Margreet A. Veening

Pubertal Development in Children Born Small for Gestational Age

UNLABELLED Reduced fetal growth appears to be associated with precocious adrenarche, early puberty and polycystic ovary syndrome with subsequent fertility problems. We investigated pubertal development and DHEAS levels in children born small for gestational age (SGA) and children born appropriate for gestational age (AGA). Physical examination was carried out twice. Mean age (+/-SD) at the first visit: SGA group, 9.1+/-1.1 yr; AGA group, 9.0+/-1.1 yr. AT FOLLOW-UP: SGA group, 11.6+/-1.0 yr; AGA group, 11.6 +/-1.1 yr. Pubertal stages of the children were assessed. Pubic hair was recorded as a measure of androgenization. Chronological age (CA) was expressed as a percentage of the age corresponding to the pubertal stage (CA/pubertal age [PA] x 100%). Estradiol, testosterone and dehydroepiandrosterone sulfate (DHEAS) were measured in all children. FIRST VISIT: All children were prepubertal without signs of pubarche. DHEAS concentrations were higher in SGA children than in AGA children (p = 0.004). FOLLOW UP Twenty SGA children and 15 AGA children were pubertal. CA/PA x 100% was lower in SGA girls than in AGA girls (p = 0.004). Since 2.5 years earlier all girls had been prepubertal, this means a more rapid progression in the SGA girls. CA/PA x 100% was similar in SGA and AGA boys (p = 0.1). DHEAS levels tended to be higher in SGA children than in AGA children (p = 0.06). These data support that a low birth weight may have long-lasting effects on pubertal development, as observed in a more rapid progression in SGA girls. In prepubertal SGA children, an exaggerated adrenarche is observed compared to AGA children, which tended to persist through puberty.

Blood pressure and body composition in long-term survivors of childhood acute lymphoblastic leukemia†

Long‐term survivors of acute lymphoblastic leukemia (ALL) in childhood are at increased risk of late effects of cancer treatment, among which are cardiovascular sequelae. Purpose of this study was to assess blood pressure and body composition in childhood ALL survivors and compare data to reference values from the general population.

Fetal Nutrition and Timing of Puberty

Over the last decade growing evidence has been documented on the relationship between intrauterine growth retardation (IUGR) and pubertal development indicating changes in timing and progression of puberty. These changes in pubertal development are part of a growing list of IUGR-related diseases, which includes type 2 diabetes mellitus, cardiovascular disease, short stature and polycystic ovary syndrome. The influence of IUGR on the mechanisms behind the onset of puberty is still elusive. In the absence of prospective studies on gonadotropin-releasing hormone pulse patterns in IUGR children, other markers of pubertal development such as age at menarche in girls and progression of puberty have been employed. We investigated pubertal development and DHEAS levels in children born small for gestational age (SGA) after third trimester growth retardation and children born appropriate for gestational age (AGA). A faster progression of puberty was found in girls but not in boys. DHEAS levels tended to be higher in SGA children than in AGA children. In animal studies using two rat models, growth and onset of puberty based on perinatal undernutrition were also investigated. In one model intrauterine growth retardation was induced by ligation of the uterine arteries (IUGR) at day 17 of gestation and in the other model postnatal food restriction (FR) was induced by increasing litter size after birth until weaning. In both models, the rats showed a persistent growth failure. Onset of puberty was defined by vaginal opening (VO) in female rats and by balanopreputial separation (BPS) in male rats. At onset of puberty IUGR and FR rats had a lower body weight compared to controls, indicating that no threshold for body weight is needed for the onset of puberty. In the IUGR female rats, the onset of puberty was delayed and in the FR female rats the onset of puberty was in time. In both IUGR and FR female rats VO and first cycle were uncoupled. In IUGR female rats, at VO, at first cycle and at the age of 6 months the ovaries showed a decline in number of follicles indicating that intrauterine malnutrition in the female rat has a permanent influence on the growth and development of follicles. In the FR female rats, at VO, the ovaries showed a normal number of follicles but an abnormal maturation pattern. At the time of first cycle and at the age of 6 months normalization in follicle growth pattern was observed. These findings suggest that postnatal undernutrition has a transient influence on follicle growth and development. In male rats, both models showed delayed onset of puberty and impaired testicular function, as shown by decreased testosterone levels. These data indicate that early malnutrition during different critical developmental time windows may result in different long-lasting effects on pubertal development in both humans and rats.

Design of the Quality of Life in Motion (QLIM) study: a randomized controlled trial to evaluate the effectiveness and cost-effectiveness of a combined physical exercise and psychosocial training program to improve physical fitness in children with cancer

BackgroundChildhood cancer and its treatment have considerable impact on a childs physical and mental wellbeing. Especially long-term administration of chemotherapy and/or radiotherapy impairs physical fitness both during and after therapy, when children often present with muscle weakness and/or low cardiorespiratory fitness. Physical exercise can improve these two elements of physical fitness, but the positive effects of physical exercise might be further increased when a childs wellbeing is simultaneously enhanced by psychosocial training. Feeling better may increase the willingness and motivation to engage in sports activities. Therefore, this multi-centre study evaluates the short and long-term changes in physical fitness of a child with a childhood malignancy, using a combined physical exercise and psychosocial intervention program, implemented during or shortly after treatment. Also examined is whether positive effects on physical fitness reduce inactivity-related adverse health problems, improve quality of life, and are cost-effective.MethodsThis multi-centre randomized controlled trial compares a combined physical and psychosocial intervention program for children with cancer, with care as usual (controls). Children with cancer (aged 8-18 years) treated with chemotherapy and/or radiotherapy, and who are no longer than 1 year post-treatment, are eligible for participation. A total of 100 children are being recruited from the paediatric oncology/haematology departments of three Dutch university medical centres. Patients are stratified according to pubertal stage (girls: age ≤10 or >10 years; boys: ≤11 or >11 years), type of malignancy (haematological or solid tumour), and moment of inclusion into the study (during or after treatment), and are randomly assigned to the intervention or control group.DiscussionChildhood cancer patients undergoing long-term cancer therapy may benefit from a combined physical exercise and psychosocial intervention program since it may maintain or enhance their physical fitness and increase their quality of life. However, the feasibility, patient need, and effectiveness of such a program should be established before the program can be implemented as part of standard care.Trial registration numberNTR1531 (The Netherlands National Trial Register)

Malignant melanoma as second malignant neoplasm in long-term childhood cancer survivors: A systematic review†

This systematic review provides information on malignant melanoma as second malignant neoplasm (SMN) after childhood cancer and evaluates its risk factors. Study reports describing incidences of SMN and malignant melanoma as SMN in a population of childhood cancer survivors (CCS) were included. Of 151,575 CCS, 4,010 (2.6%) children developed an SMN, 212 of which were melanoma (5.3% or 0.14% of all CCS). The following risk factors for malignant melanoma as SMN were identified: radiotherapy, or the combination alkylating agents and anti‐mitotic drugs. Melanomas are most frequently observed after Hodgkin disease, hereditary retinoblastoma, soft tissue sarcoma, and gonadal tumors. Pediatr Blood Cancer

Sequelae of Syndrome X in Children Born Small for Gestational Age

Objective: Low birth weight is associated with the presence of syndrome X in adults. We studied the components of this syndrome in prepubertal children born SGA (small for gestational age) and children born AGA (appropriate for gestational age). Methods: Twenty-nine SGA children, age (mean ± SD) 9.1 ± 1.1 years and 24 AGA children, age 9.0 ± 1.1 years were studied. Fasting serum lipid concentrations were determined. A hyperinsulinemic euglycemic clamp was performed to measure insulin sensitivity. Ambulatory monitoring was performed to obtain 24-hour recordings of blood pressure. Results: Prepubertal SGA children are less insulin sensitive and have a higher nighttime systolic blood pressure (SBP) after correction for BMI than children born AGA. No differences were found in lipid concentrations between the 2 groups. Conclusions: Not all components of syndrome X can yet be found in 9-year-old children born SGA; follow-up of this cohort is required.

Effects of a combined physical and psychosocial intervention program for childhood cancer patients on quality of life and psychosocial functioning: results of the QLIM randomized clinical trial

Although survival rates in childhood cancer have improved, prevention and reduction of late effects remain important. This study evaluates the effects of a combined physical exercise and psychosocial intervention on health‐related quality of life (HrQoL) and psychosocial functioning in childhood cancer patients.

Factors influencing childhood cancer patients to participate in a combined physical and psychosocial intervention program : Quality of Life in Motion

For a multi‐center randomized trial investigating the effects of a 12‐week physical and psychosocial intervention program for children with cancer, we invited 174 patients (8–18 years old) on treatment or within 1 year after treatment; about 40% participated. Reasons for non‐participation were investigated.

No Efficacy for Silicone Gel Sheeting in Prevention of Abnormal Scar Formation in Children with Cancer: A Randomized Controlled Trial

Background: Placement of a totally implantable venous access device in children with cancer often leads to hypertrophic scars after its removal. This study investigates whether the use of silicone gel sheets has a beneficial effect on scar outcome in children with cancer. Methods: In a three-arm randomized controlled trial, the effects of use of silicone gel sheets for 2 and 6 months were assessed and compared with no intervention in children with cancer after removal of the totally implantable venous access device. Silicone gel sheets were first administered 14 days after surgery. The 1-year follow-up included measurements at seven time points. Next to scar size assessment, the modified Vancouver Scar Scale was used to assess scar outcome. Results: Thirty-six children participated. For hypertrophy, no significant differences were found between the two intervention groups and the control group. However, at 1-year follow-up, the 2-month application group showed significantly smaller scars compared with the group receiving silicone gel sheet treatment for 6 months (p = 0.04), but not when compared with the control group (p = 0.22). Longitudinal multilevel analyses could not confirm these findings and showed no significant intervention effects on both outcomes. Conclusions: This study provides no strong evidence to support the use of silicone gel sheets after totally implantable venous access device removal in children with cancer. There seems to be a small benefit for scar width with application for 2 months. However, for hypertrophy, the scar outcome shows no significant difference between the control group and the 2-month and 6-month treatment groups. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, I.

WT1 deletion leading to severe 46,XY gonadal dysgenesis, Wilms tumor and gonadoblastoma: case report.

Background: Heterozygous missense mutations in the WT1 gene that affect the function of the wild-type allele have been identified in Denys-Drash syndrome, which is characterized by severe gonadal dysgenesis, early-onset nephropathy and a predisposition to renal and gonadal cancer. Intron 9 splice-site mutations that influence the balance between WT1 isoforms cause a nearly similar phenotype, known as Frasier syndrome. Nonsense mutations and deletions only lead to WT1 haploinsufficiency and, hence, to less severe gonadal dysgenesis and late-onset nephropathy. WT1 analysis is mandatory in 46,XY gonadal dysgenesis with renal abnormality. Patient: We describe a newborn with 46,XY severe partial gonadal dysgenesis, in whom structural renal anomalies and proteinuria were excluded. Gonadectomy was performed at the age of 1 month and the microscopy was thought to be suggestive for a gonadoblastoma. At the age of 9 months, the patient presented with a bilateral Wilms tumor. Results: We found a heterozygous WT1 whole-gene deletion but no other gene defects. Conclusions: This case description illustrates that a WT1 deletion might be associated with a more severe phenotype than previously thought. It also illustrates that, even in the absence of renal abnormality, it is recommended to test promptly for WT1 defects in 46,XY gonadal dysgenesis.