Low dose growth hormone treatment in infants and toddlers with Prader-Willi syndrome is comparable to higher dosage regimens

https://doi.org/10.1016/j.ghir.2017.03.001Get rights and content

Highlights

  • A GH dose of 4.5 mg/m2/week may have equivalent effect as 7 mg/m2/week on height trajectory in young children

  • Infants normalised height with a GH dose of 4.5 mg/m2/week sooner than toddlers

  • PWS specific BMI SDS reduced to between -0.5 and -1 SDS after 2 years of GHT

  • IGF-I values increased but most remained within the age-based reference range

  • Sleep studies detected mild to severe central and/or obstructive apnoea in 40% of young children prior to GHT initiation.

Abstract

Objective

Evaluate benefit and risk of low dose growth hormone treatment (GHT, 4.5 mg/m2/week) in very young children with Prader-Willi Syndrome (PWS).

Design

Prospective longitudinal clinical intervention.

Methods

We evaluated 31 infants (aged 2–12 months) and 42 toddlers (13–24 months) from the PWS-OZGROW database for height, weight and BMI using the World Health Organization standard deviation scores (SDSWHO) and PWS specific BMI (SDSPWS), bone age, insulin-like growth factor 1 (IGF-I) levels and adverse events over 3 years of GHT.

Results

At commencement of GHT infants had a lower BMI SDSWHO (− 0.88 vs 0.40) than toddlers, while toddlers had a lower height SDSWHO (− 1.44 vs − 2.09) (both P < 0.05). All increased height SDSWHO (2 year delta height infants + 1.26 SDS, toddlers + 1.21 SDS), but infants normalised height sooner, achieving a height SDS of − 0.56 within 1 year, while toddlers achieved a height SDS of − 0.88 in two years. BMI SDSWHO increased, while BMI SDSPWS decreased (both P < 0.0001) and remained negative. The GHT response did not differ with gestation (preterm 23%) or genetic subtype (deletion vs maternal uniparental disomy). Bone age advancement paralleled chronological age. All children had low serum IGF-I at baseline which increased, but remained within the age-based reference range during GHT (for 81% in first year). Four children had spinal curvature at baseline; two improved, two progressed to a brace and two developed an abnormal curve over the observation period. Mild to severe central and/or obstructive sleep apnoea were observed in 40% of children prior to GHT initiation; 11% commenced GHT on positive airway pressure (PAP), oxygen or both. Eight children ceased GHT due to onset or worsening of sleep apnoea: 2 infants in the first few months and 6 children after 6–24 months. Seven resumed GHT usually after adjusting PAP but five had adenotonsillectomy. One child ceased GHT temporarily due to respiratory illness. No other adverse events were reported. Two children substantially improved their breathing shortly after GHT initiation.

Conclusion

Initiation of GHT in infants with 4.5 mg/m2/week was beneficial and comparable in terms of auxological response to a dose of 7 mg/m2/week. Regular monitoring pre and post GH initiation assisted in early detection of adverse events. IGF-I levels increased with the lower dose but not excessively, which may lower potential long-term risks.

Introduction

In 2009 growth hormone treatment (GHT) was endorsed in Australia under the government GH program to treat children with genetically confirmed Prader-Willi Syndrome (PWS) until 18 years of age to improve linear growth and body composition [1]. PWS is caused by a lack of expression of imprinted genes on the paternally derived chromosome 15q11-13 [2]. Complications at birth are frequent and assisted delivery is necessary in the majority of cases [3]. Approximately half of the infants with PWS are transferred to a special care unit due to various problems, e.g. hypoglycaemia, inability to suckle or breathing difficulties [4], [5]. In infancy the first signs of PWS are typically hypotonia, hypogonadism, failure to thrive and developmental delay [6]. Characteristic clinical features include short stature, which is exacerbated during childhood and adolescence, and abnormal body composition, i.e. high fat mass and low lean tissue mass, which is already present in infancy [7]. Due to an increase in appetite (hyperphagia), which follows the early feeding difficulties and is already present in up to 25% of children with PWS before their third birthday [8], the child may rapidly become obese if access to food is not restricted and physical activity not encouraged. Mild to moderate intellectual disability, and behavioural and psychological problems may become apparent in later childhood [6], [9].

Children with PWS improve height and body composition with GHT [6], [10] irrespective of whether treatment is based on genetic diagnosis or on anthropometric criteria as we previously reported [11]. In young children a positive effect on motor function and muscle strength/tone has been noted [10], [12]. Developmental milestones may be reached at an earlier age and mental development and adaptive skills may be improved [13], [14]. However, in most GH studies reported to date very few children were < 1 year old when GHT was started and were grouped together in the analysis with toddlers [14], [15] or 3 to 4 year old children [16], [17]. Valuable information may have been lost as the young child goes through several nutritional phases from failure to thrive in infancy to a period of no difficulty in feeding and appropriate growth around 9 to 25 months before excessive weight gain becomes an ongoing health issue [8].

Despite the documented benefits of early initiation of GHT in PWS [6], [14], [16], there may be some hesitation to commence GHT in very young children because of the wide array of difficulties in infancy and the paucity of publications on the optimal dose and time to commence as well as safety, for example with respect to upper airway compromise secondary to lymphoid hyperplasia in infants with PWS [18], [19], [20]. In addition, concern has been raised with respect to the long-term effect of elevated levels of insulin-like growth factor-1 (IGF-I) above the reference range with the usual recommended GH dose of 7 mg/m2/week or higher [20].

In this study we aimed to evaluate:

  • The auxological response of very young children treated with a GH dose of 4.5 mg/m2/week, which is a relatively low dose compared to the recommended standard (7 mg/m2/week) in PWS [20], [21]

  • Early initiation of GHT by comparing the response of infants (aged ≤ 12 months) and toddlers (aged 13–24 months), which closely resemble the nutritional phases of the “failure to thrive stage” and the “normal feeding and growth period” respectively [8]

  • IGF-I response of both age groups to the relatively low dose of GHT

  • Occurrence of adverse events, such as respiratory compromise and scoliosis.

We also report on bone age (BA), waist circumference, hypotonia, developmental delay, spinal curvature and sleep disordered breathing over the first two years.

The recently recommended World Health Organization (WHO) and PWS specific standards were used to analyse height, weight and body mass index (BMI) standard deviation scores (SDS).

Section snippets

Subjects and methods

Data from all young children (≤ 24 months) with genetically confirmed PWS who commenced GHT were selected from the Australian PWS-OZGROW database [11], which combines de-identified patient data from the OZGROW database containing the anthropometric data of all children on the government GH program with additional information and data obtained from private patients pre 2009. All children were GH naïve. Ethics approval was obtained from the participating hospitals and universities. Parental consent

Results

Seventy nine children with genetically confirmed PWS, who started GHT within the first 2 years of life (≤ 24 months), were selected from the PWS-OZGROW database. Six had insufficient long term GH data but are included in the evaluation of adverse events. Seventy three (51% males and 49% females), had at least two years of GH treatment and were analysed in depth with multifactorial design. Sixty children completed 3 years of GHT and some up to 7 years. Thirty one (42%) of the 73 started GHT as

Discussion

Initiation of GHT at a dose of 4.5 mg/m2/week in very young children with PWS (< 2 years of age) increased linear growth and IGF-I and was associated with few adverse events in the initial treatment period (addressing priority 3 of the GH Research Society workshop [20]). There was a concomitant decrease in PWS specific BMI SDS which may have been facilitated by either direct or indirect effects of GHT through improved mobility and physical activity and hence increased energy expenditure [12], [13]

Acknowledgements

We thank the following funding sources with respect to the establishment and maintenance of the of the PWS component of the PWS-OZGROW database: Dr Elly Scheermeyer was a recipient of a Pfizer 2008 Investigator Initiated Research Grant AUS-GTR-08-001 and a Bond University 2009 Faculty Research Grant ZB02. The OZGROW Database is funded by a recurrent grant from the Australasian Paediatric Endocrine Group. We also thank Dr Yassmin Musthaffa, Dr Gary M Leong and all GH nurse coordinators for their

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