A number sign (#) is used with this entry because of evidence that Silver-Russell syndrome-4 (SRS4) is caused by heterozygous mutation in the PLAG1 gene (603026) on chromosome 8q12.

Silver-Russell syndrome-4 (SRS4) is characterized by intrauterine growth retardation followed by feeding difficulties and postnatal growth restriction. Dysmorphic facial features include triangular face and prominent forehead, and relative macrocephaly at birth may be observed (Abi Habib et al., 2018).

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

Abi Habib et al. (2018) reported a mother and 2 daughters who fulfilled the criteria for Silver-Russell syndrome (SRS). The patients had low birth length and weight and exhibited feeding difficulties during infancy, with low body mass index at age 2 years. Other features included triangular facies with prominent forehead. The authors also studied a sporadic patient who showed similar features consistent with SRS, including relative macrocephaly at birth.

The transmission pattern of SRS4 in the family reported by Abi Habib et al. (2018) was consistent with autosomal dominant inheritance.

By whole-exome sequencing in a female patient with Silver-Russell syndrome, who had normal methylation on chromosomes 7, 11, and 14, and in whom maternal uniparental disomies and chromosomal rearrangements had been excluded, Abi Habib et al. (2018) identified heterozygosity for a 1-bp deletion in the PLAG1 gene (603026.0001). The mutation was present in her affected sister and mother, but was not found in her unaffected father, in polymorphism databases, or the ExAC database. In a cohort of 192 patients with suspected SRS, the authors screened for mutations in the 3 genes of the HMGA2 (600698)-PLAG1-IGF2 (147470) pathway and identified a female patient who was heterozygous for a different 1-bp deletion in PLAG1 that was not found in her unaffected twin brother, older brother, or parents. In addition, Abi Habib et al. (2018) identified mutations in the IGF2 and HMGA2 genes in 4 more unrelated patients from the SRS cohort (see SRS3, 616489, 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 the 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.