data for the 28 girls who were treated with GH for a mean (SD) period of 85.3 (13.3) months demonstrated that the GH-induced higher insulin levels decreased to values close to or equal to pretreatment values after discontinuation of GH treatment. Changes in CH variables were not significantly related to the GH dose. Hemoglobin A1c levels never showed an abnormal value. The prevalence of impaired glucose tolerance was low, and none of the girls developed diabetes mellitus. In conclusion, long term GH treatment with dosages up to 8 IU/m2 x day in girls with TS has no adverse effects on glucose levels, but induced higher levels of insulin, indicating relative insulin resistance. The increased insulin levels during long term GH treatment decreased after discontinuation of GH treatment to values close to or equal to pretreatment values. Although the reversibility of the effects of long term GH is reassuring, the consequence of long term hyperinsulinism is still unknown.

Short stature and ovarian failure are the main features in Turner syndrome (TS). To optimize GH and estrogen treatment, we studied 68 previously untreated girls with TS, age 2-11 yr, who were randomly assigned to one of three GH dosage groups: group A, 4 IU/m2 day (approximately 0.045 mg/kg x day); group B, first yr 4, thereafter 6 IU/m2 x day (approximately 0.0675 mg/kg/day); group C, first yr 4, second yr 6, thereafter 8 IU/m2 x day (approximately 0.090 mg/kg x day). In the first 4 yr of GH treatment, no estrogens for pubertal induction were given to the girls. Thereafter, girls started with 17beta-estradiol (5 microg/kg bw x day, orally) when they had reached the age of 12 yr. Subjects were followed up until attainment of adult height or until cessation of treatment because of satisfaction with the height achieved. Seven-year data of all girls were evaluated to compare the growth-promoting effects of three GH dosages during childhood. After 7 yr, 85% of the girls had reached a height within the normal range for healthy Dutch girls. The 7-yr increment in height SD-score was significantly higher in groups B and C than in group A. In addition, we evaluated the data of 32 of the 68 girls who had completed the trial after a mean duration of treatment of 7.3 yr (range, 5.0 - 8.75). Mean (SD) height was 158.8 cm (7.1), 161.0 cm (6.8), and 162.3 cm (6.1) in groups A, B, and C, respectively. The mean (SD) difference between predicted adult height before treatment and achieved height was 12.5 cm (2.1), 14.5 cm (4.0), and 16.0 cm (4.1) for groups A, B, and C, respectively, being significantly different between group A and group C. GH treatment was well tolerated in all three GH dosage groups. In conclusion, GH treatment starting in relatively young girls with TS results in normalization of height during childhood, as well as of adult height, in most of the individuals. With this GH and estrogen treatment regimen, most girls with TS can grow and develop much more in conformity with their healthy peers.

To assess body proportions in girls with Turner syndrome (TS) during long term GH treatment, height, sitting height (SH), hand (Hand) and foot (Foot) lengths, and biacromial (Biac) and biiliacal (Biil) diameters were measured in 68 girls with TS participating in a GH dose-response trial. These previously untreated girls with TS, aged 2-11 yr, were randomly assigned to 1 of 3 GH dosage groups: group A, 4 IU/m2 x day; group B, first year 4 and thereafter 6 IU/m2 x day; group C, first year 4, second year 6, and thereafter 8 IU/m2 x day. Seven-year data were evaluated to assess the effect of GH treatment on body proportions during childhood. In addition, data from all girls who had reached adult height were evaluated to determine the effect on the adult body proportions. All results were adjusted for age and sex and expressed as SD scores using reference values of healthy Dutch girls. To describe the proportions of SH, Hand, Foot, Biac, and Biil to height, these values were adjusted for the SD score of height and were expressed as shape values, using the formula, e.g. for SH: shape SH = (SH SD score - height SD score)/square root(2 - 2 x correlation coefficient between SH and height in the reference population). Furthermore, SD scores using references of untreated girls with TS were calculated for height and SH. Values less than -2 or more than +2 were considered outside the normal range. At baseline, the shape values of all measurements were significantly higher than zero, but most mean shape values were still within the normal range. Seven-year data of 64 girls and adult height data of 32 girls showed that an increase in height was accompanied by an even higher increase in Foot, resulting in mean SD scores above zero and shape values of +2 and higher. The increase in the shape value of Foot was significantly higher in groups B and C compared to that in group A after 7 yr of GH treatment, but there were no significant differences between the GH dosage groups in the girls who had reached adult height. The shape values of SH had decreased to values closer to zero after reaching adult height, especially in group A. A similar pattern in the relationship of SH to height was seen using references of girls with TS. No significant changes in the other proportions were found after reaching adult height. In conclusion, on the average, untreated girls with TS have relatively large trunk, hands, and feet, and broad shoulders and pelvis compared to height. The increase in height after long term GH treatment is accompanied by an even higher increase in Foot and a moderate improvement of the disproportion between height and SH. Recently published reference data from untreated adults with TS and the results of a different patient group receiving a comparable GH dosage suggest that the disproportionate growth of feet has to be considered a part of the natural development in TS, but might be influenced by higher GH dosages. The development of large feet can play a role in the decision of the girl to discontinue GH treatment in the last phase of growth.

Objective: To assess the effects of long-term growth hormone (GH) treatment for short stature on left ventricular (LV) dimensions and systemic blood pressure (BP) in girls with Turner's syndrome without clinically relevant cardiac abnormalities., Study Design: LV dimensions measured by echocardiography and systemic BP were assessed before and during 7 years of GH treatment in 68 girls with Turner's syndrome participating in a randomized dose-response study. These previously untreated girls, age 2 to 11 years, were randomly assigned to 1 of 3 GH dosage groups: group A, 4 IU/m(2)/d; group B, first year 4 IU/m(2)/d, thereafter 6 IU/m(2)/d; group C, first year 4 IU/m(2)/d, second year 6 IU/m(2)/d, thereafter 8 IU/m(2)/d. After the first 4 years, girls >/=12 years of age began receiving 17beta-estradiol, 5 microg/kg body weight per day, for induction of puberty., Results: At baseline the LV dimensions of almost every girl were within the normal range, and the mean SD scores were close to zero. During 7 years of GH treatment, the growth of the left ventricle was comparable to that of healthy girls. No signs of LV hypertrophy were found. Before the start of GH treatment, mean BP was within the normal range but significantly higher than in healthy control subjects. Diastolic BP and systolic BP were above the 90th percentile in 23% and 28% of the girls, respectively. After 7 years of treatment, these percentages were 14% and 36%, respectively (not significantly different from baseline). The SD score of the diastolic BP showed a small decrease after 7 years of treatment. The growth of the left ventricle and the development of BP were not different between the GH dosage groups., Conclusions: Long-term GH treatment, even at dosages up to 8 IU/m(2)/d, does not result in LV hypertrophy or hypertension in girls with Turner's syndrome. Continued observation into adulthood is recommended to monitor the further development of the relatively high BP and to ensure that GH treatment has no long-term negative effect on the heart.

Objectives: To study final height in girls with Turner's syndrome treated with once or twice daily injections of growth hormone (GH) in combination with low dose ethinyl oestradiol., Design: Until final height was reached, the effect of fractionated subcutaneous injections given twice daily was compared with once daily injections of a total GH dose of 6 IU/m2/day. Twice daily injections were given as one third in the morning and two thirds at bedtime. All girls concurrently received low dose oestradiol (0.05 microgram ethinyl oestradiol/kg/day, increased to 0.10 microgram/kg/day after 2.25 years)., Patients: Nineteen girls with Turner's syndrome aged > or = 11 years (mean (SD) 13.6 (1.7) years)., Measurements: To determine final height gain, we assessed the difference between the attained final height and the final height predictions at the start of treatment. These final height predictions were calculated using the Bayley-Pinneau (BP) prediction method, the modified projected adult height (mPAH), the modified index of potential height (mIPHRUS), and the Turner's specific prediction method (PTSRUS)., Results: The gain in final height (mean (SD)) was not significantly different between the once daily and the twice daily regimens (7.6 (2.3) v 5.1 (3.2) cm). All girls exceeded their adult height prediction (range, 1.6-12.3 cm). Thirteen of the 19 girls had a final height gain > 5.0 cm. Mean (SD) attained final height was 155.5 (5.4) cm. A "younger bone age" at baseline and a higher increase in height standard deviation score for chronological age (Dutch-Swedish-Danish references) in the first year of GH treatment predicted a higher final height gain after GH treatment., Conclusions: Division of the total daily GH dose (6 IU/m2/day) into two thirds in the evening and one third in the morning is not advantageous over the once daily GH regimen with respect to final height gain. Treatment with a GH dose of 6 IU/m2/day in combination with low dose oestrogens can result in a significant increase in adult height in girls with Turner's syndrome, even if they start GH treatment at a relatively late age.

Objective: To inventory the problems encountered by parents of girls with Turner's syndrome., Design: Descriptive., Setting: University Hospital Rotterdam-Sophia Children's Hospital, department of Child and Adolescent Psychiatry, Rotterdam, the Netherlands., Method: In 1995, structured interviews were held with 65 parents/pairs of parents (total 119 parents) of 66 girls with Turner's syndrome (36 aged 6-11 years and 30 aged 12-18 years) who participated in studies of the effect of growth hormone treatment. The questions concerned the parents' emotional reactions immediately after hearing the diagnosis and at the time of the interview, and the inner experience of their child's development., Results: Immediately after the diagnosis, most parents felt sadness (95%) and shock (82%), approximately half were angry (61%) and ashamed (56%) and a minority felt guilt (29%). At the time of the interview (in 100 instances (84%) at least 5 years later), one-third of the parents still felt sadness, shock or anger and half felt ashamed. During the first few years of life, half the girls had been hospitalized at least three times, and feeding and sleeping also gave problems. Subsequently, the parents had problems with retarded motor development (67%), the acquisition of language (50%) and the restricted social skills of the child (67% were ragged a lot). Nearly all parents (90%) found their daughter's infertility difficult to cope with. They expected fewer opportunities for their daughter to find a job (38%) and (or) a partner (54%)., Conclusion: Parents of girls with Turner's syndrome frequently find it difficult to cope emotionally with the fact that their child has this disorder, and with the problems regarding their daughter's linguistic and motor development and subnormal social skills.

Immunologic effects of pre- and postnatal polychlorinated biphenyl (PCB)/dioxin exposure in Dutch infants from birth to 18 mo of age are explored. The total study group consisted of 207 healthy mother-infant pairs, of which 105 infants were breast-fed and 102 children were bottle-fed. Prenatal PCB exposure was estimated by the PCB sum (PCB congeners 118, 138, 153, and 180) in maternal blood and the total toxic equivalent (TEQ) level in human milk (17 dioxin and 8 dioxin-like PCB congeners). Postnatal PCB/dioxin exposure was calculated as a product of the total TEQ level in human milk multiplied by the weeks of breast-feeding. The number of periods with rhinitis, bronchitis, tonsillitis, and otitis during the first 18 mo of life was used as an estimate of the health status of the infants. Humoral immunity was measured at 18 mo of age by detecting antibody levels to mumps, measles, and rubella. White blood cell counts (monocytes, granulocytes, and lymphocytes) and immunologic marker analyses CD4+ T-lymphocytes, CD8+ T-lymphocytes, activated T-lymphocytes (HLA-DR+CD3+), as well as T cell receptor (TcR) alpha beta+, TcR gamma delta+, CD4+CD45RA+ and CD4+CD45RO+ T-lymphocytes, B-lymphocytes (CD19+ and/or CD20+) and NK cells (CD16+ and/or CD56+/CD3-) in cord blood and venous blood at 3 and 18 mo of age were assessed in a subgroup of 55 infants. There was no relationship between pre- and postnatal PCB/dioxin exposure and upper or lower respiratory tract symptoms or humoral antibody production.(ABSTRACT TRUNCATED AT 250 WORDS)