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Pharmacia Corporation, SE-112 87 Stockholm, Sweden (P.B.) and Department of Woman and Child Health, Karolinska Institute, SE-171 76 Stockholm, Sweden (E.M.R., A.C.L.)
Correspondence: Address all correspondence and requests for reprints to: Pia Burman, M.D., Ph.D., Pharmacia Corporation, Lindhagensgatan 126, SE-112 87 Stockholm, Sweden. E-mail: pia.burman{at}eu.pnu.com
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Abstract |
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 Top Abstract I. IntroductionII. GH Secretory Status...III. The Hypothalamic-Pituitary...IV. The Status of...V. Endocrine Treatment of...VI. SummaryReferences |
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I. Introduction
A. A brief description of the syndrome
B. Body composition in patients with Prader-Willi syndrome
C. Prognosis
II. GH Secretory Status in Patients with Prader-Willi Syndrome
III. The Hypothalamic-Pituitary-Gonadal Axis and Sexual Development in Prader-Willi Syndrome
IV. The Status of Other Hormonal Axes in Prader-Willi Syndrome
V. Endocrine Treatment of Patients with Prader-Willi Syndrome
A. Effects of GH treatment on stature
B. Effects of GH treatment on body composition and muscle function
C. Other effects of GH treatment
D. Side effects of GH treatment
E. Sex hormone replacement therapy
VI. Summary
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I. Introduction |
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TopAbstractI. IntroductionII. GH Secretory Status...III. The Hypothalamic-Pituitary...IV. The Status of...V. Endocrine Treatment of...VI. SummaryReferences |
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A. A brief description of the syndrome
Prader-Willi syndrome is a genetic disorder characterized by both
mental and physical abnormalities. Occurring in 70–75% of affected
individuals, the principal genetic mutation associated with the
condition is deletion of a segment of the paternally derived chromosome
15 (15q11-q13). Several other abnormalities have also been linked with
the syndrome: 20–25% of patients exhibit maternal disomy of the same
region of chromosome 15, 2–5% have imprinting center mutations, and
1% have translocations (3, 4, 5). The individual gene or
genes from within 15q11-q13 that cause the condition have yet to be
identified. More detailed reviews of the genetics associated with
Prader-Willi syndrome are given by Cassidy (4) and
Nicholls et al. (6).
Clinically, Prader-Willi syndrome is characterized by a range of mental
and physical symptoms. These include short stature, muscular hypotonia,
excessive appetite with progressive obesity, hypogonadism, mental
retardation, behavioral abnormalities, sleep disturbances (including
sleep apnea), and dysmorphic features (7, 8). The
photograph of a boy with Prader-Willi syndrome illustrates the typical
physical features of the condition (Fig. 1
). Diagnosis of Prader-Willi syndrome is
made according to a set of consensus clinical criteria that were
published in 1993 (Table 1). On this
basis, it is estimated that one child in every 10,000–25,000 live
births suffers from the syndrome (9, 10, 11). However, as
diagnosis relies on subjective identification of characteristic
symptoms and signs, it is likely that this figure is not completely
accurate. More recent studies of "at-risk" populations, including
newborns, suggest that the prevalence is likely to be around 1:15,000,
ranging from 1:10,000–1:16,000 (4, 12, 13). Mass
screening for distinctive genetic abnormalities in the 15q11-q13
chromosomal region would enable a "true" prevalence to be
calculated, but a study of this nature would not be cost effective. To
date, screening of high-risk populations (12) remains the
most efficient method of identifying patients with Prader-Willi
syndrome.
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Children with Prader-Willi syndrome usually become overweight by the age of 4 yr as a consequence of their insatiable appetite and compulsive eating (14). Unfortunately, obesity progresses with age (15, 16, 17), and historically we have observed that about one-third of individuals with Prader-Willi syndrome are more than twice their ideal body weight (18, 19). Obesity is a risk factor for many other serious conditions, including cardiovascular disease and diabetes; hence, it is a major cause of increased morbidity and mortality among patients with Prader-Willi syndrome (20, 21).
Restriction of growth is also a frequently observed sequel of Prader-Willi syndrome: approximately 90% of affected individuals are short in stature (9). This problem is illustrated by a study in which the weight and height of 71 Caucasian Americans, aged 4–24 yr, with Prader-Willi syndrome were compared with healthy subjects. The 50th centile for height in the patient group fell below the normal 5th centile by the age of 12–14 yr, whereas the 50th centile for weight in the affected individuals approximated the 95th centile in the healthy population (22). As a result of their feeding difficulties, affected infants often fail to thrive and, during the first year, this may result in growth below the 3rd percentile. Thereafter, linear growth is only slightly compromised, remaining at the 10th percentile or below until the age of 10 yr for females and 12 yr for males. After this time, height velocity often declines relative to the norm at these ages, due to a lack of growth spurt (9, 22). This growth pattern may vary in the individual child, partly as a consequence of evolving obesity or dietary interventions. Thus, it is not uncommon to see temporary growth arrest when caloric restrictions take effect after late diagnosis, or, conversely, an improvement in growth rate may be seen when obesity develops. Cassidy (4) reported that the mean adult heights achieved by men and women with Prader-Willi syndrome were 155 and 148 cm, respectively. Wollmann et al. (16), however, found that mean height was slightly higher at 162 and 150 cm for men and women, respectively, while Hauffa and colleagues (23) noticed a near final mean height of 159 cm in boys and 149 cm in girls. Nagai and co-workers (24) constructed growth curves for Japanese children with Prader-Willi syndrome and found that mean final height was approximately 141 cm in girls and 148 cm in boys. These values are considerably below -2 SD scores for healthy Japanese individuals.
During their first 6 yr of life, children with Prader-Willi syndrome often do not achieve normal levels of cognitive, motor, and language development. Indeed, according to one study, these individuals have a below-average IQ of about 70 (25). A review of cognitive ability among 575 affected individuals confirms this, showing that just 5% of patients had a normal IQ (i.e., > 85) (26). Borderline mental retardation was observed in 28% of patients, while 34%, 27%, and 5%, respectively, were mildly, moderately, or severely mentally retarded. In addition to impaired mental development, many sufferers of Prader-Willi syndrome display a range of behavioral problems (4). As mentioned earlier, these include excessive appetite and lack of food selectivity, but there is also a high incidence of stubbornness, verbal perseverance, skin picking, and temper tantrums. Furthermore, affected individuals have a tendency toward depression and a diminished ability to initiate and maintain social contacts. A high pain threshold is also characteristic of the condition, and sleep apnea and excessive daytime sleepiness are particularly common among older children. Given these problems it is not surprising that many children with Prader-Willi syndrome experience learning disabilities and often require special education services (8).
The handicaps associated with Prader-Willi syndrome have significant implications in later life, as many of those affected are incapable of independent living. According to a large survey of adults with the condition (20), the majority lived in group homes or with their family. More than one-third (35%) did not work; of those who did work, the vast majority were employed in a sheltered environment. There was still a high incidence of behavioral problems, and hospital admissions due to physical or psychiatric problems were frequent. The author reported that the identified aberrant behaviors resulted from the physical aspects of the syndrome, i.e., the relentless hunger and the psychosocial pressures of being obese, sexually immature, and cognitively limited.
B. Body composition in patients with Prader- Willi syndrome
Prader-Willi syndrome is associated with high body fat mass and
low muscle mass. Accurate determination of body composition is,
therefore, an important aspect of monitoring both the progression of
the condition and its treatment. Bioelectrical impedance analysis
(which separates fat-free mass from fat mass), skinfold thickness (in
which sc fat mass at various locations is recorded), and dual energy
x-ray absorptiometry (DEXA, which provides a measure of fat tissue,
bone, and non-bone lean mass) are the most widely used methods of
assessing body composition. Bioelectrical impedance analysis, however,
may be inadequate to measure changes in body composition in
Prader-Willi syndrome because the ratio of lean to fat mass is
decreased, requiring a special adaptation of mathematical estimates
(27). For healthy subjects, DEXA is presently regarded as
the "gold standard" because it allows different regions of the body
to be assessed, and fat, bone, and lean mass are directly visualized
and calculated. Further research is required, however, to determine
whether it is worthy of the same status in Prader-Willi syndrome. One
of the main limitations of DEXA and, indeed, of other methods, is that
muscle mass can only be deduced indirectly, as the "lean mass"
parameter comprises both water and cellular components. Accurate
evaluation of muscle mass requires additional investigations, such as
assessment of total potassium and/or extracellular water mass.
Despite their inherent limitations, data from the above methods have been found to correlate with each other. All three techniques and the "weight for height" method have also consistently confirmed distinct differences in the body composition of patients with Prader-Willi syndrome when compared with healthy controls. For example, in three studies involving young individuals affected with the condition, the mean percent body fat was 42% [n = 14 (28)], 51% [n = 5 (29)], and 47% [n = 27 (15)]. In contrast, in a population of 403 healthy Dutch individuals aged 4–20 yr, mean percent body fat was only 11% in males, 15.5% in girls less than 15 yr old, and 24% in females older than 15 yr (30). Similar results have been reported in an Australian study involving 265 healthy individuals aged 4–26 yr, with percent body fat ranging from 4.8% to 34.1% (median, 14.4%) in males and from 10.4% to 47.7% (median, 22.8%) in females (31).
Recently, Brambilla and co-workers (15) used DEXA to show
that patients with Prader-Willi syndrome had a low lean body mass (LBM)
as well as a higher ratio of fat mass to LBM compared with both healthy
individuals of normal weight and, importantly, those with simple
obesity (Fig. 2). The study also
suggested that LBM declines further with age. Young children with
Prader-Willi syndrome (<12 yr old) had an LBM that was 81–93% of
that found in the children of normal weight, whereas in older patients
LBM was only 63–83% of the normative values. Limb areas appeared to
be most compromised. In addition, bone mineral content was found to be
lower than in the healthy obese and normal weight populations. Notably,
Eiholzer and co-workers (32) have shown that, even in the
first years of life, children with Prader-Willi syndrome have an
abnormally low LBM.
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C. Prognosis
Prader-Willi syndrome is associated with increased morbidity and
premature mortality, the main cause of which is thought to be obesity
(20, 21). Many of the medical complications of obesity,
including type II diabetes mellitus, hypertension, atherosclerosis,
hyperlipidemia, compromised cardiopulmonary function, sleep
disturbance, and psychological problems, such as depression and lack of
self-esteem (38, 39, 40, 41, 42), have also been described in
Prader-Willi syndrome. Affected individuals are also at risk of
developing scoliosis, and this may be a concern when considering GH
therapy to improve growth rate. Up to 80% of patients are reported to
have a scoliosis exceeding 10°, and 15–20%
have clinically significant scoliosis (43). Similarly, the
incidence of osteoporosis is higher among patients with Prader-Willi
syndrome, to which reduced GH secretion and hypogonadism could
contribute (44). Lastly, given their high risk of
comorbidity, mental retardation, lack of employment, and limited social
and personal relationships, poor quality of life is a major concern for
patients with Prader-Willi syndrome (4, 25, 38).
It should be noted, however, that most studies of comorbidity in Prader-Willi syndrome have suffered from limited patient samples and lack of appropriate control groups. In addition, many of these reports date from a period when restricted caloric intake and training of eating habits were not widely accepted control strategies. The literature on this aspect of the disease must therefore be interpreted with care, and high quality epidemiological studies are awaited. In the following sections we review the current literature pertaining to three of the most significant comorbid conditions in Prader-Willi syndrome: glucose intolerance, vascular disease, and respiratory disease.
1. Glucose tolerance. A number of reports suggest that glucose tolerance is abnormal in individuals with Prader-Willi syndrome. Fasting plasma insulin concentration and the insulin response to glucose are often increased in affected individuals, suggesting insulin resistance (45). A reduction in the number of insulin receptors on monocytes has also been described in the syndrome, echoing a similar abnormality seen in patients with simple obesity (46).
The reported prevalence of diabetes mellitus among patients with Prader-Willi syndrome varies. For example, Hall and Smith (17) found that 5 of 14 children with Prader-Willi syndrome had diabetic glucose tolerance and one had diabetes. Similarly, Illig and co-workers (47) reported that 41% of affected patients 15 yr of age and younger (n = 34) had reduced glucose tolerance, of which 21% had diabetes. Diabetes is also common in older patients. In a study involving 23 patients aged 15–41 yr, 17% had diabetes mellitus, the majority of whom required insulin therapy (21). A high incidence of type II diabetes mellitus in adults with Prader-Willi syndrome was also shown by Cassidy et al. (48), who studied 22 individuals aged 30–55 yr over a period of 1–12 yr. Nine of the patients (41%) developed diabetes mellitus. Clinically, the diabetes presented as type II, which responded to weight reduction and oral hypoglycemic agents. Finally, in one of the largest surveys to date, the prevalence of diabetes was lower than that described by Cassidy and co-workers. Of 232 adults with Prader-Willi syndrome (age, 16–64 yr), 44 (19%) had diabetes, 29 of whom required insulin (20).
The differing rates of diabetes reported by these authors could result from differences in age and body weight between the study groups. In most of the above studies, however, a large proportion of patients were grossly obese.
In contrast to these reports, some recent studies involving children with Prader-Willi syndrome who were of normal weight or only moderately obese have demonstrated low insulin levels combined with normal serum glucose concentrations (49, 50, 51, 52). As subjects with "simple" obesity generally have elevated insulin levels, these results suggest that patients with Prader-Willi syndrome have increased insulin sensitivity, which is different from that of the grossly obese. One interpretation of these findings would be that some degree of GH insufficiency in Prader-Willi syndrome increases insulin sensitivity. Additionally, the high prevalence of diabetes cited in earlier reports may be secondary to gross obesity rather than a feature of the syndrome itself, but this is an area in which more data are needed.
2. Vascular disease. Patients with Prader-Willi syndrome appear to be at high risk of vascular disease. For example, Cassidy and co-workers (48) found that as many as 32% of patients with the condition were hypertensive (n = 22). A lower prevalence of hypertension (17%), however, was observed in a larger-scale survey (20), during which one man experienced a stroke at the age of 24 yr. Again, this study showed that comorbidity was related to weight gain, as hypertension, heart problems, and respiratory difficulties were all correlated with obesity. Several other cases of vascular disease in Prader-Willi syndrome exist in the literature. Advanced coronary atherosclerotic disease, for example, has been described in two patients who were less than 35 yr old (53, 54). One of the original patients described by Prader and co-workers (1) died at the age of 28 yr after developing diabetic vascular complications (55), and a 26-yr-old patient with Prader-Willi syndrome was recently reported to have experienced silent myocardial infarction and hyperlipidemia. The same patient also had rapidly progressive diabetic retinopathy and neuropathy (56). The authors suggested that premature atherosclerotic coronary disease might play an unrecognized role in mortality and morbidity associated with Prader-Willi syndrome. However, their conclusion is based solely on case reports, and controlled data are required before a firm link can be made. Hyperlipidemia may also be a feature of Prader-Willi syndrome, although both normal and elevated lipid levels have been reported (57, 58, 59, 60). In a study by l’Allemand and colleagues, 25% of children with Prader-Willi syndrome had elevated levels of low-density lipoprotein cholesterol and apolipoprotein B (61).
3. Respiratory disease. Impaired respiratory function is frequently observed in patients with Prader-Willi syndrome (62). Cassidy and colleagues (48) found that seven of eight affected individuals over the age of 30 yr had restrictive lung disease, and Laurance et al. (21) reported that cor pulmonale was the most common cause of death among nine patients with the condition. A further complication seen in affected patients with reduced lung function is hypercapnia (62). Until recently, this was thought to be a secondary effect of respiratory muscle weakness or the result of Pickwickian syndrome brought about by increased abdominal and thoracic fat. However, we and other investigators have now found that affected individuals have an impaired response to short periods of hypercapnia and a reduced ventilatory volume, indicating that the sensitivity of peripheral chemoreceptors to changes in blood oxygen and carbon dioxide is decreased (63, 64, 65). Thus, it seems that impaired respiratory function in Prader-Willi syndrome is not caused solely by obesity or muscle weakness.
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II. GH Secretory Status in Patients with Prader-Willi Syndrome |
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TopAbstractI. IntroductionII. GH Secretory Status...III. The Hypothalamic-Pituitary...IV. The Status of...V. Endocrine Treatment of...VI. SummaryReferences |
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and Refs. 49, 60, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78). Depending on the stimulation test used, 40–100%
of children with this condition fulfill the criteria for GH deficiency
(GHD), which is generally defined as peak GH levels of less than 10
µg/liter in response to one or two stimulation tests. The majority of
affected children also have low GH secretion when measured by frequent
blood sampling over 24 h. However, healthy, obese individuals also
show reduced GH secretion during provocation tests, when compared with
healthy, "lean" controls (79). The cause of reduced GH
secretion in obesity is not fully understood and both FFA
(80) and insulin have been proposed as mediators of this
effect (81). At least one study has shown elevated levels
of free IGF-I in individuals with "simple" obesity, suggesting a
negative feedback at the pituitary/hypothalamic level
(82). However, normal levels of free IGF-I have been found
in other studies of subjects with the same condition (83).
As a result of these findings, it has been argued that the apparent GH
insufficiency in patients with Prader-Willi syndrome simply reflects
their obesity. To determine whether this is in fact the case, a
detailed comparison of the two conditions with respect to GH-related
parameters and clinical features is required.
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), serum IGF-I levels are reduced,
whereas healthy children with simple obesity have normal or slightly
elevated IGF-I levels. Furthermore, the level of IGF-I has been shown
to correlate with body mass index (BMI) in obese children (83, 86). This is not the case in children with Prader-Willi syndrome
(77), where low IGF-I and GH levels are not limited to
those who are severely obese but have also been found in patients who
are of normal weight. Lastly, in contrast to healthy obese children
(80, 83, 87), depressed levels of IGF-binding protein 3
have been reported in affected individuals (49). Clinical features of the condition also support the presence of GHD in Prader-Willi syndrome. Both Prader-Willi syndrome and GHD are characterized by short stature, obesity with extra fat deposits over the abdomen, abnormal body composition with reduced muscle mass and decreased bone density, and, in some patients, retarded bone age (8, 16, 88). Conversely, children with simple obesity are often tall for their age and have an increased absolute fat free mass and advanced bone age (89, 90). In summary then, available data suggest that, as a group, patients with Prader-Willi syndrome are GH deficient, although the degree of GHD may vary from mild to severe insufficiency.
The occurrence of reduced GH secretion and hypogonadotropic hypogonadism (see Section III) in the majority of children with Prader-Willi syndrome, together with abnormal appetite control and high pain threshold, suggest hypothalamic-pituitary dysfunction. Autopsies of five patients with Prader-Willi syndrome performed by Swaab and co-workers (91) indicated that the paraventricular nucleus was reduced in size and there were fewer oxytocin-expressing neurons. In a later publication, Swaab (92) identified further irregularities associated with the syndrome. These included a 30% reduction in GHRH-releasing neurons in the nucleus arcuatus, a down-regulation of neuropeptide Y, and a deficiency in vasopressin. Magnetic resonance imaging has also revealed an abnormal bright spot in the posterior pituitary lobe of some affected individuals, which is considered to be a sign of hypothalamic dysfunction (93), and pituitary hypoplasia is frequently observed (94).
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III. The Hypothalamic-Pituitary-Gonadal Axis and Sexual Development in Prader-Willi Syndrome |
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TopAbstractI. IntroductionII. GH Secretory Status...III. The Hypothalamic-Pituitary...IV. The Status of...V. Endocrine Treatment of...VI. SummaryReferences |
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Puberty is generally delayed in children with Prader-Willi syndrome, and in some individuals it may never occur at all (44, 48), although there have been at least two reported cases of precocious puberty (95, 96). In fact, many children experience premature adrenarche characterized by growth of axillary and pubic hair, this being particularly common in obese individuals (97). In many affected individuals, puberty fails to progress beyond this stage. For example, Greenswag (20) studied a group of 81 females with Prader-Willi syndrome between the ages of 10 and 28 yr. During the study period only 39% of these patients experienced menarche. It seems that very obese girls with Prader-Willi syndrome may be more likely to experience puberty. A possible explanation for this is that aromatization of androgens in the fat tissue of these patients produces sufficient amounts of estrogen to prompt maturation (9). However, even if menses do occur, bleeding is usually irregular, and it is unlikely to be associated with a normal menstrual cycle. Furthermore, spontaneous breast development is difficult to assess in Prader-Willi syndrome because normal glandular development may be confused with increasing fat tissue, particularly in obese girls. Pubertal growth spurt and bone maturation are also compromised in Prader-Willi syndrome. Reduced levels of circulating sex hormones fail to provide the trigger for GH secretion, which may itself be depressed (see Section II).
Hypogonadism associated with Prader-Willi syndrome is generally due to insufficient gonadotropin secretion, i.e., hypogonadotropic hypogonadism. In confirmation of this diagnosis, investigators have found that most affected individuals demonstrate a poor response to GnRH (98, 99) that improves after prolonged clomiphene administration. Tolis et al. (100) have also observed that repeated administration of GnRH improves LH secretion. These findings point to a hypothalamic dysfunction in the regulation of gonadotropin secretion. However, it should be noted that some individuals showed a normal gonadotropin response to GnRH and that, in our own observations, some males have reached T levels within the normal range.
Wannarachue and Ruvalcaba (101) have also observed patients whose hypogonadism was not classically hypogonadotropic in nature. Of nine females, aged 11–44 yr, only one woman showed a normal LH response to clomiphene administration. Of the two men (age 23 and 28 yr), both had very small testes and elevated LH levels that responded poorly to clomiphene (FSH levels were not reported). The men also had low basal T levels that showed a significant but subnormal response to administration of human CG over 5 d. One of the men had undergone testicular biopsy of both a scrotal and a cryptorchid testis at the age of 15 yr. The microscopic picture was similar in the two biopsies: few germ cells, some thickening of the tubular basement membranes, and seemingly normal Leydig cells. The other man was biopsied at 28 yr of age; atrophy of seminiferous tubules with some hyalinization, thickened basement membranes, and clearly distinguishable Leydig cells were found. In another report of testicular histology, an 8-yr-old boy was found to have no spermatogonia in his cryptorchid testes (102).
These scattered observations in male patients with Prader-Willi syndrome may be the result of hypogonadotropic hypogonadism combined with primary testicular dysgenesis manifesting as very poor spermatogenesis (98). Gonadotropin secretion may improve in early adulthood, leading to atrophy and hyalinization of seminiferous tubules. Furthermore, some male patients have poor Leydig cell function. Hypothetically, in the early years of life, this could be explained by a lack of LH stimulation, but in later years it may be secondary to seminiferous tubular damage caused by present or previous cryptorchidism.
Until recently it was thought that all individuals with Prader-Willi syndrome were sterile. However, we are now aware of two women with Prader-Willi syndrome who have become pregnant (103, 104). In one case, a woman with maternal disomy gave birth to a healthy girl, whereas the other woman, who had a deletion of 15q11-q13, gave birth to a child with Angelman syndrome.
It is possible that the tempo of gonadal maturation varies between individuals, thereby increasing the heterogeneity of patient groups in the various studies. There is some evidence for delayed gonadal maturation, as the normalization of T levels in blood in affected men over the age of 20 yr has been observed (our personal observations). Furthermore, one affected woman, reported to have given birth at the age of 33 yr, had primary amenorrhea until the age of 29 yr (103).
The variation in hypogonadism between individuals with Prader-Willi syndrome remains to be explained.
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IV. The Status of Other Hormonal Axes in Prader-Willi Syndrome |
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TopAbstractI. IntroductionII. GH Secretory Status...III. The Hypothalamic-Pituitary...IV. The Status of...V. Endocrine Treatment of...VI. SummaryReferences |
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V. Endocrine Treatment of Patients with Prader-Willi Syndrome |
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TopAbstractI. IntroductionII. GH Secretory Status...III. The Hypothalamic-Pituitary...IV. The Status of...V. Endocrine Treatment of...VI. SummaryReferences |
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First, enteral gastric tube feeding is indicated in many neonates with Prader-Willi syndrome. Feeding difficulties commonly occur and may lead to malnutrition if not addressed. Training of balance and motor abilities is also important from an early age, as is physical training to increase muscle strength and energy consumption later in life. Other conditions, such as scoliosis, hyperopia/myopia, and cryptorchidism, should be treated if present. The behavior of affected children may be improved by imposition of regular routines and the strict reinforcement of behavioral limits. Affected children may also benefit from special education. However, the most important aspect of treating Prader-Willi syndrome is control of excessive weight gain, specifically with respect to fat. As we have previously indicated, individuals afflicted by this condition seem to have complications similar to those experienced by healthy obese people. Thus, weight reduction could be expected to have beneficial effects on morbidity and mortality. A strictly controlled diet, in conjunction with eating-habit training and regular exercise, is important from an early age and remains the basis for all therapeutic interventions. It has been noted, however, that early dietary intervention may reduce growth rate (108), possibly by unmasking GHD. To date, appetite suppressants have been mostly unsuccessful in controlling weight gain, as have surgical procedures such as gastric banding, small-intestine bypass, and jaw wiring (9). The various components of medical, psychological, and sociological care required by individuals with Prader-Willi syndrome have been extensively reviewed by Greenswag and Alexander (109).
A. Effects of GH treatment on stature
The GH-deficient state commonly associated with Prader-Willi
syndrome, as evidenced by reduced GH secretion, low serum IGF-I levels,
and clinical features typical of GHD, has provided a rationale for
trials assessing the efficacy of GH treatment. From the current
literature, more than 200 children with Prader-Willi syndrome have
received GH treatment. The duration of treatment has generally ranged
between 6 and 36 months, although some children have received GH for
longer periods. To date, three randomized controlled studies have been
reported (60, 110, 111).
Longitudinal growth was increased by GH treatment in all studies. A
summary of several studies that highlights the change in height
SD scores during the first year of treatment is shown in
Table 3 (60, 71, 75, 94, 110, 111, 112, 113). Initial positive effects on growth velocity appear to
be sustained throughout the second year of treatment (Fig. 3). Furthermore, a report involving
children treated with GH over a period of 5 yr shows that growth
continues to improve with the result that target height SD
scores can be reached (114). Long-term efficacy has also
recently been reported by Eiholzer and l’Allemand (115)
in a study involving 4 yr of treatment.
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). In most of these studies, a
controlled diet was initiated before commencement of GH therapy and
maintained throughout the trial. The results show that GH treatment
leads to an overall improvement in body composition by reducing fat
mass and increasing muscle mass (Figs. 4 and 5). A report published at the time of
writing supports these data (116). Two years of GH
treatment led to a reduction in fat mass and a sustained increase in
LBM. Data on the long-term effects of GH on body composition are,
however, limited, and recent results show that 5 yr of GH treatment may
still be insufficient to normalize LBM (117). Data from
other long-term studies do suggest that that GH treatment can help to
stabilize BMI (114, 118). Improved motor performance and
agility have also been documented in children with Prader-Willi
syndrome who received GH (60, 113, 116). Furthermore, some
reports suggest that such treatment has beneficial effects on physical
appearance, energy, and endurance, thus improving the psychosocial
functioning of affected children (70, 76, 112, 113). In a
note of caution, it is recognized that many of these observations are
based on spontaneous reports by parents and attending physicians;
therefore, further studies are required to confirm these particular
benefits.
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D. Side effects of GH treatment
The reported adverse events during GH treatment of patients with
Prader-Willi syndrome are generally similar to those observed during
treatment of children with classic GHD, Turner syndrome, or chronic
renal insufficiency. Recent studies have shown that insulin levels in
children with Prader-Willi syndrome are lower than in obese controls at
baseline but increase during GH treatment. Glucose levels tend to
remain unchanged or increase within the normal reference range
(50, 60). However, considering the limited experience of
prolonged GH treatment in these patients and the increased incidence of
diabetes mellitus associated with the condition, carbohydrate
metabolism (glucose, HbA1c) should be closely
monitored in patients receiving GH.
Scoliosis, attributed to a combination of obesity and muscular hypotonia, is common in both children and adolescents with Prader-Willi syndrome. The rapid growth associated with GH may aggravate this spinal deformity; therefore, the occurrence and development of scoliosis should be monitored during therapy. If quantification of scoliosis is difficult, e.g., in advanced obesity, x-ray monitoring should be used. In a controlled, randomized study by Carrel et al. (60), 70% of the patients had a mild scoliosis (<20°) that occurred equally between the control and treatment groups. Furthermore, there was no significant worsening of the condition in either group during the 12 months of the study. In a similar study conducted over 1 yr by Lindgren et al. (74), no patient in either the control or GH-treated group experienced progression of scoliosis to the severe stage (>20°).
E. Sex hormone replacement therapy
Treatment of hypothalamic-pituitary-gonadal failure in
Prader-Willi syndrome remains a controversial issue, and the reader is
therefore referred to an in-depth discussion by Lee (44).
Most clinicians, however, agree that cryptorchidism should be corrected
to enable detection of testicular malignancies (fertility may not be a
goal in Prader-Willi syndrome). Yet, in one survey of 99 affected men
with cryptorchidism, only 69 (70%) had undergone corrective surgery
(20). The true incidence of hypogonadism in adults with
Prader-Willi syndrome is unknown but in the same investigation only
41% of males and 18% of females received sex hormone replacement
therapy. Sex hormone replacement therapy may be beneficial to
hypogonadic patients in a number of ways. Obviously, the development of
secondary sexual characteristics would be encouraged, but there is also
potential for improvements in bone mineral content and bone mineral
density. Possibly as a result of decreased estrogen and androgen
production, these parameters are abnormally low in patients with
Prader-Willi syndrome from a relatively early age (15, 119).
We have been unable to identify any systematic studies of sex hormone replacement therapy in adolescents or adults with Prader-Willi syndrome. Until such studies are published, these patients should be treated as other hypogonadal individuals. Thus, we suggest that if hypogonadism prevails to the age of 17–18 yr in a man with Prader-Willi syndrome, low doses of T substitution should be offered. Its subsequent effect on activity, strength, endurance, and quality of life should then be followed. If aggressiveness increases, the substitution could be stopped. In female patients, bone mineral density should be monitored during and after adolescence, and estrogen therapy should be considered if it becomes low-normal. In very obese patients, peripheral conversion of adrenal androgens to estrogen might suffice for the basic needs. However, in the increasing number of lean adolescent and adult patients with this syndrome, the estrogen status should be monitored yearly. The need of substitution therapy should be judged individually against the background of the development of bone mineral density, general activity, and quality of life. Given the recent reports of pregnancy in two women with Prader-Willi syndrome, caregivers should be aware of the possible need for contraceptives.
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VI. Summary |
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A growing number of reports describe the use of GH replacement therapy in children with Prader-Willi syndrome. Early studies focused on the beneficial effects of this treatment on growth. However, it is now clear that GH treatment, when coupled with a strictly controlled diet, may help to reduce obesity and increase muscle mass. As the ultimate goal in the treatment of Prader-Willi syndrome is to reduce future morbidity and mortality, the observed improvement in body composition is, in our opinion, the main reason to use GH treatment in this group of patients. Furthermore, there is some evidence to suggest that GH treatment is associated with improved physical activity and agility in children with Prader-Willi syndrome, and published data suggest that there are few safety risks associated with GH treatment in these patients. Long-term safety studies are required, however, particularly regarding the effects of GH treatment on glucose metabolism and scoliosis.
At present, there are few reports in the literature regarding the use of sex hormone replacement therapy in affected individuals, although it is likely that such treatment would be beneficial in improving secondary sexual characteristics and helping to prevent osteoporosis.
In conclusion, Prader-Willi syndrome is associated with endocrine disorders that are often untreated. It is likely that a more active approach to correction of these hormone deficiencies would benefit individuals with this condition.
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References |
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