Prospective study of epigenetic alterations responsible for isolated hemihyperplasia/hemihypoplasia and their association with leg length discrepancy
Abstract Background Hemihyperplasia and hemihypoplasia result in leg length discrepancy (LLD) by causing skeletal asymmetry. Beckwith–Wiedemann syndrome (BWS) and Silver–Russell syndrome (SRS) are opposite growth-affecting disorders caused by opposite epigenetic alterations at the same chromosomal l...
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| Format: | Article |
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BMC
2021-10-01
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| Series: | Orphanet Journal of Rare Diseases |
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| Online Access: | https://doi.org/10.1186/s13023-021-02042-6 |
| _version_ | 1818825848353980416 |
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| author | Chang Ho Shin Chaemoon Lim Hwa Young Kim Won Joon Yoo Tae-Joon Cho In Ho Choi Jung Min Ko |
| author_facet | Chang Ho Shin Chaemoon Lim Hwa Young Kim Won Joon Yoo Tae-Joon Cho In Ho Choi Jung Min Ko |
| author_sort | Chang Ho Shin |
| collection | DOAJ |
| description | Abstract Background Hemihyperplasia and hemihypoplasia result in leg length discrepancy (LLD) by causing skeletal asymmetry. Beckwith–Wiedemann syndrome (BWS) and Silver–Russell syndrome (SRS) are opposite growth-affecting disorders caused by opposite epigenetic alterations at the same chromosomal locus, 11p15, to induce hemihyperplasia and hemihypoplasia, respectively. Because of their somatic mosaicism, BWS and SRS show a wide spectrum of clinical phenotypes. We evaluated the underlying epigenetic alterations and potential epigenotype-phenotype correlations, focusing on LLD, in a group of individuals with isolated hemihyperplasia/hemihypoplasia. Results We prospectively collected paired blood-tissue samples from 30 patients with isolated hemihyperplasia/hemihypoplasia who underwent surgery for LLD. Methylation-specific multiplex-ligation-dependent probe amplification assay (MS-MLPA) and bisulfite pyrosequencing for differentially methylated regions 1 and 2 (DMR1 and DMR2) on chromosome 11p15 were performed using the patient samples. Samples from patients showing no abnormalities in MS-MLPA or bisulfite pyrosequencing were analyzed by single nucleotide polymorphism (SNP) microarray and CDKN1C Sanger sequencing. We introduced a metric named as the methylation difference, defined as the difference in DNA methylation levels between DMR1 and DMR2. The correlation between the methylation difference and the predicted LLD at skeletal maturity, calculated using a multiplier method, was evaluated. Predicted LLD was standardized for stature. Ten patients (33%) showed epigenetic alterations in MS-MLPA and bisulfite pyrosequencing. Of these, six and four patients had epigenetic alterations related to BWS and SRS, respectively. The clinical diagnosis of hemihyperplasia/hemihypoplasia was not compatible with the epigenetic alterations in four of these ten patients. No patients showed abnormalities in SNP array or their CDKN1C sequences. The standardized predicted LLD was moderately correlated with the methylation difference using fat tissue (r = 0.53; p = 0.002) and skin tissue (r = 0.50; p = 0.005) in all patients. Conclusions Isolated hemihyperplasia and hemihypoplasia can occur as a spectrum of BWS and SRS. Although the accurate differentiation between isolated hemihyperplasia and isolated hemihypoplasia is important in tumor surveillance planning, it is often difficult to clinically differentiate these two diseases without epigenetic tests. Epigenetic tests may play a role in the prediction of LLD, which would aid in treatment planning. |
| first_indexed | 2024-12-19T00:18:17Z |
| format | Article |
| id | doaj.art-8e6e968294ca43ab89fcbbc59f880951 |
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| issn | 1750-1172 |
| language | English |
| last_indexed | 2024-12-19T00:18:17Z |
| publishDate | 2021-10-01 |
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| series | Orphanet Journal of Rare Diseases |
| spelling | doaj.art-8e6e968294ca43ab89fcbbc59f8809512022-12-21T20:45:40ZengBMCOrphanet Journal of Rare Diseases1750-11722021-10-0116111310.1186/s13023-021-02042-6Prospective study of epigenetic alterations responsible for isolated hemihyperplasia/hemihypoplasia and their association with leg length discrepancyChang Ho Shin0Chaemoon Lim1Hwa Young Kim2Won Joon Yoo3Tae-Joon Cho4In Ho Choi5Jung Min Ko6Division of Paediatric Orthopaedics, Seoul National University Children’s Hospital, Seoul National University College of MedicineDepartment of Orthopaedic Surgery, Jeju National University HospitalDivision of Clinical Genetics, Department of Paediatrics, Seoul National University Children’s Hospital, Seoul National University College of MedicineDivision of Paediatric Orthopaedics, Seoul National University Children’s Hospital, Seoul National University College of MedicineDivision of Paediatric Orthopaedics, Seoul National University Children’s Hospital, Seoul National University College of MedicineDivision of Paediatric Orthopaedics, Seoul National University Children’s Hospital, Seoul National University College of MedicineDivision of Clinical Genetics, Department of Paediatrics, Seoul National University Children’s Hospital, Seoul National University College of MedicineAbstract Background Hemihyperplasia and hemihypoplasia result in leg length discrepancy (LLD) by causing skeletal asymmetry. Beckwith–Wiedemann syndrome (BWS) and Silver–Russell syndrome (SRS) are opposite growth-affecting disorders caused by opposite epigenetic alterations at the same chromosomal locus, 11p15, to induce hemihyperplasia and hemihypoplasia, respectively. Because of their somatic mosaicism, BWS and SRS show a wide spectrum of clinical phenotypes. We evaluated the underlying epigenetic alterations and potential epigenotype-phenotype correlations, focusing on LLD, in a group of individuals with isolated hemihyperplasia/hemihypoplasia. Results We prospectively collected paired blood-tissue samples from 30 patients with isolated hemihyperplasia/hemihypoplasia who underwent surgery for LLD. Methylation-specific multiplex-ligation-dependent probe amplification assay (MS-MLPA) and bisulfite pyrosequencing for differentially methylated regions 1 and 2 (DMR1 and DMR2) on chromosome 11p15 were performed using the patient samples. Samples from patients showing no abnormalities in MS-MLPA or bisulfite pyrosequencing were analyzed by single nucleotide polymorphism (SNP) microarray and CDKN1C Sanger sequencing. We introduced a metric named as the methylation difference, defined as the difference in DNA methylation levels between DMR1 and DMR2. The correlation between the methylation difference and the predicted LLD at skeletal maturity, calculated using a multiplier method, was evaluated. Predicted LLD was standardized for stature. Ten patients (33%) showed epigenetic alterations in MS-MLPA and bisulfite pyrosequencing. Of these, six and four patients had epigenetic alterations related to BWS and SRS, respectively. The clinical diagnosis of hemihyperplasia/hemihypoplasia was not compatible with the epigenetic alterations in four of these ten patients. No patients showed abnormalities in SNP array or their CDKN1C sequences. The standardized predicted LLD was moderately correlated with the methylation difference using fat tissue (r = 0.53; p = 0.002) and skin tissue (r = 0.50; p = 0.005) in all patients. Conclusions Isolated hemihyperplasia and hemihypoplasia can occur as a spectrum of BWS and SRS. Although the accurate differentiation between isolated hemihyperplasia and isolated hemihypoplasia is important in tumor surveillance planning, it is often difficult to clinically differentiate these two diseases without epigenetic tests. Epigenetic tests may play a role in the prediction of LLD, which would aid in treatment planning.https://doi.org/10.1186/s13023-021-02042-6HemihyperplasiaHemihypoplasiaLateralized overgrowthBeckwith–Wiedemann syndromeSilver–Russell syndromeLeg length discrepancy |
| spellingShingle | Chang Ho Shin Chaemoon Lim Hwa Young Kim Won Joon Yoo Tae-Joon Cho In Ho Choi Jung Min Ko Prospective study of epigenetic alterations responsible for isolated hemihyperplasia/hemihypoplasia and their association with leg length discrepancy Orphanet Journal of Rare Diseases Hemihyperplasia Hemihypoplasia Lateralized overgrowth Beckwith–Wiedemann syndrome Silver–Russell syndrome Leg length discrepancy |
| title | Prospective study of epigenetic alterations responsible for isolated hemihyperplasia/hemihypoplasia and their association with leg length discrepancy |
| title_full | Prospective study of epigenetic alterations responsible for isolated hemihyperplasia/hemihypoplasia and their association with leg length discrepancy |
| title_fullStr | Prospective study of epigenetic alterations responsible for isolated hemihyperplasia/hemihypoplasia and their association with leg length discrepancy |
| title_full_unstemmed | Prospective study of epigenetic alterations responsible for isolated hemihyperplasia/hemihypoplasia and their association with leg length discrepancy |
| title_short | Prospective study of epigenetic alterations responsible for isolated hemihyperplasia/hemihypoplasia and their association with leg length discrepancy |
| title_sort | prospective study of epigenetic alterations responsible for isolated hemihyperplasia hemihypoplasia and their association with leg length discrepancy |
| topic | Hemihyperplasia Hemihypoplasia Lateralized overgrowth Beckwith–Wiedemann syndrome Silver–Russell syndrome Leg length discrepancy |
| url | https://doi.org/10.1186/s13023-021-02042-6 |
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