Normalization of height in girls with Turner syndrome after long-term growth hormone treatment: results of a randomized dose-response trial

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.     

Bone stiffness and failure load are related with clinical parameters in men with chronic obstructive pulmonary disease

Osteoporosis is frequently seen in patients with chronic obstructive pulmonary disease (COPD). Because research on bone structure and bone strength in COPD patients is limited, the objectives of this pilot study were as follows: (1) to compare bone structure, stiffness, and failure load, measured at the peripheral skeleton, between men with and without COPD after stratification for areal bone mineral density (aBMD); and (2) to relate clinical parameters with bone stiffness and failure load in men with COPD. We included 30 men with COPD (normal aBMD, n = 18; osteoporosis, n = 12) and 17 men without COPD (normal aBMD, n = 9; osteoporosis, n = 8). We assessed pack‐years of smoking, body mass index (BMI), fat free mass index (FFMI), pulmonary function (forced expiratory volume in 1 second [FEV₁], FEV₁/forced vital capacity [FVC], diffusion capacity for carbon monoxide [DLCO], and transfer coefficient for carbon monoxide [KCO]), and extent of emphysema. Bone structure of the distal radius and tibia was assessed by high‐resolution peripheral quantitative computed tomography (HR‐pQCT), and bone stiffness and failure load of the distal radius and tibia were estimated from micro finite element analysis (µFEA). After stratification for aBMD and COPD, men with osteoporosis showed abnormal bone structure (p < 0.01), lower bone stiffness (p < 0.01), and lower failure load (p < 0.01) compared with men with normal aBMD, and men with COPD had comparable bone structure, stiffness, and failure load compared with men without COPD. In men with COPD, lower FFMI was related with lower bone stiffness, and failure load of the radius and tibia and lower DLCO and KCO were related with lower bone stiffness and failure load of the tibia after normalization with respect to femoral neck aBMD. Thus, this pilot study could not detect differences in bone structure, stiffness, and failure load between men with and without COPD after stratification for aBMD. FFMI and gas transfer capacity of the lung were significantly related with bone stiffness and failure load in men with COPD after normalization with respect to femoral neck aBMD. © 2013 American Society for Bone and Mineral Research.     

Growth until puberty after in utero exposure to coumarins

Anticoagulation with coumarins is an effective therapy during pregnancy. Fetal exposure to coumarin derivatives during the first trimester, however, is associated with skeletal anomalies (warfarin or coumarin embryopathy). Information about long-term effects of prenatal coumarin exposure on the skeletal development is not available. We investigated growth and body proportions at school age of children exposed to coumarins in utero. A blind population-based cohort study was conducted on 307 exposed children and 267 non-exposed controls ages 8-15 years. The exposed cohort was based on a prospective registry of coumarin-treated pregnant women. Anthropometric data included height, weight, head circumference, and measurements to evaluate body proportions. The mean height of exposed children did not differ from that of the non-exposed children (mean difference 0.01 SD). In addition, no differences were found for the proportional measures. As a group, children exposed in the first trimester showed no evidence of growth impairment. Two children in this group, however, were born with signs of coumarin embryopathy and one of these displayed a deficit in height at school age. Long-term growth was not affected by a high cumulative dosage or exposure after the first trimester. We conclude that, when exposure during the first trimester is avoided, coumarin therapy during pregnancy has no demonstrable risk for the child's skeletal development.     

Complicated pancreatic inflammatory disease: diagnostic and therapeutic role of interventional radiology

Diagnostic and therapeutic interventional radiology techniques in 41 patients with complications of pancreatic inflammatory disease (noninfected pseudocyst, infected pseudocyst, phlegmon, abscess, hemorrhagic pancreatitis) are described. Computed tomography or ultrasound-guided aspiration or percutaneous pancreatic ductography enabled specific diagnoses in 43 of 45 patients (96%). In almost half the patients, diagnostic aspiration with 22-gauge needles was unsuccessful due to viscous contents or firm cavity walls. Single-step needle aspiration of noninfected pseudocysts was successful in only three of ten patients (30%). Catheter drainage cured six of seven noninfected pseudocysts (85.7%) and seven of nine infected pseudocysts (77.7%). Pancreatic phlegmons were aspirated in five patients to exclude secondary infection and help determine the need for surgery. Pancreatic abscesses were drained successfully in nine of 13 patients (69.2%); temporizing benefit was achieved in the other four who eventually underwent surgery in improved condition. Early diagnosis of the complications of pancreatitis may be established almost uniformly, and at least 70% of patients with infected or noninfected pseudocysts and pancreatic abscesses may be cured by nonoperative drainage.     

Predictive DNA testing for multiple endocrine neoplasia 2: a therapeutic challenge of prophylactic thyroidectomy in very young children

BACKGROUND: Patients with multiple endocrine neoplasia (MEN) type 2 are at risk for early medullary thyroid carcinoma (MTC). Recently, the cloning of the ret oncogene has made it possible to identify patients at risk for MEN 2 syndrome with a high degree of reliability before presenting any symptoms. METHODS: Children of families with MEN 2 were screened genetically if one of the parents was a known gene carrier of the RET proto-oncogene. If they were carriers, thyroidectomy was performed. RESULTS: The authors report five children with MEN 2 who underwent prophylactic thyroidectomy irrespective of the results of calcitonin screening tests after genetic screening had shown that they were carrier of the RET proto-oncogene. Apart from a temporary hypocalcemia in one, the operations were uneventful. Pathology results showed MTC in three children of one family with MEN 2A at age 2, 3, and 6 years. In two families with MEN 2B the thyroidectomy specimen showed bilateral MTC in a 1-year-old and a 3-year-old child. CONCLUSIONS: These findings show that MTC occurs at very young age in children with MEN 2. The authors advocate performing prophylactic thyroidectomy in the first year of life in children with MEN 2B and at age 2 years in children with MEN 2A to obtain an optimal cure rate.     

Final height in girls with Turner's syndrome treated with once or twice daily growth hormone injections

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 µg ethinyl oestradiol/kg/day, increased to 0.10 µg/kg/day after 2.25years).
PATIENTS—Nineteen girls with Turner''s syndrome aged ⩾ 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 (mIPH_RUS), and the Turner''s specific prediction method (PTS_RUS).
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.

     

The natural history of medium-chain acyl CoA dehydrogenase deficiency in the Netherlands: clinical presentation and outcome

OBJECTIVES: To describe the clinical presentation and long-term follow-up of a large cohort of patients with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. STUDY DESIGN: A nationwide, retrospective analysis of clinical presentation and follow-up in 155 Dutch patients with MCAD deficiency. RESULTS: Most patients presented between 3 months and 5.1 years of age; 13% had symptoms as neonates not exclusively related to breast-feeding. An acute presentation before the diagnosis was made resulted in a mortality of 22% (25/114), whereas 21% (19/89) developed disabilities after the diagnosis. On follow-up, a total of 44 patients reported fatigue (35%; 28/80), muscle pain (31%; 25/80), and/or reduced exercise tolerance (39%; 31/80). Cardiac evaluation in 11 adult patients revealed no abnormalities in cardiac function explaining these complaints. Children with MCAD deficiency readily become overweight. CONCLUSIONS: Mortality and morbidity were high in undiagnosed children with MCAD deficiency; establishment of the diagnosis significantly improves outcome. Strikingly, after the diagnosis and initiation of treatment, overweight and chronic complaints (fatigue, muscle pain, and reduced exercise tolerance) were prominent.     

High Imminent Vertebral Fracture Risk in Subjects With COPD With a Prevalent or Incident Vertebral Fracture

Subjects with chronic obstructive pulmonary disease (COPD) have an increased risk of vertebral fractures (VFs); however, VF incidence is largely unknown. Therefore, the aim of our study was to determine the incidence of new and/or worsening VF in subjects with COPD. Smokers and subjects with COPD (GOLD II–IV) from the ECLIPSE study with complete set of chest CT scans (baseline and 1‐ and 3‐year follow‐up) to evaluate vertebrae T₁ down to L₁ were included. If a VF was diagnosed on the last scan, detailed VF assessment of the previous scans was performed. VFs were scored according to the method of Genant as mild, moderate, or severe. Main outcome measure was the cumulative incidence of new and/or worsening VF at subject level, within 1 and 3 years. Of 1239 subjects (mean age 61 years, 757 males [61%], 999 subjects with COPD), 253 (20.5%) had ≥1 prevalent VF. The cumulative incidence of VFs was 10.1% within 1 year and 24.0% within 3 years. After adjustment for age, sex, body mass index (BMI), pack‐years, and smoking status, prevalence and incidence were similar between smokers and COPD GOLD stages. Within 1 year, 29.2% of the subjects with a prevalent VF had an incident VF, compared with 5.1% in absence of prevalent VF (hazard ratio [HR] = 5.1; 95% confidence interval [CI] 3.6–7.4) and 58.5% versus 15.0% within 3 years (HR = 3.6; 95% CI 2.9–4.6). The incidence of VF was higher with increasing number and severity of prevalent VFs. Among subjects having an incident VF within the first year, 57.3% had a subsequent VF within the next 2 years. In this study, more than half of the smokers and subjects with COPD with a prevalent VF or an incident VF within the first year sustained a subsequent VF within 3 years. The 3‐year risk was even higher in the presence of multiple or severe prevalent VFs. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.     

Training program for overweight prevention in the child's first year: Compilation and results

The current local overweight‐prevention protocols are not applied as intended by Dutch child healthcare physicians and nurses. The development of a training program for these practitioners, based on the Intervention Mapping framework, with the aim of improving overweight‐prevention in a child's first year, is described in this study. The needs assessment showed three program objectives to be relevant, namely improving: (i) awareness of the importance of early overweight‐prevention; (ii) the competence to discuss (the risk of) overweight with parents; and (iii) working systematically according to the overweight‐prevention protocol. A matrix was then created specifying the program objectives in terms of personal learning objectives and environmental change objectives, and appropriate strategies were identified. The results suggested that a more active tailored and structured change strategy improves knowledge and skills, in particular, which results in a better overall implementation of the overweight‐prevention protocol. This training program should help providers understand how the implementation of a protocol, such as the overweight‐prevention protocol, can be improved. Using the Intervention Mapping framework for systematic protocol implementation seems a valuable option.