Theo C. J. Sas

Immunologic Effects of Background Prenatal and Postnatal Exposure to Dioxins and Polychlorinated Biphenyls in Dutch Infants

ABSTRACT: 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) αβ+, TcRγδ+, 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. A higher prenatal PCB/ dioxin exposure was associated with an increase in the number of TcRγδ+ T cells at birth and with an increase in the total number of T cells and the number of CD8+ (cytotoxic), TcRαβ+, and TcRγδ+ T cells at 18 mo of age. A higher prenatal as well as postnatal PCB/dioxin exposure was associated with lower monocyte and granulocyte counts at 3 mo of age. In conclusion, our study suggests that background levels of PCB/dioxin exposure influences the human fetal and neonatal immune system.

Carbohydrate metabolism during long‐term growth hormone treatment in children with short stature born small for gestational age

To assess possible side‐effects of long‐term continuous growth hormone (GH) treatment on carbohydrate (CH) metabolism in children with short stature born small for gestational age.

Efficacy and safety of oxandrolone in growth hormone-treated girls with turner syndrome.

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.

Bone mineral density assessed by phalangeal radiographic absorptiometry before and during long-term growth hormone treatment in girls with Turner's syndrome participating in a randomized dose-response study

To assess bone mineral density (BMD) in girls with Turners syndrome before and during long-term treatment with GH, longitudinal measurements using phalangeal radiographic absorptiometry were performed in 68 girls with Turners 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/m2/d (≈0.045 mg/kg/d); group B, first year 4 IU/m2/d, thereafter 6 IU/m2/d (≈0.0675 mg/kg/d); or group C, first year 4 IU/m2/d, second year 6 IU/m2/d, thereafter 8 IU/m2/d (≈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 17β-estradiol (5 μg/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 Turners syndrome have a normal volumetric BMD. During 7 y of GH treatment with 4, 6, or 8 IU/m2/d, the BMD SD score increased significantly.

The effects of long-term growth hormone treatment on cardiac left ventricular dimensions and blood pressure in girls with Turner's syndrome

Abstract 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 Turners 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 Turners 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 17β-estradiol, 5 μg/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 Turners 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. (J Pediatr 1999;135:470-76)

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

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

Body proportions during 6 years of GH treatment in children with short stature born small for gestational age participating in a randomised, double‐blind, dose–response trial*

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 longitudinal study on bone mineral density until adulthood in girls with Turner's syndrome participating in a growth hormone injection frequency- response trial

The aim of this study was to assess the volumetric bone mineral density (BMD) in girls with Turners syndrome (TS) before and during growth hormone (GH) treatment in combination with low dose oestrogens as well as three years after discontinuation of GH treatment.

Safety and Efficacy of Oxandrolone in Growth Hormone-Treated Girls with Turner Syndrome: Evidence from Recent Studies and Recommendations for Use

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 onwards can be considered.

Patterns of Catch-Up Growth

F rom embryogenesis to young adulthood, growth rate declines dramatically. This deceleration in growth velocity is most extreme in infancy with a more subtle slowing in growth velocity throughmid-childhood, interrupted by the pubertal growth spurt, after which the growth rate gradually declines to zero. While in the first years of life the length of healthy infants can cross the percentiles toward their genetic target height (TH) SDS, height tends to remain within a narrow “channel” on the growth charts between 3 years and the onset of puberty, close to the same percentile or SDS position. The tendency to keep to this narrow and predictable track of growth is called “canalization.” An SDS change of >0.25/year is rarely seen in longitudinal growth studies on normal children. A large variety of growth-retarding illnesses, including hypothyroidism, celiac disease (CD), malnutrition, Cushing syndrome or chronic steroid treatment, and growth hormone (GH) deficiency, can lead to a slowing in growth with a downward deviation from the standard growth curve. After release from these growth-inhibiting conditions, exaggerated acceleration in linear growth can occur. In 1963, Prader et al and Tanner introduced the term “catch-up growth” to describe this period of rapid linear growth in children that followed a period of growth inhibition, leading toward their original growth channel. The term catch-up growth is also used for the growth acceleration seen in 85% of infants born small for gestational age (SGA), although in these cases there is usually no information about the foregoing downward deviation. The term catch-up growth is mostly used for height. Catch-up growth has been defined as “a height velocity above the statistical limits of normality for age or maturity during a defined period of time, following a transient period of growth inhibition; the effect of catch-up growth is to take the child towards his/her pre-retardation growth curve.” Even though this definition would imply that for a proper assessment of catch-up growth the full growth trajectory has to be evaluated (up to adult height), only few studies on catch-up growth have included all parts of this trajectory (the phases of growth inhibition, growth acceleration, growth maintenance, and puberty and the achieved adult height in comparison with the genetic growth potential). Furthermore, several alternative definitions of catch-up growth have been used, for example (in children born SGA) reaching an SDS of > 2 for the reference population or a cut-off of a change