Skeletal dysplasia

Gene: IDH2

Green List (high evidence)

Although IDH2 mutations are less frequent than IDH1 in central conventional chondrosarcomas, they are more frequent in high-grade disease (G1: 7%, G2/3: 14%, Dedifferentiated (DD): 25%). The findings also show that progression to DD chondrosarcoma is more common in tumours with IDH2. IDH2 mutations are strongly associated with TERT mutations in high-grade disease G2/3 (ACT/G1: 7%, G2/3: 14%, DD: 25%). In terms of tumour progression, the time interval between diagnosis and discovery of metastatic disease is shortest in IDH2-driven tumours. IDH2 tumours tend to be larger at presentation.
Genetic testing for IDH2, along with IDH1 and TERT promoter mutations in central conventional chondrosarcoma could be useful in patient stratification.

Created: 15 Jan 2024, 1:05 p.m. | Last Modified: 15 Jan 2024, 1:05 p.m.

Panel Version: 4.35

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Chondrosarcoma Conventional Central

Publications

• PMID: 36042521

Mode of pathogenicity
Other

Green List (high evidence)

disorganized development of skeletal components gp of SD. Several het cases with 613657 - all codon R140. Het missense variants (codon R140). Mosaic variants in enchondromas/ metaphyseal chondromatosis - ? Test sensitivity.; Review on behalf of Tracy Lester

Created: 6 Mar 2019, 11:44 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Enchondromatosis (Ollier) and Enchondromatosis with hermangiomata (Maffucci) 166000, metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (614875)

Publications

• 22057236
• 22057234
• 24049096

Mode of pathogenicity
Other - please provide details in the comments

I don't know

Comment on list classification: Keeping red for now. Associated with D-2-hydroxyglutaric aciduria 2 in OMIM but no skeletal phenotype. Also associated with somatic mosaic variants in patients with multiple enchondromas (Ollier disease) which can result in a skeletal phenotype.

Created: 11 Dec 2019, 6:06 p.m. | Last Modified: 11 Dec 2019, 6:06 p.m.

Panel Version: 1.287

Associated with D-2-hydroxyglutaric aciduria 2 #613657 in OMIM. No inheritance pattern given. Clinical features do not list skeletal characteristics.

PMID: 20847235 - Kranendijk et al. (2010) - 15 of 17 cases of D-2-hydroxyglutaric aciduria without mutation in the D2HGDH gene a heterozygous mutation was found in the IDH2 gene. 14 had an arg140-to-gln mutation (R140Q) and 1 had an arg140-to-gly mutation (R140G). Phenotypes of the patients are not given.

PMID: 24049096 - Nota et al. (2013) reported two patients with D-2-hydroxyglutaric aciduria-2, one in whom mosaicism for the R140Q mutation in IDH2 had occurred de novo. In the other the mother also had mosacism for R140Q variant. No skeletal phenotypes are reported.

PMID: 22057234 - Pansuriya etal 2011 - state that 'Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). They report somatic heterozygous mutations IDH2 (c.516G>C encoding R172S) in enchondromas (benign cartilage tumors) and in spindle cell hemangiomas (benign vascular lesions).

Conclusion - associated with D-2-hydroxyglutaric aciduria but this does not have a skeletal phenotype. Also associated with somatic mutations which can result in Ollier disease and Maffucci syndrome

Created: 7 May 2019, 7:40 p.m. | Last Modified: 20 Nov 2019, 11:56 p.m.

Panel Version: 1.221

This gene was part of an initial gene list collated by Tracy Lester, Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, February 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: IDH2; Initial rating suggestion: Green - codon R140

Created: 6 Mar 2019, 11:36 a.m.

I don't know

Comment on mode of inheritance: IDH2 variants associated with chondrosarcomas are somatic, occurring in the tumour material.

Created: 22 Jan 2024, 8:22 p.m. | Last Modified: 22 Jan 2024, 8:22 p.m.

Panel Version: 4.44

IDH2 variants have been associated with D-2-hydroxyglutaric aciduria 2 (OMIM:613657). PMID: 36042521 reports IDH2 variants at codon 172 (p.R172T, p.R172S, p.R172G) in seven cases of chondrosarcoma central conventional and two case of chondrosarcoma central dedifferentiated. The authors of PMID: 36042521 comment "IDH2 tumours present as larger tumours and on average over a decade later than IDH1 tumours". Based on the finding that the IDH1 and IDH2 tumours have similar molecular ages, the authors suggest that the IDH2 tumours have slower rate of cell division, with the result that the tumours undergo growth arrest and become calcified. They go onto speculate, that if this is the case, many IDH2 tumours would not become malignant and would only be detected if medical imaging was being used for an unrelated cause.
This gene is rated as red, because the variants are somatic, occurring in the tumour.

Created: 22 Jan 2024, 7:29 p.m. | Last Modified: 29 Jan 2024, 4:35 p.m.

Panel Version: 4.48

Comment when marking as ready: Two variants reported in D-2-hydroxyglutaric aciduria 2 613657

Created: 13 Jul 2016, 8:58 a.m.

Comment on list classification: Used diagnostically by Ana Beleza (Guy's and St Thomas' NHS Foundation Trust)

Created: 21 Jun 2016, 12:55 p.m.

Green List (high evidence)

Tier 1

Created: 17 Jun 2016, 8:05 a.m.

Mode of inheritance
Unknown

Phenotypes
D-2-hydroxyglutaric aciduria 2 613657; Maffucci syndrome 614569; Ollier disease/ Dyschondroplasia 166000

Variants in this GENE are reported as part of current diagnostic practice