Cutaneous porphyria

Summary

Cutaneous porphyria (MONDO:0009902) is a disease caused by UROS (GenCC Definitive), with 2 cohort genes and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: UROS (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 63
• Phenotypes (HPO): 50
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		200	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated
Annual incidence	<1 / 1 000 000	0.065	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

50 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0007537	Severe photosensitivity	Very frequent (80-99%)
HP:0008066	Abnormal blistering of the skin	Very frequent (80-99%)
HP:0001030	Fragile skin	Very frequent (80-99%)
HP:0500115	Increased stool urobilinogen concentration	Very frequent (80-99%)
HP:0012187	Increased erythrocyte protoporphyrin concentration	Very frequent (80-99%)
HP:0010472	Abnormal circulating porphyrin concentration	Very frequent (80-99%)
HP:0012217	Increased urinary porphobilinogen	Very frequent (80-99%)
HP:0010473	Porphyrinuria	Very frequent (80-99%)
HP:0040320	Red-brown urine	Frequent (30-79%)
HP:0100699	Scarring	Frequent (30-79%)
HP:0030756	Erythrodontia	Frequent (30-79%)
HP:0001790	Nonimmune hydrops fetalis	Frequent (30-79%)
HP:0001072	Thickened skin	Frequent (30-79%)
HP:0000953	Hyperpigmentation of the skin	Frequent (30-79%)
HP:0001010	Hypopigmentation of the skin	Frequent (30-79%)
HP:0033009	Increased fecal coproporphyrin 1	Frequent (30-79%)
HP:0008282	Unconjugated hyperbilirubinemia	Frequent (30-79%)
HP:0040322	Purple urine	Frequent (30-79%)
HP:0200041	Skin erosion	Frequent (30-79%)
HP:0005406	Recurrent bacterial skin infections	Frequent (30-79%)
HP:0001878	Hemolytic anemia	Occasional (5-29%)
HP:0012804	Corneal ulceration	Occasional (5-29%)
HP:0002219	Facial hypertrichosis	Occasional (5-29%)
HP:0011273	Anisocytosis	Occasional (5-29%)
HP:0004447	Poikilocytosis	Occasional (5-29%)
HP:0001923	Reticulocytosis	Occasional (5-29%)
HP:0020181	Reduced haptoglobin level	Occasional (5-29%)
HP:0001744	Splenomegaly	Occasional (5-29%)
HP:0001882	Leukopenia	Occasional (5-29%)
HP:0001873	Thrombocytopenia	Occasional (5-29%)
HP:0001892	Abnormal bleeding	Occasional (5-29%)
HP:0000656	Ectropion	Occasional (5-29%)
HP:0000938	Osteopenia	Occasional (5-29%)
HP:0100512	Low levels of vitamin D	Occasional (5-29%)
HP:0001560	Abnormality of the amniotic fluid	Occasional (5-29%)
HP:0011457	Loss of eyelashes	Occasional (5-29%)
HP:0004552	Scarring alopecia of scalp	Occasional (5-29%)
HP:0000939	Osteoporosis	Occasional (5-29%)
HP:0012132	Erythroid hyperplasia	Occasional (5-29%)
HP:0009025	Increased connective tissue	Occasional (5-29%)
HP:0003401	Paresthesia	Very rare (<1-4%)
HP:0000989	Pruritus	Very rare (<1-4%)
HP:0000969	Edema	Very rare (<1-4%)
HP:0000618	Blindness	Very rare (<1-4%)
HP:0100532	Scleritis	Very rare (<1-4%)
HP:0500046	Seborrhoeic blepharitis	Very rare (<1-4%)
HP:0001096	Keratoconjunctivitis	Very rare (<1-4%)
HP:0002797	Osteolysis	Very rare (<1-4%)
HP:0008069	Neoplasm of the skin	Very rare (<1-4%)
HP:0002860	Squamous cell carcinoma	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	cutaneous porphyria
Mondo ID	MONDO:0009902
MeSH	D017092
OMIM	263700
Orphanet	79277
DOID	DOID:13271
NCIT	C84697
SNOMED CT	67312003
UMLS	C5886774
MedGen	1861084
GARD	0004446
NORD	1599
Is cancer (heuristic)	no

Also known as: CEP · Congenital Erythropoietic Porphyria · congenital porphyria · cutaneous porphyria · erythropoietic porphyria · Günther disease · uroporphyrinogen III synthase, deficiency of · UROS-related erythropoietic porphyria

Data availability: 63 ClinVar variants · 6 GenCC gene-disease records · 4 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › normocytic anemia › hemolytic anemia › familial hemolytic anemia › cutaneous porphyria

Related subtypes (22): congenital nonspherocytic hemolytic anemia, elliptocytosis 2, southeast Asian ovalocytosis, overhydrated hereditary stomatocytosis, cryohydrocytosis, dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema, abetalipoproteinemia, hemolytic anemia due to diphosphoglycerate mutase deficiency, glycogen storage disease VII, hereditary cryohydrocytosis with reduced stomatin, familial pseudohyperkalemia, renal tubular acidosis, distal, 4, with hemolytic anemia, elliptocytosis 1, glycogen storage disease due to aldolase A deficiency, primary CD59 deficiency, triosephosphate isomerase deficiency, dehydrated hereditary stomatocytosis 2, Rh deficiency syndrome, hereditary spherocytosis, congenital dyserythropoietic anemia, X-linked congenital hemolytic anemia, hemolytic disease of fetus and newborn, RH-induced

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

63 retrieved; paginated sample, class counts are floors:

20 uncertain significance, 18 pathogenic, 7 benign, 5 likely pathogenic, 5 conflicting classifications of pathogenicity, 4 likely benign, 2 benign/likely benign, 1 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
3750	NM_000375.3(UROS):c.217T>C (p.Cys73Arg)	UROS	Pathogenic	criteria provided, multiple submitters, no conflicts
3751	NM_000375.3(UROS):c.158C>T (p.Pro53Leu)	UROS	Pathogenic	no assertion criteria provided
3752	NM_000375.3(UROS):c.197C>T (p.Ala66Val)	UROS	Pathogenic	no assertion criteria provided
3753	NM_000375.3(UROS):c.184A>G (p.Thr62Ala)	UROS	Pathogenic	no assertion criteria provided
3755	NM_000375.3(UROS):c.10C>T (p.Leu4Phe)	UROS	Pathogenic	criteria provided, multiple submitters, no conflicts
3756	NC_000010.11:g.125815036_125815132del	UROS	Pathogenic	no assertion criteria provided
3757	UROS, 80-BP INS	UROS	Pathogenic	no assertion criteria provided
3759	NM_000375.3(UROS):c.562G>A (p.Gly188Arg)	UROS	Pathogenic	no assertion criteria provided
3760	NM_000375.3(UROS):c.243A>T (p.Glu81Asp)	UROS	Pathogenic	no assertion criteria provided
3761	NM_000375.3(UROS):c.562G>T (p.Gly188Trp)	UROS	Pathogenic	no assertion criteria provided
3762	NM_000375.3(UROS):c.-203T>C	UROS	Pathogenic	no assertion criteria provided
3763	NM_000375.3(UROS):c.-26-183G>A	UROS	Pathogenic	criteria provided, single submitter
3764	NM_000375.3(UROS):c.-26-193C>A	UROS	Pathogenic	criteria provided, single submitter
3765	NM_000375.3(UROS):c.-26-197C>A	UROS	Pathogenic	no assertion criteria provided
3766	NM_000375.3(UROS):c.673G>A (p.Gly225Ser)	UROS	Pathogenic	criteria provided, multiple submitters, no conflicts
3767	NM_000375.3(UROS):c.63+1G>A	UROS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3768	NM_000375.3(UROS):c.395-1dup	UROS	Pathogenic	no assertion criteria provided
3769	NM_000375.3(UROS):c.743C>A (p.Pro248Gln)	UROS	Pathogenic	no assertion criteria provided
694740	NM_000375.3(UROS):c.56A>G (p.Tyr19Cys)	UROS	Pathogenic	criteria provided, single submitter
31943	NM_002049.4(GATA1):c.646C>T (p.Arg216Trp)	GATA1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066786	NM_000375.3(UROS):c.7G>T (p.Val3Phe)	UROS	Likely pathogenic	criteria provided, multiple submitters, no conflicts
30626	NM_000375.3(UROS):c.661-31T>G	UROS	Likely pathogenic	criteria provided, single submitter
3780780	NM_000375.3(UROS):c.320-1G>C	UROS	Likely pathogenic	criteria provided, single submitter
65600	NM_000375.3(UROS):c.139T>C (p.Ser47Pro)	UROS	Likely pathogenic	criteria provided, single submitter
299189	NM_000375.3(UROS):c.512T>C (p.Val171Ala)	UROS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
299190	NM_000375.3(UROS):c.475+14T>A	UROS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3754	NM_000375.3(UROS):c.683C>T (p.Thr228Met)	UROS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3758	NM_000375.3(UROS):c.244G>T (p.Val82Phe)	UROS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
713813	NM_000375.3(UROS):c.63+8G>A	UROS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2664905	NM_000375.3(UROS):c.660+4del	UROS	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
UROS	Definitive	Autosomal recessive	cutaneous porphyria	5
GATA1	Supportive	Autosomal recessive	cutaneous porphyria	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
UROS	Orphanet:79277	Congenital erythropoietic porphyria
GATA1	Orphanet:124	Diamond-Blackfan anemia
GATA1	Orphanet:231393	Beta-thalassemia-X-linked thrombocytopenia syndrome
GATA1	Orphanet:363727	X-linked dyserythropoietic anemia with abnormal platelets and neutropenia
GATA1	Orphanet:420611	Transient myeloproliferative syndrome
GATA1	Orphanet:67044	Thrombocytopenia with congenital dyserythropoietic anemia
GATA1	Orphanet:79277	Congenital erythropoietic porphyria
GATA1	Orphanet:86849	Acute basophilic leukemia
GATA1	Orphanet:99887	Acute megakaryoblastic leukemia in children with Down syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
UROS	HGNC:12592	ENSG00000188690	P10746	Uroporphyrinogen-III synthase	gencc,clinvar
GATA1	HGNC:4170	ENSG00000102145	P15976	Erythroid transcription factor	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
UROS	Uroporphyrinogen-III synthase	Catalyzes cyclization of the linear tetrapyrrole, hydroxymethylbilane, to the macrocyclic uroporphyrinogen III, the branch point for the various sub-pathways leading to the wide diversity of porphyrins.
GATA1	Erythroid transcription factor	Transcriptional activator or repressor which serves as a general switch factor for erythroid development.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Enzyme (other)	1	6.0×	0.228
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
UROS	Enzyme (other)	yes	4.2.1.75	4pyrrol_synth_uPrphyn_synth, 4pyrrol_syn_uPrphyn_synt_sf, UROS/Hem4
GATA1	Transcription factor	no		Znf_GATA, Znf_NHR/GATA, Transcription_factor_GATA

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
caudate nucleus	1
nucleus accumbens	1
putamen	1
blood	1
bone marrow	1
trabecular bone tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
UROS	277	ubiquitous	marker	nucleus accumbens, caudate nucleus, putamen
GATA1	138	tissue_specific	marker	trabecular bone tissue, blood, bone marrow

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GATA1	4,810
UROS	1,155

Intra-cohort edges

A	B	Sources
GATA1	UROS	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
UROS	P10746	1
GATA1	P15976	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Heme biosynthesis	1	380.7×	0.011	UROS
RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function	1	60.1×	0.028	GATA1
RUNX1 regulates transcription of genes involved in differentiation of HSCs	1	47.6×	0.028	GATA1
Factors involved in megakaryocyte development and platelet production	1	33.2×	0.030	GATA1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
uroporphyrinogen III biosynthetic process	1	8426.0×	0.002	UROS
regulation of primitive erythrocyte differentiation	1	4213.0×	0.002	GATA1
basophil differentiation	1	4213.0×	0.002	GATA1
eosinophil fate commitment	1	4213.0×	0.002	GATA1
regulation of definitive erythrocyte differentiation	1	2808.7×	0.002	GATA1
cellular response to amine stimulus	1	2808.7×	0.002	UROS
regulation of glycoprotein biosynthetic process	1	2106.5×	0.002	GATA1
eosinophil differentiation	1	2106.5×	0.002	GATA1
primitive erythrocyte differentiation	1	2106.5×	0.002	GATA1
response to platinum ion	1	2106.5×	0.002	UROS
myeloid cell apoptotic process	1	1053.2×	0.004	GATA1
cellular response to arsenic-containing substance	1	1053.2×	0.004	UROS
negative regulation of myeloid cell apoptotic process	1	936.2×	0.004	GATA1
obsolete protoporphyrinogen IX biosynthetic process	1	842.6×	0.004	UROS
heme B biosynthetic process	1	842.6×	0.004	UROS
heme A biosynthetic process	1	766.0×	0.004	UROS
positive regulation of mast cell degranulation	1	766.0×	0.004	GATA1
osteoblast proliferation	1	702.2×	0.004	GATA1
cellular response to follicle-stimulating hormone stimulus	1	702.2×	0.004	GATA1
megakaryocyte differentiation	1	601.9×	0.004	GATA1
positive regulation of osteoblast proliferation	1	601.9×	0.004	GATA1
Sertoli cell development	1	561.7×	0.004	GATA1
dendritic cell differentiation	1	526.6×	0.004	GATA1
negative regulation of bone mineralization	1	468.1×	0.004	GATA1
platelet formation	1	351.1×	0.005	GATA1
heme biosynthetic process	1	300.9×	0.006	UROS
animal organ regeneration	1	300.9×	0.006	GATA1
erythrocyte development	1	263.3×	0.006	GATA1
positive regulation of erythrocyte differentiation	1	255.3×	0.006	GATA1
homeostasis of number of cells within a tissue	1	221.7×	0.007	GATA1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
UROS	0	0
GATA1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
UROS	5	Binding:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
UROS	4.2.1.75	uroporphyrinogen-III synthase

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	UROS
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	GATA1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
UROS	5	—
GATA1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07024316	PHASE1/PHASE2	RECRUITING	A Study to Investigate the Improvement of Photosensitivity in Terms of Skin Lesions Associated With CEP Following Administration of Oral ATL-001 (Ciclopirox Oral Solution) in Participants Aged >18 Years of Age With CEP
NCT01561157	Not specified	RECRUITING	Longitudinal Study of the Porphyrias