Ann Lab Med.  2021 Jul;41(4):401-408. 10.3343/alm.2021.41.4.401.

Clinical Application of Sequential Epigenetic Analysis for Diagnosis of Silver–Russell Syndrome

• Kim SY
• Shin CH
• Lee YA
• Shin CH
• Yang SW
• Cho TJ
• Ko JM

• KMID: 2512720
• DOI: http://doi.org/10.3343/alm.2021.41.4.401

Abstract

Background
Silver-Russell syndrome (SRS) is a pre- or post-natal growth retardation disorder caused by (epi)genetic alterations. We evaluated the molecular basis and clinical value of sequential epigenetic analysis in pediatric patients with SRS.
Methods
Twenty-eight patients who met ≥ 3 Netchine-Harbison clinical scoring system (NH-CSS) criteria for SRS were enrolled;26 (92.9%) were born small for gestational age, and 25 (89.3%) showed postnatal growth failure. Relative macrocephaly, body asymmetry, and feeding difficulty were noted in 18 (64.3%), 13 (46.4%), and 9 (32.1%) patients, respectively. Methylation-specific multiplex ligation-dependent probe amplification (MSMLPA) on chromosome 11p15 was performed as the first diagnostic step. Subsequently, bisulfite pyrosequencing (BP) for imprinting center 1 and 2 (IC1 and IC2) at chromosome 11p15, MEST on chromosome 7q32.2, and MEG3 on chromosome 14q32.2 was performed.
Results
. Seventeen (60.7%) patients exhibited methylation defects, including loss of IC1 methylation (N = 14; 11 detected by MS-MLPA and three detected by BP) and maternal uniparental disomy 7 (N = 3). The diagnostic yield was comparable between patients who met three or four of the NH-CSS criteria (53.8% vs 50.0%). Patients with methylation defects responded better to growth hormone treatment.
Conclusions
NH-CSS is a powerful tool for SRS screening. However, in practice, genetic analysis should be considered even in patients with a low NH-CSS score. BP analysis detected additional methylation defects that were missed by MS-MLPA and might be considered as a first-line diagnostic tool for SRS.

Keyword

Silver–Russell syndrome; Netchine-Harbison clinical scoring system (NHCSS); Epigenetic analysis; Methylation defects; Bisulfite pyrosequencing

Figure

• 

  Fig. 1 Height changes during recombinant human growth hormone (rhGH) treatment in 10 patients. The values after each patient number in parentheses indicate the tendency of standard deviation scores (SDS) of the height of the patient at the beginning and at the last point of rhGH treatment. Pt, patient.

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