Silver-Russell Syndrome following in Vitro Fertilization

To the Editor, A number of observations have revealed an increased frequency of genomic imprinting disorders among children born using assisted reproduction technology (ART), pointing to a relationship between these procedures and methylation defects. It has been speculated that these defects result from interference of the ART procedures with the establishment or maintenance of imprinting through different stages of development. Based on analysis of the Beckwith-Wiedemann syndrome (MIM 130650) cases born after in vitro fertilization (IVF), a relative risk of 4.2 has been estimated, although this figure could well be biased by the patients’ recruitment criteria [1]. Silver-Russell Syndrome (SRS [MIM 180860]) is a clinically and genetically heterogeneous condition of primordial growth retardation that spares head growth; in approximately half of the cases, it causes a growth asymmetry in the limbs, trunk, or face [2]. We report a patient with SRS born after IVF, characterized by molecular testing. He was the only son of nonconsaguineous Caucasian parents. The 38-year-old mother and the 42year-old father had opted for IVF because of unilateral fallopian tube closure. Maternal oocytes taken after gonadotropin stimulation were mixed with paternal sperm collected using a condom. Ten fertilized ova were obtained, and 2 of them were transferred to the maternal uterus. A single living fetus was evidenced by standard ultrasound scan (US) at 7 weeks of gestation (WG). No exposure to teratogenic agents during pregnancy was reported. Serologic tests for cytomegalovirus, toxoplasmosis, and rubella and triple serum marker screening were negative. Amniocentesis at 16 WG revealed a normal male karyotype. A standard US at 22 WG disclosed a development corresponding to 18 weeks without evidence of fetal distress. The newborn was delivered by cesarean section because of breech presentation at 37 WG. Birth weight was 2050 g (,3rd centile), length 42.5 cm (3rd centile), and occipitalfrontal circumference (OFC) 34.4 cm (75th centile). Physical examination at 4 months disclosed an OFC of 42 cm (50th centile), length 51.5 cm, and weight 4330 g (both ,3rd centile) with mild asymmetry and left hemimacrosoma resulting in a discrepancy of 1.5 cm in leg length (Fig. 1a). There were mild facial dysmorphisms (Fig. 1b,c) and bilateral 5th finger clinodactyly (Fig. 1d). The infant had feeding difficulties, which were treated with multiple meals and required nasogastric and gastrostomy tube feeding. At 13 months the weight was 10.200 kg (50th centile), length 74.7 cm (10th to 25th centile), and OFC 49 cm (90th centile). He walked unaided at the age of 15 months. Thyroid, growth hormone, and insuline-like growth hormone-1 hormonal tests were normal. Analysis of DNA methylation of the chromosome 11p15.5 imprinted gene cluster by bisulfite treatment coupled with restriction enzyme digestion (methylation restriction-polymerase chain reaction or combined bisulfate restriction analysis), disclosed a partial hypomethylation of the Imprinting Center 1 (IC1) (Fig. 2) [3]. (Supplemental material on the methods utilized is available online.) This is an additional example of a patient with a methylation defect conceived with ART. Like most SRS patients that present asymmetric growth, he carries an epimutation of the 11p15.5 region. The partial rather than complete loss of methylation of the paternal IC1 in these patients suggests that the asymmetric growth could result from a mosaic distribution of a postfertilization error. Given the variable SRS phenotype and a reported 2.6 relative risk of low birth weight unrelated to prematurity and twin gestations in the IVF population, a number of these smallfor-gestational-age infants within this population could represent undiagnosed cases of SRS.