The second day of ESPE 2014 saw the first of the new research communications, with sessions including adrenal, diabetes, growth and neuroendocrinology.

Transforming life quality in HPP

Another of these sessions covered bone and mineral research, and included a 3-year update on 11 infants and children with hypophosphatasia (HPP) who were treated with the experimental drug asfotase alfa. The initial 1-year results, published in The New England Journal of Medicine in 2012, showed healing of rickets and improved pulmonary function. In two presentations today, the researchers reported significant improvements in the children’s growth, development and function during 3 years of treatment, with measures approaching normal values for children of the same age.

Katherine Madson (Shriners Hospitals for Children, St Louis, Missouri, USA) reported that muscle strength, based on hip abduction assessment, improved to an average 83% of normal values from a baseline of 48%. There were similar improvements in 6-minute walk distance, with most gains observed within the first 6 months, and most children attained normal values for composite strength and agility on the Bruininks-Oseretsky Test of Motor Proficiency 2nd edition. Their height z-scores also increased, indicating catch-up growth.

In the second presentation, Nicholas Bishop (Sheffield Children’s Hospital, UK) reported similar improvements in length and weight trajectories. Fine motor function improved to within the normal range and gross motor function to a little below the normal range; however, Bishop noted that these values were based on only a few patients, partly because of parents’ reluctance to let them undergo full motor function testing.

Bishop stressed the importance of prompt treatment, saying that delays appeared to result in poor outcomes. He said that the “key element” is “diagnose early, treat early”.

Asfotase alfa had a good safety profile, with most adverse events being normal childhood illnesses and the only treatment-related events being injection-site reactions.

Session co-Chair Nick Shaw (Birmingham Children’s Hospital, UK) questioned Madson about the value of using a potentially expensive new drug in older children, in whom HPP is not life-threatening as it is in infants. She responded that HPP was a major quality of life issue for the children in their study, who could not ambulate well, jump or run, and whose parents were considering adapting their homes around their children’s handicaps. The researchers were “surprised to see how fast the muscle weakness resolved”, she said, citing the case of one child who could initially climb stairs only by pulling himself up, and 15 days later could walk up carrying items.

Stem cell promise

One of the day’s two plenary lectures was given by Robin Lovell-Badge (MRC National Institute for Medical Research, London, UK). He provided an overview of the genes involved in sex determination, in pituitary stem cells, and the potential implications for future treatment of disorders of sexual development (DSDs).

He said that one Y-linked gene – SRY – seems to be responsible for triggering the development of male gender in mammals. Male sex development is maintained by SOX9, whereas expression of this gene is suppressed in females, through expression of FOXL2.

Thus, the maintenance of the ovaries depends on FOXL2 suppressing SOX9, whereas maintenance of testes requires the expression of SOX9, and also DMRT1. This raises some treatment possibilities for DSDs, said Lovell-Badge, such as suppression of FOXL2 in patients with XY ovotestes or of DMRT1 in XX ovotestes or testes. He even raised the possibility that fertility could be preserved if treatment is started sufficiently early.

Moving on to stem cells, pituitary progenitor cells, which express SOX2 and SOX9, have different functions according to age. In the embryo, they predominantly differentiate into endocrine cells, postnatally they both differentiate and self-renew, and in the adult they largely self-renew. However, Lovell-Badge’s team have found that these cells can be provoked into differentiation in adult animals, for example, by treating males with oestrogen or by adrenalectomy, confirming their identity as pituitary stem cells.

Looking ahead, Lovell-Badge said that using these stem cells to regenerate endocrine cells would be a significant improvement over substitution therapies, which “do not mimic endogenous secretion patterns, have side effects and are costly”.

He also questioned whether use of substitution therapies might be affecting the existing pituitary stem cell population and “compromising its ability to do what it would normally do” in response to life changes such as pregnancy, menopause and old age.

Hypoadrenalism treatment comes of age

Today’s afternoon sessions included a symposium on hypoadrenalism, opened by “a whirlwind overview” of recent developments in congenital adrenal insufficiency, given by John Achermann (UCL Institute of Child Health, London, UK). In a recurring theme of this conference, his talk led on to the benefits of genetic analysis. His group uses high-throughput genetic testing and has constructed a “genomic atlas” of adrenal and gonadal development to help identify causative mutations in patients. He noted that the various forms of congenital adrenal insufficiency have overlapping clinical and biochemical features. Therefore, identifying the specific cause can help to predict disease course, monitor and counsel patients, identify at-risk family members, and personalise treatment.

Indeed, he stressed that identifying the specific form of congenital adrenal insufficiency “can change management for life”.

Achermann was followed by William Rainey (University of Michigan, Ann Arbor, USA), who detailed the changes in gene expression and hormonal reduction that accompany the expansion of the adrenal reticularis, or the adrenarche. Then Wiebke Arlt (University of Birmingham, UK) looked at what happens when children with congenital adrenal hyperplasia (CAH) reach adulthood.

One of her main points was that a large majority of patients are “lost in transition” from paediatric to adult healthcare. The number of patients with classic CAH recruited to a national UK study was less than 10% of the expected number of cases based on observed rates of classic CAH in children.

Around half the patients were undertreated, with a smaller proportion overtreated, and few had achieved androstenedione and 17OH-progesterone levels within the desired range.

One notable problem in a relatively young cohort was obesity and metabolic disorders, such as insulin resistance and hypercholesterolemia. Arlt stressed that genotype, indicating the severity of CAH, was not associated with outcomes, suggesting that the poor metabolic outcomes were a result of treatment. In particular, dexamethasone treatment was associated with metabolic disorders, so Arlt said this should be avoided except as a last resort, instead recommending hydrocortisone as the steroid of choice in these patients.

By Eleanor McDermid, Senior medwireNews Reporter

More from ESPE 2014