Clinical Scoring System for Silver-Russell Syndrome
Clinical Scoring System for Silver-Russell Syndrome
Background Multiple clinical scoring systems have been proposed for Silver-Russell syndrome (SRS). Here we aimed to test a clinical scoring system for SRS and to analyse the correlation between (epi)genotype and phenotype.
Subjects and methods Sixty-nine patients were examined by two physicians. Clinical scores were generated for all patients, with a new, six-item scoring system: (1) small for gestational age, birth length and/or weight ≤−2SDS, (2) postnatal growth retardation (height ≤−2SDS), (3) relative macrocephaly at birth, (4) body asymmetry, (5) feeding difficulties and/or body mass index (BMI) ≤−2SDS in toddlers; (6) protruding forehead at the age of 1–3 years. Subjects were considered to have likely SRS if they met at least four of these six criteria. Molecular investigations were performed blind to the clinical data.
Results The 69 patients were classified into two groups (Likely-SRS (n=60), Unlikely-SRS (n=9)). Forty-six Likely-SRS patients (76.7%) displayed either 11p15 ICR1 hypomethylation (n=35; 58.3%) or maternal UPD of chromosome 7 (mUPD7) (n=11; 18.3%). Eight Unlikely-SRS patients had neither ICR1 hypomethylation nor mUPD7, whereas one patient had mUPD7. The clinical score and molecular results yielded four groups that differed significantly overall and for individual scoring system factors. Further molecular screening led identifying chromosomal abnormalities in Likely-SRS-double-negative and Unlikely-SRS groups. Four Likely-SRS-double negative patients carried a DLK1/GTL2 IG-DMR hypomethylation, a mUPD16; a mUPD20 and a de novo 1q21 microdeletion.
Conclusions This new scoring system is very sensitive (98%) for the detection of patients with SRS with demonstrated molecular abnormalities. Given its clinical and molecular heterogeneity, SRS could be considered as a spectrum.
Silver-Russell syndrome (SRS, OMIM #180860; called also Russell-Silver syndrome, RSS, in the USA) is a clinically and genetically heterogeneous syndrome involving prenatal and postnatal growth retardation first described by Silver et al and Russell. Many other studies have since reported additional features, providing a complex clinical description of SRS. The clinical presentation of SRS is now known to cover a spectrum of signs that are easy to recognise in typical cases but may be difficult to diagnose clinically in less severely affected individuals. Furthermore, the facial characteristics of SRS tend to become attenuated as the patient grows up, making it difficult to diagnose SRS in older children and adults. Finally, some of the more common typical features of SRS overlap with those of other syndromic intrauterine growth retardation disorders (such as 3M or Mulibrey-nanism syndromes, eg).
There is growing evidence that a definition of SRS based on a compilation of features rather than a checklist of characteristics is required. Unfortunately, there is still no clear consensus about how SRS should be defined. This renders clinical diagnosis difficult, leading to underdiagnosis in some situations and overdiagnosis in others. Five attempts have been made to create a clinical definition of SRS, or an 'SRS scoring system'. The various systems developed display some similarities, but also differences. In the paper describing the most recent of these systems, the Birmingham model, the four scoring systems that had previously been developed were evaluated, but on retrospective clinical data collected by different physicians, which could not, therefore, necessarily be considered reliable.
Despite the existence of these numerous clinical scoring systems, the identification of appropriate patients for molecular testing remains a challenge, because many of the features of SRS are non-specific or mild, and some may disappear over time.
Two primary molecular causes of SRS have been identified. In about 10% of cases, SRS is due to maternal UPD of chromosome 7 (mUPD7). The major abnormality, present in 50–60% of cases, was only recently identified: hypomethylation of the paternal allele of the 11p15 imprinting centre region 1 (ICR1) regulating the IGF2/H19 locus. Rare genetic or cytogenetic abnormalities have also been identified, but these abnormalities account for less than 2% of cases. The molecular cause of SRS thus remains unknown in about 30–40% of cases.
On the basis of our considerable clinical experience with patients with SRS, we conducted a prospective study in which 69 patients with suspected SRS were assessed clinically and then underwent state-of-the-art molecular investigations. The results obtained were then used to validate a modified scoring system adapted from the original scoring system developed by Netchine et al in which small for gestational age (SGA) was no longer an obligate factor. We have shown that this new scoring system was highly sensitive for identification of the subjects most likely to test positive for one of the known molecular causes of SRS, and for distinguishing these subjects from those not likely to test positive. This new scoring system is easy to use and flexible enough to be run even if data are missing for one or more factors. The combination of variables in this scoring system may be considered an improvement over those previously published.
Abstract and Introduction
Abstract
Background Multiple clinical scoring systems have been proposed for Silver-Russell syndrome (SRS). Here we aimed to test a clinical scoring system for SRS and to analyse the correlation between (epi)genotype and phenotype.
Subjects and methods Sixty-nine patients were examined by two physicians. Clinical scores were generated for all patients, with a new, six-item scoring system: (1) small for gestational age, birth length and/or weight ≤−2SDS, (2) postnatal growth retardation (height ≤−2SDS), (3) relative macrocephaly at birth, (4) body asymmetry, (5) feeding difficulties and/or body mass index (BMI) ≤−2SDS in toddlers; (6) protruding forehead at the age of 1–3 years. Subjects were considered to have likely SRS if they met at least four of these six criteria. Molecular investigations were performed blind to the clinical data.
Results The 69 patients were classified into two groups (Likely-SRS (n=60), Unlikely-SRS (n=9)). Forty-six Likely-SRS patients (76.7%) displayed either 11p15 ICR1 hypomethylation (n=35; 58.3%) or maternal UPD of chromosome 7 (mUPD7) (n=11; 18.3%). Eight Unlikely-SRS patients had neither ICR1 hypomethylation nor mUPD7, whereas one patient had mUPD7. The clinical score and molecular results yielded four groups that differed significantly overall and for individual scoring system factors. Further molecular screening led identifying chromosomal abnormalities in Likely-SRS-double-negative and Unlikely-SRS groups. Four Likely-SRS-double negative patients carried a DLK1/GTL2 IG-DMR hypomethylation, a mUPD16; a mUPD20 and a de novo 1q21 microdeletion.
Conclusions This new scoring system is very sensitive (98%) for the detection of patients with SRS with demonstrated molecular abnormalities. Given its clinical and molecular heterogeneity, SRS could be considered as a spectrum.
Introduction
Silver-Russell syndrome (SRS, OMIM #180860; called also Russell-Silver syndrome, RSS, in the USA) is a clinically and genetically heterogeneous syndrome involving prenatal and postnatal growth retardation first described by Silver et al and Russell. Many other studies have since reported additional features, providing a complex clinical description of SRS. The clinical presentation of SRS is now known to cover a spectrum of signs that are easy to recognise in typical cases but may be difficult to diagnose clinically in less severely affected individuals. Furthermore, the facial characteristics of SRS tend to become attenuated as the patient grows up, making it difficult to diagnose SRS in older children and adults. Finally, some of the more common typical features of SRS overlap with those of other syndromic intrauterine growth retardation disorders (such as 3M or Mulibrey-nanism syndromes, eg).
There is growing evidence that a definition of SRS based on a compilation of features rather than a checklist of characteristics is required. Unfortunately, there is still no clear consensus about how SRS should be defined. This renders clinical diagnosis difficult, leading to underdiagnosis in some situations and overdiagnosis in others. Five attempts have been made to create a clinical definition of SRS, or an 'SRS scoring system'. The various systems developed display some similarities, but also differences. In the paper describing the most recent of these systems, the Birmingham model, the four scoring systems that had previously been developed were evaluated, but on retrospective clinical data collected by different physicians, which could not, therefore, necessarily be considered reliable.
Despite the existence of these numerous clinical scoring systems, the identification of appropriate patients for molecular testing remains a challenge, because many of the features of SRS are non-specific or mild, and some may disappear over time.
Two primary molecular causes of SRS have been identified. In about 10% of cases, SRS is due to maternal UPD of chromosome 7 (mUPD7). The major abnormality, present in 50–60% of cases, was only recently identified: hypomethylation of the paternal allele of the 11p15 imprinting centre region 1 (ICR1) regulating the IGF2/H19 locus. Rare genetic or cytogenetic abnormalities have also been identified, but these abnormalities account for less than 2% of cases. The molecular cause of SRS thus remains unknown in about 30–40% of cases.
On the basis of our considerable clinical experience with patients with SRS, we conducted a prospective study in which 69 patients with suspected SRS were assessed clinically and then underwent state-of-the-art molecular investigations. The results obtained were then used to validate a modified scoring system adapted from the original scoring system developed by Netchine et al in which small for gestational age (SGA) was no longer an obligate factor. We have shown that this new scoring system was highly sensitive for identification of the subjects most likely to test positive for one of the known molecular causes of SRS, and for distinguishing these subjects from those not likely to test positive. This new scoring system is easy to use and flexible enough to be run even if data are missing for one or more factors. The combination of variables in this scoring system may be considered an improvement over those previously published.
