Mortality patterns in Dutch diabetes outpatients.

AIM: Diabetes mellitus is a major cause of death. Outpatients with diabetes have more complications than patients in general practice; mortality patterns have only been studied in the total diabetes population. This study aims to assess mortality, causes, and predictors in outpatients with diabetes. MATERIALS AND METHODS: A cohort study, included people with diabetes mellitus from the nationwide Dutch Paediatric and Adult Registry of Diabetes (DPARD) visiting diabetes outpatient clinics in 2016-2020. DPARD data were linked to Statistics Netherlands (CBS), comprising data on mortality, ethnicity and education. All-cause and cardiovascular mortality rates were estimated using Cox proportional hazard regression. RESULTS: During a median follow-up of 3.1 years among 12 992 people with diabetes, mortality rates per 10 000 person-years were 67.7 in adult type 1 diabetes and 324.2 in type 2 diabetes. The major cause of non-cardiovascular death was malignancy. During the pandemic years of influenza (2018) and COVID (2020), mortality rates peaked. Age, smoking and an estimated glomerular filtration rate of <60 ml/min were associated with all-cause mortality. In type 2 diabetes, additional factors were male sex, body mass index <20 kg/m2, diabetes duration <1 year and hypertension. CONCLUSIONS: Mortality among Dutch outpatients with diabetes is high. Smoking and renal failure were associated with mortality in both types. Further focus on early detection and treatment of mortality-associated factors may improve clinical outcomes.

Effects and Safety of Growth Hormone Treatment in Six Children with Pycnodysostosis.

INTRODUCTION: Pycnodysostosis is an extremely rare skeletal dysplasia caused by cathepsin K deficiency. It is characterized by extreme short stature with adult height (AH) in males typically less than 150 cm and in females less than 130 cm. Our objective was to evaluate the effect and safety of growth hormone (GH) treatment in 6 patients with pycnodysostosis treated according to the Dutch national pycnodysostosis guideline. CASE PRESENTATION: Six subjects (4 boys, 2 girls) presented with pycnodysostosis, treated with GH 1.4 mg/m2/day (∼0.046 mg/kg/day) for ≥1 year. Median (IQR) age at start of GH was 10.4 years (5.7; 12.2) and median height 113.5 cm (93.3; 129.3) (-4.2 SDS [-4.8; -3.6]). All children were prepubertal at start of GH. After 1 year of GH, median height gain was 7.6 cm (6.5; 8.5) (0.3 SDS [-0.3; 0.7]). Three children are still treated with GH, and the other three subjects reached AH: 1 boy reached an AH of 157.0 cm (-3.8 SDS) after 6.3 years of GH, and 2 girls reached an AH of 138.5 cm (-5.2 SDS) after 4.8 years of GH and 148.0 cm (-3.6 SDS) after 6.4 years of GH, respectively. This last girl received additional GnRH analogue treatment. In all subjects, height SDS remained stable or improved during and after GH treatment. No serious adverse advents were found. Serum IGF-I remained below the +2 SDS. CONCLUSION: Our data suggest that GH may prevent the decline in height which can be observed in children with pycnodysostosis. Further research is needed to confirm this. Also, the effect of other growth-promoting strategies such as treatment with an additional GnRH analogue warrants further investigation.

Osteoporosis in children and adolescents: how to treat and monitor?

Osteoporosis is a condition of increased bone fragility associated with fractures. Apart from primary genetic osteoporotic conditions, secondary osteoporosis in children is being increasingly recognized. As a result, there is growing interest in its prevention and treatment. Important goals of care are to prevent fractures, increase bone mass and trabecular and cortical thickness, reshape vertebral fractures, prevent (or correct) skeletal deformities, and improve mobility, independence, and quality of life. Secondary pediatric osteoporosis is often of multifactorial origin since affected children frequently have more than one acquired factor that is detrimental to bone health. Typical conditions causing osteoporosis are leukemias, progressive muscle or neurological disorders, as well as chronic inflammatory conditions and their treatment. Management of children with osteoporosis involves a multidisciplinary team involving pediatric experts from different subspecialties. With regard to prevention and early intervention, it is important to provide optimal management of any underlying systemic conditions including avoidance, or dose-reduction, of osteotoxic medications. Basic supporting life-style measures, such as appropriate nutrition, including adequate calcium intake and vitamin D, and physical activity are recommended, where possible. When pediatric treatment criteria for osteoporosis are met, antiresorptive drugs constitute the first pharmacological line treatment. CONCLUSION: This clinical review focuses on the prevention, treatment, and follow-up of children with, or at risk of developing, osteoporosis and the transition from pediatric to adult care. WHAT IS KNOWN: • Osteoporosis and associated fractures can cause significant morbidity and reduce the quality of life. • The developing skeleton has huge potential for recovery and reshaping, thus early detection of fractures, assessment of recovery potential, and treatment of children with osteoporosis can prevent future fractures, deformities, and scoliosis, improve function and mobility, and reduce pain. WHAT IS NEW: • Osteoporosis in children and adolescents requires a multidisciplinary approach with a thorough assessment of recovery potential, and indication for therapy should be personalized. • Although bisphosphonates still represent the drug most commonly used to increase bone mass, improve mobility, and reduce pain and recurrence of fractures, new agents are being developed and could be beneficial in children with specific conditions.

Transition readiness among adolescents with rare endocrine conditions.

OBJECTIVE: Adolescents and young adults (AYA) with common endocrine disorders show a high dropout (up to 50%) after the transfer from paediatric to adult endocrinology. Little is known about transition readiness in rare endocrine conditions (rEC). This study aims to assess medical self-management skills (SMS) among AYA with rEC in relation to age and gender, in order to understand dropout and increase transition readiness. DESIGN: Cross-sectional study using web-based medical self-management questionnaires. METHODS: Questionnaires consisting of 54 questions in seven domains were filled out by the adolescents before the first shared appointment with both paediatric and adult endocrinologist. RESULTS: Fifty-seven patients (median age 17 years, 25/57 females) participated and generally scored well on most items. However, one out of seven did not know the name of their disorder, one sixth of the glucocorticoid users did not know that dose should be adapted in case of illness or surgery, over one-fifth had never ordered their repeat prescriptions themselves and two-thirds had never had a conversation alone with their doctor. CONCLUSIONS: Several SMS among patients with rEC are insufficient, with regard to medical knowledge, practical skills and communication. As SMS are only weakly related to non-modifiable factors, such as age and gender, we recommend focussing on other factors to increase transition readiness. The timing, amount and 'mode' of medical information should be individualised. Transition checklists should be used to detect shortcomings in practical skills and communication, which can subsequently be trained with the help of parents, caregivers and/or e-technology.

Estrogen Replacement in Turner Syndrome: Literature Review and Practical Considerations.

Context: Most girls with Turner syndrome (TS) have hypergonadotropic hypogonadism and need hormonal replacement for induction of puberty and then for maintaining secondary sex characteristics, attaining peak bone mass, and uterine growth. The optimal estrogen replacement regimen is still being studied. Evidence Acquisition: We conducted a systematic search of PubMed for studies related to TS and puberty. Evidence Synthesis: The goals of replacement are to mimic normal timing and progression of physical and social development while minimizing risks. Treatment should begin at age 11 to 12 years, with dose increases over 2 to 3 years. Initiation with low-dose estradiol (E2) is crucial to preserve growth potential. Delaying estrogen replacement may be deleterious to bone and uterine health. For adults who have undergone pubertal development, we suggest transdermal estrogen and oral progestin and discuss other approaches. We discuss linear growth, lipids, liver function, blood pressure, neurocognition, socialization, and bone and uterine health as related to hormonal replacement. Conclusion: Evidence supports the effectiveness of starting pubertal estrogen replacement with low-dose transdermal E2. When transdermal E2 is unavailable or the patient prefers, evidence supports use of oral micronized E2 or an intramuscular preparation. Only when these are unavailable should ethinyl E2 be prescribed. We recommend against the use of conjugated estrogens. Once progestin is added, many women prefer the ease of use of a pill containing both an estrogen and a progestin. The risks and benefits of different types of preparations, with examples, are discussed.

Degree of methylation of ZAC1 (PLAGL1) is associated with prenatal and post-natal growth in healthy infants of the EDEN mother child cohort.

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.

Effect of oxandrolone on glucose metabolism in growth hormone-treated girls with Turner syndrome.

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.

The effect of oxandrolone on voice frequency in growth hormone-treated girls with Turner syndrome.

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.

The effect of the weak androgen oxandrolone on psychological and behavioral characteristics in growth hormone-treated girls with Turner syndrome.

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.

Final height in girls with turner syndrome after long-term growth hormone treatment in three dosages and low dose estrogens.

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.