FINAL MEETING REPORT
Welcome
Programme at a Glance
Scientific Programme
Aim of the Scientific Programme
Committees
Venue
Registration
Accommodation
Social Programme
Payment
Cancellation
CME Credits
Contact

Comprehensive care of patients with PWS – consensus, questions and future directions

This report as a PDF file: PWS_Final_Meeting_Report.pdf

Final meeting report till Bullet points from the 2nd Expert Meeting on PWS

This report as a PDF file: Comprehensive clinical Overview of the 2nd Expert Meeting on PWS.pdf

Second Expert Meeting 26–27 October 2006, Toulouse
 

The following report summarizes the key messages to emerge from the Second Expert Meeting on PWS, held in Toulouse, 26–27 October 2006. In addition, a comprehensive clinical overview of the meeting is intended for publication early in 2007.

• Objective: to highlight the key findings from a medical survey (1471 patients) and reports of deaths (178 patients) from the Prader–Willi Syndrome Association (PWSA) in the USA.
• Some interesting differences in the frequency of certain medical problems are becoming apparent between patients of different age groups and genetic subtypes, and between those who have and have not received growth hormone (GH) treatment.
• Deaths most often appear to be obesity related, but cases of gastric rupture and necrosis and of choking have been reported, highlighting factors that might be amenable to prevention.
• Over the past decade, the age of diagnosis has fallen, allowing earlier intervention to prevent morbidity, improve care and allow earlier initiation of GH replacement if needed.
• Further studies will be needed to determine the biological and statistical significance of these findings from the PWSA (USA).
• Useful information on rare disorders can be gleaned from large parent- and patient-based organizations. Medical professionals and scientists can use this information to aid and guide research and care.

• Death reports were available from 17 Japanese PWS patients, only one of whom was treated with GH. Data were collected over 15 years.
• The deaths of ten infants and young children were sudden and associated with milk aspiration or viral infection (especially rotavirus).
• The deaths of four adult patients were associated with complications secondary to morbid obesity and diabetes mellitus.
• Two patients died in the bathtub.
• Two patients were reported to have cardiomyopathy.

• This pharmacoepidemiological database, coordinated by Pfizer, was designed to aid investigation of the long-term efficacy and safety of GH therapy.
• In August 2006, there were 1242 patients in KIGS, 53% of whom were boys. The median GH treatment duration was 1.9 years, with data available for a total of 2538 treatment years.
• GH treatment results:
  • change in height standard deviation score (SDS) –1.6 to –0.6
  • change in body mass index (BMI) SDS +2.0 to +1.8
  • first-year height velocity correlated positively with GH dose and weight, and negatively with age and height deficit from genetic target.
• Adverse events:
  • total 184/1000 treatment years
  • serious 32/1000 treatment years, including six deaths in total
  • adverse drug reactions 4/1000 treatment years.
• The rate of adverse events and adverse reactions was similar to that in Turner syndrome, but the rate of serious adverse events was greater in PWS (mostly due to scoliosis).

• Considerations for an epidemiological study:
  • size of population
  • which disease/condition?
  • how rare?
  • what sample size is needed?
• For common conditions, population sampling can be used, e.g. in the Health and Lifestyle Survey.
• Rare conditions require a different methodology. For PWS, a case ascertainment population study has been used to measure birth incidence.
• General considerations for sourcing patients:
  • be over-inclusive
  • verify condition by appropriate diagnostic test(s)
  • ethics
  • how/whether to include non-responders.
• Cambridge epidemiological survey estimated lower limit of birth incidence: 1 in 29 000; population prevalence: 1 in 52 000.

• European Research Database: allows reliable and lawful collection of data across several countries, funded by the European Union.
• The rarity of PWS and the need to subdivide the population (e.g. by genetic subtype or age) means that countries should collaborate to collect data on sufficient numbers of patients.
• The user-friendly database is currently under development.
• www.pwseu.eu

• As part of the NIH funded Rare Diseases Clinical Research Network (RDCRN), the Prader-Willi syndrome (PWS) and Early-onset Morbid Obesity (EMO) component seeks to:
   
  • establish a well-defined natural history for these conditions in children and adults
  • establish a genotype-phenotype correlation in PWS
  • collect data on clinical history, physical examination, intelligence, behaviour, body composition, nutrition and DNA/RNA
  • evaluate the effects of GH treatment started at different ages
  • search for new gene defects in the poorly characterized EMO group
  • compare individuals with PWS with other individuals with EMO

• PWS patients display a range of ‘behavioural phenotypes’:
  • hyperphagia
  • repetitive and ritualistic behaviours
  • skin picking
  • mood disorders
  • psychotic illness.
• Conceptual models to explain these phenotypes include:
  • genetic predisposition
  • developmental arrest
  • psychological mechanisms.
• Hyperphagia is a cardinal feature of the behavioural phenotype.
• There are implications for treatment – different approaches may be needed for different behaviours.

• There are shared behavioural features between PWS and autism spectrum disorders.
• Preliminary data suggest that there is more autistic symptomatology amongst patients with uniparental disomy (UPD) than amongst patients with gene deletions.
• Overlap between PWS and autism spectrum disorders falls under the following categories:
  • behavioural
  • social and cognitive, underlying functioning
  • genetic.

• A 3-year UK-wide study of psychiatric illness included 119 adults with genetically confirmed PWS (34 UPD, 85 deletion).
• Amongst those found to be positive for psychopathology (22 UPD, 24 deletion), phenomenology and clinical features were found to be similar in the two genetic subtypes.
• Psychotic illness was more common in patients with UPD, whereas non-psychotic depressive illness was more apparent (unmasked) in deletion patients.
• These findings have clinical implications: there is a need for prompt diagnosis and appropriate interventions.
• The study suggests that psychosis in both PWS subtypes is caused by abnormal expression of imprinted genes on chromosome 15.

• A randomized controlled study included 43 Dutch infants aged 6 months to 3 years with PWS.
• Psychomotor development in PWS was studied before and during GH treatment and compared with controls.
  • Motor development improved, and mental development tended to improve with GH treatment.
  • A lower motor developmental age at the start of treatment was associated with more benefit from GH.
• Association between mental development and sleep-related breathing disorders (SRBD):
  • some infants with PWS and obstructive sleep apnoea syndrome (OSAS) had lower mental development scores. Treatment of OSAS might improve mental development.

• Polysomnography (PSG) was used to study the prevalence of SRBD and effects of GH treatment in 53 children.
• Before the start of GH treatment:
   
  • frequent apnoea/hypopnoea (median 5/hour)
  • mostly central apnoea
  • obstructive apnoea was rare in non-obese children, but occurred in 50% of obese children.
• During GH treatment:
  • SRBDs were not aggravated by GH treatment. Central apnoea may even be reduced.
• Obstructive apnoea increased during upper respiratory tract infections (URTIs).
• Normal PSG does not exclude deterioration during URTI.

• PWS patients are at increased risk of:
   
  • SRBDs
  • disturbances of circadian cycle
  • abnormal sleep architecture.
• PSG is recommended, particularly before and after the onset of GH treatment.

• All individuals with PWS had some degree of SRBD prior to GH treatment.
• GH treatment with insulin-like growth factor I (IGF-I)/IGF-binding protein-3 levels in the mid–normal range improved SRBD, predominantly central apnoea.
• URTI worsened obstructive sleep apnoea.
• Very high IGF-I levels were associated with worsening of sleep apnoea, perhaps due to increasing tonsillar/adenoid tissue volume.
• Clinical implications:
  • Adjust GH dose on the basis of IGF-I levels
  • If symptoms of sleep apnoea emerge during GH therapy, the patient should be investigated with PSG and measurement of IGF-I levels.

• Segmental duplications in the human and mouse PWS genomic region lead to genetic instability and incomplete genomic sequence.
• Hypothalamic deficiency may not be the single cause of PWS. Using mouse PWS model (deleted for the entire PW region) a foetal defect in pancreatic islet development has been identified. PWS mouse genes are also expressed in insulinoma beta-cells in pancreas. These mice have foetal and neonatal pancreatic insufficiency. They present a severe hypoglycemia which is probably the cause of early death.
• In the mouse PW-like region, between Necdin and the IC, a new long non-coding gene has been characterized. It is a host transcript for new miRNAs, Mirh1 (in 39 copies) which is not conserved in human. Mirh1 is homologous to mir 344. The promoter-exon 1 of the long non-coding host transcript is highly conserved in mammals.
• All candidate genes in the PW region might be regulated under the control of the transcriptional factor NRF1.
   

• Two types of deletions occur in PWS. Type I (the larger one) and Type II (the smaller one).
• In TI deletions, four genes (GCP5, CYFIP1, NIPA1, NIPA2) are absent.
• Subjects with Type I deletions have more behavioural and psychological problems than individuals with Type II deletions.
• Using quantitative RT-PCR, the four genes cited above were investigated in patients and control mRNAs. A positive correlation was found with NIPA2 expression, in adaptive behaviour and cognition and a negative correlation with maladaptive scores.
• The coefficient of determination suggested that expression of the four individual genes accounted for as much as 75% of the variation in scores.
• In addition, the joint impact of the four genes explained from 24% to 99% of the assessment scores obtained from the subjects further supporting their role in cognition and behaviour in PWS.

• Aberrant imprints (imprinting defects) account for approximately 1% of patients with PWS. Imprinting Center (IC) deletions represent only 15 % of this type of defects. These IC deletions are issued from a familial transmission or germ line mosaicism. In those cases a recurrence risk can be as high as 50%.
• In the majority of patients (85%) no IC deletion was revealed and hypermethylation only is detected. This abnormal methylation pattern most likely results from an error in imprint erasure in a paternal germ cell.
• Apparently, there is no association between a particular haplotype and a defect in imprint erasure.

• Small non-coding RNAs (~ 80-300 nt) contain two short sequence motifs, interact with a specific set of proteins and accumulate as RiboNucleoParticles in the nucleus (either in the nucleolus (snoRNAs) and/or in the Cajal bodies (scaRNAs). Many of them contain conserved antisense element(s): (10-20 nt) against rRNAs, UsnRNAs, tRNAs, mRNAs.
• The biological functions of imprinted C/D snoRNAs (in particular in the PWS region) are still highly elusive.
• The minimal critical region, from patient studies, includes the entire HBII-85 snoRNA gene cluster and also HBII-438a suggesting that HBII-85 snoRNA is likely to play a major role in the PWS.
• The lack of expression of HBII-52 snoRNA genes is not sufficient to result in PWS, however its potential role (that is still not proven) in regulating the editing and splicing of the 5HT-2C (serotoninergic) receptor offers new insights in the role of the serotonin pathway in PWS.
  
  

• Ghrelin may be one player amongst a number of neuroendocrine factors that contribute to hyperphagia and obesity in PWS.
• Ghrelin is the only known orexigenic hormone.
• Plasma ghrelin levels:
  • increase before meals to stimulate hunger, and decline after food
  • are inversely related to BMI, body fat and insulin
  • decrease with age.
• Plasma levels of ghrelin in PWS have similar dynamics as in controls and obese patients, but are at higher levels.
• Somatostatin acutely decreases plasma ghrelin, but does not decrease appetite.
• Inconsistent results have been obtained with GH treatment in PWS. In some studies, no effect has been found, but in the speaker’s own study, plasma total ghrelin (but not the active acylated ghrelin) was significantly decreased by GH treatment.
• In the future, blocking the action of ghrelin, using oligonucleotides (‘Spiegelmers’) for example, may help to clarify the physiological role of ghrelin.

• Various peripheral signals (of which ghrelin is one) act to control appetite.
• Interaction of peripheral signals, the autonomic nervous system and higher brain centres link the homeostatic state, response to food stimuli and food intake.
• Delayed meal termination and impaired satiation, as well as earlier meal initiation and return of hunger, occur in PWS patients, despite delayed gastric emptying.
• No defects of leptin, gastrin, obestatin, somatostatin, glucagon, cholecystokinin, gastric inhibitory peptide, peptide YY or glucagon-like peptide-1 contribute to hyperphagia. Elevated ghrelin, pancreatic polypeptide deficiency and, perhaps, relative hypoinsulinaemia may contribute to hyperphagia.
• Functional magnetic resonance imaging and positron emission tomography show abnormal corticolimbic activity after oral glucose or eating a meal, suggesting increased reward, emotional and motivational responses in PWS patients.
• Relative, rather than absolute, resistance to peripheral satiety signals suggest the possibility of therapeutic interventions.

• Hypothalamic dysfunction can explain many of the symptoms of PWS.
• The paraventricular nucleus (PVN) is a centre for autonomic hormonal and appetite regulation.
• In PWS patients:
  • the volume of the PVN and the total number of PVN cells are decreased
  • the number of oxytocin neurons in the PVN is decreased.
• No abnormalities in neuropeptide Y, agouti-related protein, pro-opiomelanocortin, gonadotrophin-releasing hormone, melanin-concentrating hormone receptor 1, ghrelin receptor or orexin have been found that could explain the phenotype of PWS.
• Preliminary studies have found Alzheimer’s-like neurofibrillary tangles in the hypothalamus of older patients with PWS.

• Nineteen infants diagnosed with PWS at <2 months followed by a multidisciplinary team.
• Compared with an historical cohort:

• duration of hospitalization time significantly reduced
• duration of gastric tube feeding significantly reduced

• 70 % of the children had GH deficiency, in all patients IGF-I was reduced.
• GH treatment started at a mean age of 1.9 years in 10 infants.
• Of all children, only one became obese by 3 years of age (lower rate of obesity than historical cohort, but non significant).
• Long-term follow-up continues.
• Need to gain consensus on recommendations for management in these young patients as well as guidance for parents.

• Nutritional phases in PWS are more complex than the two phases traditionally described, with excessively increased weight occurring before the onset of hyperphagia.
• The following phases were proposed:

1 a)   Hypotonia with difficulties in feeding (0–6 months)
   b)   No difficulty feeding, growing along curve (3–24 months)
2 a)   Weight increase without increasing calories (1.5–3 years)
   b)   Weight increase with increase in calories (2–12 years)
3       Hyperphagic, never feels full (3–21+ years)
4       As with 3, but now less hunger

• Preliminary data seem to indicate that GH delays phase 2, but children still go into phase 3.
• Better understanding of the various nutritional phases of PWS may help in the treatment and management of the condition.

• Children with PWS have abnormal musculature and psychomotor delays.
• Infants with PWS are unable to overcome gravity while moving. These early years are a sensitive period and possibly critical for long-term effects on motor development and skill acquisition.
• Decreased muscle mass and force constrains the development of fundamental skills, hand–eye coordination, locomotion and language.
• Developed an age-specific child-centred functional training programme that enables child to learn skills. Number of repetitions very important.
• Celebration of success is important.
• Expect beneficial effects of this intensive programme on muscle mass and composition, motor development, motor learning capacity, parental interaction, self-esteem, enjoyment and motivation.
• By increasing muscle mass GH treatment might further potentate the effects of this program.

• GH treatment results in an improvement in growth rate, metabolic profile, body composition, physical function, agility and neurodevelopment.
• The response to GH is greatest in the first 12 months of treatment.
• Body composition effects seems dose dependent.
• The safety profile of GH treatment is reassuring.
• Long-term studies will further increase our understanding of the effects of GH treatment in PWS patients.

• Prevalence rate of scoliosis is 40 – 50 % without gender difference.
• Severity of scoliosis correlates with BMI and female gender.
• Obesity worsens scoliosis and increases the risk for additional kyphosis.
• No clear conclusions yet on effect of GH – need prospective study.
• Bracing and surgery are often employed in treatment.
• There is a 30 % rate of major complications associated with surgery in PWS.
• Surgical teams should have expertise in patients with neuromuscular disease, if not PWS itself.
   

• Sex steroids not used universally and not always deficient.
• Primary arguments for using sex steroids are known benefits to bone health, muscle mass metabolic protection and possible benefits to mental, emotional and physical well-being.
• Doses are typically minimalized and titrated based on individual assessment. Specifics evidence-based recommendations are not available.
• Management includes developmentally appropriate and individualized management of sexual issues.

• Two very different circumstances regarding use of GH in adults.
• 1) In GH naïve adult, limited data on the benefits and risks of hGH; results of ongoing studies are expected soon. Placebo controlled trials will be important to this group of patients with PWS.
• Confirming GH deficiency through IGF-I levels and GH stimulation tests would appear to be appropriate.
• 2) The transition from childhood to adult management issues include the acceptability of cessation by patients and families, the need for repeat GH stimulation testing, and the timing and rate of dose reduction. General consensus on the need for IGF-I monitoring.
• Potential benefits of GH in adult include: improvement in peak bone mass, in metabolic profile, body composition, physical and mental well-being across the life span.

• Prevention of obesity remains principally through environmental controls.
• Anecdotal evidence and limited placebo-controlled trials of topiramate and various appetite suppressants has not revealed any benefit.
• Anecdotal and published reports of marked morbidity and mortality from bariatric surgery in patients with PWS.

• Psychiatric presentations were distinguished into 3 groups: 1) disruptive behaviour, 2) increase in usual repetitive and perseverative behaviors, and 3) development of psychotic episodes.
• Diagnostic assessment is multidisciplinary and includes thorough developmental, physical and psychiatric assessments in search of multiple underlying factors.
• Physical symptoms of vomiting, headache, fever and onset of incontinence may precede behavioural changes (psychotic episodes).
• Correct management goals depend upon recognizing both intrinsic and extrinsic factors rather than by simply treating symptoms.
• Psychotic episodes are treated using medications.

•  The following precautions were noted: the need to start at low doses and avoidance of short term sedation with benzodiazepines.
• Lack of data on the natural history of psychiatric illness in PWS and the need for long term medication.

• In cases of acute psychiatric deterioration with risk of harm to self and others, short term psychiatric hospitalization in an appropriate food-controlled environment may be required. Consultation with or referral to professionals familiar with the syndrome is essential.

To the top