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Case reports of sudden fatalities, primarily respiratory,
in children with Prader-Willi Syndrome (PWS) receiving growth hormone (GH)
therapy caused alarm and prompted a voluntary label change to include a new
warning. Benefits of GH treatment in these patients include improved linear
growth, increased muscle mass and amelioration of hypotonia, and decreased
total body fat. Sleep-disordered breathing is common in PWS, both obstructive
(from pharyngeal narrowing, respiratory muscle hypotonia, and later compounded
by obesity) and central (hypothalamic dysfunction with abnormal arousal and
response to hypercarbia which can be further blunted by obesity).
Miller and colleagues
performed a prospective study of the respiratory effects of 6 weeks of GH
treatment in 25 patients with genetically confirmed PWS. All patients underwent
standard overnight polysomnography (PS) at baseline (either naïve or
voluntarily withdrawn from GH treatment for 3 months) and after 6 weeks of GH
(0.24 mg/kg/wk for children and 0.0006 mg/kg/day for adults, based on ideal
body weight); two of the patients were also retested after 6 months. Subjects
ranged in age from 5 months to 39 years. All had sleep-disordered breathing
during the baseline PS, with both obstructive and central apneic events. After
6 weeks of treatment, 19 of the patients (76%) had improvement of the
apnea/hypoxia index (AHI); the frequency of central events decreased by a
median of 1.7 events/hr, while the frequency of obstructive events did not
change significantly. However, 6 patients (24%) had worsening of obstructive
sleep apnea/hypopnea, related to upper respiratory tract infections (URIs) and
tonsillar hypertrophy. Two of these patients had high insulin-like growth
factor (IGF)-I levels for bone age (z scores of +1 and +2; the others had IGF-I
z scores of 0). After GH dose reduction and normalization of IGF-I level, one
patient had an improved AHI on repeat PS while the other had increased AHI and a
URI at the time of the repeat study. Body-mass index was not related to PS
results.
The authors concluded that PS should be performed in all
PWS patients at baseline, after 6 weeks of treatment with GH, and with
otorhinolaryngolic evaluation whenever symptoms of sleep apnea or snoring
develop. Adenotonsillectomy and titrating GH dose to achieve an IGF-I z score
of 0 were also recommended as needed. Finally, they supported the warning of GH
manufacturers contraindicating GH use in PWS patients with CRI or lung
infections.
Miller
J, Silverstein J, Shuster J, Driscoll DJ, Wagner M. Short-term effects
of growth hormone on sleep abnormalities in Prader-Willi Syndrome. J Clin
Endocrinol Metab. 2005; epub (10.1210/jc.2005-1279).
First Editor’s
Comment: I applaud the authors
for performing a prospective study to directly address the question of GH
effects on respiratory function in PWS patients, and I agree with the proposed
pathophysiologic mechanisms. However, the finding of sudden death in
individuals with hypothalamic dysfunction and the recurrent theme of
exacerbation by intercurrent infections make me wonder about central adrenal
insufficiency, which was not mentioned. Indeed, a PubMed search of adrenal
insufficiency and PWS produced only one paper.1 In this
retrospective series report of 8 children and 2 adults with unexpected death or
critical illness, 3 of the children had below-average sized adrenal glands on
autopsy; childhood illnesses in general under the age of 2 years were
associated with high fever and rapid demise or near-demise. Increased mortality
among individuals with GH deficiency (GHD) despite GH treatment has been
attributed to under-diagnosed and under-treated central adrenal insufficiency,
and recent papers highlighted the increased risk for central adrenal insufficiency
even in patients with idiopathic GHD or familial isolated GHD.2,3
Thus, in addition to the recommendations by Miller et al, I would encourage
monitoring of adrenal function in PWS patients.
Adda Grimberg, MD
Second Editor’s Comment: Excellent points made
by the authors of the paper and the editorial comment of Dr. Grimberg. I urge
caution and continuous monitoring of PWS patients throughout their life, not
just after initiating GH therapy, and particularly when ill.
Fima Lifshitz, MD
References - (linked to  )
-
Stevenson DA, Anaya TM, Clayton-Smith J, et al. Unexpected
death and critical illness in Prader-Willi syndrome: report of ten individuals. Am
J Med Genet A. 2004;124:158 - 164.
-
Lange
M, Feldt-Rasmussen U, Svendsen OL, Kastrup KW, Juul A, Muller J. High
risk of adrenal insufficiency in adults previously treated for idiopathic
childhood onset growth hormone deficiency. J Clin Endocrinol Metab.
2003;88:5784 - 5789.
-
Mullis PE, Robinson IC, Salemi S, et al. Isolated
autosomal dominant growth hormone deficiency: an evolving pituitary deficit?
A multicenter follow-up study. J Clin Endocrinol Metab. 2005;90:2089
- 2096.
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Current GGH - Vol. 24 No. 1
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