Document Detail

Clinically distinct epigenetic subgroups in Silver-Russell syndrome: the degree of H19 hypomethylation associates with phenotype severity and genital and skeletal anomalies.
MedLine Citation:
PMID:  19017756     Owner:  NLM     Status:  MEDLINE    
CONTEXT: The H19 imprinting control region (ICR), located on chromosome 11p15.5, has been reported hypomethylated in 20-65% of Silver-Russell syndrome (SRS) patients.
OBJECTIVE: We investigated the methylation status of 11p15.5 ICRs in SRS patients and children born small for gestational age (SGA) to clarify the relationship between phenotype and H19 methylation status.
METHODS: We performed methylation screens of the H19 and KCNQ1OT1 ICRs in 42 SRS patients, including seven maternal uniparental disomy of chromosome 7 patients, and 90 SGA children without SRS. Clinical data were evaluated from patient records, and seven hypomethylated patients were clinically and radiologically reexamined.
RESULTS: H19 ICR hypomethylation was found in 62% of SRS patients but in no SGA children. A clinical severity score demonstrated strong correlation between hypomethylation level and phenotype severity. Hypomethylation related to a more severe SRS phenotype, in which especially asymmetry and micrognathia were significantly more common. Extremely hypomethylated patients had abnormally high lumbar vertebrae, lumbar hypomobility, elbow subluxations, and distinct hand and foot anomalies. They also presented with congenital aplasia of the uterus and upper vagina, equivalent to the Mayer-Rokitansky-Küster-Hauser syndrome in females, and cryptorchidism and testicular agenesis in males.
CONCLUSIONS: We found a dose-response relationship between the degree of H19 hypomethylation and phenotype severity in SRS. We report for the first time the association of specific anomalies of the spine, elbows, hands and feet, and genital defects in SRS with severe H19 hypomethylation. Classical SRS features were found in H19 hypomethylation and milder symptoms in maternal uniparental disomy of chromosome 7, thus distinguishing two separate clinical and etiological subgroups.
Sara Bruce; Katariina Hannula-Jouppi; Jari Peltonen; Juha Kere; Marita Lipsanen-Nyman
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-11-18
Journal Detail:
Title:  The Journal of clinical endocrinology and metabolism     Volume:  94     ISSN:  0021-972X     ISO Abbreviation:  J. Clin. Endocrinol. Metab.     Publication Date:  2009 Feb 
Date Detail:
Created Date:  2009-02-05     Completed Date:  2009-03-30     Revised Date:  2011-10-07    
Medline Journal Info:
Nlm Unique ID:  0375362     Medline TA:  J Clin Endocrinol Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  579-87     Citation Subset:  AIM; IM    
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
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MeSH Terms
Abnormalities, Multiple / classification,  genetics*
Bone Development / genetics
Bone and Bones / abnormalities*
Child Development / physiology
DNA Methylation* / physiology
Epigenesis, Genetic / physiology*
Genitalia / abnormalities*,  growth & development
Infant, Newborn
Infant, Small for Gestational Age
Potassium Channels, Voltage-Gated / genetics
RNA, Untranslated / genetics*
Severity of Illness Index
Reg. No./Substance:
0/H19 long non-coding RNA; 0/KCNQ1OT1 protein, human; 0/Potassium Channels, Voltage-Gated; 0/RNA, Untranslated

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