Clinical Description
Perinatal. Fetal size is generally within the normal range. Prenatal hypotonia usually results in decreased fetal movement, abnormal fetal position at delivery, and increased incidence of assisted delivery or cesarean section. Birth weight and body mass index (BMI) are on average 15% less than in normal sibs [Miller et al 2011].
Hypotonia. Infantile hypotonia is a nearly universal finding, causing decreased movement and lethargy with decreased spontaneous arousal, weak cry, and poor reflexes, including poor suck. The hypotonia is central in origin, and neuromuscular studies including muscle biopsy, when done for diagnostic purposes, are generally normal or show nonspecific signs of disuse.
The poor suck, lethargy, and poor appetite result in failure to thrive in early infancy, and enteral tube feeding or the use of special nipples is generally required for a variable period of time, usually weeks to months. By the time that the child is drinking from a cup or eating solids, a period of approximately normal eating behavior occurs.
The hypotonia improves over time. Adults remain mildly hypotonic with decreased muscle bulk and tone.
Developmental delay. Delayed motor development is present in 90%-100% of children with PWS, with average early milestones achieved at about double the normal age (e.g., sitting at 12 months, walking at 24 months). Language milestones are also typically delayed. Intellectual disabilities are generally evident by the time the child reaches preschool age. Testing indicates that most persons with PWS fall in the mildly intellectually disabled range (mean IQ: 60s to 70s), with approximately 40% having borderline disability or low-normal intelligence and approximately 20% having moderate disability. Regardless of measured IQ, most children with PWS have multiple severe learning disabilities and poor academic performance for their intellectual abilities [Whittington et al 2004a]. Although a small proportion of affected individuals have extremely impaired language development, verbal ability is a relative strength for most. Based on the authors' experiences, a small percentage of individuals with PWS are able to attend and graduate from college.
Hypogonadism. In both sexes, hypogonadism is present and manifests as genital hypoplasia, incomplete pubertal development, and infertility in the vast majority. Genital hypoplasia is evident at birth and throughout life.
Males. The penis may be small, and most characteristic is a hypoplastic scrotum that is small, poorly rugated, and poorly pigmented. Unilateral or bilateral cryptorchidism is present in 80%-90% of males.
Females. The genital hypoplasia is often overlooked; however, the labia majora and minora and the clitoris are generally small from birth.
The hypogonadism is usually associated with low serum concentration of gonadotropins and causes incomplete, delayed, and sometimes disordered pubertal development. Precocious adrenarche occurs in approximately 15%-20%. Infertility is the rule, although a few instances of reproduction in females have been reported [Akefeldt et al 1999; Schulze et al 2001; Vats & Cassidy, unpublished data]. Although the hypogonadism in PWS has long been believed to be entirely hypothalamic in origin, recent studies have suggested a combination of hypothalamic and primary gonadal deficiencies [Eldar-Geva et al 2009, Hirsch et al 2009, Eldar-Geva et al 2010, Gross-Tsur et al 2012], a conclusion largely based on the absence of hypogonadotropism and abnormally low inhibin B levels in some affected individuals of both sexes.
In one study of 84 individuals with PWS (half males, half females) age two to 35 years [Crinò et al 2003], the following were identified:
Males. Cryptorchidism 100%, small testes 76%, scrotal hypoplasia 69%
Females. Labia minora and/or clitoral hypoplasia 76%, primary amenorrhea 56%, spontaneous menarche (mostly spotting) 44% of those older than age 15 years
Both sexes. Premature pubarche 14%, precocious puberty 3.6% (1 male, 2 females)
Appetite and obesity. In contrast to the long-held view that there are only two distinct nutritional phases in PWS (i.e., failure to thrive followed by hyperphagia leading to obesity) a multicenter study [Miller et al 2011] found that the transition between nutritional phases is much more complex, with seven different nutritional phases through which individuals with PWS typically progress ().
Table 2.
Nutritional Phases in PWS
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Phase | Median Ages | Clinical Characteristics |
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0 | Prenatal - birth | Decreased fetal movements & lower birth weight than sibs |
1a | 0-9 months | Hypotonia with difficulty feeding & decreased appetite |
1b | 9-25 months | Improved feeding & appetite; growing appropriately |
2a | 2.1-4.5 years | Weight increasing without appetite increase or excess calories |
2b | 4.5-8 years | Increased appetite & calories, but can feel full |
3 | 8 years - adulthood | Hyperphagic, rarely feels full |
4 | Adulthood | Appetite no longer insatiable for some |
The hyperphagia that occurs in PWS is believed to be caused by a hypothalamic abnormality resulting in lack of satiety. Food-seeking behavior, with hoarding or foraging for food, eating of inedibles, and stealing of food or money to buy food, are common. In most, gastric emptying is delayed, and vomiting is rare. Obesity results from these behaviors and from decreased total caloric requirement. The latter is due to decreased resting energy expenditure resulting from decreased activity and decreased lean body mass (primarily muscle) compared with unaffected individuals. The obesity in PWS is primarily central (abdomen, buttocks, and thighs) in both sexes, and interestingly, there is less visceral fat in obese individuals than would be expected for the degree of obesity. Obesity and its complications are the major causes of morbidity and mortality (see Morbidity and mortality).
Several independent groups have shown that ghrelin levels are significantly elevated in hyperphagic older children and adults with PWS before and after meals [Cummings et al 2002, DelParigi et al 2002, Haqq et al 2003b]. Ghrelin is a potent circulating orexigenic hormone that is produced mainly in the stomach. Circulating ghrelin levels rise after fasting and are suppressed by food intake. The appetite-inducing effect acts through the appetite regulating pathway in the hypothalamus. Ghrelin levels are lower in non-PWS obese individuals than in lean controls, and they decrease with age [Scerif et al 2011].
A small study of nine non-hyperphagic children with PWS (age 17-60 months) found similar levels of circulating ghrelin as in the eight control children matched for BMI, age, and sex [Erdie-Lalena et al 2006]. By contrast, in two much larger and younger study cohorts of children and adolescents with PWS ghrelin levels were significantly elevated in the PWS group at any age compared to controls [Feigerlová et al 2008, Kweh et al 2015]. In fact, the highest ghrelin levels in PWS were found in the youngest children. Thus, in these two large studies the hyperghrelinemia occurred at an age long before the development of obesity and increased appetite in PWS. Furthermore, several groups have now shown that pharmacologic reduction of ghrelin to normal levels in PWS, using either short- or long-acting agents, did not affect the weight, appetite, or eating behavior in hyperphagic individuals [Haqq et al 2003a, Tan et al 2004, De Waele et al 2008]. At this time there are no consistently identified hormonal abnormalities to explain the hyperphagia, and the metabolic correlates of hyperphagia in PWS remain uncertain.
Endocrinologic concerns. Up to 25% of adults with PWS (particularly those with significant obesity) have type 2 diabetes [Butler et al 2002] with a mean age of onset of 20 years. In the last 15 years, earlier diagnosis and education of parents, use of growth hormone therapy, and the frequency of group homes specific for PWS have led to reduction in the development of morbid obesity (and as a result, in type 2 diabetes) among individuals with PWS.
Central hypothyroidism, with a normal thyroid-stimulating hormone value and low free thyroxine level, has been documented in up to 25% of individuals with PWS, with a mean age of diagnosis and treatment of two years [Miller et al 2008, Diene et al 2010].
Central adrenal insufficiency (CAI) following overnight single-dose metyrapone tests was noted in 60% of children with PWS in one study, suggesting that this may be the cause of the high incidence of sudden death in this population [de Lind van Wijngaarden et al 2008]. It is known that introducing GH therapy can precipitate adrenal crisis in individuals with incipient adrenal insufficiency by accelerating the peripheral metabolism of cortisol, which may explain the correlation between the incidence of sudden death at the beginning of GH treatment and CAI in individuals with PWS [Scaroni et al 2008]. However, subsequent studies have found normal cortisol responses to low- and high-dose synacthen testing, as well as to insulin tolerance testing [Nyunt et al 2010, Farholt et al 2011]; thus, whether CAI is a true issue for individuals with PWS remains uncertain at this time and no consensus exists among endocrinologists as to whether evaluation for CAI should be performed on every individual with PWS or only those with symptoms consistent with adrenal insufficiency.
Sleep abnormalities are well documented and include reduced REM (rapid eye movement) latency, altered sleep architecture, oxygen desaturation, and both central and obstructive apnea [Festen et al 2006, Priano et al 2006]. Primary hypothalamic dysfunction is thought to be the cause of the alterations in sleep microstructure and abnormalities in ventilation during sleep, with studies showing low levels of orexin and hypocretin in the cerebrospinal fluid and decreased levels of acetyl-cholinergic neurons in the pedunculo-pontine tegmental nucleus [Dauvilliers et al 2003, Nevsimalova et al 2005, Bruni et al 2010, Hayashi et al 2011]. Some individuals with PWS have excessive daytime sleepiness, which resembles narcolepsy, with rapid onset of REM sleep and decrease in non-REM sleep instability [Bruni et al 2010].
Behavior. A characteristic behavior profile with temper tantrums, stubbornness, controlling and manipulative behavior, compulsivity, and difficulty with change in routine becomes evident in early childhood in 70%-90% of individuals with PWS.
Many of the behavioral characteristics are suggestive of autism; one study showed that 19% of 59 individuals with PWS versus 15% of age-, sex-, and IQ-matched controls satisfy diagnostic criteria for autism [
Descheemaeker et al 2006].
In another study of 58 children, attention deficit/hyperactivity symptoms and insistence on sameness were common and of early onset [
Wigren & Hansen 2005].
This behavior disorder has been reported to increase with age and body mass index (BMI) [
Steinhausen et al 2004], although it diminishes considerably in older adults [
Dykens 2004].
Behavioral and psychiatric problems interfere most with the quality of life in adolescence and adulthood.
Growth. Short stature, if not apparent in childhood, is almost always present during the second decade in the absence of growth hormone (GH) replacement, and lack of a pubertal growth spurt results in an average untreated height of 155 cm for males and 148 cm for females. The hands and feet grow slowly and are generally below the fifth centile by age ten years, with an average adult female foot size of 20.3 cm and average adult male foot size of 22.3 cm. Growth charts for affected infants and children not treated with growth hormone have been published [Butler et al 2011, Butler et al 2015] and growth charts for growth hormone-treated children with PWS have been developed [MG Butler & DJ Driscoll, unpublished data].
Data from at least 15 studies involving more than 300 affected children [Burman et al 2001] document reduced GH secretion in PWS. GH deficiency is also seen in adults with PWS [Grugni et al 2006, Höybye 2007].
Dysmorphic features. Characteristic facial features (narrow bifrontal diameter, almond-shaped palpebral fissures, narrow nasal bridge, thin vermilion of the upper lip with down-turned corners of the mouth) may or may not be apparent at birth and slowly evolve over time.
Hypopigmentation of hair, eyes, and skin is frequently found in patients with a deletion due to loss of a single copy of the gene OCA2.
Ophthalmic issues. Strabismus is seen in 60%-70%.
Skeletal findings. Hip dysplasia occurs in approximately 10%-20% [West & Ballock 2004, Shim et al 2010]. Bone fractures are a risk due to the increased frequency of osteopenia and osteoporosis.
Scoliosis, present in 40%-80%, varies in age of onset and severity.
Other. Rates of the following are increased:
Possibility of recurrent respiratory infections (in ≤50% of individuals)
Leg edema and ulceration (especially in the obese)
Skin picking
Altered temperature sensation
Decreased saliva flow
High vomiting threshold
Seizures (in 10%-20%)
Morbidity and mortality. Mortality rate in PWS is higher than in controls with intellectual disability, with obesity and its complications being factors [Einfeld et al 2006]. Based on a population study, the death rate was estimated at 3% per year [Butler et al 2002], although a later study of the same population showed the rate to be decreasing to 1.25% per annum with improved management [Whittington et al 2015]. Two multicenter series of individuals who died of PWS have been reported [Schrander-Stumpel et al 2004, Stevenson et al 2004], and an extensive case and literature review of 64 cases of death in PWS was performed [Tauber et al 2008]. Respiratory and other febrile illnesses were the most frequent causes of death in children, and obesity-related cardiovascular problems and gastric causes or sleep apnea were most frequent in adults. Other causes of morbidity include diabetes mellitus, thrombophlebitis, and skin problems (e.g., chronic edema, infection from skin picking).
A few individuals have been reported to have respiratory or gastrointestinal infections resulting in unexpected death; of these, three who died as a result were noted to have small adrenal glands [Stevenson et al 2004], although this is not a common finding. The report of central adrenal insufficiency (CAI) in 60% of tested individuals [de Lind van Wijngaarden et al 2008] suggests a possible explanation for some of these unexpected and sudden deaths. Other studies have not demonstrated a high incidence [Farholt et al 2011, Grugni et al 2013] of CAI in PWS.
Acute gastric distention and necrosis have been reported in a number of individuals with PWS [Stevenson et al 2007a], particularly following an eating binge among those who are thin but were previously obese. It may be unrecognized because of high pain threshold and can be fatal.
Choking, especially on hot dogs, has been reported as cause of death in approximately 8% of deaths in individuals with PWS [Stevenson et al 2007b].
Concern about the possible contribution of growth hormone (GH) administration to unexpected death has been raised by reported deaths of individuals within a few months of starting GH therapy [Eiholzer 2005, Sacco & Di Giorgio 2005]. The few reported deaths were mostly in obese individuals who had pre-existing respiratory or cardiac disorders with evidence of upper airway obstruction and uncorrected tonsillar and adenoidal hypertrophy. In the database of one pharmaceutical company, five of 675 children treated with GH died suddenly of respiratory problems [Craig et al 2006]. In another study, the rate of death in affected individuals on and off GH did not differ [Nagai et al 2005]. A study of the natural history of PWS in one region of the UK found the overall death rate of individuals with PWS to be as high as 3% per year without GH therapy [Whittington et al 2001]. Thus, the relationship of GH administration to unexpected death remains unclear. However, it is advisable to obtain a sleep study before the initiation of GH therapy and again four to eight weeks after the beginning of GH therapy to ensure that GH treatment has not caused or worsened sleep-disordered breathing [Miller et al 2006b]. A long-term study of 48 treated children suggests that the benefits of treatment with GH greatly exceed the risks [Carrel et al 2010].
Neuroimaging. In one study, all 20 individuals with PWS who were evaluated had brain abnormalities that were not found in 21 sibs or 16 individuals with early-onset morbid obesity who did not have PWS [Miller et al 2007]. All had ventriculomegaly; 50% had decreased volume of brain tissue in the parietal-occipital lobe; 60% had Sylvan fissure polymicrogyria; and 65% had incomplete insular closure. In another study, these authors reported white matter lesions in some people with PWS [Miller et al 2006a]. A study of brain MRIs from 91 individuals with PWS from another group showed reduced pituitary height in 49% and some neuroradiologic abnormality in 67% [Iughetti et al 2008]. The implications of these findings are unknown.