medwireNews: Temple syndrome (TS14) has a broader range of phenotypic features than previously recognised and the presentation may change with increasing age, indicates an analysis of children attending two European referral centres.
“Our findings inform the clinical management strategies for TS14 and give patients and caregivers foreknowledge of the expected trajectory of TS14”, say Justin Davies (Southampton Children’s Hospital, UK) and co-workers, who used their research to create a novel diagnostic scoring system to identify children who should be tested for the disorder.
The investigators describe TS14 as an “ultra-rare, under-recognized multisystem growth disorder” that may be caused by loss of methylation of the paternally methylated 14q32 control region, or by deletion of key genes within the region or the entire region.
They explain that TS14 has known overlapping clinical features with Silver–Russell syndrome (SRS) and Prader–Willi syndrome (PWS) and screening for 14q32 methylation is included for children with clinical suspicion of SRS but not yet for those with PWS features.
To better characterise TS14, the team collated phenotypic and other information from patients with molecularly confirmed TS14 who attended the Rotterdam Centre in the Netherlands (n=26) or the Southampton Centre in the UK (n=45).
Approximately half (48%) of participants were girls and the average age at time of diagnosis was 2.96 years. The most common diagnosis was maternal uniparental disomy of chromosome 14 (52%), followed by loss of methylation (41%), multilocus imprinting disorder (8%) and deletion (6%), with one patient having an unknown subtype.
The team reports that the majority (68%) of patients were born small for gestational age. While 73% had short stature at age 1–3 years, this rate decreased to 58% at age 3–5 years, 34% at age 5–8 years, and 15% at age 11–13 years. Insulin-like growth factor (IGF)-1 levels were at least –2 standard deviation score (SDS) in all the patients but only 27% had GH deficiency confirmed.
GH therapy was more commonly used in children in the Netherlands than the UK (88.5 vs 41.0%), beginning from a median age of 5.7 years and catch-up growth was achieved from 5–8 years. “Near-final and final adult height outcomes appeared greater in those treated with GH,” the investigators note.
At time of presentation, bone age was delayed in 12.5% of children, normal in 59.0% and advanced in 28.0% but advanced bone age was more common in the Netherlands than the UK (38 vs 8%). The differences between bone age and chronological age ranged from –2.1 to 5.6 years.
Most (87%) of the children were recorded as having early difficulties with feeding, with 57% requiring a nasogastric tube for a median of 4 weeks.
Overall, 47% of participants had overweight or obesity, with a BMI SDS of 0 to –2.5 among those younger than 3 years of age and 0–2 for those older than 5 years. BMI trajectory was independent of GH therapy. Excessive appetite was reported by caregivers in 44% of children and hyperphagia in 20%, with food-seeking behaviour reported in a similar 22%.
Central precocious puberty was also common (62%) but was twice as common in girls as boys and affected all the girls with loss of methylation. The median age of puberty onset was 8 years, with the earliest ages of onset being 6.5–7.9 years in boys and 5.0–5.3 years in girls.
The team also highlights other features that were common in the cohort including metabolic disturbances, such as dyslipidaemia and hypoglycaemia, the musculoskeletal features of hypotonia, scoliosis, and hypermobility, and neurocognitive features including motor and speech delay, autism spectrum disorder and the need for special educational support.
Of note, 60% of patient in the UK and 23% of those in the Netherlands were recorded as having a high pain threshold, and other characteristics frequently recorded in the combined cohort included reflux and constipation, repeated ear infections, hearing impairments, micrognathia, dental crowding, small hands and feet, clinodactyly, and single palmar crease.
Davies et al observe that just 56.5% of the cohort met three or more of the criteria on the Netchine–Harbinson clinical scoring system (NH–CSS), the threshold used for prompting molecular testing for SRS.
“Patients with TS14 may meet sufficient NH-CSS criteria (particularly [small for gestational age] and postnatal growth retardation) for clinical suspicion of SRS, but the presence of additional signs (eg, neonatal hypotonia, good appetite, rapid weight gain in early childhood) or the emergence of additional features (eg, precocious puberty, neurodevelopmental problems) should increase clinical suspicion of TS14”, they advise.
The team therefore devised a clinical scoring system to guide clinicians on when to refer patients for TS14 molecular testing. To optimise early detection and management, 1 point each is awarded to features occurring in the first year, including low birthweight, postnatal feeding difficulties and hypotonia, while 0.5 points each is awarded to those occurring after 1 year of age, including motor or speech delay, precocious puberty, short stature, small hands or feet, and central obesity.
Overall, 93% of the children in the cohort met the 2-point or higher threshold for TS14 molecular testing, the team reports.
“Our findings show the need for age-specific management, as well as age-specific information to guide expectations for caregivers of TS14 children,” the authors emphasise, highlighting that “optimal nutritional and growth management strategy varies with age” and surveillance for other comorbidities, including precocious puberty and scoliosis, should also be age-appropriate.
They conclude that the “management strategy for TS14 should be distinct” from those for PWS and SRS despite their overlapping clinical features.
By Lynda illiams
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