Patients with Prader-Willi syndrome (PWS) are recognized to have a tendency of sudden, unexpected death (SED), but its exact cause is unknown because of paucity of such case reports. Since growth hormone (GH) treatment was applied to PWS patients worldwide, several cases of death have been reported. However, whether the therapy is directly related to their SED remains unknown, too. We collected 13 deceased PWS patients (Group A, aged 9 months to 34 years) who had never received GH therapy, and seven deceased patients (Group B, all boys aged 0.7-15 years) having received the therapy from the registration in PWS-patient-support associations and from the literature, respectively. We then compared the cause of SED between the two groups. Irrespective of GH therapy, SED of infants under age 1 year was associated with milk aspiration or hypothalamic dysregulation of respiration, while SED of patients in early childhood or adolescence occurred at sleeping in association with preceding viral infections. In contrast, SED of four adult (>20 years of age) patients who never received GH therapy was associated with complications, such as leg cellulites and pulmonary embolism, secondary to massive obesity and diabetes mellitus (DM). Two Group-B patients (aged 14 and 20 years) without any obesity-related or diabetes-related complications died of drowning in a bath tub, and their drowning death could be related to poor respiratory control. These findings indicated that the cause of SED is not essentially different between PWS patients with and without GH treatment. Deceased PWS patients may have had underlying respiratory dysregulation and hypothalamic dysfunction, and GH therapy might have led to certain obstructive respiratory disturbances that exacerbated the respiratory conditions. This will call clinicians' attention when using GH in PWS patients, for example, careful determination of the dose of GH and careful monitoring of patient's respiratory conditions, especially in male obese patients with respiratory problems.

Growth hormone (GH) therapy for short stature in patients with Prader-Willi syndrome (PWS) has started worldwide, and various favorable effects have been reported. However, the possibility of progression of scoliosis arises as a new problem of the GH therapy. In this study, we analyzed whether 72 patients who have been followed up in our hospital have such a problem. They included 46 males and 26 females (41 patients with the GH therapy and 31 without it) aged from one to 49 years. Consequently, 33 (45.8%) of 72 patients had scoliosis with the Cobb angle of >10 degrees. Twenty (48.8%) of forty-one patients who received a GH therapy and 13 (41.9%) of 31 patients without the therapy had scoliosis, the frequency of scoliosis between the two groups showing no statistical difference (P = 0.56). Height velocity of scoliotic and non-scoliotic patients during the first year of the therapy was 8.59 +/- 1.92 and 10.70 +/- 2.54 cm, respectively, showing a significant difference (P < 0.001). This shows that accelerated height velocity may not induce scoliosis. Comparison of starting age of a GH treatment revealed that non-scoliotic patients received the therapy earlier than scoliotic patients (P = 0.021). Among 20 scoliotic patients who received the GH therapy, the degree of scoliosis progressed during the therapy in six patients, improved in three and fluctuated in one. Many patients showed progression of scoliosis with age irrespective of the use of GH, and some patients improved their scoliosis during the GH therapy. These findings showed that a GH therapy increases height velocity of PWS patients but does not necessarily develop scoliosis, and early start of the therapy may not be an exacerbating factor of scoliosis.

We report a 4-year-old boy, a 6-month-old girl, and a 17-week-old fetus all with a chromosomal imbalance derived from a balanced translocation t(13;15)(q34;q26.1) of their father. The boy had a partial trisomy for 15q26.1-qter (46,XY,der(13)t(13;15)(q34;q26.1)) and postnatal overgrowth, as well as craniosynostosis, facial anomalies, and finger joint contractures, while the girl with the same chromosomal aberration did not show overgrowth, although she had similar craniofacial and skeletal abnormalities. The fetus had a partial monosomy for 15q26.1-qter and intrauterine growth retardation (IUGR). Fluorescence in situ hybridization (FISH) analysis with a BAC clone covering the insulin-like growth factor 1 receptor gene (IGF1R) that is located to 15q25-q26 revealed three copies in the boy, one copy in the fetus, and two copies in their phenotypically normal father. Since deletion of IGF1Rhas repeatedly been reported to be associated with IUGR, it is tempting to speculate that the dosage of IGF1R may have determined growth in these children.

Marked anthropometric changes are seen in Prader-Willi syndrome (PWS). Emaciation is observed during infancy, whereas severe obesity is found in older children and adults. Growth hormone (GH) treatment modifies the anthropometric changes in PWS patients. In this study, we examined changes in the body composition of 51 PWS patients (age range, 6-54 years; median, 16.5 years), with a focus on the amount of abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), VAT/SAT ratio, and serum levels of adipocytokines (adiponectin, leptin, and resistin). The relationships between VAT, SAT, and adipocytokines, and lipid abnormalities and type 2 diabetes in 24 patients with obese PWS were also evaluated. With increasing age, SAT and VAT both increased markedly, but in 18 patients receiving GH treatment, VAT remained low at ≤30 cm(2) . In the GH-completed patients (n = 19), VAT and SAT increased with age to levels similar to those in non-GH-treated patients (n = 14). In the obese group, adiponectin decreased as VAT increased (r = -0.35, P = 0.11). Leptin (r = 0.67, P < 0.001) and resistin (r = 0.45, P = 0.04) showed positive correlations with SAT. Total cholesterol, low-density lipoprotein, and triglyceride levels correlated negatively with adiponectin (r = -0.59, r = -0.56, r = -0.56, respectively, P < 0.05) and hemoglobin A1c (r = -0.42, P = 0.08). To maintain lower VAT and prevent cardiovascular disease risk factors, GH treatment may be advisable even in adult patients with PWS.

Prader-Willi syndrome (PWS), a complex genetic disorder, arises from suppressed expression of paternally inherited imprinted genes on chromosome 15q11-q13. Characteristics include short stature, intellectual disability, behavioral problems, hypogonadism, obesity, and reduced bone and muscle mass. Testosterone replacement (TR) remains controversial due to concerns regarding behavioral problems. To evaluate the effects of TR on secondary sexual characteristics, body composition, and behavior in adult males with PWS, 22 male PWS patients over the age of 16 with behavioral scores of less than grade 4 on the Modified Overt Aggression Scale (MOAS) underwent monthly intramuscular TR (125 mg). Pubertal change, body composition and behavior were evaluated before and after 24 months of therapy. Serum testosterone, LH, and FSH did not change. Increased pubic hair was observed in 16 of 22 patients (72.7%). Percent body fat decreased from 47.55 ± 2.06% to 39.75 ± 1.60% (n = 18) (P = 0.018). Bone mineral density increased from 0.8505 ± 0.0426 g/cm(2) to 0.9035 ± 0.0465 g/cm(2) (n = 18) (P = 0.036), and lean body mass increased from 18093.4 ± 863.0 g to 20312.1 ± 1027.2 g (n = 18) (P = 0.009). The MOAS was unchanged, from 4.5 ± 2.0 at the beginning of the study to 3.0 ± 1.7 at the end of study indicating no increase in aggression. No behavioral problems were observed. Based on this pilot study, TR with 125 mg monthly is a potentially safe and useful intervention for adult males with PWS.

Long-term treatment with growth hormone (GH) in patients with Prader-Willi syndrome (PWS) improves not only height velocity, height standard deviation score, and final height, but also the degree of obesity and body composition abnormalities. Anecdotally, PWS patients tend to suffer from severe obesity and its complications after cessation of GH therapy. However, there have been no studies to investigate changes in body mass index (BMI) and adipose tissue distribution after cessation of GH therapy in young PWS patients. Therefore, we investigated changes in the BMI-standard deviation score (SDS) and adipose tissue distribution after cessation of GH therapy in PWS patients. We evaluated 14 PWS patients. BMI-SDS was calculated at 0, 6, 12, 18, and 24 months before and after cessation of GH treatment. We also evaluated subcutaneous adipose tissue (SAT) (cm(2)) and visceral adipose tissue (VAT) (cm(2)) area in 8 of the 14 study patients with single slice abdominal computed tomography at the level of the umbilicus. The BMI-SDS significantly increased at 6, 12, 18, and 24 months after cessation of GH therapy (P = 0.039, P = 0.008, P = 0.003, P = 0.003, respectively). There was a tendency toward increases in VAT at 12 and 24 months after cessation of GH therapy, but the increases did not reach statistical significance (P = 0.062, P = 0.125, respectively). Therefore, cessation of GH therapy in PWS patients worsened BMI. To maintain good body composition and prevent complications of obesity, long-term use of GH in adult PWS patients may be advisable.

Growth hormone (GH) therapy is now widely given to Prader-Willi syndrome (PWS) patients to encourage growth in body height and to prevent obesity. Scoliosis, one of the complications in this syndrome, is thought to be accelerated in parallel with a rapid increase in body height, especially during adolescence. To determine whether GH therapy aggravates scoliosis and to identify any factor which might predict the progression of scoliosis, we studied 35 (22 males and 13 female) PWS patients between the ages of 2-16 years on GH therapy whose scoliosis was followed with spinal X-rays every 6 months. Thirteen (37.1%) of 35 patients had scoliosis with a Cobb angle of over 10°. Scoliosis was unchanged in five patients (14.3%), became worse in six (17.1%) and improved in two (5.7%). All 22 (62.9%) of 35 patients who did not have scoliosis did not develop scoliosis with GH therapy. Since abnormal paraspinal muscle development was thought to induce scoliosis, we measured cross-sectional areas of paraspinal muscles by using one slice CT scan at the level of the umbilicus at the level of L4. Since there was a delay in the increase in total paravertebral muscle area and prolonged asymmetry in patients with progressive scoliosis, both were thought to be useful predictors of progressive scoliosis in PWS patients with GH therapy.

Long-term treatment with GH in patients with PWS improved height velocity, height SDS, final height, and the degree of obesity. These data encourage the long-term use of GH in these patients.