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Phenotype of genetically confirmed Silver-Russell syndrome beyond childhood

Phenotype of genetically confirmed Silver-Russell syndrome beyond childhood
Phenotype of genetically confirmed Silver-Russell syndrome beyond childhood
Background Silver-Russell syndrome is an imprinting disorder that restricts growth, resulting in short adult stature that may be ameliorated by treatment. Approximately 50% of patients have loss of methylation of the imprinting control region (H19/IGF2:IG-DMR) on 11p15.5 and 5%–10% have maternal uniparental disomy of chromosome 7. Most published research focuses on the childhood phenotype. Our aim was to describe the phenotypic characteristics of older patients with SRS.

Methods A retrospective cohort of 33 individuals with a confirmed molecular diagnosis of SRS aged 13 years or above were carefully phenotyped.

Results The median age of the cohort was 29.6 years; 60.6% had a height SD score (SDS) ≤−2 SDS despite 70% having received growth hormone treatment. Relative macrocephaly, feeding difficulties and a facial appearance typical of children with SRS were no longer discriminatory diagnostic features. In those aged ≥18 years, impaired glucose tolerance in 25%, hypertension in 33% and hypercholesterolaemia in 52% were noted. While 9/33 accessed special education support, university degrees were completed in 40.0% (>21 years). There was no significant correlation between quality of life and height SDS. 9/25 were parents and none of the 17 offsprings had SRS.

Conclusion Historical treatment regimens for SRS were not sufficient for normal adult growth and further research to optimise treatment is justified. Clinical childhood diagnostic scoring systems are not applicable to patients presenting in adulthood and SRS diagnosis requires molecular confirmation. Metabolic ill-health warrants further investigation but SRS is compatible with a normal quality of life including normal fertility in many cases.
Silver Russell syndrome, imprinting, short stature, uniparental disomy
0022-2593
683-691
Lokulo-Sodipe, Oluwakemi
d428f857-0e58-4964-b1f0-136af7432805
Ballard, Lisa
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Child, Jenny
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Inskip, Hazel
5fb4470a-9379-49b2-a533-9da8e61058b7
Byrne, Christopher
1370b997-cead-4229-83a7-53301ed2a43c
Moore, Gudrun E.
d071953a-3ee2-4b6d-80a0-3ddfca274e15
Ishida, Miho
615e5c2d-ea24-42a0-8b8b-c3711c6435a6
Wakeling, Emma L.
8ae66ff5-bca4-4c71-8f71-7157329bebda
Fenwick, Angela
95a1f4fa-7f6f-4c07-a93b-9ea39c231c31
Mackay, Deborah
588a653e-9785-4a00-be71-4e547850ee4a
Davies, Justin
9f18fcad-f488-4c72-ac23-c154995443a9
Temple, I. Karen
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Lokulo-Sodipe, Oluwakemi
d428f857-0e58-4964-b1f0-136af7432805
Ballard, Lisa
48a7b1af-4d2b-4ec7-8927-84361a3c62a9
Child, Jenny
2d053263-ccc6-4876-a8a4-4cda40c3fc3a
Inskip, Hazel
5fb4470a-9379-49b2-a533-9da8e61058b7
Byrne, Christopher
1370b997-cead-4229-83a7-53301ed2a43c
Moore, Gudrun E.
d071953a-3ee2-4b6d-80a0-3ddfca274e15
Ishida, Miho
615e5c2d-ea24-42a0-8b8b-c3711c6435a6
Wakeling, Emma L.
8ae66ff5-bca4-4c71-8f71-7157329bebda
Fenwick, Angela
95a1f4fa-7f6f-4c07-a93b-9ea39c231c31
Mackay, Deborah
588a653e-9785-4a00-be71-4e547850ee4a
Davies, Justin
9f18fcad-f488-4c72-ac23-c154995443a9
Temple, I. Karen
d63e7c66-9fb0-46c8-855d-ee2607e6c226

Lokulo-Sodipe, Oluwakemi, Ballard, Lisa, Child, Jenny, Inskip, Hazel, Byrne, Christopher, Moore, Gudrun E., Ishida, Miho, Wakeling, Emma L., Fenwick, Angela, Mackay, Deborah, Davies, Justin and Temple, I. Karen (2020) Phenotype of genetically confirmed Silver-Russell syndrome beyond childhood. Journal of Medical Genetics, 57 (10), 683-691. (doi:10.1136/jmedgenet-2019-106561).

Record type: Article

Abstract

Background Silver-Russell syndrome is an imprinting disorder that restricts growth, resulting in short adult stature that may be ameliorated by treatment. Approximately 50% of patients have loss of methylation of the imprinting control region (H19/IGF2:IG-DMR) on 11p15.5 and 5%–10% have maternal uniparental disomy of chromosome 7. Most published research focuses on the childhood phenotype. Our aim was to describe the phenotypic characteristics of older patients with SRS.

Methods A retrospective cohort of 33 individuals with a confirmed molecular diagnosis of SRS aged 13 years or above were carefully phenotyped.

Results The median age of the cohort was 29.6 years; 60.6% had a height SD score (SDS) ≤−2 SDS despite 70% having received growth hormone treatment. Relative macrocephaly, feeding difficulties and a facial appearance typical of children with SRS were no longer discriminatory diagnostic features. In those aged ≥18 years, impaired glucose tolerance in 25%, hypertension in 33% and hypercholesterolaemia in 52% were noted. While 9/33 accessed special education support, university degrees were completed in 40.0% (>21 years). There was no significant correlation between quality of life and height SDS. 9/25 were parents and none of the 17 offsprings had SRS.

Conclusion Historical treatment regimens for SRS were not sufficient for normal adult growth and further research to optimise treatment is justified. Clinical childhood diagnostic scoring systems are not applicable to patients presenting in adulthood and SRS diagnosis requires molecular confirmation. Metabolic ill-health warrants further investigation but SRS is compatible with a normal quality of life including normal fertility in many cases.

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More information

Accepted/In Press date: 10 January 2020
e-pub ahead of print date: 13 February 2020
Published date: 1 October 2020
Additional Information: © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.
Keywords: Silver Russell syndrome, imprinting, short stature, uniparental disomy

Identifiers

Local EPrints ID: 437350
URI: http://eprints.soton.ac.uk/id/eprint/437350
ISSN: 0022-2593
PURE UUID: b9317457-7fe7-4e2c-bfe0-94fe7f0f6cb5
ORCID for Oluwakemi Lokulo-Sodipe: ORCID iD orcid.org/0000-0002-8169-3384
ORCID for Hazel Inskip: ORCID iD orcid.org/0000-0001-8897-1749
ORCID for Christopher Byrne: ORCID iD orcid.org/0000-0001-6322-7753
ORCID for Deborah Mackay: ORCID iD orcid.org/0000-0003-3088-4401
ORCID for I. Karen Temple: ORCID iD orcid.org/0000-0002-6045-1781

Catalogue record

Date deposited: 24 Jan 2020 17:32
Last modified: 26 Nov 2021 06:13

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Contributors

Author: Oluwakemi Lokulo-Sodipe ORCID iD
Author: Lisa Ballard
Author: Jenny Child
Author: Hazel Inskip ORCID iD
Author: Gudrun E. Moore
Author: Miho Ishida
Author: Emma L. Wakeling
Author: Angela Fenwick
Author: Deborah Mackay ORCID iD
Author: Justin Davies
Author: I. Karen Temple ORCID iD

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