Unravelling the mysteries of Silver-Russell syndrome

The Annual Meeting of the Irish Endocrine Society saw the keynote lecture delivered by Prof Justin Davies, Consultant Paediatric Endocrinologist, University Hospital Southampton, UK, and Professor of Paediatric Endocrinology, University of Southampton, UK. Prof Davies spoke on the topic of ‘Silver-Russell syndrome or Temple syndrome: Challenges in diagnosis and management’.

Prof Davies explained that Silver-Russell syndrome and Temple syndrome are imprinting disorders, “and imprinting disorders, in general, profoundly influence growth, metabolism, and neurocognition. As paediatricians and paediatric endocrinologists, these two [are recognised as] important causes of short stature, secondary to being born small for gestational age (SGA).”

Prof Davies explained that these syndromes are often missed or diagnosed late, which can lead to poor outcomes for children with these conditions, and both syndromes require bespoke management. Prof Davies explained that he and his colleagues are aiming to look at outcomes from these conditions in older people and adults.

He provided an overview of Silver-Russell syndrome, explaining that Temple syndrome is the main differential diagnosis for Silver-Russell syndrome. He also presented some case studies derived from his specialist imprinting disorder service.

Prof Davies and colleagues use the Netchine-Harbison Clinical Scoring System for diagnosing Silver-Russell syndrome, which was first described in the 1950s, he explained.

“We now know that Silver-Russell syndrome is a molecularly heterogenous, epigenetic disorder, and is characterised by pre- and postnatal growth failure associated with typical phenotypic features,” he told the attendees.

“It’s classified as an ultra-rare disorder – it has an incidence of between one in 30,000 to 100,000… the molecular diagnosis is achieved in about 60 per cent of these children and the two most common molecular diagnoses are loss of methylation at the 11p15 locus and maternal uniparental disomy of chromosome 7. These two genetic aetiologies account for around 60 per cent of cases, and you also have much rarer monogenic causes, which account for 5 per cent of Silver-Russell syndrome cases.”

This means that around 40 per cent of children do not have a molecular diagnosis of Silver-Russell syndrome and this can lead to diagnostic confusion and delay, he told the meeting.

He went on to describe the management challenges with Silver-Russell syndrome. “Management goals change radically with age and that can be very difficult for caregivers to accept, so it’s very useful when a genetic diagnosis has been made to be clear from the outset that the advice you are giving at one age may be completely reversed at another,” said Prof Davies.

The predominant issue in the first years of life is poor nutrition, he explained, and that is due to a profound loss of appetite. “Sometimes these babies will take an hour or even two hours to complete a meal,” said Prof Davies.

“That can lead to a significant nutritional deficit, so the aim at this stage is to optimise the nutrition to recover calorie-related height deficits – the reduction in height due to poor nutrition.”

He continued: “We try to avoid using nasogastric tubes or gastrostomy, because we worry about how that impacts on appetite development in these children, but occasionally the situation means that you do have to use these.” More than 60 per cent of these children will have profound eating difficulties, he added. These problems tend to reduce as the child gets older: “That’s very helpful to be able to tell parents when they are in the middle of trying to manage this very difficult situation.”

Prof Davies concluded: “These disorders have profound effects on growth, appetite, metabolism, and neurocognition. They are often masquerading in our populations of children that we are managing for short stature or SGA and they require different management strategies,” he said.

“The health consequences of both of these conditions is becoming better understood, and there is some emerging evidence of the health consequences of MLID [multi-locus imprinting disorder].”

There is a pressing need to improve recognition and early referral in both conditions, he explained, and evidence is also accumulating on the diverse and complex medical needs of patients with Silver-Russell syndrome or Temple syndrome. “Management requires surveillance and co-ordinated multidisciplinary care, and these place a significant demand on healthcare resources,” he added.

He urged the attendees to consider a differential diagnosis of Silver-Russell syndrome, Prader-Willi syndrome, and short-stature SGA in Temple syndrome. This condition has a distinctly different management strategy to Silver-Russell syndrome, he added.