Distinguishing genetic alterations versus (Epi)mutations in silver–russell syndrome and focus on the IGF1R gene

Alessandro Vimercati; Pierpaola Tannorella; Sara Guzzetti; Luciano Calzari; Davide Gentilini; Emanuela Manfredini; Giulia Gori; Rossella Gaudino; Vincenzo Antona; Maria Piccione; Cecilia Daolio; Renata Auricchio; Fabio Sirchia; Antonella Minelli; Elena Rossi; Melissa Bellini; Giacomo Biasucci; Raucci Annalisa Russo; Gabriella Pozzobon; Giuseppa Patti; Flavia Napoli; Lidia Larizza; Mohamad Maghnie; Silvia Russo

doi:10.1530/ey.22.4.1

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ESPE Yearbook of Paediatric Endocrinology (2025) 22 4.1 | DOI: 10.1530/ey.22.4.1

ESPEYB25 4. Growth and Growth Factors Novel Genetic Insights (3 abstracts)

4.1. Distinguishing genetic alterations versus (Epi)mutations in silver-russell syndrome and focus on the IGF1R gene

Alessandro Vimercati , Pierpaola Tannorella , Sara Guzzetti , Luciano Calzari , Davide Gentilini , Emanuela Manfredini , Giulia Gori , Rossella Gaudino , Vincenzo Antona , Maria Piccione , Cecilia Daolio , Renata Auricchio , Fabio Sirchia , Antonella Minelli , Elena Rossi , Melissa Bellini , Giacomo Biasucci , Annalisa Russo Raucci , Gabriella Pozzobon , Giuseppa Patti , Flavia Napoli , Lidia Larizza , Mohamad Maghnie & Silvia Russo

J Clin Endocrinol Metab 2025 Mar 17;110(4):e932-e944. PMID: 39412159 doi: 10.1210/clinem/dgae730

Brief Summary: Silver–Russell Syndrome (SRS) is a rare growth disorder that presents a significant diagnostic challenge: approximately 40% of clinically suspected SRS cases remain without a molecular diagnosis. This study aimed to identify the underlying genetic variants in 132 genetically undiagnosed SRS patients who fulfilled the Netchine–Harbison Clinical Scoring System (NH-CSS) criteria (score ≥4) and lacked known (epi)genetic alterations. Using whole-exome and targeted sequencing, the researchers achieved a diagnostic yield of 9.1% in this challenging cohort.

Pathogenic variants were discovered in the major SRS genes (IGF2, PLAG1, HMGA2), accounting for 3% of cases. Notably, the study identified novel missense and in-frame deletion variants in PLAG1, whereas only truncating variants had previously been reported.

Similarly, pathogenic variants in the IGF1R gene were identified in 3% of patients. These variants are associated with IGF-1 resistance (IGF1RES), which clinically overlaps with SRS. Importantly, 4 previously unreported likely pathogenic missense variants in IGF1R were described. Altogether, variants in IGF2, PLAG1, HMGA2, and IGF1R explained 3.6% of SRS cases with NH-CSS ≥4.

The study also provided valuable genotype–phenotype correlations: body asymmetry was more frequent in (epi)genetic SRS (72% in IC1_LoM cases) compared with genetic SRS (0–25% in IGF2, HMGA2, PLAG1) and IGF1R patients (1.5%), highlighting the link between mosaicism and asymmetry. Relative macrocephaly at birth and postnatally was more common in (epi)genetic SRS (79–80% in IC1_LoM) than in genetic SRS (e.g., 20–27% in IGF1R). Conversely, postnatal microcephaly was observed more often in genetic SRS and IGF1R patients. Familial cases were frequent, especially in HMGA2 (60%), PLAG1 (78%), and IGF1R (89%) variants, with affected parents often showing incomplete or milder phenotypes.

In conclusion, this study broadens the molecular spectrum of SRS and, given the diagnostic yield and clinical overlap, strongly supports including IGF1R sequencing in the SRS diagnostic workflow. Furthermore, it underscores the importance of parental clinical assessment and genetic counselling due to the high prevalence of familial cases, even among parents with subtle or absent clinical features.

References: 1. Wakeling EL, Brioude F, Lokulo-Sodipe O, et al. Diagnosis and management of Silver-Russell syndrome: first international consensus statement. Nat Rev Endocrinol. 2017;13(2):105-124.2. Russo S, Calzari L, Mussa A, et al. A multi-method approach to the molecular diagnosis of overt and borderline 11p15.5 defects underlying Silver-Russell and Beckwith-Wiedemann syndromes. Clin Epigenetics. 2016;8(1):23.