Endocrinological Abnormalities in Prader-Willi Syndrome

Ten patients with typical Prader-Willi syndrome were studied for their short stature, hypogonadism, and obesity. Tne following results were obtained.

• 1) GH secretion was variable, ranging from subnormal to normal, although all shared short stature in common.
• 2) Two of the 4 adolescent patients were diagnosed as having hypo-gonadotropic hypogonadism. The remainder disclosed normal response to LH-RH stimulation. Of the two patients with normal LH-RH stimulation test, one showed normal testosterone production.
• 3) In one child who developed overt diabetes, there remained elevated basal plasma insulin and depressed RBC-insulin binding, despite weight control. There appears to be a significant heterogeneity in endo crinological derangement of Prader-Willi syndrome.

     

Hypotonic infants and the Prader-Willi Syndrome

OBJECTIVE: To describe 6 patients with less than 3 years of age that were diagnosed with Prader-Willi syndrome (PWS) due to hypotonia, poor sucking, slight facial anomalies and minor abnormalities of hands and feet. PWS is a neurobehavioural disorder characterized by two distinct phases; in the first, the neonate presents variable degree of hypotonia, feeding problems with none or poor sucking; hypogonadism, characteristic facial features with almond shaped eyes, narrow bifrontal diameter and down-turned corners of the mouth. Neuropsichymotor development is delayed. Hypotonia is non progressive and tends to improve between 8 and 11 months of age. The second phase then starts and is characterized by increasing hyperphagia and obesity, among other features. Unfortunately, most PWS patients are diagnosed only after obesity is installed. METHODS: Methylation, microsatellites analysis and karyotypic studies by traditional and in situ hybridization techniques were done. RESULTS: A deletion of chromosome segment 15q11q13 was disclosed in 4 and maternal disomy in two patients. CONCLUSION: The diagnosis of PWS is generally established after the onset of obesity. So, we suggest that the genetic analysis must be carried out in children with severe hypotonia of unknown cause, poor sucking and some facial features of PWS (small hands and feet, hypogonadism, hypopigmentation, almond eyes and narrow bifrontal diameter). This can allow the early diagnosis and avoid invasive exams necessary for neuromuscular disorder diagnosis like muscle biopsy and electroneuromiography, wich frequently are associated with inconclusives results.     

Obsessions and Compulsions in Prader-Willi Syndrome

This study examines the nature, severity and correlates of non-food obsessions and compulsions in 91 people with Prader-Willi syndrome (PWS) aged 5–47 years (mean age = 19 years). Prominent symptoms, seen in 37–58% of the sample, included hoarding; ordering and arranging; concerns with symmetry and exactness; rewriting; and needs to tell, know or ask. A remarkably high proportion of participants had moderate to severe symptom severity ratings; 64% showed symptom-related distress, and 80% showed symptom-related adaptive impairment. The study also compared obsessive-compulsive symptoms in 43 adults with PWS to age- and sex-matched non-retarded adults with obsessive-compulsive disorder (OCD). The PWS and OCD groups showed similar levels of symptom severity and numbers of compulsions; they also showed more areas of symptom similarity than difference. Increased risks of OCD in persons with PWS are strongly indicated. Implications are discussed for pharmacotherapy, behavioral therapy and family support.     

Growth Hormone Secretion in Prader-Willi Syndrome

ABSTRACT. Integrated 12-hour growth hormone secretion studies, peak growth hormone response to clonidine provocation. Somatomedin-C levels, T-4 and TSH levels were studied in six growth-retarded children with the Prader-Willi syndrome, of whom five had a 15 q-karyotype. Only one of the subjects was obese. All showed abnormally low growth hormone secretion. None achieved a nocturnal peak above 10 μg/l, none had a mean nocturnal level over 1.8, and none showed a level above 8 μg/l after clonidine provocation. These findings contrasted with normal TSH in all and normal T-4 in five. These findings suggest that the poor linear growth in the Prader-Willi syndrome is caused by a true deficiency of growth hormone secretion, and that the low growth hormone levels observed in such cases are not an artifact of obesity     

Autopsy Findings in the Prader-Willi Syndrome

Autopsy findings in two cases of Prader-Willi syndrome were described. Case 1. was a 4–3/12 year-old boy who had hypotonia in the neonatal period, hypogonadism, mental retardation and obesity. Autopsy revealed edema, congestion and focal bleeding in the lung, cardiac hypertrophy, localized degeneration of corpus callosum, nesidioblastosis, fatty liver and absence of testicular tissue. Case 2. was a3–11/12 year-old boy who had hypotonia in the neonatal period, hypogonadism, mental retardation, obesity and recurrent respiratory tract infections. Autopsy revealed multiple thrombosis, pulmonary changes including edema, congestion, focal bleeding and infarcts, cardiac hypertrophy, fatty liver and absence of testicular tissue. These findings were thought to be summarized in the following three categories; 1) terminal changes characterized by pulmonary edema and congestion and cardiomegaly probably due to respiratory failure, 2) aquired changes due to metabolic abnormalities in this syndrome including fatty liver, nesidioblastosis and focal degeneration of the central nervous system; and 3) congenital abnormalities characterizing hypogonadism. (Acta Paediatr Jpn 23(3):289–293 1981)     

Clinical and Molecular Characterization of Prader-Willi Syndrome

Objectives

To describe the clinical presentations and molecular diagnosis to aid the clinicians in early diagnosis and appropriate management of Prader-Willi syndrome (PWS).

Methods

Thirty-four clinically diagnosed PWS cases were enrolled after obtaining informed consent/assent. Demographic details, clinical data and anthropometry were recorded using structured proforma. The facial dysmorphology was evaluated. Appropriate genetic testing was performed to confirm the diagnosis.

Results

At diagnosis, the most common clinical features included obesity (59%) and short stature (53%). Distinct dysmorphic features were observed in 67%. Neonatal hypotonia with feeding difficulty, delayed development in infancy and childhood behavioral problems were reported in 94%, 94% and 74% respectively. Food seeking behavior and hyperphagia was reported in 67%. Seizures were reported in 47%. All children had underdeveloped external genitalia. Growth hormone (GH) deficiency and impaired glucose tolerance were found in 56% and 50% respectively. Sleep related problems were seen in 67%. Skin and rectal picking were reported in 67%. FISH confirmed micro-deletion was found in 64.7% and abnormal methylation in 35%, of which uniparental disomy was confirmed in 14.7%.

Conclusions

Clinical suspicion is vital for early detection of PWS. Confirmation of the diagnosis requires complex multi-tier molecular genetic testing.

     

Prader-Willi Syndrome after age 15 years.

Twenty-four patients, all of them over 15 years, with the Prader-Willi syndrome are described. Obesity, often extreme, associated with an insatiable appetite, was their principal handicap and this was made worse by educational subnormality and hypogonadism. Three of the them developed diabetes. Each attended a special school or an adult training centre. Although most of them were of short stature and had scoliosis, 2 were tall but they even more severely mentally retarded than is usually the case. Nine other patients died aged between 3 and 23 years. The most common cause of death was cor pulmonale.     

Histopathological Background of Muscle Hypotonia in Children with the Prader-Willi Syndrome

To elucidate the pathogenesis of hypotonia in the Prader-Willi syndrome, a histological approach towards the five cases was adopted, and traditional histological, histochemical and electron microscopic studies were perfomed. As a result, in light microscopic study type 2 fiber atrophy was found in all the five cases examined, and a combination with type 2 predominance in 3 cases. In addition, localized myopathic change was found in one case and regenerated fiber in another. In electron microscopic study, dilatation of sercoplasmic reticulum, mitochondrial swelling, increased glycogen particles, disappearance of myofilament and partial streaming of Z disc were observed. The presence of these findings led us to propose the hypothesis that there were some disorders in trophic influence on the muscle from the central nervous sytem, mainly in intrauterine life, of subjects with the Prader-Willi syndrome. (Acta Paediatr Jpn 23(3): 294–300 1981)     

Growth hormone and respiratory compromise in Prader-Willi Syndrome

Recombinant human growth hormone (rhGH) therapy in Prader-Willi syndrome (PWS) causes increased basal metabolic rate and oxygen consumption, and hence increased ventilatory load. The case of an adolescent with PWS who experienced respiratory deterioration with an increase in rhGH and improvement with cessation of therapy is reported.     

The Current Status of Prader-Willi Syndrome in Japan

A survey study was done on the Prader-Willi syndrome in Japan during the 5-year period between 1975 and 1979. The total number of cases was 137 and detailed data were obtained on 61 cases. The patients had muscular hypotonia during infancy. After the age of 3 years, obesity developed and diabetes mellitus was often observed in the cases older than 9 years. As for minor anomalies, almond eyes were the most common, and next was a fish-shaped mouth. In some cases, hypogonadism was due to hypofunction of the testes, though in others it was due to a disorder of the hypothalamus.     

A survey of 22 individuals with Prader-Willi Syndrome in New South Wales

Abstract Twenty-two individuals with Prader-Willi Syndrome in New South Wales were surveyed. The results show that males were diagnosed at a significantly earlier age than females and suggest a recent trend towards earlier diagnosis. The advantages of early diagnosis are discussed. In those in whom cytogenetic studies had been performed, 47% were found to have a deletion involving chromosome 15q11–13. Profound neonatal hypotonia had been present in all cases. Obesity became apparent between 1.5 and 10 years (mean = 3.8 years). Facial dysmorphism was reported in 83% and acromicria in 100%. Sixty-two per cent of subjects were regarded as less pigmented than first degree relatives. Cognitive assessments were performed on nine subjects. Two (22%) were functioning in the normal range of intelligence. Behaviour problems, both food-related and non-food-related, were present in the majority and placed considerable stress on the family caring for the individual with Prader-Willi Syndrome.     

Growth hormone and respiratory compromise in Prader-Willi Syndrome.

Recombinant human growth hormone (rhGH) therapy in Prader-Willi syndrome (PWS) causes increased basal metabolic rate and oxygen consumption, and hence increased ventilatory load. The case of an adolescent with PWS who experienced respiratory deterioration with an increase in rhGH and improvement with cessation of therapy is reported.     

Improving body composition and physical activity in Prader-Willi Syndrome

OBJECTIVE: To determine if muscle training in Prader-Willi Syndrome (PWS) can improve local body composition, physical capacity, and activity. STUDY DESIGN: Seventeen children and adolescents with PWS and 18 control children were enrolled in a daily short calf muscle training program for 3 months. Before (t(0)) and after 3 months of training (t(3m)), spontaneous physical activity and exercise capacity were assessed by pedometer registrations and activity protocols. Local body composition was determined by calf circumference and skinfold measurements at t(0), t(3m), and 3 months after t(3m) (t(6m)). RESULTS: During training, calf skinfold decreased from 1.1 to 0.8 SD (P <.01) and calf circumference in PWS increased from 1.4 to 1.9 SD (P <.05), reflecting improved muscle mass. At t(3m), a significant increase in spontaneous physical activity (from 45% to 71%, compared with baseline data of control children, P <.05) and physical capacity (from 31%-78%, P <.01) was found. CONCLUSIONS: In persons with PWS, a well-defined and easy-to-accomplish training program improves local body composition and has generalized effects on physical activity and capacity, opening up a new therapeutic option to improve metabolic conditions.