Hypomethylation of the H19 gene causes not only Silver-Russell syndrome (SRS) but also isolated asymmetry or an SRS-like phenotype

Abstract

The H19 differentially methylated region (DMR) controls the allele-specific expression of both the imprinted H19 tumor-suppressor gene and the IGF2 growth factor. Hypermethylation of this DMR--and subsequently of the H19 promoter region--is a major cause of the clinical features of gigantism and/or asymmetry seen in Beckwith-Wiedemann syndrome or in isolated hemihypertrophy. Here, we report a series of patients with hypomethylation of the H19 locus. Their main clinical features of asymmetry and growth retardation are the opposite of those seen in patients with hypermethylation of this region. In addition, we show that complete hypomethylation of the H19 promoter is found in two of three patients with the full clinical spectrum of Silver-Russell syndrome. This syndrome is also characterized by growth retardation and asymmetry, among other clinical features. We conclude that patients with these clinical features should be analyzed for H19 hypomethylation.

Figure 1

a, Schematic representation of the H19/IGF2 region of chromosome 11p15. Probe 1 is the deletion detection probe, probe 2, the promoter methylation detection probe. CTCF-binding sites within the DMR are indicated by blackened circles. b, Results of the H19 probe 2 hybridization. MI = methylation index. c, Results of the KCNQ1OT1 hybridization. d, Results of the H19 probe 1 hybridization. P1–P9 are the patients described in this study; C1 and C2 are normal controls; H1 and H2 are patients with hemihypertrophy and hypermethylation of H19. ND = not determined.

Figure 2

a, Patient 1, aged 2 years and 9 mo. Note triangular, asymmetric face, long eyelashes, thin lips, and mild retrognathia. A coloboma is present in the left eye. b, Asymmetry of the legs (left leg larger). c, Mild ulnar deviation of digits 3, 4, and 5, with shortening of the index finger and clinodactyly of the little finger. d, Patient 2, aged 9 mo. Broad forehead; small viscerocranium; triangular, asymmetric face; long eyelashes; thin lips with downturned corners of the mouth; and mild retrognathia. e, Asymmetry of the legs (left leg larger), internal rotation of the left arm, flexion deformity of the left wrist, and abnormal position of the feet (status after multiple surgical corrections). f, Patient 2, aged 4 years and 1 mo. Facial features are less characteristic of SRS. g, Patient 4, aged 5 mo. Note small viscerocranium, triangular face, large eyes with sunset phenomena, and thin lips with downturned corners of the mouth. h, Patient 9, aged 3 years and 3 mo. Note mild asymmetry of the face (right side larger), broad forehead, flat philtrum, and thin upper lip. i, Asymmetry (right side larger) of the body. j, Asymmetry of the hands (right hand larger), mild clinodactyly of little finger.

Figure 3

a, Chromosomal order (given in megabases, from the telomere of the short arm) of chromosome 7 markers used for UPD screening. b, Chromosomal order (given in megabases, from the telomere of the short arm) of chromosome 11 markers used for UPD screening.