A number sign (#) is used with this entry because of evidence that Silver-Russell syndrome-3 (SRS3) is caused by heterozygosity for paternally inherited mutations in the IGF2 gene (147470) on chromosome 11p15.

Silver-Russell syndrome-3 (SRS3) is characterized by intrauterine growth retardation with relative macrocephaly, followed by feeding difficulties and postnatal growth restriction. Dysmorphic facial features include triangular face, prominent forehead, and low-set ears. Other variable features include limb defects, genitourinary and cardiovascular anomalies, hearing impairment, and developmental delay (Begemann et al., 2015; Yamoto et al., 2017).

For a discussion of genetic heterogeneity of Silver-Russell syndrome, see SRS1 (180860).

Begemann et al. (2015) reported a 4-generation family in which 4 affected individuals had severe prenatal and postnatal growth restriction and a distinctive triangular face with prominent forehead and low-set ears. The proband was a 26-year-old man born with hypotrophy and relative macrocephaly, who also exhibited right ulnar ray defect (missing digits 3-5) and contracture of the right elbow with pterygium. He had severe feeding problems that necessitated a nasogastric tube for the first 3 years of life. His 21-year-old affected sister was born by cesarean section due to progressive oligohydramnion and fetal growth restriction; she required feeding through a nasogastric tube for 6 months. Their 20-year-old male cousin was also born by cesarean section due to poor fetal growth, and had ambiguous genitalia with penoscrotal hypospadias and unilateral cryptorchidism. The proband and his sister had low to low-normal intelligence and attended special schools, whereas their cousin had intelligence scores at or above the 50th percentile and attended high school. The proband's daughter was small at birth and had severe feeding problems; at age 18 months, she had relative macrocephaly with severe frontal bossing, small hands and feet, hypotonia, and developmental delay. Endocrine analysis showed IGF2 deficiency in the 2 affected sibs and their cousin; all 3 had normal levels of IGF1 (147440) and IGFBP3 (146732), and spontaneous secretion of growth hormone (GH1; 139250) at night and after stimulation with arginine was normal to high-normal.

Yamoto et al. (2017) reported an 18-month-old Japanese boy born with intrauterine growth retardation (IUGR) and relative macrocephaly, who had feeding difficulties and postnatal growth restriction. Dysmorphic features included triangular face, prominent forehead, low-set ears, cleft palate, and micrognathia, as well as digital anomalies, including bilateral hand and left foot ectrodactyly, toe polydactyly and syndactyly, and clinodactyly. He also had genitourinary anomalies, with micropenis, hypospadias, abnormal scrotum, and cryptorchidism. Examination at 18 months showed short stature (length, -4.2 SD), low weight (-2.9 SD), and relative macrocephaly (-1.6 SD). He had borderline hearing impairment and developmental delay, speaking single words at the age of 16 months and sitting without support at 17 months. He did not show body asymmetry. Serum IGF1 and IGFBP3 were markedly elevated; GH provocation test was not performed. The proband was diagnosed with Silver-Russell syndrome (SRS), and the authors noted similarities to the affected individuals in the family described by Begemann et al. (2015), who also had growth failure and dysmorphic features consistent with SRS.

Liu et al. (2017) studied a 13-year-old Chinese boy who was small for gestational age with relative macrocephaly at birth. He had severe feeding difficulties in the neonatal period, and examination at 4.5 years of age showed short stature and low weight (both -3.3 SD). He had dysmorphic facial features, with triangular face, micrognathia, and low-set ears. Asymmetric body, hands, and feet were apparent. Other features included ambiguous genitalia with small penis and hydrocele, hypotonia, and high-pitched voice. GH therapy was effective in promoting growth. Endocrine evaluation showed low serum IGF1 and IFGBP3 levels (-2 SD). The authors noted that the proband met the clinical diagnostic criteria for SRS.

Poulton et al. (2018) described a 4-year-old Australian Aboriginal girl who at birth exhibited reduced length and weight with relative macrocephaly, prominent forehead, hypertelorism, deep-set eyes, depressed nasal bridge, micrognathia, clinodactyly, and shoulder dimples. Severe feeding difficulties with persistent vomiting resulted in gastrostomy tube placement at age 16 months. A small muscular VSD closed spontaneously by 1 year of age. She exhibited developmental delay, with walking at 22 months and limited vocabulary at age 2 years. Growth hormone therapy at 3 years of age was successful, with a gain of 3 cm over 6 months.

Rockstroh et al. (2019) reported a 5.5-year-old German boy with SRS, who had pre- and postnatal growth restriction with relative macrocephaly. Cleft palate contributed to feeding difficulties in early childhood, resulting in significant underweight by 3.4 years of age (body mass index, 12.2). Other features included long philtrum, high forehead, retrognathia, and clinodactyly, as well as patent ductus arteriosus that closed spontaneously and penoscrotal transposition that was surgically corrected.

Masunaga et al. (2020) studied 5 unrelated Japanese patients with mutations in IGF2, reviewing the features of these and 10 previously reported patients with IGF2-associated SRS (SRS3). Compared to patients with SRS1, due to HG19/IGF2 epimutations, SRS3 was associated with low frequency of hemihypoplasia, high frequency of feeding difficulty and/or reduced body mass index (BMI), and mild degree of relative macrocephaly, together with occasional development of severe limb malformations, high frequency of cardiovascular anomalies and developmental delay, and low serum IGF2 levels. Masunaga et al. (2020) noted that 1 of the Japanese patients (patient 5), who exhibited somatic mosaicism for a missense mutation in IGF2 gene, did not completely fulfill the criteria for SRS, although the child had growth failure, low BMI, and mental retardation, as well as elevated GH, IFG1, and IGFBP3 levels. The authors also emphasized the difficulty in recognizing the SRS phenotype in patients who have conspicuous non-SRS features and lack the characteristic hemihypoplasia.

In 4 members of a 4-generation family with severe growth restriction, in whom known Silver-Russell syndrome-associated molecular alterations had been excluded, Begemann et al. (2015) performed exome sequencing and identified a heterozygous nonsense mutation in the IGF2 gene (S64X; 147470.0004) that segregated fully with the disorder. Affected individuals inherited the mutation from their healthy fathers, and it originated from the healthy paternal grandmother. Clinical features occurred only in those who inherited the variant allele through paternal transmission, consistent with maternal imprinting of IGF2.

By whole-exome sequencing in an 18-month-old Japanese boy with SRS, who did not have copy number variants or any rare variant in genes known to be associated with growth failure, limb/digital malformations, undermasculinized genitalia, or developmental delay, Yamoto et al. (2017) identified heterozygosity for a de novo indel variant in the IFG2 gene (616489.0005). Methylation analyses indicated that the mutation was inherited from the paternal allele.

In a 13-year-old Chinese boy with SRS, who was negative for ICR1 (616186) hypomethylation and for mutation in the IGF1 and IGF1R (147370), Liu et al. (2017) identified heterozygosity for a de novo missense mutation in the IGF2 gene (G34D; 616489.0006) that arose on the paternal allele and was not found in public variant databases.

From a cohort of 192 patients with a suspected diagnosis of SRS, Abi Habib et al. (2018) identified 2 unrelated patients with heterozygous de novo mutations in the IGF2 gene. In 6 more patients from 4 families in the SRS cohort, they identified mutations in the PLAG1 (603026) and HMGA2 (600698) genes (see SRS4, 618907 and SRS5, 618908, respectively). Experiments in Hep3b cells demonstrated that HMGA2 and PLAG1 both positively regulate expression of the IGF2 promoter P3, independently and via an HMGA2-PLAG1-IGF2 pathway. The authors noted that disruption of any gene in the pathway results in a decrease in IGF2 expression and produces an SRS phenotype similar to that of patients carrying 11p15.5 epigenetic defects (SRS1; 180860), except for body asymmetry, which is not expected to occur since the molecular defects are present in all cells of the body, unlike the mosaic epigenetic changes at the 11p15.5 locus.

In a 4-year-old Australian Aboriginal girl with SRS, Poulton et al. (2018) identified heterozygosity for a de novo splicing mutation in the IGF2 gene (616489.0007), occurring on the paternal allele. The authors noted that recurrent manifestations in IGF2-associated SRS include developmental delay as well as limb and cardiac anomalies.

In a 5.5-year-old German boy with SRS, who was negative for uniparental disomy of chromosome 7 and for epimutations in the ICR1/ICR2 region, Rockstroh et al. (2019) identified heterozygosity for a de novo 1-bp deletion in the IGF2 gene (616489.0008) that arose on the paternal allele. The authors tabulated the features of 9 reported patients with IGF2-associated SRS and noted that the clinical characteristics were very similar in all, with all showing IUGR and reduced levels of IGF2.

Masunaga et al. (2020) studied 5 unrelated Japanese patients who had heterozygous de novo mutations in the IGF2 gene, including 1 splice site and 4 missense mutations, which were not found in in-house or public variant databases. Reviewing previously reported IGF2 mutations, the authors noted that the mutations were widely distributed on IGF2 with no mutation hotspots or ethnic differences.