ESPE 2016 Highlights: Day Two
The second day of ESPE saw the first of the free communication sessions, with researchers presenting their latest findings.
A first-line medical option for acromegaly
In a well-attended session on pituitary research, Cecile Thomas-Teinturier (Hôpital de Bicétre, Paris, France) reported that pegvisomant treatment produced “drastic decreases” in the growth rate of children with acromegaly.
Six of the eight patients (median 12.4 years) received somatostatin analogues (three after surgical debulking of the culprit pituitary macroadenoma) and achieved a median reduction in growth velocity of 2 cm/year, but their median growth velocity was still very high, at 7 cm/year, and they had persistently increased insulin-like growth factor 1 (IGF-1) levels.
But four children given pegvisomant (one as monotherapy; three with somatostatin analogues) achieved a median growth velocity reduction of 7.5 cm/year, with a corresponding reduction in IGF-1 levels. Thomas-Teinturier suggested, therefore, that pegvisomant could represent a first-line therapy, ahead of surgical debulking.
In response to an audience question, she said that they saw no adverse effects with pegvisomant, with liver enzymes remaining within normal parameters.
Other pituitary research communications included the news that sodium oxybate treatment is associated with a reduction in body mass index in overweight/obese patients with type 1 narcolepsy and that subfertility after treatment for primitive neuroectodermal tumours is common, particularly in patients who undergo additional chemotherapy (31.8% vs 13.2% after radiotherapy alone).
Researchers also reported that 49% of patients with optic nerve hypoplasia (ONH) developed pituitary hormone dysfunction, with 90% of these occurring within 5 years of ONH diagnosis; that the severity of neuro-endocrine morbidity after treatment for craniopharyngioma is entirely related to surgical factors; and that children can develop pituitary dysfunction many years after traumatic brain injury, even if their initial hormone work-up in the months after the event is normal.
A royal receptor
The first plenary of the day – the third of the conference – was given by Rajesh Thakker (University of Oxford, UK), who succeeded in delving into the finer points of the calcium-sensing receptor (CaSR) structure and function, while keeping it engaging and relevant for clinicians. He referred to the CaSR as the “King Henry VIII of receptors”, being as it is responsible for, not just one, but at least seven different disorders. Over 250 mutations have been reported so far, said Thakker. Many have no effect, but for those that do the phenotype depends partly on whether they are loss-of-function or gain-of-function mutations, resulting in hypercalcaemic or hypocalcaemic disorders, respectively.
And knowing the underlying mutations has clinical implications, said Thakker, given the frequency with which CaSR mutations are present in patients – in 65% of patients with familial hypocalciuric hypercalcemia (FHH), for example. He outlined the research that led to the discovery of the mutation underlying FFH type 3 – the most severe form – and ultimately to the successful treatment of three patients with cinacalcet.
The second plenary, presented by Robert Feil (Institute of Molecular Genetics, CNRS, Montpellier, France), gave “a flavour” of genomic imprinting, the process by which DNA methylation of specific regions results in the silencing of one allele of a gene (either the maternal or paternal gene). The phenomenon is quite recent in evolutionary terms, said Feil, having arisen during the Jurassic period, and, as well as being a physiological process, underlies disorders such as Silver-Russell syndrome.
Weighing up DSD management
The afternoon programme included a session addressing the controversies surrounding disorders of sexual development (DSDs). It centred on a challenging case, presented by Martine Cools (University Hospital Ghent, Belgium), of a 46,XY patient, adopted by Belgian parents from an Indian orphanage. The child, who was 2 years old, had been raised as a female until presentation, and the team’s investigations revealed no strong arguments for immediate assignment to either gender.
Four presenters then explored the issues surrounding such a case, beginning with the surgical options and controversies. Sarah Creighton (University College London, UK) opened by saying that “surgery has been the cornerstone of multidisciplinary management for many years [but] that situation needs an urgent review.”
The accepted aims of surgery include improved appearance, to allow sexual intercourse, to improve psychological outcomes and relieve parental anxiety, said Creighton, but long-term follow-up of these patients suggests poor cosmetic and anatomical outcomes and offers no evidence to support the other aims.
She believes it “highly unlikely” that any study will produce evidence firmly for or against early gender assignment surgery, but notes that there is no accepted alternative.
However, in his closely related presentation, Pierre Mouriquand (Hôpital Femme Mère Enfant, Lyon, France) stressed that long-term surgical outcome data are based on “obsolete” techniques used 20 years ago. He also highlighted the hugely variable approaches to DSD management across the world.
Mouriquand offered an overview of the current preferred surgical options for the different forms of DSD, and weighed up the pros and cons of early and late surgery. The pros of early surgery include surgical factors such as easier separation of the vagina from the urethra, and patient-related factors such as lower psychological impact, while cons include the irreversibility of the procedure and the lack of individual consent. For late surgery, the pros are individual consent and avoiding surgery on developing organs, whereas the cons include higher morbidity and the unknown psychological consequences of growing up with atypical genitalia.
The audience next heard from Franco D’Alberton (S Orsola-Malpighi University Hospital of Bologna, Italy), who gave a psychological perspective. He explained that the “nearly mandatory” cutoff of 2 years old for assigning gender originates from “core gender identity” studies, but that this is now under discussion, with recent evidence suggesting that gender identity changes can occur much later in life.
“It seems to me that one of the most difficult psychological challenges is to be able to accept the uncertainties of knowing that we don’t have new tools to substitute the old ones,” said D’Alberton.
He stressed the importance of creating the right environment to support DSD patients’ personal, emotional, social and sexual development. “In order to do that, we have to be humble and open to every new possibility,” he said.
The next presentation, by Claudia Wiesemann (Goettingen University, Germany), offered an ethical viewpoint, with Wiesemann drawing a sharp distinction between ethics in theory and in practice. For example, if one aims to identify the person whose rights or interests are at stake, is that the child, the parents, or indeed the future adult?
She noted that such a complex situation, where there are a range of interests at stake, even within the patient themselves, may require a trade-off between different rights and interests. And she also discussed “those rare situations” in which doctors may have to oppose the wishes of the parents for the sake of the child’s interests and offered criteria to help to determine when such an intervention is justified.
Then the focus returned to the case study, with the audience asked to vote on how the child should be managed. A few voted to raise the child as non-binary, a few for female gender assignment, none for male, and there were a few light-hearted votes for referral to another centre. But most voted for the option that Cools’ team actually took, which was to continue to treat the child as female and continue to monitor development with a view to intervening when the situation became clearer.
However, Cools reported that after another 6 months, the child’s adoptive parents found it increasingly hard to be without a firm answer and started treating the child as male, to see if they would react. And although the child did not initially react, over time they seemed to become more settled and the parents felt that treating the child as male was the right approach. The child had correction of hypospadias at the age of 5 years, at his and his parents’ request, said Cools, and at the age of 9 years is happy, with a “trusting relationship” with his adoptive parents.