BackgroundThe strict and demanding dietary treatment and mild cognitive abnormalities seen in PKU treated from a young age can be expected to affect the health-related quality of life (HRQoL) of patients and their families. Our aim was to describe the HRQoL of patients with PKU from a large international study, using generic HRQoL measures and an innovative PKU-specific HRQoL questionnaire (PKU-QOL). Analyses were exploratory, performed post-hoc on data collected primarily to validate the PKU-QOL.MethodsA multicentre, prospective, non-interventional, observational study conducted in France, Germany, Italy, The Netherlands, Spain, Turkey and the UK. Patients diagnosed with PKU aged ≥9 years old and treated with a Phe-restricted diet and/or Phe-free amino acid protein supplements and/or pharmacological therapy were included in the study; parents of at least one patient with PKU aged <18 years were also included. HRQoL was assessed by generic measures (Pediatric Quality-of-Life Inventory; Medical Outcome Survey 36 item Short Form; Child Health Questionnaire 28 item Parent Form) and the newly developed PKU-QOL. Mean generic domain scores were interpreted using published reference values from the general population. PKU-QOL domain scores were described overall and in different subgroups of patients defined according to severity of PKU, overall assessment of patient’s health status by the investigator and treatment with tetrahydrobiopterin (BH4).ResultsData from 559 subjects were analysed: 306 patients (92 children, 110 adolescents, 104 adults) and 253 parents. Mean domain scores of generic measures in the study were comparable to the general population. The highest PKU-QOL impact scores (indicating greater impact) were for emotional impact of PKU, anxiety about blood Phe levels, guilt regarding poor adherence to dietary restrictions or Phe-free amino acid supplement intake and anxiety regarding blood Phe levels during pregnancy. Patients with mild/moderate PKU and those receiving BH4 reported lower practical and emotional impacts of the diet and Phe-free amino acid supplement intake.ConclusionPatients with PKU showed good HRQoL in the study, both with the generic and PKU-specific measures. Negative impacts of PKU on a patient’s life, including the emotional impact of PKU and its management, was delineated by the PKU-QOLs across all age groups.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0294-x) contains supplementary material, which is available to authorized users.

ObjectiveThe easypod connect observational study (ECOS) assessed treatment adherence among paediatric patients receiving growth hormone (GH) via the easypod electronic injection device.DesignECOS was an open-label, observational, longitudinal study conducted in 24 countries between 2010 and 2016, enrolling children treated with GH.MethodsThe primary endpoint was the rate of treatment adherence during 5 years of follow-up. Impact of adherence on growth outcomes was assessed using Spearman’s product–moment correlations.Results and conclusionsOverall, 1190 patients had easypod data available for ≥3 months; most patients had GH deficiency (75%); 606 of these patients were GH naïve at baseline. Over the first year of monitoring, the median rate of adherence was 93.7% among patients overall and >93.0% in GH-naïve patients, irrespective of the treatment indication. Clinically meaningful improvements in growth rates were observed after 1 year of treatment across all GH indications. Adherence decreased with increasing treatment duration, but the overall median adherence rate remained high after 3 years of follow-up: 87.2% (n = 409), 75.5% after 4 years (n = 143) and 70.2% after 5 years (n = 43). Statistically significant correlations between adherence and 1-year change in height standard deviation score (P < 0.001 for patients overall) and height velocity (P < 0.001) were observed.ConclusionsECOS produced accurate, real-time adherence data in a large population of GH-treated children over 5 years of follow-up. Using the easypod connect system, physicians can potentially identify patients with inadequate adherence and poor response to treatment, enabling them to take appropriate action to help them maximise the benefits of GH treatment.

The growth hormone (GH)–insulin-like growth factor (IGF)-I axis is a key endocrine mechanism regulating linear growth in children. While paediatricians have a good knowledge of GH secretion and assessment, understanding and use of measurements of the components of the IGF system are less current in clinical practice. The physiological function of this axis is to increase the anabolic cellular processes of protein synthesis and mitosis, and reduction of apoptosis, with each being regulated in the appropriate target tissue. Measurement of serum IGF-I and IGF-binding protein (IGFBP)-3 concentrations can complement assessment of GH status in the investigation of short stature and contribute to prediction of growth response during GH therapy. IGF-I monitoring during GH therapy also informs the clinician about adherence and provides a safety reference to avoid over-dosing during long-term management.

BackgroundQuantifying the association between adherence and the growth response to growth hormone (GH) treatment is hampered by suboptimal methods of measuring adherence, confounders associated with the growth response, and restriction of the outcome parameters to yearly growth velocities.AimTo investigate the effect of adherence on the two-year growth response to GH treatment in prepubertal children with idiopathic isolated growth hormone deficiency (GHD) participating in the easypod connect observational study (ECOS), a 5-year, Phase IV open-label study to continuously assess real-world adherence via the easypod electronic drug-delivery device.Patients and methodsOutcome measures were change in height standard deviation score (ΔHSDS), index of responsiveness (IoR), and parameters of two catch-up growth (CUG) curve functions (monomolecular growth curve and second degree polynomial) with adj-HSDS (HSDS minus Target height (TH) SDS) as dependent variable. Inclusion criteria were GHD, naïve to GH treatment, known TH, age <10y in girls and <12y in boys, ≥3 measurements, HSDS <-2 at start, complete data on growth and adherence in the first and second year. Linear regression analyses were performed to test the association between adherence (continuous and high vs. low) and the outcome measures, also adjusted for potential clinical confounders (age at start, adj-HSDS at start, birth weight SDS, gestational age (<37 weeks vs ≥37 weeks), GH dose, GH max (n = 58)). The formula of IoR already adjusts for confounders.ResultsIn total, 95 patients complied with the inclusion criteria. The strongest associations were found between high adherence in the second year (≥91% as cut-off value) and IoR 2y (+0.62), and average adherence and high adherence (≥78%) in the first two years and ΔHSDS 0-2y (+0.11 SD per 1 injection/week, and +0.34 SD for high vs. low adherence).ConclusionSuboptimal adherence negatively affected the growth response in the first two years of GH treatment.

Objective: To evaluate the influence of factors intrinsic to the Japanese population on consequences of growth hormone deficiency (GHD) and effects of GH treatment in adult Japanese hypopituitary patients with GHD. Study design: A 24-week, randomised, placebo-controlled, double-blind study in 64 patients in Japan, with GHD onset during adulthood (AO; n ¼ 27) or childhood (CO; n ¼ 37). Body composition measured by dual-energy X-ray absorptiometry (DXA) was evaluated centrally. Serum IGF-I, IGF binding protein-3 (IGFBP-3) and lipid levels were determined centrally. Results: In contrast to Caucasian patients, there were no significant differences before treatment between AO and CO patients for body mass index (BMI), lean body mass (LBM) and fat mass (FM). Baseline BMI was $ 25 kg/m 2 for 32.8% of patients. For all patients combined, a significant increase in LBM and decrease in FM (P , 0.001 for each) was seen with GH treatment. Serum IGF-I and IGFBP-3 were significantly lower at baseline in CO compared with AO patients, similar to Caucasian patients, and were increased in both onsets following GH treatment. Serum total and low-density lipoprotein (LDL)-cholesterol concentrations did not differ between AO and CO patients at baseline and were elevated compared with normal ranges. GH-induced decreases were significant compared with placebo for both total (P ¼ 0.036) and LDL-cholesterol (P ¼ 0.040). Glycosylated haemoglobin was increased with GH compared with placebo treatment (P ¼ 0.016) but remained within the upper limit of normal for all patients at endpoint. Conclusions: Adult Japanese hypopituitary patients with GHD demonstrated obesity relative to healthy Japanese subjects but the clinical presentation differed from that of Caucasian patients. GH treatment improved body composition and serum cholesterol profiles of adult Japanese hypopituitary patients with GHD. European Journal of Endocrinology 151 343-350

Early diagnosis is a key objective in clinical medicine, and early detection of pathological short stature has tangible benefits for growth prognosis and the well-being of the child. Despite late diagnosis being common in growth disorders, programmes of height screening in primary care are not universal in developed countries and may be random or non-existent. A notable exception is automated growth monitoring in Finland, where an algorithm to detect abnormal growth is integrated into children's electronic health records, resulting in increased diagnoses of pathological short stature. Evidence-based anthropometric criteria for referral of short stature to secondary or tertiary care are now published, due largely to excellent studies in the Netherlands. Following referral of the short child, the protocol for laboratory investigations remains somewhat controversial because in healthy children their diagnostic yield can be too low for cost-effectiveness. However, outside of tertiary academic paediatric endocrinology centres, baseline screening tests are considered worthwhile and may speed up diagnosis and treatment. Finally, auxological cut-offs cannot replace good clinical practice, and the understanding that early and effective management depends on commitment to a diagnosis and individualisation of therapy in the short child cannot be overemphasised.

Background Poor adherence to long-term recombinant human growth hormone (r-hGH) treatment can lead to suboptimal clinical outcomes; consequently, supporting and monitoring adherence is a crucial part of patient management. We assessed adherence to r-hGH treatment in children with growth disorders over 48 months using a connected monitoring device (easypod™), which automatically transmits adherence data via an online portal (easypod™ connect); both sit within an adherence decision support system (ADSS). We also investigated the effect of age and sex on adherence. Methods Data from children transmitting over 10 injections between January 2007 and February 2019 were analyzed. Adherence (mg injected/mg prescribed) was categorized as high (≥85%), intermediate (> 56–84%) or low (≤56%) and assessed at seven time points from the start of treatment up to 48 months. Adherence was investigated over time and stratified by puberty status and sex. Mean transmission rate in each adherence category (total number of transmissions/total number of children) at each time point was calculated as a proxy measure of engagement in disease and treatment management. Descriptive analyses were performed. Results Longitudinal records were available for 13,553 children. Overall, 71% ( n = 9578) had high adherence, 22% ( n = 2989) intermediate and 7% ( n = 986) low. The proportion of children with high adherence decreased over time from 87% ( n = 12,964) to 65% ( n = 957) and was higher in pre-pubertal than pubertal children (girls: 80% [ n = 1270] vs 70% [ n = 4496]; boys 79% [ n = 2573] vs 65% [ n = 5214]). Children with high adherence had a higher mean number of transmissions (12.5 [SD 24.9]) than children with intermediate (7.2 [SD 15.3]) or low (3.5 [SD 5.7]) adherence. Conclusions High adherence was seen in patients administering r-hGH using the connected device. Children with high adherence were most likely to regularly transmit data. Pubertal children showed lower adherence. We show the potential to develop an ADSS to analyze trends in real-world adherence data. This may prove useful to direct interventions to improve adherence while the ability to readily share data with healthcare professionals may itself improve adherence.

The consequences of lifelong untreated childhood-onset GH deficiency (COGHD) on adult bone and especially fracture prevalence are largely unknown due to the lack of data on long-term outcome of untreated patients. Therefore, we studied adult Russian patients (n = 66; 28 females and 38 males) with idiopathic GH-untreated COGHD. Patients had isolated GH deficiency (IGHD; n = 18, age 23 +/- 10 yr) or multiple pituitary hormone deficiency (MPHD) with open (OMPHD; n = 27, age 23 +/- 5 yr) or closed growth plates (CMPHD; n = 21, age 55 +/- 12 yr). Bone mineral content (BMC) and bone mineral density (BMD) values were compared with 821 normal Russian controls. Fracture prevalence was ascertained from medical history and compared with similar data from 333 normal controls. Height sd score was -4.6 (range, -1.8 to -8.1). This represents 82% of the height of normal Russian adults. BMC of the lumbar spine, femoral neck, and total body of patients with IGHD was 54, 71, and 59%, respectively, of that of age- and sex-matched controls (all P < 0 0.001). A similarly decreased BMC (42-69% of expected values) was found for all bone regions of patients with both OMPHD and CMPHD. Mean areal BMD measurements (g/cm(2)) varied (Z scores between -1.8 and -3.0), but the calculated true bone density (g/cm(3)) was normal in patients with IGHD or CMPHD and only slightly decreased (Z score, -0.8) in patients with OMPHD. Lifetime low-energy fracture prevalence was normal in patients with IGHD but substantially exceeded the expected prevalence in OMPHD (odds ratio of fracture = 3.0; 0.6 fractures per patient; P < 0.0001) or CMPHD patients (odds ratio for fracture = 7.4; 2.2 fractures per patient; P < 0.0001). In conclusion, IGHD and MPHD of childhood onset very substantially impair adult height and BMC. Although areal BMD is frankly decreased, volumetric bone density is unaffected, but nevertheless, the fracture prevalence in patients with MPHD is markedly increased. These observations demonstrate that not only volumetric density but also bone mass and shape are major determinants of bone strength.