Review
Respiratory Complications in Children with Prader Willi Syndrome

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Summary

Prader Willi syndrome, resulting from the partial deletion or lack of expression of a region of genes on the paternal chromosome 15, has a number of phenotypic features which predispose affected patients to ventilatory problems. These include generalised hypotonia, abnormal arousal and ventilatory responses to hypoxia and hypercapnia, scoliosis and frequently, obesity. The spectrum of the resulting respiratory complications thus runs from sleep disordered breathing, to aspiration and respiratory functional impairment. While the use of growth hormone, in conjunction with multidisciplinary clinical management, is currently the cornerstone of clinical care of these patients, concerns have been raised following reports of sudden death shortly after growth hormone initiation. This review summarizes the respiratory complications commonly seen and draws together the published literature on the impact of growth hormone in relation to various respiratory parameters, aiming to provide the reader with the necessary information to manage these patients as safely as possible.

Introduction

Prader Willi syndrome (PWS) is a multisystem genetic disorder arising from the lack of expression of paternally derived genes on chromosome 15q11-q13. Genes in this locus are physiologically imprinted and thus silenced on the maternally inherited chromosome. Hence PWS develops if paternal alleles are missing (e.g. paternal deletion of 15q11-q13 or maternal uniparental disomy), silenced (e.g. imprinting errors) or defective (e.g. paternal chromosomal translocation) [1].

Characteristic features include narrow face, almond shaped eyes, small mouth with thin upper lip, neonatal hypotonia and poor suck, developmental delay, hypogonadism and behavioural problems (Table 1). The classical phenotype presents with poor feeding and failure to thrive in the neonatal period, followed by the subsequent development of hyperphagia and obesity. It is now recognized that there are four main nutritional phases, the first phase when the infant is hypotonic, is accompanied with feeding difficulties, poor suck and while initially there may be failure to thrive, this soon improves and the infant's growth velocity is then maintained. The second phase (typical onset between 18-36 months) sees the child's weight start to increase, crossing weight centiles initially without a significant increase in calorie intake or increased interest in food, though eventually there is increased interest in food, an accompanying increase in calorie intake, and the child often becomes overweight or obese. In phase 3, there is very aggressive food seeking behaviour, reduced satiety and patients can consume up to three times the amount of food compared with controls, despite having delayed gastric emptying. Onset of this phase is variable and can occur between 3-15 years. In the final phase, phase 4, the patient may still have an increased appetite, but this is not as unrelenting as in phase 3 [2]. Not all PWS patients go through all of these phases and better clinical management, in particular specialist dietetic advice and the early use of growth hormone (GH) (see later elaboration) may well be altering the phenotype of the condition.

The original consensus diagnostic criteria were proposed by Holm et al in 1993 [3]. However, with the advent of definitive genetic testing, the utility of clinical diagnostic criteria changed to that of raising diagnostic suspicion prompting genetic testing. Consequently, the 1993 criteria were revised in 2001, to lower the threshold for the triggering of genetic testing [4]. These latest criteria are summarized in Table 1.

The potential for patients with PWS to develop severe respiratory disturbances has been recognized for several decades now. This article attempts to summarize the research into the respiratory complications seen in this condition.

Section snippets

Respiratory responses to hypoxia and hypercarbia

Abnormalities in ventilatory control have been demonstrated in PWS patients. Gozal et al studied the ventilatory responses in 17 PWS adults when awake, comparing them with the responses seen in age, gender and body mass index (BMI) matched controls [5]. All subjects had normal end-tidal PCO2 and arterial oxygen saturations when awake at baseline. Whilst breathing 100% oxygen (3 min hyperoxic challenge) resulted in decreased minute ventilation (VE) in the control subjects, a paradoxical increase

Other respiratory concerns in PWS:

The 2 other major respiratory complications seen in PWS patients are aspiration and respiratory function impairment secondary to hypotonia/respiratory muscle weakness.

Impact of growth hormone on the respiratory system

GH has been demonstrated to have significant beneficial effects in PWS patients, improving body composition, physical activity and attainment of developmental and cognitive milestones [35]. However, there was considerable concern surrounding its safety following several reports of sudden death in PWS patients shortly after GH initiation [36].

Although there was no direct evidence that GH caused the deaths, given the safety concerns, the company manufacturing Somatropin issued a warning in 2003,

Conclusions

Patients with PWS are at risk of several potentially serious respiratory complications and while most of the published work has concentrated on sleep disordered breathing, it is important to be aware also of the risks of aspiration and restrictive lung defects, so as not to delay both investigation and appropriate therapy. Recent best practice guidelines on the diagnosis and management of patients with PWS recommend a multidisciplinary approach, with a pulmonologist +/-sleep specialist forming

Educational aims

  • To provide an overview of the range of sleep breathing abnormalities associated with Prader Willi syndrome.

  • To highlight the respiratory complications that can be seen in children with Prader Willi syndrome.

  • To discuss the impact of growth hormone on these complications.

Practice points

  • Abnormalities in ventilatory responses to hypoxia and hypercarbia have been demonstrated in patients with PWS

  • They are at risk of sleep disordered breathing – obstructive sleep apnoea, central sleep apnoea and nocturnal hypoventilation have all been described

  • They may have silent aspiration and clinical assessment by a speech and language therapist and a videofluoroscopy should be considered if a child with PWS suffers from recurrent chest infections

  • Pulmonary function tests in PWS children who

Directions for Future Research

  • Understanding the exact underlying mechanisms through which GH therapy impacts on breathing in PWS patients.

  • Understanding the long term effects of GH therapy so that optimal long term monitoring strategies can be put in place.

  • Definitive studies to determine whether hypocretin deficiency is responsible for hypersomnolence and cataplexy in PWS patients.

CME Section

You can receive 1 CME credit by successfully answering these questions online.

  • (A)

    Visit the journal CME site at http://www.prrjournal.com.

  • (B)

    Complete the answers online, and receive your final score upon completion of the test.

  • (C)

    Should you successfully complete the test, you may download your accreditation certificate (subject to an administrative charge), accredited by the European Board for Accreditation in Pneumology.

CME Questions

  • 1.

    Prader-Willi syndrome [PWS] occurs due to:

  • (a)

    A maternal deletion at the 15q11 site on Chromosome 15

  • (b)

    Uniparental disomy with inheritance of 2 paternal copies of 15q11

  • (c)

    Genetic anticipation with an expansile site at 15q11

  • (d)

    Genomic Imprinting at the Chromosome 15q11 site

  • (e)

    Secondary acquisition in those with Angelmann syndrome

  • 2.

    The following are recognised complications of PWS

  • (a)

    Poor feeding

  • (b)

    Poor weight gain

  • (c)

    Hypotonia

  • (d)

    Obesity

  • (e)

    All of the above

  • 3.

    The following are recognised respiratory complications of PWS

  • (a)

    Asthma

  • (b)

Acknowledgements

The authors would like to thank Alison Kelly, Highly Specialist Speech and Language Therapist for kindly providing Figure 4 and for providing feedback on the section on aspiration. They are also very grateful to Dr. I Balfour-Lynn for reviewing the manuscript and providing constructive feedback.

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