Severe cutaneous adverse reaction

Summary

Severe cutaneous adverse reaction (MONDO:0005594) is a disease with 2 cohort genes (3 GWAS associations across 3 studies) and 155 clinical trials. Top therapeutic interventions include sodium chloride, bimatoprost, and bleomycin.

At a glance

• Cohort genes: 2
• GWAS associations: 3
• Clinical trials: 155

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	severe cutaneous adverse reaction
Mondo ID	MONDO:0005594
EFO	EFO:0006346
MeSH	D002921
UMLS	C5554042
MedGen	1843455
MedDRA	20000020
Is cancer (heuristic)	no

Also known as: SCAR

Data availability: 3 GWAS associations (3 studies).

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › severe cutaneous adverse reaction

Related subtypes (71): dermatitis, cutaneous mucinosis, skin neoplasm, pyoderma, chronic ulcer of skin, systemic sclerosis, sunburn, paronychia, Achenbach syndrome, erythema multiforme, erythematosquamous dermatosis, exanthem, facial dermatosis, hand dermatosis, keratosis, leg dermatosis, lichen disease, lipodystrophy, mongolian spot, reactive cutaneous fibrous lesion, rosacea, scalp dermatosis, sebaceous gland disorder, skin atrophy, skin sarcoidosis, sweat gland disorder, vesiculobullous skin disease, hyperglobulinemic purpura, ainhum, cheilitis glandularis, erythema palmare hereditarium, multiple benign circumferential skin creases on limbs, actinic prurigo, congenital lethal erythroderma, Parana hard-skin syndrome, Bazex-Dupre-Christol syndrome, nephrogenic systemic fibrosis, erosive pustular dermatosis of the scalp, pseudoxanthoma elasticum-like papillary dermal elastolysis, toxic dermatosis, oral erosive lichen, chronic actinic dermatitis, Jessner lymphocytic infiltration of the skin, acquired kinky hair syndrome, primary cutaneous plasmacytosis, cutaneous pseudolymphoma, corticosteroid-sensitive aseptic abscess syndrome, interstitial granulomatous dermatitis with arthritis, epidermal disease, skin pigmentation disorder, skin vascular disease, Wells syndrome, solar urticaria, pellagra, hereditary epidermal appendage anomaly, keratosis pilaris, dermis disorder, aquagenic pruritus, Boudhina Yedes Khiari syndrome, non-neoplastic nevus, cutaneous sclerosis, pityriasis rotunda, hematohidrosis, skin disorder caused by infection, livedoid vasculopathy, prurigo nodularis, granuloma faciale, sclerema neonatorum, hereditary skin disorder, hand-foot syndrome, Nicolau syndrome

Subtypes (3): drug rash with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome/toxic epidermal necrolysis overlap syndrome

Genetics & variants

GWAS landscape

3 GWAS associations across 3 studies. Top hits map to 4 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs192543598	2e-12	POLR1HASP, POLR1HASP	G	18.11
rs187926838	5e-08	ALK	G	12.1
rs116071718	2e-06	MUC22	?	3.99

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST008492	Park HW	2018	68	0	The Fas Signaling Pathway Is a Common Genetic Risk Factor for Severe Cutaneous Drug Adverse Reactions Across Diverse Drugs.
GCST002558	Chung WH	2014	60	0	Genetic variants associated with phenytoin-related severe cutaneous adverse reactions.
GCST008386	Nicoletti P	2019	43	10,701	Shared genetic risk factors across carbamazepine-induced hypersensitivity reactions.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	3

MAF distribution

Bucket	Variants
common (>=0.05)	1
low_freq (0.01-0.05)	1
rare (<0.01)	1
unknown	0

Functional consequences

Consequence	Count
intron_variant	3

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs192543598	6	29963568	A>G	0.01	intron_variant	POLR1HASP, POLR1HASP	2e-12	Tier 4: intronic/intergenic
rs187926838	2	29595425	A>G	0.007	intron_variant	ALK	5e-08	Tier 4: intronic/intergenic
rs116071718	6	31022304	T>A,C	0.05	intron_variant	MUC22	2e-06	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALK	Orphanet:146	Differentiated thyroid carcinoma
ALK	Orphanet:178342	Inflammatory myofibroblastic tumor
ALK	Orphanet:251877	Ganglioneuroblastoma
ALK	Orphanet:251992	Ganglioneuroma
ALK	Orphanet:300895	ALK-positive anaplastic large cell lymphoma
ALK	Orphanet:364043	ALK-positive large B-cell lymphoma
ALK	Orphanet:626	Large/giant congenital melanocytic nevus
ALK	Orphanet:635	Neuroblastoma

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MUC22	HGNC:39755	ENSG00000261272	E2RYF6	Mucin-22	gwas
ALK	HGNC:427	ENSG00000171094	Q9UM73	ALK tyrosine kinase receptor	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALK	ALK tyrosine kinase receptor	Neuronal receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MUC22	Other/Unknown	no		Mucin_dom, Mucin-22-like
ALK	Kinase	yes	2.7.10.1	Prot_kinase_dom, MAM_dom, Ser-Thr/Tyr_kinase_cat_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	1
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	2
esophagus mucosa	1
lower esophagus mucosa	1
male germ cell	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MUC22	19		yes	male germ line stem cell (sensu Vertebrata) in testis, lower esophagus mucosa, esophagus mucosa
ALK	181	broad	marker	sperm, male germ cell, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALK	4,792
MUC22	323

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALK	Q9UM73	79

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MUC22	E2RYF6	67.14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Drug resistance of ALK mutants	1	11420.0×	2e-04	ALK
ASP-3026-resistant ALK mutants	1	11420.0×	2e-04	ALK
NVP-TAE684-resistant ALK mutants	1	11420.0×	2e-04	ALK
alectinib-resistant ALK mutants	1	11420.0×	2e-04	ALK
brigatinib-resistant ALK mutants	1	11420.0×	2e-04	ALK
ceritinib-resistant ALK mutants	1	11420.0×	2e-04	ALK
crizotinib-resistant ALK mutants	1	11420.0×	2e-04	ALK
lorlatinib-resistant ALK mutants	1	11420.0×	2e-04	ALK
MDK and PTN in ALK signaling	1	2855.0×	7e-04	ALK
ALK mutants bind TKIs	1	951.7×	0.002	ALK
Signaling by ALK	1	571.0×	0.003	ALK
Signaling by ALK in cancer	1	271.9×	0.005	ALK
Signaling by ALK fusions and activated point mutants	1	150.3×	0.009	ALK
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.021	ALK
Signaling by Receptor Tyrosine Kinases	1	51.7×	0.022	ALK
Disease	1	13.1×	0.081	ALK
Signal Transduction	1	10.2×	0.098	ALK

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to environmental enrichment	1	8426.0×	0.002	ALK
regulation of dopamine receptor signaling pathway	1	4213.0×	0.002	ALK
swimming behavior	1	3370.4×	0.002	ALK
response to stress	1	2407.4×	0.002	ALK
peptidyl-tyrosine autophosphorylation	1	1872.4×	0.002	ALK
phosphorylation	1	1296.3×	0.002	ALK
positive regulation of dendrite development	1	991.3×	0.003	ALK
negative regulation of lipid catabolic process	1	842.6×	0.003	ALK
regulation of neuron differentiation	1	732.7×	0.003	ALK
adult behavior	1	468.1×	0.004	ALK
energy homeostasis	1	271.8×	0.006	ALK
neuron development	1	255.3×	0.006	ALK
hippocampus development	1	230.8×	0.006	ALK
obsolete positive regulation of NF-kappaB transcription factor activity	1	205.5×	0.007	ALK
cell surface receptor protein tyrosine kinase signaling pathway	1	173.7×	0.007	ALK
protein autophosphorylation	1	145.3×	0.008	ALK
regulation of cell population proliferation	1	115.4×	0.010	ALK
regulation of apoptotic process	1	83.4×	0.013	ALK
signal transduction	1	16.1×	0.062	ALK

Therapeutics

Drugs indicated for this disease

0 approved, 4 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Onabotulinumtoxina	Phase 3 (in late-stage trials)
Putrescine	Phase 3 (in late-stage trials)
Sodium Chloride	Phase 3 (in late-stage trials)
Urea	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Abobotulinumtoxina, Lipoic Acid, Alpha, Trichloroacetic Acid.

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ALK	CERITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ALK	61	4
MUC22	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CERITINIB	4	ALK
BOSUTINIB	4	ALK
CRIZOTINIB	4	ALK
ALECTINIB	4	ALK
ENTRECTINIB	4	ALK
LORLATINIB	4	ALK
GILTERITINIB	4	ALK
OSIMERTINIB	4	ALK
BRIGATINIB	4	ALK
REPOTRECTINIB	4	ALK
FEDRATINIB	4	ALK
RUXOLITINIB	4	ALK
INFIGRATINIB PHOSPHATE	4	ALK
INFIGRATINIB	4	ALK
PALBOCICLIB	4	ALK
VANDETANIB	4	ALK
UPADACITINIB	4	ALK
PAZOPANIB	4	ALK
NINTEDANIB	4	ALK
SUNITINIB	4	ALK
ERLOTINIB	4	ALK
MIDOSTAURIN	4	ALK
DACTOLISIB	3	ALK
LINIFANIB	3	ALK
SEMAXANIB	3	ALK
CANERTINIB	3	ALK
ROCILETINIB	3	ALK
ALVOCIDIB	3	ALK
CEDIRANIB	3	ALK
QUERCETIN	3	ALK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ALK	1,815	Binding:1801, Functional:13, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALK	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
ALK	1,815

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
CERITINIB	4	ALK
BOSUTINIB	4	ALK
CRIZOTINIB	4	ALK
ALECTINIB	4	ALK
ENTRECTINIB	4	ALK
LORLATINIB	4	ALK
GILTERITINIB	4	ALK
OSIMERTINIB	4	ALK
BRIGATINIB	4	ALK
REPOTRECTINIB	4	ALK
FEDRATINIB	4	ALK
RUXOLITINIB	4	ALK
INFIGRATINIB PHOSPHATE	4	ALK
INFIGRATINIB	4	ALK
PALBOCICLIB	4	ALK
VANDETANIB	4	ALK
UPADACITINIB	4	ALK
PAZOPANIB	4	ALK
NINTEDANIB	4	ALK
SUNITINIB	4	ALK
ERLOTINIB	4	ALK
MIDOSTAURIN	4	ALK
DACTOLISIB	3	ALK
LINIFANIB	3	ALK
SEMAXANIB	3	ALK
CANERTINIB	3	ALK
ROCILETINIB	3	ALK
ALVOCIDIB	3	ALK
CEDIRANIB	3	ALK
QUERCETIN	3	ALK

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ALK
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MUC22

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MUC22	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 155.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	109
PHASE4	8
PHASE2	8
PHASE1/PHASE2	7
PHASE1	7
EARLY_PHASE1	7
PHASE3	5
PHASE2/PHASE3	4

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00450775	PHASE4	COMPLETED	Evaluation of the Efficacy, Tolerability, and Patient Acceptance of Dermatix Q for the Prevention and Management of Scars
NCT01056211	PHASE4	COMPLETED	1540nm Non Ablative Fractional Laser Treatment of Scars
NCT01112371	PHASE4	COMPLETED	Contractubex Treatment in Scars After Abdominal Caesarean Section
NCT01459666	PHASE4	TERMINATED	Forehead Scars Following Mohs Micrographic Surgery and Reconstruction for Skin Cancer
NCT02518035	PHASE4	UNKNOWN	Silicone Gel to Improve Scar in Microtia Patients
NCT04046679	PHASE4	UNKNOWN	Bleomycin Infusion (MMP®) to Repigment Achromic Scars
NCT05149118	PHASE4	COMPLETED	Effect of PDRN in Post-operative Scars
NCT05271708	PHASE4	COMPLETED	Explore the Short- and Mid-term Effects of Fespixon in Scar Cosmesis Following Cervical or Abdominal Surgery
NCT05478551	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Randomized Controlled Trial Examining the Efficacy of Botulinum Toxin in Biopsy Scar Minimization
NCT00609908	PHASE3	COMPLETED	The Technique of Skin Stretching for Acute Burn Treatment and Scar Reconstruction
NCT01429402	PHASE3	UNKNOWN	Botulinum Toxin to Improve Results in Cleft Lip Repair
NCT02886988	PHASE2/PHASE3	COMPLETED	Early Postoperative Prevention and Treatment of Median Sternotomy Scars With Botulinum Toxin Type A Injection
NCT03294382	PHASE3	UNKNOWN	Botulinum Toxin to Improve Results in Epicanthoplasty
NCT03887377	PHASE2/PHASE3	COMPLETED	The Efficacy and Molecular Mechanism of Botulinum Toxin in the Reduction of Breast Reduction Mammoplasty Scar Formation
NCT04331080	PHASE2/PHASE3	COMPLETED	A Study of Granexin® Gel for the Reduction of Scar Formation in Surgical Wounds Following Bilateral Anchor Incision Breast Surgery
NCT05528328	PHASE3	UNKNOWN	Post-surgical Scars After the Use of CACIPLIQ20
NCT06909812	PHASE3	COMPLETED	Silicone vs Pirfenidone in the Treatment of Hypertrophic Scars and Keloids
NCT05501327	PHASE2	RECRUITING	Dose Regimen Study of SLI-F06 in Healthy Volunteers
NCT06122090	PHASE2	RECRUITING	Treatment of Hypopigmented Scars With Bimatoprost
NCT07576608	PHASE2	RECRUITING	A Phase II Study of 9MW3811 in Patients With Pathological Scar
NCT00129428	PHASE1/PHASE2	COMPLETED	Ultraviolet B (UVB) Light Therapy in the Treatment of Skin Conditions With Altered Dermal Matrix
NCT00585286	PHASE1/PHASE2	COMPLETED	Fractional Resurfacing Device for Treatment of Acne Scarring
NCT01177358	PHASE2	COMPLETED	Botox in the Healing of Surgical Wounds of the Neck
NCT01438125	PHASE2	COMPLETED	MF-4181 for the Reduction of Scars Secondary to Abdominoplasty or Laparoscopy/Laparotomy Gynecologic Procedures
NCT02336997	PHASE1/PHASE2	UNKNOWN	Evaluation of the Effect of Autologous Fat and SVF Transplantation in Promoting Mechanical-stretch Induced in Vivo Skin Regeneration
NCT02809001	PHASE1/PHASE2	COMPLETED	The Effects of Autologous Fat Transfer on Preventing Expanded Skin From Expansion Failure
NCT03639883	PHASE1/PHASE2	COMPLETED	A Safety and Efficacy Study to Evaluate AIV001 in Wound Healing Following Surgical Incision
NCT03795116	PHASE2	COMPLETED	Light Emitting Diode-Red Light (LED-RL) Phototherapy for Skin Scarring Prevention
NCT03880058	PHASE1/PHASE2	COMPLETED	Safety and Efficacy of SLI-F06 in Wound Healing and Scar Appearance
NCT03887208	PHASE1/PHASE2	COMPLETED	Therapy of Scars and Cutis Laxa With Autologous Adipose Derived Mesenchymal Stem Cells
NCT04186273	PHASE2	UNKNOWN	Clinical Safety and Scar Prevention Study of a Topical Antifibrotic Compound FS2.
NCT05838833	PHASE2	UNKNOWN	Ointment to Prevent Scar After Thyroidectomy
NCT00580736	PHASE1	COMPLETED	Optical Clearing of the Skin in Conjunction With Laser Treatments
NCT01005992	PHASE1	UNKNOWN	Fractional Photothermolysis for the Treatment of Burn Scars
NCT02145130	PHASE1	COMPLETED	Phase I Study for Autologous Dermal Substitutes and Dermo-epidermal Skin Substitutes for Treatment of Skin Defects
NCT02590042	PHASE1	UNKNOWN	Safety of Adipose-Derived Stem Cell Stromal Vascular Fraction
NCT02630303	PHASE1	COMPLETED	High Fluence Light Emitting Diode-Red Light (LED-RL) in Human Skin
NCT03433222	PHASE1	UNKNOWN	Phase 1 Study of HF-LED-RL in Fitzpatrick Skin Types I to III
NCT04827875	PHASE1	COMPLETED	Safety and Efficacy of AIV001 on Scar Formation and Keloid Recurrence Following Keloidectomy
NCT03561376	EARLY_PHASE1	RECRUITING	Zinc Oxide Versus Petrolatum Following Skin Surgery

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SODIUM CHLORIDE	4	7
BIMATOPROST	4	1
BLEOMYCIN	4	1
BOTULINUM TOXIN TYPE A	4	1
DEXAMETHASONE SODIUM PHOSPHATE	4	1
LIDOCAINE HYDROCHLORIDE	4	1
METHYLPREDNISOLONE ACETATE	4	1
ONABOTULINUMTOXINA	4	1
PIRFENIDONE	4	1
TRIAMCINOLONE	4	1
2-OCTYL CYANOACRYLATE	3	1
AVOTERMIN	3	1
CENTELLA ASIATICA EXTRACT	3	1
PARAFFIN	3	1
PETROLATUM	3	1
TOCOTRIENOL	3	1
PLECTRANTHUS AMBOINICUS EXTRACT	1	1
CHEMBL4303730	0	1
CHEMBL1200637	0	1
CHEMBL1200844	0	1
CHEMBL4743806	0	1