A total of 64 patients were included in this study: 44 with11p15 methylation abnormalities and 20 with mUPD7. The mean age in the two groups was similar: 6.3 years (range 0.8–26.8) for ICR1 hypomethylation; 7.3 years (range 1.3–17.9) for mUPD7.
The majority of patients with abnormal 11p15 methylation had abnormalities restricted to ICR1. One patient reported on previously was known to have mosaic mUPD11,25
and two more had maternal duplication of ICR1 and ICR2 (see supplementary text and figure 3 online). All three of these patients have typical SRS features.
In one family an affected brother and sister were found to have ICR1 hypomethylation. Their parents and two other unaffected siblings had normal methylation patterns.
Of the patients with ICR1 hypomethylation, 61% had at least four of the five key features, compared with just 20% of patients with mUPD7 (p=0.003). The mean scores for patients with ICR1 hypomethylation and mUPD7 were 3.7 and 3.0, respectively. However, the greatest range in severity was associated with ICR1 hypomethylation (range 2–5, compared with 2–4 for mUPD7). Four (9%) patients with ICR1 hypomethylation and five (25%) with mUPD7 had just one or two of these features. Of these, four were referred for testing on the basis of asymmetry (hemihypotrophy) and five due to prenatal and/or postnatal growth failure.
Two patients with normal growth parameters were referred for investigation of asymmetry. One patient with mUPD7 had typical facial features, but birth weight −1.53 SD and height −1.3 SD at 7 years. Another patient with 11p15 hypomethylation had fifth finger clinodactyly, but no other features of SRS, with birth weight −1.33 SD and height +0.2 SD at 10 months.
The frequency of clinical features found in the two molecular subgroups is summarised in .
Clinical features in patients with Silver–Russell syndrome with hypomethylation of the imprinting control region (ICR) 1 and maternal uniparental disomy of chromosome 7 (mUPD7)
From maternal recollection, IUGR was suspected in 89% cases with ICR1 hypomethylation and 70% with mUPD7 (p=0.08). In both groups, the average gestation at which IUGR was detected was 23 weeks, probably reflecting the fact that most women have anomaly scans at around this stage of pregnancy.
Overall, 78% of patients had a birth weight ≤−2SDS with a wide range, particularly among patients with ICR1 hypomethylation (range −4.88 to −0.5 SD, mean −2.49 SD). Patients with mUPD7 had a mean birth weight of −2.24 SD (range −3.29 to −1.29 SD). Birth weight was therefore more frequently ≤−2SDS with ICR1 hypomethylation, whereas height at examination was more frequently ≤−2 SDS with mUPD7.
In total, 30% of patients had received growth hormone. Insufficient retrospective data were available to analyse the difference in the effect of growth hormone treatment. In patients not treated with growth hormone, those with ICR1 hypomethylation (53%) were less likely to show postnatal reduction in height SDS than those with mUPD7 (78%) (p=0.26). Eight patients had reached their final height, five of which had been treated with growth hormone (see supplementary table online). Numbers were too small to allow meaningful analysis of the effect of growth hormone on final height.
Global developmental delay was described in 34% cases. Severe delay was uncommon, being described in only two children, both with ICR1 hypomethylation. One was diagnosed following investigation for asymmetry. However, he was felt to be very atypical for SRS, his growth parameters were normal, and further investigation is ongoing to look for an additional cause of his problems. The other had suffered a cardiac arrest at 9 months following repair of a ventricular septal defect. If these two children are excluded from the analysis, moderate delay was seen in one (2%) patient with ICR1 hypomethylation and two (10%) with mUPD7. In the remainder, developmental problems were mild. In those patients without global delay, gross motor delay was still common, with mean age at walking of ~20 months in both groups.
Behavioural problems were uncommon and mild. Three children (one with mUPD7 and two with ICR1 hypomethylation) were reported by their parents as being hyperactive. Only one child had been referred for further assessment for behavioural problems.
Major congenital abnormalities were markedly more common in those patients with ICR1 hypomethylation (). Camptodactyly was seen in 19% overall and appears to gradually progress in severity with age. Restriction of movement in other joints was confined to patients with ICR1 hypomethylation. Only upper limbs were affected, with four patients having limited elbow extension bilaterally/unilaterally and one having bilateral reduction of shoulder movements.
Congenital anomalies in patients with Silver–Russell syndrome with hypomethylation of the imprinting control region (ICR) 1 and maternal uniparental disomy of chromosome 7 (mUPD7)
Excessive sweating was reported by 67% of parents. This may have represented hypoglycaemia, but in most cases had not been formally investigated. Since there was no significant difference in the frequency of documented evidence of hypoglycaemia in either group, it is unlikely to account for the difference in rate of global developmental delay.
Feeding difficulties were scored according to severity (1=normal, 2=mild, 3=frequent/long feeds, 4=prolonged nasogastric feeds, 5=gastrostomy insertion). The average score for mUPD7 was slightly higher than that for ICR1 hypomethylation (mean (SD) 4.7 (1.3) and 3.4 (1.4), respectively), although this did not reach statistical significance (p=0.48).
Intriguingly, one patient with mUPD7, aged 14.9 years, was described as having intermittent episodes of head shaking. Another patient, aged 14.2 years, has a slight tremor affecting his left arm. One further patient with mUPD7 had myoclonic jerks in infancy (from 3 weeks to 1 year), which had subsequently resolved. No patients with ICR1 hypomethylation had similar problems.
and show facial features for many of the patients with ICR1 hypomethylation and mUPD7 included in this study. The photographs illustrate how facial features become less striking with age. Owing to difficulties obtaining early pictures and growth data from many of the older patients, clinical features such as frontal bossing, triangular face and micrognathia were scored according to the appearance of the patient at examination (). In addition, data were analysed for triangular facies and frontal bossing in those patients under 5 years at examination. As expected, this showed increased frequency of specific features at this age (triangular face in 67% of ICR1 hypomethlyation and 100% of mUPD7; frontal bossing in 81% of ICR1 hypomethylation and 67% of mUPD7).
Figure 1 Facial appearance of patients with hypomethylation of the imprinting control region (ICR) 1 at different ages. Group A: 1.4–3.3 years; group B: 3.3–4.7 years; group C: 5.9–9.5 years; group D: 9.8–26.6 years. (more ...)
Facial appearance of patients with maternal uniparental disomy of chromosome 7 with increasing age. Group A: 1.3–3.8 years; group B: 4.0–7.9 years; group C: 10.0–14.2 years.
Correlation with methylation index
Data on methylation index was available for 29 of the 44 patients with ICR1 hypomethylation. Clinical score, birth weight SDS, postnatal height SDS, severity of feeding difficulties, and the presence of developmental delay, asymmetry and/or congenital anomalies were all analysed for correlation with level of ICR1 hypomethylation. No evidence was found for correlation between the level of ICR1 hypomethylation and clinical severity ().
Correlation of level of hypomethylation of the imprinting control region (ICR) 1 with clinical severity
Assisted reproductive technology (ART)
All five cases conceived as a result of in vitro fertilisation treatment, including one via ovum donation and one via intracytoplasmic sperm injection, were in the ICR1 hypomethylation group. However, this difference between the groups did not reach statistical significance.