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Background: Hypothyroid crisis, or myxoedema coma, is a rare condition with high mortality and must be treated promptly. Even though it may be unfavourable, most guidelines only focus on intravenous drug administration due to lack of data on oral treatment., Methods/results: The course of oral treatment in two patients admitted in our hospital is described. Patients were treated with levothyroxine 1.3 μg/kg and liothyronine 25 μg twice daily, followed after 1 week with only levothyroxine 1.3 μg/kg daily. Oral treatment was successful in both patients without complications or side-effects., Conclusions: Oral substitution is an appropriate alternative to intravenous substitution, which has potential disadvantages and is associated with higher mortality., Learning Points: Hypothyroid crisis or myxoedema coma is a rare condition with a high mortality rate, so early diagnosis and prompt treatment are necessary.High-dose intravenous treatment is associated with higher mortality, so oral substitution may be an acceptable approach, especially as intravenous medicines are not widely available., Competing Interests: Conflicts of Interests: The authors declare there are no competing interests., (© EFIM 2021.)

Thionamides (such as thiamazole/methimazole) are a common first line treatment for Graves' disease. Common side effects include rash, urticaria, and arthralgia. However, thionamide treatment has also been associated with a variety of auto-immune syndromes. Here, we describe a patient presenting with mild arthritis after starting thiamazole. Although severe presentation warrants acute withdrawal of the causative agent, our case suggests that milder forms can be successfully treated with anti-inflammatory drugs alone. Recognition of the syndrome is key to warrant timely and effective treatment.

Context: Patients with Prader-Willi syndrome (PWS) are severely at risk to develop morbid obesity, diabetes mellitus type 2, and cardiovascular disease, leading to high mortality. They have an increased fat mass (FM) and decreased lean body mass (LBM). During childhood, GH treatment counteracts the natural course of increasing obesity. Discontinuation of GH treatment at attainment of adult height (AH) might deteriorate their improved clinical condition, whereas continuation might benefit them., Objective: To investigate the effects of GH versus placebo on body composition in young adults with PWS who were GH treated for many years during childhood and had attained AH., Design: Two-year, randomized, double-blind, placebo-controlled crossover study with stratification for gender and body mass index in 27 young adults with PWS., Setting: PWS Reference Center in The Netherlands., Intervention: Crossover intervention with GH (0.67 mg/m 2 · d) and placebo, both during 1 year., Main Outcome Measures: Body composition, measured by dual-energy x-ray absorptiometry., Results: During placebo, FM increased (relative change +21.5%; P < .001). Compared with placebo, GH treatment resulted in lower FM (-2.9 kg; P = .004) and higher LBM (+1.5 kg; P = .005), representing relative changes of -17.3% FM and +3.5% LBM. Both limb and trunk FM percentage were lower during GH versus placebo (relative change +17.3% and +15.6%; P < .001 and P = .007, respectively). No GH-related adverse events occurred., Conclusions: GH-treated young adults with PWS who have attained AH benefit from continuation of GH treatment. FM increases during placebo, whereas GH versus placebo results in lower FM and higher LBM. Thus, GH treatment maintains the improved body composition without safety concerns.

The aim of this study was to investigate the effect of growth hormone treatment on adaptive functioning in children with Prader-Willi syndrome. Vineland Adaptive Behavior Scale (VABS) was assessed during a randomized controlled trial (RCT) and after 7 years of growth hormone treatment. In the RCT, 75 children (42 infants and 33 prepubertal children) with Prader-Willi syndrome were included. Subsequently, 53 children were treated with long-term growth hormone. Our study demonstrates a marked delay in adaptive functioning in infants and children with Prader-Willi syndrome, which was associated with older age and lower intelligence. Results of the repeated measurements show that the earlier growth hormone treatment was started during infancy, the better the adaptive skills were on the long-term.

Context: Longitudinal data on bone mineral density (BMD) in children and adolescents with Prader-Willi Syndrome (PWS) during long-term GH treatment are not available., Objective: This study aimed to determine effects of long-term GH treatment and puberty on BMD of total body (BMDTB), lumbar spine (BMDLS), and bone mineral apparent density of the lumbar spine (BMADLS) in children with PWS., Design and Setting: This was a prospective longitudinal study of a Dutch PWS cohort., Participants: Seventy-seven children with PWS who remained prepubertal during GH treatment for 4 years and 64 children with PWS who received GH treatment for 9 years participated in the study., Intervention: The children received GH treatment, 1 mg/m(2)/day (≅ 0.035 mg/kg/d)., Main Outcome Measures: BMDTB, BMDLS, and BMADLS was measured by using the same dual-energy x-ray absorptiometry machine for all annual measurements., Results: In the prepubertal group, BMDTB standard deviation score (SDS) and BMDLSSDS significantly increased during 4 years of GH treatment whereas BMADLSSDS remained stable. During adolescence, BMDTBSDS and BMADLSSDS decreased significantly, in girls from the age of 11 years and in boys from the ages of 14 and 16 years, respectively, but all BMD parameters remained within the normal range. Higher Tanner stages tended to be associated with lower BMDTBSDS (P = .083) and a significantly lower BMADLSSDS (P = .016). After 9 years of GH treatment, lean body mass SDS was the most powerful predictor of BMDTBSDS and BMDLSSDS in adolescents with PWS., Conclusions: This long-term GH study demonstrates that BMDTB, BMDLS, and BMADLS remain stable in prepubertal children with PWS but decreases during adolescence, parallel to incomplete pubertal development. Based on our findings, clinicians should start sex hormone therapy from the age of 11 years in girls and 14 years in boys unless there is a normal progression of puberty.

Background: The most important reason for treating children with Prader-Willi syndrome (PWS) with GH is to optimize their body composition., Objectives: The aim of this ongoing study was to determine whether long-term GH treatment can counteract the clinical course of increasing obesity in PWS by maintaining the improved body composition brought during early treatment., Setting: This was a multicenter prospective cohort study., Methods: We have been following 60 prepubertal children for 8 years of continuous GH treatment (1 mg/m(2)/d ≈ 0.035 mg/kg/d) and used the same dual-energy x-ray absorptiometry machine for annual measurements of lean body mass and percent fat., Results: After a significant increase during the first year of GH treatment (P < .0001), lean body mass remained stable for 7 years at a level above baseline (P < .0001). After a significant decrease in the first year, percent fat SD score (SDS) and body mass index SDS remained stable at a level not significantly higher than at baseline (P = .06, P = .14, resp.). However, body mass index SDSPWS was significantly lower after 8 years of GH treatment than at baseline (P < .0001). After 8 years of treatment, height SDS and head circumference SDS had completely normalized. IGF-1 SDS increased to +2.36 SDS during the first year of treatment (P < .0001) and remained stable since then. GH treatment did not adversely affect glucose homeostasis, serum lipids, blood pressure, and bone maturation., Conclusion: This 8-year study demonstrates that GH treatment is a potent force for counteracting the clinical course of obesity in children with PWS.

Background: Disulfiram is a substance often used to treat alcohol dependency. The agent may be effective when used as supportive therapy. Disulfiram causes an accumulation of acetaldehyde when alcohol is consumed, which results in unpleasant sensations such as warmth, nausea, vomiting and headache., Case Description: A patient was brought into the emergency ward with a suspected alcohol intoxication. As it turned out, she had experienced a severe disulfiram-ethanol reaction which had led to hypotensive shock; extensive abnormalities were seen on the ECG. The patient was admitted to the intensive care unit. High-dose norepinephrine treatment was needed to bring the blood pressure back to normal. The use of disulfiram was only discovered at a later stage., Conclusion: In rare cases, a disulfiram-ethanol reaction can lead to life-threatening situations. Descriptions of toxicity at acetaldehyde levels of 5 mg/l are found in the literature. In this article, we describe a life-threatening reaction which developed at a level between only 2.3-3.0 mg/l. This case shows that the provision of information on a patient's use of medications and adequate communication are just as important as toxicological screening in the laboratory.

Background: Knowledge about the effects of GH treatment on cognitive functioning in children with Prader-Willi syndrome (PWS) is limited., Methods: Fifty prepubertal children aged 3.5 to 14 yr were studied in a randomized controlled GH trial during 2 yr, followed by a longitudinal study during 4 yr of GH treatment. Cognitive functioning was measured biennially by short forms of the WPPSI-R or WISC-R, depending on age. Total IQ (TIQ) score was estimated based on two subtest scores., Results: During the randomized controlled trial, mean sd scores of all subtests and mean TIQ score remained similar compared to baseline in GH-treated children with PWS, whereas in untreated controls mean subtest sd scores and mean TIQ score decreased and became lower compared to baseline. This decline was significant for the Similarities (P = 0.04) and Vocabulary (P = 0.03) subtests. After 4 yr of GH treatment, mean sd scores on the Similarities and Block design subtests were significantly higher than at baseline (P = 0.01 and P = 0.03, respectively), and scores on Vocabulary and TIQ remained similar compared to baseline. At baseline, children with a maternal uniparental disomy had a significantly lower score on the Block design subtest (P = 0.01) but a larger increment on this subtest during 4 yr of GH treatment than children with a deletion. Lower baseline scores correlated significantly with higher increases in Similarities (P = 0.04) and Block design (P < 0.0001) sd scores., Conclusions: Our study shows that GH treatment prevents deterioration of certain cognitive skills in children with PWS on the short term and significantly improves abstract reasoning and visuospatial skills during 4 yr of GH treatment. Furthermore, children with a greater deficit had more benefit from GH treatment.

Context: The pathophysiology of hypogonadism in boys with Prader-Willi Syndrome (PWS) remains uncertain. Several reports described hypogonadotropic hypogonadism, some reported primary gonadal failure, and others a combination of both., Objectives: The aim of the study was to evaluate gonadal function over time in boys with PWS and the effect of GH treatment., Measurements: We made a longitudinal assessment of inhibin B, FSH, testosterone, and LH levels in prepubertal boys and male adolescents with PWS., Patients and Methods: We studied 68 boys participating in the Dutch PWS Cohort study. Serum inhibin B, FSH, LH, and testosterone levels were compared with reference values., Results: Boys with PWS had normal inhibin B levels between 6 months and 10 yr of age, but after onset of puberty, inhibin B levels declined to less than the 5th percentile, and FSH levels increased to more than the 95th percentile. Two years after the onset of puberty and in young adults, inhibin B levels were significantly lower (P=0.008 and P<0.0001), and FSH levels were significantly higher (P=0.034 and P<0.0001) than at onset of puberty. Testosterone levels increased but remained below the 5th percentile, and LH levels increased but not above the 95th percentile. Age showed a significant correlation with inhibin B levels (r=-0.31; P=0.001) after 9 yr of age. GH treatment had no significant effect on inhibin B levels., Conclusion: Our study indicates that the majority of male patients with PWS have primary testicular failure, which becomes apparent after onset of puberty. Hypogonadotropic hypogonadism did not appear to be the main reason of hypogonadism in most boys.

Context: Premature pubarche (PP) is reported in children with Prader-Willi Syndrome (PWS). Pubarche is preceded by adrenarche - an increase in serum levels of adrenal androgens, most specifically dehydroepiandrosterone sulphate (DHEAS)., Objectives: To assess DHEAS levels, the age at and progression of pubarche and the prevalence of PP in children with PWS., Design/patients: In the Dutch PWS Cohort Study, 120 children (6 months-17 years) are prospectively followed. Their age at onset of pubarche and various pubic hair stages and prevalence of PP were determined. Serum DHEAS levels were assessed in 97 children., Results: Median serum DHEAS levels were significantly higher in children with PWS than in healthy age-matched controls at ages 3-6 years (girls: P = 0·004 and boys: P = 0·010) and 6-10 years (girls: P = 0·045 and boys: P = 0·001). Age and gender significantly influenced DHEAS levels in children with PWS. The median [P10-P90] age at onset of pubarche in children with PWS was significantly younger than in healthy peers, 9·04[6·75-11·84] years in PWS girls (P < 0·0001) and 10·31 [8·65-12·29] years in PWS boys (P = 0·003). The prevalence of PP in children with PWS was 30·0% in girls and 16·1% in boys., Conclusions: Compared to healthy children, children with PWS have significantly higher DHEAS levels from 3 to 10 years of age. They are younger at onset of pubarche and have a higher prevalence of premature pubarche. DHEAS levels in PWS are influenced by age and gender. Our findings indicate earlier maturation of the zona reticularis of the adrenal glands in children with PWS., (© 2011 Blackwell Publishing Ltd.)

Context: Reports on the cardiovascular and metabolic risk profile in children with Prader-Willi syndrome (PWS) and the effects of GH treatment are scarce. Acylation-stimulating protein (ASP) stimulates glucose uptake and triglyceride storage in adipose tissue., Objectives: The aim was to study the metabolic and cardiovascular risk profile and ASP levels and to investigate the effects of GH treatment., Design: We conducted a randomized controlled GH trial. Infants and prepubertal children were assigned to receive GH (1 mg/m(2) . d) or to serve as controls for 12 and 24 months, respectively., Patients: Eighty-five children with PWS (mean +/- sd age of 4.9 +/- 3.0 yr) participated in the study., Main Outcome Measures: We measured fat percentage (fat%) with dual-energy x-ray absorptiometry, blood pressure, fasting insulin and glucose levels, serum lipids, and ASP levels., Results: Mean +/- SD fat% was 28.4 +/- 6.2 in infants and 36.9 +/- 8.5 in prepubertal children. Fat% sd score (SDS) was above 2 SDS in 95% of prepubertal children. In addition, 63% of infants and 73% of prepubertal children demonstrated at least one cardiovascular risk factor, defined as hypertension or dyslipidemia. The metabolic syndrome was demonstrated in 5% of all children. Mean +/- sd baseline ASP was 107 +/- 45 nmol/liter (normal < 58 nmol/liter) and correlated with fat mass and TG levels. GH improved fat%SDS and the HDLc/LDLc ratio (P < 0.0001 and P = 0.04). GH had no effect on mean ASP levels in this population., Conclusions: Many children with PWS had dyslipidemia and high ASP levels. GH improved fat% and high-density lipoprotein cholesterol/low-density lipoprotein cholesterol, but not ASP. High ASP levels may prevent complete normalization of fat%SDS during GH treatment but may contribute in keeping glucose and insulin levels within normal range.

Background: Children with Prader-Willi syndrome (PWS) have abnormal body composition and impaired growth. Short-term GH treatment has beneficial effects., Objectives: The aim of the study was to investigate effects of long-term continuous GH treatment on body composition, growth, bone maturation, and safety parameters., Setting: We conducted a multicenter prospective trial., Design: Fifty-five children with a mean +/- sd age of 5.9 +/- 3.2 yr were followed during 4 yr of continuous GH treatment (1 mg/m(2) . d). Data were annually obtained in one center: fat percentage (fat%) and lean body mass (LBM) by dual-energy x-ray absorptiometry, height, weight, head circumference, bone age, blood pressure, and fasting IGF-I, IGF binding protein-3, glucose, insulin, glycosylated hemoglobin, total cholesterol, high-density lipoprotein, and low-density lipoprotein. sd scores (SDS) were calculated according to Dutch and PWS reference values (SDS and SDS(PWS))., Results: Fat%SDS was significantly lower after 4 yr of GH treatment (P < 0.0001). LBMSDS significantly increased during the first year (P = 0.02) but returned to baseline values the second year and remained unchanged thereafter. Mean +/- sd height normalized from -2.27 +/- 1.2 SDS to -0.24 +/- 1.2 SDS (P < 0.0001). Head circumference SDS increased from -0.79 +/- 1.0 at start to 0.07 +/- 1.1 SDS after 4 yr. BMISDS(PWS) significantly decreased. Mean +/- sd IGF-I and the IGF-I/IGF binding protein-3 ratio significantly increased to 2.08 +/- 1.1 and 2.32 +/- 0.9 SDS, respectively. GH treatment had no adverse effects on bone maturation, blood pressure, glucose homeostasis, and serum lipids., Conclusions: Our study in children with PWS shows that 4 yr of continuous GH treatment (1 mg/m(2) . d) improves body composition by decreasing fat%SDS and stabilizing LBMSDS and head circumference SDS and normalizes heightSDS without adverse effects. Thus, long-term continuous GH treatment is an effective and safe therapy for children with PWS.

Background: Bone mineral density (BMD) is unknown in children with Prader-Willi syndrome (PWS), but is decreased in adults with PWS. In patients with GH deficiency, BMD increases during GH treatment., Objectives: The aim of the study was to evaluate BMD in children with PWS and to study the effects of GH treatment., Design: We conducted a randomized controlled GH trial. Forty-six prepubertal children were randomized into either a GH-treated group (1.0 mg/m(2) . d) or a control group for 2 yr. At start, 6, 12, and 24 months of study, total body and lumbar spine BMD were measured by dual-energy x-ray absorptiometry, and lumbar spine bone mineral apparent density (BMAD) was calculated., Results: Baseline total body and lumbar spine BMD sd score (SDS) were normal [mean (sd), -0.2 SDS (1.1) and -0.4 SDS (1.2), respectively]. BMADSDS, which corrects for short stature, was also normal [mean (sd), 0.40 SDS (1.1)]. Total body BMDSDS decreased during the first 6 months of GH (P < 0.0001), but increased during the second year of treatment. After 24 months of study, total body and lumbar spine BMDSDS, and the BMADSDS did not significantly differ between GH-treated children and randomized controls (P = 0.30, P = 0.44, and P = 0.47, respectively). Results were similar when corrected for body mass index SDS. Repeated measurements analysis showed a significant positive association between IGF-I SDS and total body and lumbar spine BMDSDS, but not with BMADSDS., Conclusions: Our results show that prepubertal children with PWS have a normal BMD. GH treatment had no effect on BMD, except for a temporary decrease of total body BMDSDS in the first 6 months.

Background: The annual death rate of patients with Prader-Willi syndrome (PWS) is high (3%). Many deaths of children are sudden and unexplained. Sleep apneas have been suggested to play a role in sudden deaths. Recently, we discovered that 60% of patients with PWS suffer from central adrenal insufficiency (CAI) during stress., Objective: The aim was to study the relationship between CAI and sleep-related breathing disorders., Design: In 20 children with PWS who underwent a metyrapone test (30 mg/kg at 2330 h), sleep-related breathing was evaluated by polysomnography before the metyrapone test. In addition, we recorded sleep-related breathing in 10 children with PWS during their metyrapone test. CAI was diagnosed when ACTH levels during the metyrapone test were below 33 pmol/liter at 0730 h. All tests were performed during healthy condition., Setting: The study was conducted in a pediatric intensive care unit and specialized sleep center., Results: Median (interquartile range) age was 8.4 yr (6.5-10.2). After metyrapone administration, median (interquartile range) central apnea index (number/hour) increased significantly from 2.2 (0.4-4.7) to 5.2 (1.5-7.9) (P = 0.007). The increase tended to be higher in children with CAI [2.8 (2.0-3.9) vs. 1.0 (-0.2 to 2.6); P = 0.09]. During polysomnography before the metyrapone test, sleep-related breathing was worse in children with CAI, who had a significantly higher central apnea index and tended to have a lower minimum oxygen saturation compared to those without CAI (P = 0.03 and P = 0.07)., Conclusions: In children with PWS, the central apnea index increased significantly after metyrapone administration, particularly in those with CAI during stress. In addition, children with CAI had a higher central apnea index compared to those without several months before the metyrapone test.

Context: The prevalence of scoliosis in children with Prader-Willi syndrome (PWS) is 30-80%, depending on age. Although reports about effects of GH treatment on scoliosis in children with PWS are limited, scoliosis is generally considered a contraindication for GH treatment., Objective: The aim was to study the effects of GH treatment on the onset of scoliosis and curve progression in children with PWS., Design: We conducted a multicenter, randomized, controlled GH study in infants and prepubertal and pubertal children. Infants and prepubertal children were randomized into a GH-treated group (1.0 mg/m(2) . d) and a control group for 1 and 2 yr, respectively. Pubertal children were randomized to receive somatropin 1.0 or 1.5 mg/m(2) . d. Yearly, x-rays of the spine were taken, and height, weight, truncal lean body mass (with dual energy x-ray absorptiometry), and IGF-I were measured., Patients: A total of 91 children with PWS (median age, 4.7 yr; interquartile range, 2.1-7.4) participated in the study., Main Outcome Measures: We measured the onset of scoliosis (Cobb >10 degrees ) and scoliotic curve progression., Results: GH-treated children had similar onset of scoliosis and curve progression as randomized controls (P = 0.27-0.79 and P = 0.18-0.98, respectively). GH treatment, IGF-I sd score (SDS), and catch-up growth had no adverse effect on the onset of scoliosis or curve progression, even after adjustment for confounders. Height SDS, truncal lean body mass, and IGF-I SDS were significantly higher in GH-treated children than in randomized controls. At baseline, a higher IGF-I SDS was associated with a lower severity of scoliosis., Conclusions: Scoliosis should no longer be considered a contraindication for GH treatment in children with PWS.

Background: The reported prevalence of scoliosis in children with Prader-Willi syndrome varies from 15% to 86%., Objective: To study the prevalence of scoliosis and the effects of age, gender, body mass index (BMI), total lean body mass (LBM), LBM of the trunk (trunkLBM) and genotype., Design: Radiographs were taken, length and weight were measured (BMI standard deviation scores (BMI SDS) and body surface area (BSA)), and dual energy x-ray absorptiometry was performed, measuring LBM and trunkLBM., Patients: 96 children, median (interquartile range) age 4.8 years (2.1 to 7.5), were included in a multicentre study. None received growth hormone treatment., Main Outcome Measures: Two types of scoliosis were identified: (1) long C-curve type scoliosis (LCS) and (2) idiopathic scoliosis (IS). Children were divided into age categories (infants, 0-3 years; juveniles, 3-10 years; adolescents, 10-16 years)., Results: The prevalence of scoliosis was 37.5% and increased with age (infants and juveniles, approximately 30%; adolescents, 80%); 44% of children with scoliosis had a Cobb angle above 20 degrees . Children with scoliosis were significantly older than those without. Children with LCS were younger and more hypotonic than those with IS: median (interquartile range) age 4.4 years (1.7-5.9) vs 11.1 years (6.5-12.1) (p = 0.002) and trunkLBM/BSA ratio 7080 (6745-7571) vs 7830 (6932-8157) (p = 0.043)., Conclusions: The prevalence of scoliosis in children with Prader-Willi syndrome is high (37.5%). Many children with scoliosis (13%) had undergone brace treatment or surgery. The type of scoliosis is affected by age and trunkLBM/BSA ratio.

Context: The annual death rate of Prader-Willi syndrome (PWS) patients is very high (3%). Many of these deaths are sudden and unexplained., Objective: Because most deaths occur during moderate infections and PWS patients suffer from various hypothalamic insufficiencies, we investigated whether PWS patients suffer from central adrenal insufficiency (CAI) during stressful conditions., Design: Overnight single-dose metyrapone tests were performed. Metyrapone (30 mg/kg) was administered at 2330 h. At 0400, 0600, and 0730 h, ACTH, 11-deoxycortisol, cortisol, and glucose levels were measured. Diurnal salivary cortisol profiles were assessed on a different day at wake-up, 30 min after wake-up, at 1400 h, and at 2000 h., Setting: The study was conducted in a pediatric intensive care unit., Patients: Patients included 25 randomly selected PWS patients., Main Outcome Measure: Patients were considered as having CAI when ACTH levels remained below 33 pmol/liter at 0730 h., Results: Median (interquartile range) age was 9.7 (6.8-13.6) yr. Fifteen patients (60%) had an insufficient ACTH response (CAI, P < 0.001). There was no significant difference in age, gender, genotype, and body mass index SD score between patients with CAI and those without. Morning salivary cortisol levels and diurnal profiles were normal in all children, suggesting that CAI becomes apparent only during stressful conditions., Conclusions: Strikingly, 60% of our PWS patients had CAI. The high percentage of CAI in PWS patients might explain the high rate of sudden death in these patients, particularly during infection-related stress. Based on our data, one should consider treatment with hydrocortisone during acute illness in PWS patients unless CAI has recently been ruled out with a metyrapone test.