Respiratory disorders were the most common cause of death, and there were no differences in cause of death between the hGH treated and untreated group. Sudden death and the possible association with hGH therapy may be related to the increased risk for central adrenal insufficiency see below , especially in the setting of an acute respiratory illness [ 60 ].
Central adrenal insufficiency occurs in PWS but the frequency is unclear. Children and adults with PWS are at risk for adrenal insufficiency due to the generalized hypothalamic dysfunction. In a case series of unexpected death in PWS, autopsies performed in 3 out of 4 young children who presented with febrile or other acute illnesses revealed small adrenal glands by weight criteria. Also reported is an adolescent male with PWS who developed symptomatic adrenal insufficiency during spine surgery that resolved promptly after administration of glucocorticoid [ 62 ].
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None of these patients were reported to have been on hGH. Thus hGH may further blunt the stress response to an acute illness when the hypothalamic-pituitary-adrenal axis is already not functioning optimally. Baseline hormone levels were not different in those who tested sufficient versus insufficient suggesting that there is a deficit in the reserve necessary for the stress response [ 63 ]. The true prevalence of central adrenal insufficiency in PWS remains unclear and is an area in need of further investigation.
As a result, no consensus exists on the appropriate evaluation and management of central adrenal insufficiency in PWS. Obtaining cortisol and ACTH levels during an acute illness or other stressful situation may provide useful diagnostic information. One group recommends considering stress-dose steroids for all patients with PWS during stress, to include mild upper respiratory infections, since patients with PWS often do not show significant signs of illness such as fever or vomiting [ 63 ]. Another group recommends considering prophylactic stress dose steroids for major surgery or at least having them readily available to administer for symptoms of adrenal insufficiency [ 62 ].
In our practice, we discuss with all families the possibility of adrenal insufficiency during stress and provide our patients with stress doses of hydrocortisone to store at home for administration during significant illness. We also recommend peri-operative stress dose steroids. Hypogonadism is a consistent feature of both males and females with PWS. Clinical presentation includes genital hypoplasia, delayed or incomplete puberty, and infertility in the vast majority. Genital hypoplasia is evident at birth. In females it manifests as clitoral and labia minora hypoplasia and can easily be overlooked on physical examination.
Males commonly have cryptorchidism, a poorly rugated, under pigmented, hypo plastic scrotum, and may have a small penis.
One author recommends considering a trial of human chorionic gonadotropin hCG to promote testicular descent for potential avoidance of surgical correction and general anesthesia given the risk for respiratory complications. HCG may also increase scrotal size and penile length, which can improve orchidopexy outcomes and facilitate later standing micturition [ 3 ]. However, there are no published data regarding the efficacy of this practice in patients with PWS. Surgical correction of cryptorchidism should be completed in the first or second year of life [ 3 , 4 ].
Hypogonadism was classically thought to be hypothalamic in etiology, similar to many other manifestations of PWS.
However, recent evidence has emerged supporting primary gonadal failure as a significant contributor to male hypogonadism [ 69 — 71 ]. Other studies have also shown a combined picture of hypogonadotropic hypogonadism with relatively low LH levels, and primary hypogonadism with low inhibin B and relatively high FSH levels [ 71 , 72 ]. Gonadal function has also been evaluated longitudinally in 61 girls with PWS.
The primordial follicle pool and the number of small antral follicles were conserved. However, maturation of follicles and progression of pubertal development were impaired. LH levels were relatively low for the low estradiol levels observed, and FSH levels were normal. Pubertal onset was similar in timing to the normal population, but progression was delayed [ 73 ]. Treatment of precocious puberty with gonadotropin releasing hormone GnRH analogs is not indicated as pubertal advancement is not sustained [ 4 ].
Many patients with PWS require hormonal treatment for induction, promotion or maintenance of puberty. Benefits of sex steroid replacement include positive effects on bone health, muscle mass, and possibly general well-being. No consensus exists as to the most appropriate regimen for pubertal induction or promotion but experts agree that the dosing and timing should reflect as closely as possible the process of normal puberty [ 4 ].
Available data suggest that sex steroid deficiency contributes to low bone density in adults with PWS [ 77 , 78 ]. Testosterone administration should be considered in males with PWS as for any other hypogonadal patient. Androgen therapy can be more physiologically administered using testosterone patches and gel preparations. These delivery systems avoid the peaks and troughs of injections, which may be of particular importance in PWS because of historical concerns about aggressive behaviors with testosterone treatment [ 4 ].
However, patients may have difficulty with topical treatment due to skin irritation and skin picking behaviors. The potential for fertility in females with PWS necessitates discussion of sexuality and birth control at an appropriate age. Similar to other endocrinopathies in PWS, the etiology is thought to be central in origin. Studies investigating the natural history of hypothyroidism in patients with PWS, as well as the effects of thyroid hormone treatment, are needed. Diabetes and impaired glucose tolerance are much less frequent in children with PWS. A study of 74 children with PWS at a median age of Several studies have demonstrated that subjects with PWS, not receiving hGH therapy, had lower insulin levels and greater insulin sensitivity compared to controls matched for degree of obesity [ 86 , 87 ].
Proposed reasons for the increased insulin sensitivity in PWS include relative diffuse as opposed to visceral obesity, lower GH levels, and higher ghrelin levels for the degree of obesity [ 88 , 89 ]. Periodic surveillance for diabetes and features of the metabolic syndrome should be undertaken in obese individuals as is recommended for obesity in the general population. Early diagnosis and comprehensive care of patients with PWS have improved outcomes. Areas where further research is needed include the etiology and management of hyperphagia, risks and management of high IGF-1 levels associated with relatively low hGH doses, optimal surveillance of sleep disordered breathing, further elucidation of the effect of hGH on cognition, the impact of hGH therapy in adulthood, frequency and management of adrenal insufficiency, and the frequency and natural history of hypothyroidism.
She has a special interest in childhood and adolescent obesity. Genet Med. J Clin Endocrinol Metab.
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- How is Prader-Willi Syndrome Diagnosed? - Foundation for Prader-Willi Research?
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Correspondence to Karen S Vogt. JE contributed substantially to the writing of this manuscript. KV drafted the outline of the manuscript and contributed to the writing. Both authors read and approved the final manuscript.
Prader-Willi syndrome - Better Health Channel
This article is published under license to BioMed Central Ltd. Reprints and Permissions. The number of children who are affected by Prader-Willi syndrome is about 1 in 50, of the population. It affects boys and girls and all ethnic groups equally. Older mothers have a slightly increased risk of having a child with Prader-Willi syndrome but no other risk factors have been found. Although this is a genetic disease that results from loss of part of the chromosome 15 inherited from the father, this is nearly always something that has arisen spontaneously in a single sperm or fertilised egg.
Therefore, there is not usually any increased risk of having a second child with Prader-Willi syndrome. In very rare cases, less than 1 in every , when there is a translocation or an inherited imprinting defect present in the father, there may be an increased risk of having a second child with Prader-Willi syndrome. Treatment and management of Prader-Willi syndrome involves many different medical and social care professionals.