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Standards of Care for People with PWS [2022 Conference Video]

In this video, Dr. Diane Stafford, Pediatric Endocrinologist at Stanford, discusses standards of care for people with PWS across the age continuum.

In this one-hour video, Dr. Diane Stafford, Pediatric Endocrinologist at Stanford University, discusses standards of care for patients with PWS across the age continuum, including medical needs, currently available medications, supplements, and behavior management.

Click below to watch the video. If you're short on time, scroll down for timestamps to find the portions you're most interested in.

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Presentation Summary With Timestamps

00:06 Introduction of Dr. Stafford by Rachel Fisher, mom to an 11-year-old in Denver, Colorado

  • Overview of the topics to be covered: standards of care for people with PWS across the age continuum, including medical needs, currently available medications, supplements, and behavior management.
  • Dr. Stanford is a clinical professor of pediatrics at Stanford University School of Medicine in the Division of Pediatric Endocrinology.
  • She has been caring for patients with PWS for more than 20 years, both at Stanford and previously at Boston Children’s Hospital.
  • She has a particular interest in variations in puberty. 
  • She is chair of the PWS CLIC, a clinical investigation collaborative working with FPWR to improve care of those with PWS through collaborative investigation and research

1:24 Dr. Stafford

  • PWS CLIC is a group of physicians and non-physicians such as psychologists whose goal is to gather sufficient information from all the different smaller communities that we all function in to create a clinical database of information about patients with PWS.
  • The idea is to be able to investigate things like the timing of puberty and other things that are still a bit mysterious in the world of PWS.
  • The Collaborative would like to engage families and parents so that we can make sure the work they are doing is useful to the PWS community as a whole.
  • Disclosures: Dr. Stafford is one of the sub investigators at Stanford for Selena’s Destiny PWS Trial and the principal investigator for ARD-101 and for Radius-SCOUT

03:35 Objectives

  • Multispeciality needs at different ages
  • Currently available medications
  • Supplements
  • Behavioral interventions

4:20 Multidisciplinary Care

  • People with PWS can require lots of different kinds of specialists
    • Genetics—involved in diagnosis of children with PWS
    • Endocrinology—involved early following diagnosis
    • pulmonary/sleep medicine
    • Gastroenterology/nutrition
    • Orthopedics
    • Physical Therapy/Occupational Therapy/Speech Therapy
    • Behavioral Medicine/Neuropsychology
    • Neurology
  • In some cases, there’s a huge interdisciplinary group that is necessary for caring for PWS patients. Needs vary across lifespan.

5:05 Neonates and Infants (to 1 Year)

  • Evaluation
    • Feeding
    • Growth & development
    • Tone
    • Gonadal development
    • Vision
  • Medical referrals
    • Genetics
    • Endocrine
    • Ophthalmology
    • Pulmonary 
    • Nutrition
    • OT, PT, ST
    • Neurology, Urology prn
    • Audiology
  • Laboratory Evaluation
    • IGF1, IGFBP#
    • Thyroid studies
    • 25-OH vitamin D
    • CBC
    • B12 level prn
    • Adrenal eval
    • Iron studies
  • Diagnostics
    • PSG (before starting GH and 8-12 weeks after starting)
    • Echocardiogram if murmur
    • Hip US (DDH)
    • Feeding eval
    • Scoliosis screening
  • Medications/Supplements
    • Growth hormone
    • Multivitamin
    • Trial the supplements
    • HCG in males with cryptorchidism  (undescended testes, 3-18 months old); consider orchiopexy

10:25 1-5 Years

  • A lot of commonality with 0-1 year standards of care (a few additions listed below)
  • Still looking at growth and development as well as hearing, vision, feeding, and scoliosis.
  • Behavior becomes more of an issue in 1-5 year olds because they’re more active, they’re expressing themselves in one way or another. 
  • Sleep becomes more of an issue, as do GI and nutrition and feeding.
  • Medical referrals are quite similar to the 0-1 age, with the addition that once children get to this age, you can think about modifying PT to include things like hippotherapy, aquatic therapy, and other things that may strengthen core tone.
  • May also make referrals to behavioral specialists.
  • Children now have teeth, so starting them with good dental care is important.
  • Neurology prn. Most children do not need.
  • Whether or not to start lipid panels is being debated.
  • Sleep study may want to be repeated if dealing with excessive sleepiness.
  • Scoliosis screening will start, and some will be referred to orthopedics.
  • Consider neuropsychiatric diagnosis, depending on behavior at home.

14:15 5-13 Years

  • Children are at different stages of development, physically and emotionally.
  • Evaluation
    • Will still need to evaluate growth, vision, hearing, and the previously mentioned things.
    • But will add an evaluation of pubertal development.
    • There is an increased rate of what is referred to as premature adrenarche or premature pubarche in children with PWS that is essentially early development of body hair and body odor. This is independent of true pubertal development.
    • As an endocrinologist, one of the hardest things to explain is that body hair and body odor are actually driven by something different than what drives true puberty.
    • It’s important to do a good evaluation for pubertal staging because of the increased risk for precocious puberty in children with PWS, even though frequently can have delays or stalls in pubertal development. Keeping an eye on that is very important.
    • This is the age where skin picking becomes more common in a lot of children and so they should have regular monitoring for the presence of skin picking and infections that may need antibiotics or referral to dermatology.
    • Continued evaluation for scoliosis, sleep disorders, behavioral disorders
    • Also gastroenterology and nutrition are important because of an increased rate of constipation and other GI effects in PWS that we always want to keep an eye on.
  • Medical referrals
    • As children become school age, the school will take over for educational evaluations and individualized education plans (IEPs).
    • If the school is not able to do the evaluation, in particular the neuropsychiatric evaluation that children really need, they end up being evaluated outside.
    • Parents should keep an eye on the balance between what the school thinks the child needs and what your child needs.
    • As children get older, they may also become obese.
    • This often requires the addition of diabetes screening: Hemoglobin A1C, which is a measure of overall blood sugar over the course of a 3-month period. Also fasting insulin and glucose to look for the presence of pre-diabetes or early glucose intolerance.
    • Early intervention can help stop the progression to true diabetes that requires more intensive therapy.
  • Diagnostics
    • By this age, lipid panels are often done, especially in families where there is a family history of lipid abnormalities.
    • Pubertal evaluation to look at the hormones related to puberty.
    • Polysomnography as needed.
    • Feeding evaluations.
    • MSLT sleep latency testing, which is a different kind of sleep test from polysomnography, which actually looks for narcolepsy or daytime sleepiness.
    • Pulmonary function testing if they seem to be having difficulties.
    • Scoliosis screening with X-ray.
    • Neuropsychiatric and neurobehavioral evaluations.
  • Medications
    • Growth hormone
    • Modafinil, used to treat type 2 diabetes
    • Stimulants, for daytime sleepiness
    • N-acetylcysteine, used to decrease skin picking
    • SSRIs
    • Antipsychotics, used for anxiety and other issues
    • Metformin
    • Supplements

20:23 13-21 Years

  • Evaluation
  • This age is a challenge for parents of any child, and it gets to be more complicated from an evaluation standpoint.
    • Need to start thinking about implications of cardiovascular dysfunction in patients who may have long-standing obesity and obstructive sleep apnea, both of which can cause cardiovascular complications.
    • Skin examination
    • Good examination of pubertal development. The pubertal development of children with PWS is all over the place; it goes from very early to quite delayed.
    • Need to be looking at the presence of testosterone and estrogen, trying to decide whether they are progressing as appropriate or whether supplementation is needed.
    • Continued monitoring for scoliosis, and trying to figure out good exercise habits since older kids have fewer opportunities for recess and gym.
  • Medical referrals are similar to those for younger children, as well as laboratory evaluations.
  • There are some changes related to puberty that need to be monitored.
    • Looking at pelvic ultrasound for girls to assess the maturity of the uterus to assess the estrogen exposure.
  • DEXA is a way to assess bone mass and bone density; it looks at lean body mass and fat mass; can be helpful at this age because children with PWS that have hypotonia are prone to having relatively low bone density. We build up bone density early in life, and if we don’t have it, people are more prone to osteoporosis and fractures later in life.
  • Medications at this age are going to include growth hormone, hormone replacement therapy, if it’s indicated, and GLP-1 receptor agonists, which are a relatively new treatment for type 2 diabetes that improves insulin secretion and sensitivity and can help with weight loss.

26:44 Adulthood

  • Adults tend to need more specialists, for example:
    • Weight management
    • Cardiovascular
    • Sleep disorders
    • Behavioral disorders
    • GI/nutrition
  • Diagnostics may include DEXA, pelvic ultrasound, swallow studies
  • Medications are similar, but in the type 2 diabetes world there are different medications for people over 18.

28:47 Growth Hormone Therapy

  • Standards of care have shifted from the old way of waiting until children are having trouble growing to say that a PWS diagnosis is sufficient to start someone on growth hormone therapy.
  • Goals of therapy: improved growth, lean mass, motor development, and normalization of body habitus—overall health.
  • GH insufficiency/deficiency. Not clear how many people with PWS would meet conventional diagnostic criteria or growth hormone deficiency or growth hormone insufficiency. But they often have neurosecretory defect, which means they don’t secrete growth hormone in a normal way.
  • We’ve learned over time that starting growth hormone therapy earlier has advantages.
  • Evaluation for sleep apnea prior to therapy and after 3 months. This comes from data on deaths of several older patients who were already obese and were started on growth hormones.
  • General recommendation is to start growth hormone early and if you have obstructive sleep apnea, treat that. Hormones will actually improve muscle mass and make sleep apnea better.
  • Consensus statement arose from a systemic review of the literature to discover the best evidence. 43 international experts determined that sleep apnea was not felt to be an exclusion criteria.
  • Scoliosis should not necessarily be considered a contraindication to growth hormone. However, when a child with scoliosis is on growth hormone, the endocrinologist and the orthopedists are actually working together to find out what's actually in the best interest of the child.
  • Consensus did recommend exclusion criteria of severe obesity, uncontrolled diabetes mellitus, untreated severe obstructive sleep apnea, active cancer or psychosis. 

28:20 Adult Growth Hormone Use

  • Improvements have been shown in body composition, muscle characteristics, motor function, exercise capacity, metabolic parameters, quality of life, and cognitive function.
  • No indication of growth hormone therapy unless there is evidence of hormone deficiency. Need to document this through stimulation testing, low IGF-1, or other methods in order to get approval in the US.

33:40 Growth Hormone Dosing

  • Starting dose of 0.1-0.2 mg/day based on age, presence of edema, prior ghGH exposure and sensitivity, and concomitant oral estrogen use. 
  • Dose depends on clinical response, age, and sex.

36:55 Hormone Replacement Therapy

  • Hormone replacement therapy (HRT) is done on a basis of hypogonadism
  • When hypogonadism is diagnosed early and managed, HRT helps 
    • Development of secondary sexual characteristics
    • Improved growth (pubertal growth spurt)
    • Improved quality of life
    • Increased bone density
    • Increased muscle mass
  • Sex steroid replacement (estrogen in girls, testosterone in boys) is needed.
  • Timing is variable but usually around the time of normal puberty: 10-11 in girls, 12-13 in boys.
  • Criteria for a diagnosis of delayed puberty is lack of pubertal development: lack of breast development in girls, lack of testicular enlargement or clear puberty in boys, but timing is variable.
  • HRT for patients begins slowly, Not going to give everybody adult doses of estrogen and testosterone. 
  • Hopefully practitioners will create more of a standard of care with respect to induction of puberty in patients with PWS. 
    • In adult females the definition of the need for hormonal replacement is based either on oligomenorrhea (infrequent periods) or amenorrhea (no periods) or a finding of low bone mineral density.
    • In males replacement is the same as it would be for hypogonadal males without PWS, which is by measuring testosterone and determining if it is an appropriate level for age.

41:09 Narcolepsy and Daytime Sleepiness

  • Abnormal sleep-wake cycles with typical characteristics
    • Insomnia
    • Cataplexy (loss of muscle)
    • Hallucinations associated with drowsiness
    • Sleep paralysis
  • Two main treatments for daytime sleepiness
    • Modafinil-100—200 mg in the morning, depending on age, resulting in improvement in daytime alertness and also improved behavioral and attention.
    • Pitolisant-currently in clinical trials and may be more effective in PWS.
  • Supplements for daytime sleepiness:
    • COQ10, involved in production of ATP in the mitochondria
      • Those with deficiency feel less energetic, have reduced muscle function, and decreased metabolic rate.
      • No observed weight loss effects in PWS, but possible benefits for psychomotor development.
      • Doses vary from 1-30 mg/kg/day in infants and up to 200 mg/day in older children and adults (100 mg/day usually sufficient)
    • Carnitine
      • Natural antioxidant that improves cellular energy metabolism
      • Has been shown in other conditions to improve hypotonia, ataxia, activity levels, and alertness
      • Typical dose: 50mg/kg/day divided twice a day

45:07 Behavioral Interventions

  • Speech therapy
    • Improves receptive and expressive language, sign language
    • Improving communication can decrease frustration.
  • Nutrition: food-related preoccupations and foraging may underlie behavioral and emotional disturbances; nutrition counseling is essential.
  • Applied Behavioral Therapy: no comprehensive studies in PWS, but positive results in people with autism.
  • Cognitive behavioral interventions: habit-reversal training (awareness training, competing response training, and social support) have shown promise in treating chronic skin-picking behavior.
  • Serotonin agonists (SSRIs) have been most successful in reducing temper outbursts and improving compulsive behavior (Weratonin imbalance related to repetitive behavior, OCD, depression, anxiety, and self-injurious behavior in non-PWS population).
  • Topiramate: anti-seizure medication has been tried as an appetite-regulating medication; one study showed it did not help food-related behaviors but did reduce skin-picking.
  • Controlled and randomized studies have yet to be performed.
  • Future studies should explore differential treatment effects of individuals with PWS based on subtyping and the potential efficacy of combined psychotherapy and pharmacology.

46:21 Multidisciplinary Care

  • Multidisciplinary care is very important.
  • What is most important for parents is to determine who is going to coordinate care. Is this the physician, the geneticist? The endocrinologist?
  • Is there an actual coordinated care service where you will get care?
  • Endocrinologists end up doing a lot of this coordination because they see PWS patients most frequently. They are on growth hormones so they see them every 3-4 months.
  • Endocrinologists know the sleep specialists, the orthopedists, the GI doctors, etc.
  • Have the discussion with the primary care physician to determine who is going to actually make sure that the child is getting multidisciplinary care. 
  • Discussion with providers up front can make sure that we’re providing all the care that our children with PWS need.

49:11 Q & A

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