Optimal timing of recombinant growth hormone therapy in Prader-Willi syndrome: the case for very early initiation

Prader-Willi syndrome (PWS) is one of the most complex genetic conditions encountered in paediatric practice, which requires lifelong multidisciplinary management that extends to almost every aspect of a patient's health. Its incidence ranges between 1 in 10,000 to 30,000 live births globally [1,2], this syndrome is one of the most common chromosomal disorders causing childhood obesity, that is characterised by its significant hyperphagia. The underlying genetics involve the loss of expression of paternally inherited genes within the chromosome 15q11-q13 region, which happens through three possible ways: paternal deletion (accounting for approximately 60% of cases), maternal uniparental disomy (about 35%), or defects in the imprinting centre (1-3%) [2,3].PWS is characterised by overwhelming dysfunction of the hypothalamic-pituitary axis (HPA), which gives rise to a distinguishing pattern of endocrine abnormalities. These include growth hormone deficiency (GHD) or insufficiency, hypogonadism, hypothyroidism, and severely disrupted appetite and energy regulation [3,4]. This central neuroendocrine dysfunction, rather than primary pituitary failure, explains why growth hormone issues are essentially universal in PWS and plays a major role in shaping the syndrome's clinical presentation. Affected individuals typically exhibit severe neonatal hypotonia and failure to thrive, progressive hyperphagia and obesity beginning in early childhood, short stature, unfavourable body composition characterized by reduced lean mass and excessive fat accumulation, and developmental delays across physical, cognitive and language domains [1,5].Over the past two decades, recombinant human growth hormone (rhGH) therapy has become a cornerstone in PWS management, addressing not merely growth failure but also the metabolic, neurodevelopmental, and functional challenges that define this condition. Metaanalyses have demonstrated robust improvements with rhGH treatment, including mean height gains of approximately +1.67 standard deviation scores (SDS), reductions in BMI zscores of around -0.67 SDS, and decreases in fat mass proportion of approximately -6.5% SDS [6]. Beyond these measurable improvements in growth and body composition, accumulating evidence suggests that rhGH therapy may enhance motor development, cognitive function, speech, and overall quality of life, particularly when treatment begins during critical developmental windows in infancy [7,8,9]. Despite this convincing evidence, considerable variation exists in clinical practice regarding the optimal timing for initiating rhGH therapy. While international consensus guidelines support early consideration of rhGH treatment for children with genetically confirmed PWS [10,1], regulatory approvals and real-world practices differ substantially across countries and regions.Several factors fuel this ongoing debate: concerns about potentially worsening sleep-disordered breathing in already vulnerable infants, possible effects on scoliosis progression, metabolic considerations requiring vigilant monitoring, and, importantly, gaps in the existing evidence base. Many published studies involve relatively small patient cohorts, use varied outcome measures (especially for neurodevelopmental endpoints), lack long-term follow-up extending into adolescence and adulthood, and provide limited population-level safety surveillance for rare but serious adverse events [11,12].We write this commentary to highlight the growing body of evidence that supports early initiation of rhGH therapy, specifically within the first year of life, in patients with genetically confirmed PWS. Our aim is to synthesize recent clinical evidence, address safety considerations, and provide practical clinical context for optimizing treatment timing to maximize long-term outcomes in this complex disorder.To appreciate why timing matters so much in rhGH therapy, we must first understand how PWS advances when left untreated. The syndrome progresses through distinct clinical phases, each presenting unique challenges that require treatment decisions.The earliest sign of PWS is typically severe hypotonia, often apparent at birth or within the first days of life. Affected newborns present with marked weakness, profoundly reduced muscle tone, a weak cry, and poor sucking reflex, features that frequently necessitate nasogastric or gastrostomy tube feeding [1,5]. This phase is marked by failure to thrive despite adequate caloric intake, reflecting both the feeding difficulties and the underlying metabolic and hormonal disturbances. Motor milestones are significantly delayed; affected infants usually achieve head control, independent sitting, and walking much later than their appropriately developing peers. Without intervention, growth velocity remains below normal, and body composition begins shifting toward reduced lean mass and increased fat mass during this early period, while the infant appears undernourished [5,9].A dramatic transition typically occurs between 18 months and 3 years of age, when hyperphagia emerges and appetite regulation becomes profoundly dysregulated. Children develop an insatiable drive to eat, engage in food-seeking behaviours, and lack any sense of satiety, leading to rapid and severe obesity if strict environmental controls are not maintained [1,5]. During this phase, the full spectrum of developmental delays becomes evident: cognitive impairment (typically ranging from mild to moderate intellectual disability), speech and language delays, behavioural challenges (including temper outbursts, rigidity, and obsessive-compulsive features), and ongoing motor coordination difficulties. Growth velocity continues below normal, and without GH therapy, most children track well below their genetic height potential. The unfavourable body composition, characterized by low muscle mass and high fat mass, becomes increasingly pronounced and contributes to reduced physical activity, further exacerba