Imprinted genes, characterized by monoallelic expressions (either maternal or paternal), they are crucial for normal growth and development. Disruption of their monoallelic expressions leads to imprinting disorders (ImpDis). The aim of this study is to achieve proper diagnosis of ImpDis in Egyptian patients through clinical evaluation and genetic testing, emphasizing certain clinical manifestations that may indicate ImpDis to provide accurate diagnosis and genetic counseling. Fifty-three patients, either clinically evaluated for Impaired Disposition (ImpDis) or suspected to have it, were referred from the outpatient genetic clinics at the National Research Center, Egypt. Nineteen patients displayed clinical manifestations of ImpDis syndromes, while 34 showed signs affecting growth, which suggested ImpDis. These growth-related symptoms included growth retardation, feeding problems, failure to thrive, hypoglycemia, obesity, hemihypertrophy, asymmetry, and overgrowth. Of the 19 patients with syndromic ImpDis, 8 were clinically diagnosed with Silver-Russell syndrome (SRS), 7 with Prader-Willi syndrome (PWS), and 4 with Beckwith-Wiedemann syndrome (BWS). We employed methylation-specific multiple ligation-dependent probe amplification (MS-MLPA) for all patients, SNP-array testing for 12 patients, and whole exome sequencing (WES) for one patient. In patients with Silver-Russell syndrome (SRS), one patient exhibited hypermethylation of the GRB10 and MEST genes, along with segmental uniparental disomy (UPD) on chromosome 7 (patient 1). Another patient had a variant in the HMGA2 gene (NM_001300918.1:c.310dup), which, according to the American College of Medical Genetics (ACMG) criteria, was classified as PM2 VUS (patient 2). In patients with Prader-Willi syndrome (PWS), one patient showed hypermethylation of the SNPRN gene (patient 3). In patients with Beckwith-Wiedemann syndrome (BWS), two displayed hypomethylation of the KCNQ-CR region (patients 4 and 5). Among the group of patients with symptoms suggestive of ImpDis, no methylation defects were detected through MS-MLPA. It is crucial to diagnose ImpDis accurately, as understanding the exact cause of ImpDis is important for genetic counseling and personalized medicine. Early diagnosis enables timely interventions, which can improve developmental outcomes. Precision in diagnosis helps differentiate between conditions with overlapping clinical features. HMGA2 mutation should be verified in SRs patients with negative 11p15 methylation defect and matUPD7.

Silver-Russell Syndrome (SRS) is a genetic disorder characterized by intrauterine and postnatal growth restriction. Most cases are caused by an imprinting error either with hypomethylation of the Imprinted Control Region 1 at 11p15.5, or maternal uniparental disomy of chromosome 7. Approximately 40% of the cases have unknown etiology, thus distinct mechanisms have been described in association with the syndrome. Here, we present a case of monozygotic twin sisters with a clinical diagnosis of SRS, mild intellectual disability and epilepsy who carry a balanced translocation between chromosomes 3 and 12 that interrupts the NAALADL2 and HMGA2 genes, respectively. Disruption of HMGA2, a gene previously described as causative of SRS, confirms the initial diagnosis. NAALADL2 gene has been recently proposed as a candidate for intellectual disability and could partially contribute to our patient's phenotype. Silver-Russell Syndrome (SRS) is typically characterized by gestational growth restriction resulting in affected individuals being born small for gestational age, with relative macrocephaly at birth (head circumference ≥1.5 standard deviations [SD] above birth weight and/or length), prominent forehead with frontal bossing, and frequently body asymmetry. This is typically followed by postnatal growth failure, and in some cases progressive limb length discrepancy and feeding difficulties. Additional clinical features include triangular facies, fifth finger clinodactyly, and micrognathia with narrow chin. Except for the limb length asymmetry, growth failure is proportionate and head growth typically normal. The average adult height in untreated individuals is ~3.1±1.4 SD below the mean. The Netchine-Harbison Clinical Scoring System (NH-CSS) is a sensitive diagnostic scoring system. Clinical diagnosis can be established in an individual who meets at least four of the NH-CSS clinical criteria – prominent forehead/frontal bossing and relative macrocephaly at birth plus two additional findings – and in whom other disorders have been ruled out. SRS is a genetically heterogeneous condition. Genetic testing confirms clinical diagnosis in approximately 60% of affected individuals. Hypomethylation of the imprinting control region 1 (ICR1) at 11p15.5 causes SRS in 35%-67% of individuals, and maternal uniparental disomy of chromosome 7 (upd(7)mat) causes SRS in 7%-10% of individuals. There are a small number of individuals with SRS who have duplications, deletions, or translocations involving the imprinting centers at 11p15.5 or duplications, deletions, or translocations involving chromosome 7. Rarely, affected individuals with pathogenic variants in CDKN1C, IGF2, PLAG1, and HMGA2 have been described. However, approximately 30%-40% of individuals who meet NH-CSS clinical criteria for SRS have negative molecular and/or cytogenetic testing. Treatment of manifestations: Multidisciplinary follow up and early specific intervention are necessary for optimal management of affected individuals, including early referral to an endocrinologist. Treatment may include growth hormone therapy. Hypoglycemia should be prevented or aggressively managed. Strategies for feeding issues include nutritional and caloric supplementation, medication for gastroesophageal reflux, therapy for oral motor problems and oral aversion, cyproheptadine for appetite stimulation, and enteral tube feeding as needed. Lower limb length discrepancy exceeding 2 cm requires intervention. In the majority of affected older children, distraction osteogenesis is recommended. Severe micrognathia or cleft palate should be managed by a multidisciplinary craniofacial team. Males with cryptorchidism or hypospadias should be referred to a urologist. Males with micropenis and females with internal genitourinary anomalies benefit from a referral to a multidisciplinary disorders of sex development (DSD) center. Physical, occupational, speech, and language therapy with an individualized education plan are used to treat developmental delays. Psychological counseling can be used as needed to address psychosocial and body image issues. Surveillance: Monitoring of growth velocity, blood glucose concentration, and urine ketones for hypoglycemia in infants and as needed in older children; evaluation of nutritional status and oral intake at each visit as well as managing tube feedings if needed; limb length assessment at each well child visit in early childhood for evidence of asymmetric growth; evaluation for scoliosis, signs of precocious puberty, genitourinary issues, dental crowding and malocclusion, and speech-language development at each visit. Agents/circumstances to avoid: Prolonged fasting in infants and young children because of the risk for hypoglycemia; elective surgery whenever possible due to risk of hypoglycemia, hypothermia, difficult healing, and difficult intubation. Risk to family members: In most families, a proband with SRS represents a simplex case (a single affected family member) and has SRS as a result of an apparent de novo epigenetic or genetic alteration. While the majority of families are presumed to have a very low recurrence risk, SRS can occur as the result of a genetic alteration associated with up to a 50% recurrence risk depending on the nature of the genetic alteration and the sex of the transmitting parent. Rare familial cases of SRS have been reported with several underlying mechanisms, including maternally inherited 11p15 duplications, maternally inherited CDKN1C gain-of-function pathogenic variants, paternally inherited IGF2 loss-of-function pathogenic variants, paternally inherited small deletions close to the boundaries of the ICR1, and paternally or maternally inherited deletions and intragenic pathogenic variants involving PLAG1 or HMGA2. Reliable SRS recurrence risk assessment therefore requires identification of the causative genetic mechanism in the proband. Prenatal testing: Reliable prenatal testing for loss of paternal methylation at the 11p1.5 ICR1 H19/IGF2 region is not possible. Prenatal testing for the following SRS-related genetic mechanisms is possible provided the genetic mechanism has been demonstrated to be causative in an affected family member: upd(7)mat, SRS-related chromosomal abnormalities, intragenic CDKN1C, IGF2, HMGA2, or PLAG1 pathogenic variants, and deletions involving HMGA2 or PLAG1. The prenatal finding of a genetic alteration consistent with SRS cannot be used to reliably predict clinical outcome because children with SRS demonstrate varying responses to growth hormone, variable late catch-up growth, and variable developmental outcomes.

Silver-Russell syndrome (SRS) is an imprinting disorder mainly characterized by pre- and postnatal growth restriction. Most SRS cases are due to 11p15.5 loss of methylation (11p15.5 LOM) or maternal uniparental disomy of chromosome 7 [UPD(7)mat], but several patients remain molecularly undiagnosed. This study describes the molecular investigation of children with a clinical diagnosis or suspicion of SRS at a tertiary center specialized in growth disorders. Thirty-nine patients were evaluated with multiplex ligation-dependent probe amplification, chromosomal microarray and/or massively parallel sequencing. The most common result was 11p15.5 LOM (n = 17; 43.5%), followed by UPD(7)mat (n = 2; 5.1%). Additionally, we found maternal duplications of the imprinting centers in 11p15.5 (n = 2; 5.1%), and genetic defects in SRS-causing genes (IGF2 and HMGA2) (n = 3; 7.7%; two mutations and one deletion). Alternative molecular diagnoses included UPD(14)mat (n = 1; 2,6%), UPD(20)mat (n = 1;2,6%), copy number variants (n = 2; 5.1%), and mutations in genes associated with other growth disorders (n = 4; 10.3%), leading to diagnoses of Temple syndrome, Mulchandani-Bhoj-Conlin syndrome, IGF-1 resistance (IGF1R), Bloom syndrome (BLM), Gabriele-De Vries syndrome (YY1), Intellectual developmental disorder autosomal dominant 50 with behavioral abnormalities (NAA15), and Intellectual developmental disorder 64 (ZNF292). These findings underscore the importance of establishing the molecular diagnosis of SRS and its differential diagnoses to guide appropriate management and genetic counseling.

Silver-Russell syndrome (SRS, MIM#180860) is an imprinting disorder characterized by prenatal and postnatal growth retardation, relative macrocephaly at birth, prominent forehead, feeding difficulties, and body asymmetry. Clinical diagnosis is based on at least 4 out of 6 clinical signs (Netchine-Harbison clinical scoring system). The main molecular mechanisms are loss of methylation at the paternal H19/IGF2:IG-DMR (30-60%) at the 11p15 chromosomal region and maternal uniparental disomy of chromosome 7 (5-10%). While it is well known that deregulation of 11p15 imprinted genes (IGF2, H19, and CDKN1C) contributes to the SRS phenotype, those on chromosome 7 (GRB10, PEG10, and MEST) are still in discussion. We report two brothers clinically diagnosed with SRS (postnatal growth delay, relative macrocephaly at birth, feeding difficulties, and SRS facies). One patient also has distal tremors and a treated growth hormone deficiency. CGH-array revealed a deletion of 109 Kb including PEG10 and SGCE genes, inherited from their unaffected father. Whole Exome Sequencing did not disclose other causative variants. PEG10 functions as a transcriptional repressor of cyclin-dependent kinase inhibitors, including CDKN1C, for which maternal gain-of-function variants are linked to SRS. Real-time PCR studies showed a downregulation of PEG10 and an upregulation of CDKN1C expression only in the affected brothers. Interestingly, IGF2 was upregulated in the patient 1 under GH administration. Our findings provide the first evidence supporting the role of PEG10 in the pathogenesis of Silver-Russell Syndrome, mediated by a gain-of-function effect on the CDKN1C expression, offering new insights into the molecular mechanisms underlying this condition. The online version contains supplementary material available at 10.1038/s41598-025-32983-y.

Silver-Russell syndrome (SRS) is a clinically and genetically heterogeneous imprinting disorder. The most common molecular defects are loss of methylation of the H19/IGF2:IG-DMR on chromosome 11p15.5, followed by maternal uniparental disomy of chromosome 7. Further molecular lesions are genetic variants in the PLAG1 oncogene, as well as in the transcription factor HMGA2 and the fetal growth factor IGF2. A phenotypic overlap exists between SRS and Temple syndrome (TS14) that is also characterized by growth restriction but associated with abnormalities in the imprinted chromosome 14q32 gene cluster. In TS14 patients, the germline MEG3/DLK1: IG-DMR is hypomethylated and the MEG8:Int2-DMR gains methylation probably as consequence of transcriptional readthrough from the MEG3 promoter on the paternal chromosome. However, the functional role of the MEG8 DMR remains unknown. We analysed the DNA methylation of 11-12 imprinted regions in 17 cases with clinical SRS features and heterozygous for a PLAG1 variant. We observed a specific loss of methylation of the MEG8:Int2-DMR in the ten cases carrying pathogenic PLAG1 variants that result in stable aberrant proteins. Normal MEG8 methylation was observed in the cases carrying variants of uncertain pathogenicity or gene deletions. Most of the PLAG1 cases are familial and both epigenetic and genetic defects co-segregated within the families. Additionally, we assessed the methylation status of the MEG8:Int2-DMR in several SRS patients with HMGA2 or IGF2 variants, H19/IGF2:IG-DMR-LoM and upd(7)mat and all of them showed normal methylation. Our results indicate that pathogenic PLAG1 variants leading to stable aberrant PLAG1 proteins and possibly acting in a dominant-negative manner influence methylation of the MEG8 locus. This study suggests a new pathogenetic mechanism of the PLAG1 gene in SRS, involving imprinted genes in the chr14q32 cluster through deregulation of the MEG8:Int2-DMR and provides an epigenetic signature that may be used to assess the damaging potential of the PLAG1 variants.