Noonan syndrome (NS) is a relatively common autosomal dominant disorder (1:1000 to 1:2500 live births) characterised by facial dysmorphism, short stature, chest deformities and congenital heart defects. Variable developmental delay and intellectual disability are also observed in some patients.
Disease-causing mutations in genes of the RAS/MAPK pathway are identified in 70–80% of affected patients (1). PTPN11 (protein tyrosine phosphatase, nonreceptor type 11) gene was the first causative gene identified in this condition and encodes a tyrosine phosphatase protein. Nearly 40–50% of patients with NS harbour heterozygous pathogenic variants in this gene.
The diagnosis of NS is based on classical clinic features and can be confirmed by the identification of a heterozygous pathogenic variant in one of the causative genes.
Currently, the diagnosis has been established mainly by multigene sequencing analysis (whole exome or target panel sequencing).
rhGH has been shown to be safe for patients with NS, mainly based on data from retrospective studies with a limited number of patients (3). For this reason, some concerns still remain about an increase in cancer risk and worsening of hypertrophic myocardiopathy in patients with NS treated with rhGH (4). Patients with specific mutations in PTPN11, KRAS and RIT1 can have a high rate of myeloproliferative disorder during the first 5 years of life. In those patients with genetic variants highly associated with myeloproliferative disorders, the decision to start rhGH therapy should be carefully discussed and only begun after the age of 5 years. Future studies are necessary to better define the impact of specific genotypes on growth response and safety of patients with NS treated with rhGH. However, some insights are already possible by identifying the molecular basis of a patient with NS.
- Tajan M, Paccoud R, Branka S, et al. The RASopathy Family: Consequences of Germline Activation of the RAS/MAPK Pathway. Endocr Rev doi: 10.1210/er.2017-00232
- Malaquias AC, Brasil AS, Pereira AC, et al. Growth standards of patients with Noonan and Noonan-like syndromes with mutations in the RAS/MAPK pathway. Am J Med Genet A 2012; doi: 10.1002/ajmg/a/35519
- Noonan JA, Kappelgaard AM. The efficacy and safety of growth hormone therapy in children with noonan syndrome: a review of the evidence. Horm Res Paediatr 2015; doi: 10.1159/000369012
- Malaquias AC, Noronha RM, Souza TTO, et al. Impact of Growth Hormone Therapy on Adult Height in Patients with PTPN11 Mutations Related to Noonan Syndrome. Horm Res Paediatr 2019: doi: 10.1159/000500264
- US Food & Drug Administration. Somatropin Information, as of 23 July 2015. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/somatropin-information
- Binder G, Wittekindt N, Ranke MB. Noonan Syndrome: Genetics and Responsiveness to Growth Hormone Therapy. Horm Res Paediatr 2007; doi: 10.1159/000097552
Delayed puberty (DP) is common in the developed world, affecting over 2% of adolescents, and is associated with adverse health outcomes including short stature, reduced bone mineral density and compromised psychosocial health. The majority of patients have constitutional or self-limited DP, which is often familial, most commonly segregating in an autosomal dominant pattern. However, the key genetic regulators in self-limited DP are largely unknown , Figure 1.
Figure 1 – Schematic representing the genes (encircled) known to be involved in the pathogenesis of self-limited DP, and their overlap with cHH and loci identified by genome-wide association studies of age of puberty in the general population. Important genes identified in precocious puberty (DLK1 and MKRN3) and the Kisspeptin gene (KISS1) and its receptor (KISS1R) are also included.
Ieuan Hughes, MD FRCP FRCPCH FMedSci
Congenital adrenal hyperplasia: optimising cardiometabolic outcomes
The introduction of glucocorticoid replacement for congenital adrenal hyperplasia (CAH) has revolutionised the outlook for patients with this lifelong condition, preventing life-threatening salt-wasting crises. However, accumulating evidence shows persistently increased morbidity, and even mortality, in CAH patients, and links it not only to the disease, but also to the treatment.
Here we review key publications, selected by Ieuan Hughes, Emeritus Professor of Paediatrics from Addenbrooke’s Hospital in Cambridge, UK, which summarise the current knowledge and show how clinicians and the pharmaceutical industry are beginning to respond to this challenge.
For patients with the salt-wasting (classical) form of CAH, the introduction of glucocorticoid treatment in the 1950s turned the condition into a chronic illness, rather than a guarantee of early death.
And Hughes says that CAH was initially viewed as simple to treat: “Take your hydrocortisone, go away, no problem.”
Yet a 2014 Swedish registry study showed that the problem of salt-wasting crises was reduced, rather than entirely vanquished.1 The mortality rate was 3.9% among 588 CAH patients, compared with 1.6% among nearly 59,000 controls, and 42% of the deaths in CAH patients were due to adrenal crises. Other causes of death were cardiovascular, cancer, accident and suicide, and occurred at a similar rate as in controls. However, study authors Henrik Falhammar (Karolinska University Hospital, Stockholm, Sweden) and colleagues noted that half the cardiovascular deaths in CAH patients occurred concurrently with a severe infection, suggesting that an adrenal crisis could have contributed to these deaths.
The findings imply suboptimal glucocorticoid treatment, a point highlighted in a study of 203 CAH patients treated at specialist endocrine centres in the UK.2 Levels of the androgen precursor andostenedione were suppressed in between 10% and 29% of patients and elevated in around a third. Researcher Wiebke Arlt (University of Birmingham, UK) and colleagues found that, overall, only a third of patients had levels within the target range, and the same was true of renin levels in patients receiving mineralocorticoid replacement.
“Paediatricians have prided themselves – allegedly anyway – including myself, that we’ve done a good job,” says Hughes.
Paediatricians were not only keeping CAH patients alive, he says, but also achieving fairly good growth, helping them attain adult heights that, although lower than expected for their family, were still well within population norms.
“And then of course we hand them over to the adult physicians and they come back to us – quite rightly…”
Because the adult physicians, making detailed study of their patients’ health, were becoming aware of increased cardiometabolic morbidity in adult CAH patients. For example, Arlt et al found CAH patients were more often obese relative to the UK population, and frequently had metabolic abnormalities, with 46% having hypercholesterolaemia and 29% having insulin resistance, while around a third had osteopenia.
Similarly, Falhammar et al followed up their mortality study with a look at cardiometabolic morbidities, finding that these were almost fourfold more likely to occur in CAH patients relative to controls from the Swedish population, while cardiovascular disease was nearly threefold more common.3 Specific conditions that were elevated in CAH patients included thyrotoxicosis, venous thromboembolism, atrial fibrillation, obesity and diabetes.
Another study found evidence of cardiovascular morbidity in CAH patients at a worryingly young age.4 Ivani Silva (Universidade Federal de Minas Gerais, Belo Horizonte, Brazil) and team assessed 38 pubertal CAH patients, aged 20 years or younger, and controls matched for age, gender and pubertal status. They showed that, relative to the controls, the CAH patients had significantly increased carotid intima-media thickness – an early sign of atherosclerosis. This was not restricted to overweight patients, but was seen only in females.
So cardiometabolic morbidity is “something that’s now being taken very seriously,” says Hughes.
These studies have not only flagged high cardiometabolic risk in CAH patients, they have also begun to link it directly to CAH treatment. A cross-sectional study of 196 adults with CAH found that patients with more severe disease received higher glucocorticoid doses without achieving better disease control – higher dose was actually associated with higher androgen levels.5 Moreover, the increased glucocorticoid doses were also associated with elevated blood pressure.
Although researcher Richard Ross (Royal Hallamshire Hospital, Sheffield, UK) and team found that dexamethasone – the most potent of the glucocorticoids used in the study patients – was associated with the lowest androgen levels, this came at the expense of greater insulin resistance.
A study from Hughes’ own group took a closer look at insulin resistance in 37 CAH patients and 41 healthy controls.6 The 25 patients with classical CAH, which is diagnosed and treated early in life, had significantly greater fat mass than the controls, which the researchers attributed to the long-term effects of glucocorticoid treatment.
“Add to that the obesity epidemic and you’ve got a pretty powerful cocktail of problems,” observes Hughes.
By contrast, the 12 children with nonclassical CAH, which is usually diagnosed later in childhood, had greater lean body mass and blood pressure than the controls, and significant increases in several measures of insulin resistance. Hughes attributes these changes to the patients’ prolonged exposure to excess androgen levels in early childhood, saying that androgen “in itself is a pretty potent stimulator of insulin resistance.”
The most recent guidelines for CAH management, from 2010, acknowledge the difficulty of optimising treatment, calling it “a difficult balance between hyperandrogenism and hypercortisolism”, and noting that efforts to completely normalise androgen levels “typically result in overtreatment”.7
The guidelines also advise against long-acting glucocorticoids in children, because of their growth-suppressing effects, instead recommending hydrocortisone three times daily at the lowest possible dose to avoid compromising growth.
Hughes believes that paediatric endocrinologists “are doing much better now than we used to”, saying that the daily hydrocortisone dose, which “in the past has been too much”, has been brought down. “And that’s being translated into better growth and outcome in the short term.”
However, paediatric CAH patients experience the usual deluge of childhood colds and illnesses, each one placing the body under stress and prompting a temporary increase in hydrocortisone dose. Necessary though this is, Hughes wonders if “collectively, we have been overdosing them.”
Added to that is the highly variable pharmacokinetics of hydrocortisone, not only between different stages of childhood, but also between different children, aptly demonstrated in a paper from Peter Hindmarsh (UCL Institute of Child Health, London, UK) and Evangelia Charmandari (University of Athens Medical School, Greece).8 The researchers gave 48 children the same hydrocortisone bolus, but found that its half-life in the different patients ranged from 40 to 225 minutes. Although all children attained a similar peak plasma cortisol concentration, the speed of absorption varied widely, with time to peak concentration ranging from 20 to 118 minutes and the additional time taken for the concentration to fall below 100 nmol/L ranging from 140 to 540 minutes.
This suggests that hydrocortisone dosing should be highly individualised, and perhaps more frequent, with the study authors moving towards four doses per day on the basis of their findings.
But in some cases, clearance of hydrocortisone may be so rapid that even a six-times-daily dosing schedule is insufficient to achieve androgen control. An ingenious solution for this is continuous delivery via an adapted insulin pump, as illustrated in a case study, also by Hindmarsh.9
Pump delivery avoids gaps in hydrocortisone exposure and increased need for hydrocortisone during physiological stress can be managed simply by increasing the infusion rate or using the bolus function. Hindmarsh’s team has implemented this in three children, achieving 24-hour cortisol levels within the normal range, normalised 17-hydroxyprogesterone (17-OHP) levels and large improvements in school attendance and quality of life.
Although an effective means of mimicking physiological hormone production, an insulin pump cannot match the simplicity of oral treatment. And pharmaceutical companies are beginning to develop oral drug formulations that more closely replicate physiological production. Two slow-release formulations are currently undergoing clinical testing: Plenadren (ViroPharma SPRL, Brussels, Belgium) and Chronocort (Diurnal Ltd, Cardiff, UK).
In a phase II study of Chronocort, Ashwini Mallappa (National Institutes of Health Clinical Center, Bethesda, Maryland, USA) and colleagues found that the rates of elevated androstenedione and 17-OHP levels among 16 adult CAH patients decreased significantly with Chronocort treatment relative to conventional therapy (33.7 vs 12.0% and 33.2 vs 12.0%, respectively).10 After 6 months of Chronocort treatment, 73% and 59% had normal androstenedione and 17-OHP levels, respectively.
Hughes highlights that the more physiological replacement appeared to allow further dose reductions, with eight of the 16 patients requiring a dose reduction (although two other patients needed a dose increase).
Chronocort is taken twice daily, and therefore suppresses the overnight rise in adrenocorticotrophic hormone (ACTH) seen with Plenadren, which is taken just once daily.11
Hughes says that combating the overnight ACTH rise “probably is important, but on the other hand, if you want to be a pragmatist you’re more likely to take your medicine if it’s a once-daily thing as opposed to a twice-daily thing.”
Plenadran is a little further down the clinical testing route than Chronocort, being approved and now the subject of a post-authorisation safety registry, which includes CAH patients.12 But both formulations still need to be tested in paediatric patients.
“I hope that perhaps getting these so-called more physiological replacement regimens will in due course improve morbidity in adult life,” says Hughes.
But he adds: “It will take a generation to see that.”
The role of growth hormone (GH) has been established for many decades, but it is only with the advent of advanced molecular genetic techniques that researchers have started to piece together the precise pathways leading to growth.
Here we review seven key papers, chosen by Professor Andrew Dauber, from Cincinnati Children’s Hospital Medical Center in Ohio, USA, which document the pivotal findings that shed light on the process of signalling through the GH/insulin-like growth factor (IGF)-I axis.
The research largely represents the extreme end of the growth disorder spectrum, with a single mutation having a profound effect on a patient’s height, but Dauber stresses that “they teach us a lot about the underlying physiology and the role that those genes play in normal biology.”