Siobhan T. Pittock, M.B., B.Ch., Pediatric Endocrinology, Mayo Clinic: Hi, I'm Siobhan Pittock and I'm a pediatric endocrinologist at Mayo Clinic. Today I'd like to talk to you about Prader-Willi syndrome which is a rare genetic disorder that occurs in about one in 30,000 live births. It's caused by a lack of expression of patternly derived genes on Chromosome 15q11. The condition is characterized by very poor tone but with floppy babies who feed poorly and later development of obesity due to excessive appetite and short stature and poor gonadal function. These children require care from multiple subspecialists and the pediatric endocrinologist really plays a central part in their plan of care throughout childhood and adolescence. This is because the condition, unfortunately, is associated with several endocrine concerns. These children are short. If left untreated, boys of Prader-Willi syndrome grow to a mean final adult age of five foot, four and girls grow to about four foot, 11. Their short stature is due to a combination of growth hormone deficiency and also because of hypogonadism, they don't get that normal puberty growth spurt.

Prader-Willi syndrome is an FDA-approved indication for treatment with growth hormone therapy and children typically respond well. Initially the indication was just for short stature associated with Prader-Willi syndrome, but since it's been used, we are finding that the benefits of growth hormone treatment go beyond just improving final adult height. In children, they improve muscle tone and so improve motor development. They have an improvement in bone mineral density accrual and they also have improvement in lean body mass as it compares to fat mass. Some short-term studies in adults with growth hormone deficiency also show that they benefit lean body mass and also muscle tone.

Another big endocrine disorder in Prader-Willi syndrome is hypogonadism. Hypogonadism effects both boys and girls with Prader-Willi syndrome. It's a central cause of hypogonadism for both sexes but boys also have some primary testicular dysfunction. So these children often don't go into puberty at a normal time and we do our best to mimic normal adolescence through gradual introduction of sex steroids. Testosterone is given either transdermally or intramuscularly to boys and estrogen is given either orally or transdermally to girls. Often times, in adulthood, these patients will remain hypogonadal and will require treatment also. The estrogen level in girls is often not as low as we would expect and that's due to their obesity. They have amortization of androgens and so the estrogen levels are not as low as would be expected in other situations of hypogonadism. From the standpoint of fertility, fertility has been described in girls with Prader-Willi syndrome but there are no reports of paternity in males.

Another major clinical problem for patients with Prader-Willi syndrome is obesity. In fact these children in infancy tend to be thin because of poor feeding related to their poor tone, but in toddlerhood on into childhood, their tone improves to the point that they can eat well and they develop markedly increased appetite. If left unchecked, children with Prader-Willi syndrome, on average consume about three times the calories of their peers. The obesity is not only due, however, to their increased caloric intake, they also have poor muscle tone which results in decreased energy expenditure. Unfortunately, the obesity in Prader-Willi syndrome has been very difficult to treat. There have been multiple drug trials which have not really been very useful. The surgery has been tried in a limited number of patients and has again not found very useful mainly because, despite the surgery, the hyperphagia or insatiable appetite persists postoperatively. In fact surgical experience with Prader-Willi syndrome also shows a very high rate of complications in these patients really precluding its use in general.

One of the complications which is seen relatively frequently in patients with Prader-Willi syndrome after bariatric surgery is gastric perforation simply due to continued insatiable appetite, continued eating, and perforation of their surgical site. So really the mainstay of obesity management is diet and exercise and some very intensive dietary intervention programs have been found to be useful.

Another medical problem facing these patients is osteoporosis. The osteoporosis again can occur for many reasons and these children have growth hormone deficiency which is known to increase the risk of osteoporosis. They're also hypogonadal, another risk for osteoporosis. They also have poor muscle tone, yet another risk factor for osteoporosis. So in childhood, what we try and do is treat the growth hormone deficiency, if present, to treat the hypogonadism, if present, and encourage weight-bearing exercise as the patients can. We also feel that appropriate calcium and vitamin D intake is important just as it is for any other adolescent. In adulthood, osteoporosis needs to be screened for, and if bone mineral density is lower than expected or is falling, really providers should be considering either growth hormone treatment, if the patient is growth hormone deficient, or treatment of hypogonadism.

After growth hormone was in use for several years, there were multiple case reports of children with Prader-Willi syndrome who were on growth hormone treatment dying suddenly, usually in the context of a mild upper respiratory illness. This was very concerning. Obviously there was a worry that growth hormone was increasing the risk of sudden death. In fact no data was available up to this point rates of sudden death syndrome and it does appear from data gathered subsequently that these children are at increased risk of sudden death. Looking for potential causes of sudden death, sleep studies have been performed and these children do have very high rates of apnea and hypopnea and these apneas and hypopneas are both central and obstructive. When studies have been done both before growth hormone treatment and subsequent to growth hormone treatment, it appears that growth hormone does not cause any worsening in sleep disorder breathing. Because of this very high rate of sleep disorder breathing in Prader-Willi syndrome, we feel that it's very important that these children are evaluated by sleep specialists and many of our patients with Prader-Willi syndrome actually benefit from either CPAP or BiPAP.

In the quest to discover potential causes of sudden death in Prader-Willi syndrome, the concern has also arisen that these children may have adrenal insufficiency knowing that they do have other hypothalamic problems, and several small studies do show that there is a high rate of failure of the metyrapone test suggesting that they do have some degree of adrenal insufficiency. Larger studies have yet to be performed but certainly it seems like a low-risk treatment with potential great benefits so I advocate a treatment of these children with Prader-Willi syndrome with stress-dosage steroids during intercurrent illness.

While growth hormone was initially FDA-approved for treatment of short stature in Prader-Willi syndrome, more recent studies since we've been using it have shown that the benefits of growth hormone exceed just benefits as they relate to stature. In children, they also improve muscle tone and so improve motor development in young children. They also improve bone density and they improve lean body mass, improving the lean body-to-fat ratio. Several short-term studies and adults with Prader-Willi who have growth hormone deficiency also suggest improvement in lean body mass and improvement in bone mineral density. So the growth hormone has become a very important form of treatment for patients with Prader-Willi syndrome not only patients who are concerned about final adult height, but potentially lots of other very helpful areas too.

In summary, Prader-Willi syndrome is a complicated medical problem. There are many endocrine problems associated with the disorder and these children need to follow with pediatric endocrinologists through childhood along with multiple others subspecialists.

Nov. 19, 2022