Genetic Factors Associated with Phenytoin-Related Skin Reactions

J Millichap; John Millichap

doi:10.15844/pedneurbriefs-28-9-1

Authors:

J Gordon Millichap ,

Northwestern University Feinberg School of Medicine, US

John J Millichap

Northwestern University Feinberg School of Medicine, US

Abstract

How to Cite: Millichap, J.G. and Millichap, J.J., 2014. Genetic Factors Associated with Phenytoin-Related Skin Reactions. Pediatric Neurology Briefs, 28(9), pp.65–66. DOI: http://doi.org/10.15844/pedneurbriefs-28-9-1

Investigators at the Taipei Medical University Hospital and other centers in Taiwan conducted a case-control study in 2002-2014 among 105 cases with phenytoin-related severe cutaneous adverse reactions (n = 61 Stevens-Johnson syndrome/toxic epidermal necrolysis and n = 44 drug reactions with eosinophilia and systemic symptoms), 78 cases with maculopapular exanthema, 130 phenytoin-tolerant control participants, and 3655 population controls from Taiwan, Japan, and Malaysia. A genome-wide association study (GWAS), direct sequencing of the associated loci, and replication analysis discovered a cluster of 16 single-nucleotide polymorphisms in CYP2C genes at 10q23.33 that reached genome-wide significance. Direct sequencing of CYP2C identified a missense variant that showed significant association with phenytoin-related severe cutaneous adverse reactions. A meta-analysis using the data from all three populations showed an overall odds ratio of 11 (P< .00001) for CYP2C9*3 association with phenytoin-related severe cutaneous adverse reactions. Delayed clearance of plasma phenytoin was detected in patients with severe skin reactions, especially CYP2C9*3 carriers. [1]

COMMENTARY. Phenytoin-associated hypersensitivity skin reactions are a serious and sometimes fatal adverse side effect. Anticonvulsants with a lesser or no tendency to hypersensitivity skin reactions include levetiracetam, topamax, vigabatrin, ethosuximide, and gabapentin. Anticonvulsants in addition to phenytoin with increased risk of erythema multiforme, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) include carbamazepine, oxcarbazepine, valproate, phenobarbital, and lamotrigine. The combination of carbamazepine and acetaminophen further increases the risk of hypersensitivity skin reactions [2]. Erythema multiforme as a synergistic side effect to a combination of phenytoin therapy and cranial radiotherapy is also reported [3]. The routine use of postoperative phenytoin as a prophylactic anticonvulsant in the absence of a history of seizures is discouraged [4, 5].

The US FDA cautions that phenytoin or fosphenytoin should not be prescribed as an alternative to carbamazepine in patients who carry HLA-B*15.02, although the association with severe cutaneous reactions in Asians is weaker than that found with carbamazepine [6]. Current studies find that the HLA-DRB1*15.01 allele is a risk factor for AED-induced SJS/TEN among Han Chinese, whereas HLA-A*33.03, HLA-B*58.01, and HLA-DRB1*03.01 alleles may be protectors against AED-induced skin reactions, especially CBZ-SJS/TEN [7]. Patients of Han ethnicity living in northeastern China and having EPHX1 c.337T > C polymorphisms also show an increased risk of developing CBZ-SJS/TEN, related to an increased concentration of a CBZ metabolite, CBZ-10,11-epoxide [8]. The discovery of a functional link of genetic variants to the phenytoin, carbamazepine, and other aromatic AED-related hypersensitivity cutaneous reactions might lead to prospective preventive genetic testing.

References

Chung, WH Chang, WC Lee, YS Wu, YY Yang, CH Ho, HC et al. for the Taiwan Severe Cutaneous Adverse Reaction Consortium and the Japan Pharmacogenomics Data Science Consortium (2014). Genetic variants associated with phenytoin-related severe cutaneous adverse reactions. JAMA Aug 6 2014312(5): 525–34, DOI: https://doi.org/10.1001/jama.2014.7859 [PubMed]

Gau, SS, Chao, PF, Lin, YJ, Chang, CJ and Gau, CS (2008). The association between carbamazepine and valproate and adverse cutaneous drug reactions in patients with bipolar disorder: a nested matched case-control study. J Clin Psychopharmacol Oct 200828(5): 509–17, DOI: https://doi.org/10.1097/JCP.0b013e3181845610 [PubMed]

Khafaga, YM Jamshed, A Allam, AA Mourad, WA Ezzat, A Al Eisa, A et al. (1999). Stevens-Johnson syndrome in patients on phenytoin and cranial radiotherapy. Acta Oncol 38(1): 111–6, DOI: https://doi.org/10.1080/028418699431898 [PubMed]

Young, B, Rapp, RP, Norton, JA, Haack, D and Walsh, JW (1983). Failure of prophylactically administered phenytoin to prevent post-traumatic seizures in children. Child's Brain 10(3): 185–92, DOI: https://doi.org/10.1159/000120113 [PubMed]

Rapp, RP, Norton, JA, Young, B and Tibbs, PA (1983). Cutaneous reactions in head-injured patients receiving phenytoin for seizure prophylaxis. Neurosurgery Sep 198313(3): 272–5. [PubMed]

Locharernkul, C Loplumlert, J Limotai, C Korkij, W Desudchit, T Tongkobpetch, S et al. (2008). Carbamazepine and phenytoin induced Stevens-Johnson syndrome is associated with HLA-B*1502 allele in Thai population. Epilepsia Dec 200849(12): 2087–91, DOI: https://doi.org/10.1111/j.1528-1167.2008.01719.x [PubMed]

Wang, W, Hu, FY, Wu, XT, An, DM, Yan, B and Zhou, D (2014). Genetic predictors of Stevens-Johnson syndrome and toxic epidermal necrolysis induced by aromatic antiepileptic drugs among the Chinese Han population. Epilepsy Behav Jun 17 201437C: 16–19, DOI: https://doi.org/10.1016/j.yebeh.2014.05.025 [PubMed]

He, XJ Jian, LY He, XL Tang, M Wu, Y Xu, YY et al. (2014). Association of ABCB1, CYP3A4, EPHX1, FAS, SCN1A, MICA, and BAG6 polymorphisms with the risk of carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in Chinese Han patients with epilepsy. Epilepsia Aug 201455(8): 1301–6, DOI: https://doi.org/10.1111/epi.12655 [PubMed]

[CIT0001] Chung, WH Chang, WC Lee, YS Wu, YY Yang, CH Ho, HC et al. for the Taiwan Severe Cutaneous Adverse Reaction Consortium and the Japan Pharmacogenomics Data Science Consortium (2014). Genetic variants associated with phenytoin-related severe cutaneous adverse reactions. JAMA Aug 6 2014312(5): 525–34, DOI: https://doi.org/10.1001/jama.2014.7859 [PubMed]

[CIT0002] Gau, SS, Chao, PF, Lin, YJ, Chang, CJ and Gau, CS (2008). The association between carbamazepine and valproate and adverse cutaneous drug reactions in patients with bipolar disorder: a nested matched case-control study. J Clin Psychopharmacol Oct 200828(5): 509–17, DOI: https://doi.org/10.1097/JCP.0b013e3181845610 [PubMed]

[CIT0003] Khafaga, YM Jamshed, A Allam, AA Mourad, WA Ezzat, A Al Eisa, A et al. (1999). Stevens-Johnson syndrome in patients on phenytoin and cranial radiotherapy. Acta Oncol 38(1): 111–6, DOI: https://doi.org/10.1080/028418699431898 [PubMed]

[CIT0004] Young, B, Rapp, RP, Norton, JA, Haack, D and Walsh, JW (1983). Failure of prophylactically administered phenytoin to prevent post-traumatic seizures in children. Child's Brain 10(3): 185–92, DOI: https://doi.org/10.1159/000120113 [PubMed]

[CIT0005] Rapp, RP, Norton, JA, Young, B and Tibbs, PA (1983). Cutaneous reactions in head-injured patients receiving phenytoin for seizure prophylaxis. Neurosurgery Sep 198313(3): 272–5. [PubMed]

[CIT0006] Locharernkul, C Loplumlert, J Limotai, C Korkij, W Desudchit, T Tongkobpetch, S et al. (2008). Carbamazepine and phenytoin induced Stevens-Johnson syndrome is associated with HLA-B*1502 allele in Thai population. Epilepsia Dec 200849(12): 2087–91, DOI: https://doi.org/10.1111/j.1528-1167.2008.01719.x [PubMed]

[CIT0007] Wang, W, Hu, FY, Wu, XT, An, DM, Yan, B and Zhou, D (2014). Genetic predictors of Stevens-Johnson syndrome and toxic epidermal necrolysis induced by aromatic antiepileptic drugs among the Chinese Han population. Epilepsy Behav Jun 17 201437C: 16–19, DOI: https://doi.org/10.1016/j.yebeh.2014.05.025 [PubMed]

[CIT0008] He, XJ Jian, LY He, XL Tang, M Wu, Y Xu, YY et al. (2014). Association of ABCB1, CYP3A4, EPHX1, FAS, SCN1A, MICA, and BAG6 polymorphisms with the risk of carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in Chinese Han patients with epilepsy. Epilepsia Aug 201455(8): 1301–6, DOI: https://doi.org/10.1111/epi.12655 [PubMed]

Reading: Genetic Factors Associated with Phenytoin-Related Skin Reactions

Antiepileptic Medications

Genetic Factors Associated with Phenytoin-Related Skin Reactions

Authors:

J Gordon Millichap ,

Northwestern University Feinberg School of Medicine, US

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John J Millichap

Northwestern University Feinberg School of Medicine, US

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Abstract

References