A genetic panel helps to diagnose children with growth disorders and gets them the appropriate treatment

Short stature affects around 2% of children in the UK and a significant proportion may have a treatable underlying medical problem causing the growth failure. Although many factors affect childhood growth e.g. psychosocial, environment and nutrition, genetic factors are the most significant, comprising around 80-90%.

About half of short children referred to specialty paediatric endocrinology clinics have a treatable disease causing their poor growth, but 80-90% of patients do not currently obtain a diagnosis. More than 35% growth disorders are currently estimated to have a genetic basis. Speedy diagnosis is vital, so children can begin treatment.

Significant reduction in time to diagnosis

Professor Storr established a short stature genetic sequencing service at Queen Mary in 2008, initially with industry support from Ipsen Pharmaceuticals. She subsequently received a Barts Charity grant, which funded the development of a novel next-generation sequencing (NGS) short stature gene panel (SSGP) in 2017.

Queen Mary’s diagnostic panel has reduced time to diagnosis from 6-12 months, to 3 months. More than 60% of patients referred now have a specific genetic diagnosis that allows targeted treatment and management plans. The Centre for Endocrinology at Queen Mary is now recognised as an international referral centre for genetic testing of patients with undiagnosed growth failure.

Wide-ranging screening

The short stature gene panel screens the whole genome sequence (coding and non-coding) of more than 60 genes in a single assay and is continuously evolving to incorporate newly discovered/putative disease genes.

This grant also allowed the team to investigate undiagnosed patients for other novel causes of short stature using copy number variation (CNV). Both methods have identified novel disease mechanisms missed by conventional techniques. Now more than 60% of patients will receive a diagnose and better understand the cause of their short stature.

How has Professor Storr’s genetic panel helped children with short stature?

Normal growth is a strong indicator of childhood health and well-being. Around 360,000 of UK children are affected by short stature. Around half of these children have a serious underlying disease.

Although many factors affect childhood growth, including nutrition, environment and psychosocial factors, genetic determinants are the most significant, comprising ~80-90% of cases.

An early, accurate diagnosis offers the best chance of tackling the underlying disease, its complications, and of helping the child to achieve normal height. If there are delays in starting therapy, or if children are given the wrong treatment, this can cause irreversible harm, and can incur unnecessary costs for the NHS.

At present, less than 20% of UK children (around 70,000 children) with short stature reach a clear diagnosis, even with the best diagnostic efforts, and diagnostic delays are extremely common.

Professor Storr’s team were able to show how next-generation sequencing helped in the diagnosis of patients with short stature. They also helped to identify wide-ranging overlapping diagnoses which may present with a classical growth hormone insensitivity (GHI) phenotype.

A centre of international significance

The centre at Queen Mary is now recognised as an international referral centre for genetic testing of patients with undiagnosed growth failure. They have established the existence of non-classical GHI, which was not previously accepted as a clinical entity.

The team has collaborated with groups in Brazil, Mexico and the Netherlands, and this has allowed diagnoses of other patients with rare genetic variants.

Reduced diagnostic times for providing an accurate diagnosis

Storr’s group is the only centre in the UK with a whole genome short stature gene panel. Their website builds awareness among professionals around the world, and they work closely with the Child Growth Foundation, which has over 2,600 members. Referrals have come in from all over the UK, as well as from around the world, including Kuwait, Jordan, India, Thailand, Egypt, Sri Lanka and Mexico.

As a result, referrals for genetic testing of short stature patients have doubled between 2014 and 2020.

Time to diagnosis has decreased from around 6-12 months, to 3 months, and the time frame is reducing as the panel becomes more established. Rates of diagnoses have also doubled, from 30% of patients to more than 60%. Having a diagnosis has been life-changing for patients.

Specific treatment can be directed by accurate diagnoses

A clear genetic diagnosis has meant that five patients with Turner syndrome, metabolic disorders and skeletal dysplasia have been able to receive specific treatment and management for their conditions.

Two patients were diagnosed with Fanconi anaemia/Bloom syndrome. This diagnosis meant that hGH therapy was stopped because it carried a risk of malignancy.

Twenty-six patients received diagnoses that showed they should be screened and monitored for comorbidities such as cardiac abnormalities in Noonan syndrome. Patients with hGH and 47 GH-IGF-1 axis defects were able to begin rhIGF-1 therapy.

Funding granted to patients who need it

Many UK Clinical Commissioning Groups/international regulatory bodies need genetic confirmation of growth hormone insensitivity before they will release funding for rhIGF-1 therapy.

Before genetic sequencing was offered, many patients did not qualify for funding. Since 2013, around 40 children in the UK began rhIGF-1 therapy. Approximately 20 international patients are also now on rhIGF-1 therapy as a result of Queen Mary’s testing.