Genomic imprinting is an epigenetic modification that enables the expression of certain genes in a parent-of-origin manner (paternal or maternal origin). The proper setting of imprinting marks plays an important role in intrauterine and postnatal growth (Eggermann et al., 2021). Aberrant imprinting signatures are associated with imprinting disorders (ImpDis), resulting in growth disturbance as a major clinical hallmark (Eggermann, 2024). Imprinted genes cluster at specific chromosomal regions called imprinting control regions (ICs), and their expression is commonly regulated by altered methylations, either by loss or gain of methylation (Elhamamsy, 2017). The changes in the coding sequences or CNVs could also affect the expressed allele (Mackay et al., 2022). The 11p15.5 chromosomal region has two important ICs, IC1 and IC2. IC1 includes the H19/IGF2 which is methylated on the paternal allele. IC2 harbors CDKN1C/KCNQ1OT1 which is maternally methylated (Eggermann et al., 2016). Opposite epigenetic and genomic disturbances in this chromosomal region contribute to two ImpDis known as Silver-Russell syndrome (SRS, OMIM 180860) and Beckwith–Wiedemann syndrome (BWS, OMIM 130650).

SRS is characterized by prenatal and postnatal growth restriction, relative macrocephaly, body asymmetry and characteristic facial features (Ishida, 2016). The patients usually have feeding difficulties, endocrine and metabolic abnormalities since infancy, which not only lead to short stature but also cause nutritional disorders that might affect neurodevelopment (Russell, 1954). As opposed to SRS, BWS is characterized by macroglossia, pre- or postnatal macrosomia, abdominal wall defects, and an increased risk for embryonal tumors (Ibrahim et al., 2014). Typically, duplications of the maternal allele at chromosome 11p15.5 or loss of methylation (LOM) of IC1 enhancing the expression of IGF2 result in SRS, whereas duplications of the paternal allele or gain of methylation (GOM) of IC1 are associated with BWS (Gicquel et al., 2005; Kraft et al., 2019). Although the two diseases are considered to be related to genetic anomalies on the same chromosome, the pathogenic alterations and phenotypes are heterogeneous.

Accurate diagnosis of SRS is a challenge since postnatal growth overlap with other diseases, and facial features ease with age. The estimated incidence of SRS was between 1/75,000 and 1/100,000 worldwide (Eggermann et al., 2015). However, the actual incidence of SRS may be underestimated, as a large part of the affected population is not diagnosed. Yakoreva et al. published a nationwide incidence as high as 1/15,866 in an epidemiological study (Yakoreva et al., 2019). The Netchine-Harbison clinical score system (NH-CSS) recommends the clinical diagnostic criteria for SRS (Wakeling et al., 2017). In 65% of patients with SRS, an underlying molecular aberration can be detected (Lokulo-Sodipe et al., 2020). About 50% of SRS patients have LOM of IC1 on chromosome 11p15.5, and about 5%–10% of patients carry maternal uniparental disomy (UPD) of chromosome 7 (UPD (7) mat) (Lokulo-Sodipe et al., 2020; Netchine et al., 2007). In addition, UPD (14) mat was also reported in SRS (Ioannides et al., 2014). In the remaining 30%–40% of patients, the molecular etiology remains unclear. Patients diagnosed timely might partially benefit from growth hormone (GH) replacement, and they require ongoing monitoring for medical issues into adulthood. Early interventions such as enriched nutrition and GH treatment can improve final height and neurological outcomes (Lokulo-Sodipe et al., 2022). In the present study, we reported a rare SRS case with 11p15.4–15.5 duplication, which was transmitted across three generations and diagnosed prenatally for better prenatal consultation and postnatal management. Our findings might add to the complexity of the molecular etiology of SRS.

DNA was extracted from the samples and chromosome microarray analysis (CMA) was performed using the Affymetrix CytoScan 750K Array following the manufacturer’s instructions.

MLPA was performed with the SALSA MS-MLPA Probemix ME028-C1 BWS/RSS (MRC-Holland, Amsterdam, Netherlands), according to the manufacturer’s protocol. The kit contains probes evaluating the presence of deletions and duplications in the 11p15.5 genomic region, which includes the following genes: H19, IGF2, KCNQ1, KCNQ1OT1, CDKN1C; and methylation status of imprinting centers, IC1 and IC2. PCR products were analyzed using ABI 3130xl Genetic Analyzer (Applied Biosystems, USA) and Genemark v.1.51 software.

LOM of IC2, as both paternal and maternal alleles are unmethylated, with inactivation of CDKN1C, has been observed in 50% of BWS, (Brioude et al., 2018). However, IC2 alterations are rare in SRS. In the previous study, Mio C et al. reported a case of a girl with a mild SRS phenotype associated with a paternally inherited 1.4 kb deletion of IC2 (Mio et al., 2021). In the current study, we presented a SRS phenotype due to maternal IC2 repeats and methylation. CDKN1C located on IC2 is a cyclin-dependent kinase inhibitor that regulates cell proliferation and promotes cell cycle arrest. Normally, IC2 is methylated on the maternal allele KCNQ1OT1, thus KCNQ1OT1 is repressed, allowing the expression CDKN1C (Chang and Bartolomei, 2020). Once maternal IC2 was activated by repeats or missense mutation, loss of CDKN1C expression might occur, contributing to SRS (Binder et al., 2020). CNV of maternal 11p15 accounts for only about 1% of the molecular pathogenic causes of SRS (Ishida, 2016). In the present case, the duplication of 11p15.4–15.5 mainly contained repeats of IC2 and enhanced maternal IC2 methylation. Considering the physiological and pathological effects of IC2, combined with the typical clinical manifestations (FGR, feeding difficulties, postnatal growth retardation, and distinctive features such as forehead protrusion and facial asymmetry), SRS was diagnosed. Although the mother and grandfather had the same CNV of 11p15, as for the mother, IC2 was paternal hypomethylated, similar to the physiological state, resulting in normal phenotypes. FGR and 11p15.4–15.5 duplication were found in two successive fetuses in this woman, and the location and length of the duplications were basically the same in both fetuses, indicating the conservative inheritance of imprinted genes. Meanwhile, the methylation of IC2 only increased in the maternal origin while remaining physiologically low in the paternal origin, indicating the epigenetic characteristics of imprinted genes during inheritance. It can be inferred that the woman has a 50% chance of passing 11p15 duplications carrying repeated IC2 with enhanced methylation to her offspring in each pregnancy. Through literature review, we learned that SRS caused by maternal 11p15 duplication containing IC2 is rare.Boonen SE reported maternally inherited duplication of 0.88 Mb including the CDKN1C gene causing intra-uterine growth restriction and postnatal short stature (Boonen et al., 2016). In some SRS cases, manifestations lasted for a short time, eased with age, and had a good prognosis (Hamza et al., 2023). Prenatal molecular diagnosis including detection of methylation levels at IC1 and IC2, as well as CNV at 11p15.5 can improve the diagnosis rate of affected individuals, enrich the genetic spectrum of the disease, contribute to incidence data, and enable growth trajectory monitoring and timely interventions for these patients early in life.

Follow-up and interventions for SRS need to be tailored according to specific manifestations at different stages. Most children with SRS have poor appetite and feeding difficulties during infancy, accompanied by gastroesophageal reflux and esophagitis (Blissett et al., 2001). Dietary adjustments, oral training, enteral feeding, and nutrient supplementation can be considered to increase infants’ appetite and ensure adequate calorie intake to prevent malnutrition. Most feeding problems ease with age. Those who have not completed catch-up growth by the age of 2 years should be closely monitored for physical development indicators, and growth hormone therapy should be initiated at the age of 4 years for those whose height is < −2.5 SD, on the basis of adequate caloric intake (Lee et al., 2003). Growth hormone therapy can significantly improve height in children with SRS (Chang and Bartolomei, 2020). In addition to nutrition and height, attention should also be paid to osteoporosis, obesity, type 2 diabetes, hypertension, and other diseases, as well as the social and psychological health of these children (Toumba et al., 2010).