Growth Hormone Therapy and Noonan Syndrome

Growth Hormone Therapy and Noonan Syndrome

Short stature affects 83% of children with Noonan Syndrome (NS). The use of Growth Hormone (GH) to treat short stature in NS is a controversial topic due to its conflicting results, cost, duration of treatment and safety concerns. In this Blog Post we examine the reasons why short stature occurs in NS as well as the efficacy and safety of GH as evidenced by the existing medical literature.

Why are People with Noonan Syndrome Short?

Short stature is one of the main features of NS; 50% of all adults with NS are below the 3^rd centile for height. GH is produced by our bodies and it plays a primary role in growth and physical development. Children with NS have adequate blood serum levels of GH so there is clearly no problem with GH production. However individuals with NS have lower-than-normal levels of IGF-1; a major mediator of GH action. Thus, the main mechanism for short stature in NS is thought to be due to inhibition of GH receptor activity within the cells of the body.

NS is one of the Rasopathies – meaning it is one of many genetic diseases caused by a mutation within genes involved in the RAS/MAPK pathway. The RAS/MAPK pathway has a negative or inhibitive influence on IGF-1 production. Without adequate levels of IGF-1 the GH actions within the cell are diminished and thus it cannot exert its influence ‘downstream’. A good analogy to this problem is the ‘message’ from the GH receptors at the cell membrane are not ‘passed on’ to the other cell structures. In summary NS individuals don’t have GH insufficiency – they have GH resistance.

What do the studies say about GH Therapy?

There is a lack of high quality, published Random Controlled Trials (RCTs) on the effects of GH for people with NS.

Compounding the veracity of results for GH treatment is the fact that people with NS have delayed puberty and may and often can grow late into their 2^nd and even 3^rd decade. Whilst 83% of children with NS have short stature (more than 2 standard deviations below the mean height in average population), short stature only remain for 40% and 50% of adult males and females respectively. This is why the lack of quality data in adult growth trajectories in NS may affect interpretation of GH therapy efficacy.

There is a real need for more qualitative studies to be performed as there is not enough robust data to allow strong recommendations for the efficacy of GH therapy in children with NS.

These concerns aside the summation of GH studies shows that individuals who undergo GH treatment gain 5-10 cm of height. This may seem like an insignificant result given the cost, time and burden of treatment but such a gain may mean an individual with NS is within a normative height range post treatment.

Almost all studies show that the earlier GH therapy begins the better the results. A waning effect of GH therapy has been noted – with individuals experiencing less improvement each year of treatment. The mechanism of this is unclear but it is thought to be linked to the GH resistance present within people with NS due to their RAS/MAPK pathway mutations. However a 2012 study showed this waning effect can be eliminated by increasing the dose of GH with each successive year of treatment.

The psychological impact of GH treatment on children has not been studied.

What are the safety concerns with GH therapy?

None of the published studies have reported serious adverse effects of GH therapy. However there are many concerns raised by GH therapy in children and these must be considered by parents/carers before choosing to commence GH treatment for their child.

Preventing growth

GH therapy has an accelerating effect on bone maturation and as such there is a possibility it may terminate bone growth early – preventing an individual from attaining their final adult height.

Cancer Risk

NS carries an increased risk of cancer and GH has the potential to increase the rate of cancer growth. The potential for GH therapy to increase the risk of malignancy creates a need for long term surveillance after treatment has ceased. This would be done by regular blood tests and/or diagnostic imaging. Thankfully the limited studies performed on GH therapy in NS have not shown any increased cancer risk.

Adverse Cardiac Events

GH therapy can increase ventricle wall thickness which may eventually lead to Hypertrophic cardiomyopathy (HCM). As HCM is more prevalent in NS already this is of particular concern. Thankfully the consensus of the majority of studies have shown no cardiac changes in NS patients both during and after receiving GH therapy. The few studies that have reported adverse cardiac reactions post GH have been in less than 1.6% of all participants. It should also be noted there are no studies or data on the negative effects of GH on individuals with NS who possess HCM prior to commencing treatment.

Conclusion

In summary, due to their RAS/MAPK pathway mutation people with NS will often have short stature due to GH resistance at a cellular level. GH therapy can improve height by as much as 10cm in some individuals but there is a waning effect of GH efficacy and for best results GH therapy should commence earlier rather than later. There is a lack of high quality studies into the adverse effects of GH therapy particularly in regards to GH increasing cancer risk, heart wall thickness and people who possess HCM prior to GH treatment.

When a parent/carer weighs the decision to commence GH therapy it must be remembered that many NS individuals continue to grow into their 2^nd and even 3^rd decade and the psychological effect of GH therapy has not been studied. However there appears to be no significant adverse health effects of GH in the research completed so far and an increase in height of 10cm may greatly benefit an individual’s self-esteem and appearance. If you have any questions or concerns about GH therapy please contact us at the NSAA: https://noonansyndrome.com.au/contact/

References

Giacomozzi, C., et.al.(2014). The Impact of Growth Hormone Therapy on Adult Height in Noonan Syndrome: A Systematic Review. Hormone Research in Peadiatrics, Vol. 83. 167-176.

Massart, F., Berteloni, S., Miccoli, M., Baggiani, A.(2014). Height Outcome of the Recombinant Human Growth Hormone Treatment in Subjects with Noonan Syndrome: A Meta Analysis. Journal of Genetic Syndromes and Gene Therapy, Vol. 5 (5) 238.

Raynal, P.(2014). Growth Hormone and Noonan Syndrome: update in dysfunctional signaling aspects and in therapy for short stature. Hormonal Studies. doi: 10.7243/2052-8000-2-1.