Acrodermatitis enteropathica

Summary

Acrodermatitis enteropathica (MONDO:0008713) is a disease caused by SLC39A4 (GenCC Definitive), with 1 cohort gene and 2 clinical trials.

At a glance

• Prevalence: Unknown (Europe) [Orphanet-validated]
• Causal gene: SLC39A4 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 280
• Phenotypes (HPO): 31
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.2	Denmark	Validated
Point prevalence	1-9 / 1 000 000		Denmark	Not yet validated

Signs & symptoms

Clinical features (HPO)

31 HPO clinical features (Orphanet curated; top 31 by frequency):

HPO ID	Term	Frequency
HP:0000492	Abnormal eyelid morphology	Very frequent (80-99%)
HP:0000534	Abnormal eyebrow morphology	Very frequent (80-99%)
HP:0000958	Dry skin	Very frequent (80-99%)
HP:0001596	Alopecia	Very frequent (80-99%)
HP:0002024	Malabsorption	Very frequent (80-99%)
HP:0002028	Chronic diarrhea	Very frequent (80-99%)
HP:0002120	Cerebral cortical atrophy	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0008066	Abnormal blistering of the skin	Very frequent (80-99%)
HP:0010783	Erythema	Very frequent (80-99%)
HP:0011354	Generalized abnormality of skin	Very frequent (80-99%)
HP:0200039	Pustule	Very frequent (80-99%)
HP:0000157	Abnormality of the tongue	Frequent (30-79%)
HP:0000206	Glossitis	Frequent (30-79%)
HP:0000221	Furrowed tongue	Frequent (30-79%)
HP:0000498	Blepharitis	Frequent (30-79%)
HP:0000509	Conjunctivitis	Frequent (30-79%)
HP:0000613	Photophobia	Frequent (30-79%)
HP:0000712	Emotional lability	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001597	Abnormality of the nail	Frequent (30-79%)
HP:0001807	Ridged nail	Frequent (30-79%)
HP:0001818	Paronychia	Frequent (30-79%)
HP:0008402	Ridged fingernail	Frequent (30-79%)
HP:0100825	Cheilitis	Frequent (30-79%)
HP:0200042	Skin ulcer	Frequent (30-79%)
HP:0000505	Visual impairment	Occasional (5-29%)
HP:0001824	Weight loss	Occasional (5-29%)
HP:0002039	Anorexia	Occasional (5-29%)
HP:0004396	Poor appetite	Occasional (5-29%)
HP:0200020	Corneal erosion	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	acrodermatitis enteropathica
Mondo ID	MONDO:0008713
MeSH	C538178
OMIM	201100
Orphanet	37
DOID	DOID:0050605
ICD-11	1813939482
NCIT	C128802
SNOMED CT	37702000
UMLS	C0221036
MedGen	66355
GARD	0005723
NORD	721
Is cancer (heuristic)	no

Also known as: acrodermatitis enteropathica · acrodermatitis enteropathica zinc deficiency type · acrodermatitis enteropathica, zinc deficiency type · acrodermatitis enteropathica, zinc-deficiency type · ae · AEZ · Brandt syndrome · Danbolt-Cross syndrome · enteropathica · inherited zinc deficiency

Data availability: 280 ClinVar variants · 6 GenCC gene-disease records · 4 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn metal metabolism disorder › acrodermatitis enteropathica

Related subtypes (8): familial periodic paralysis, hereditary hemochromatosis, atransferrinemia, Wilson disease, Menkes disease, familial primary hypomagnesemia, pseudohypoparathyroidism, sulfite oxidase deficiency due to molybdenum cofactor deficiency

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

280 retrieved; paginated sample, class counts are floors:

89 uncertain significance, 47 likely benign, 47 likely pathogenic, 34 conflicting classifications of pathogenicity, 20 benign, 17 pathogenic/likely pathogenic, 15 pathogenic, 11 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069887	NM_130849.4(SLC39A4):c.1203G>A (p.Trp401Ter)	SLC39A4	Pathogenic	criteria provided, multiple submitters, no conflicts
1075104	NM_130849.4(SLC39A4):c.1193_1199dup (p.Trp401fs)	SLC39A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075429	NM_130849.4(SLC39A4):c.1066del (p.Val356fs)	SLC39A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1410913	NM_130849.4(SLC39A4):c.1396dup (p.His466fs)	SLC39A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452525	NM_130849.4(SLC39A4):c.1174_1195del (p.Glu392fs)	SLC39A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455861	NM_130849.4(SLC39A4):c.192+19G>A	SLC39A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456654	NM_130849.4(SLC39A4):c.862del (p.Gly287_Val288insTer)	SLC39A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457500	NM_130849.4(SLC39A4):c.1763G>A (p.Trp588Ter)	SLC39A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1481691	NM_130849.4(SLC39A4):c.475-2A>G	SLC39A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1903268	NM_130849.4(SLC39A4):c.1386del (p.Lys463fs)	SLC39A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1986114	NM_130849.4(SLC39A4):c.18_22del (p.Leu7fs)	SLC39A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2141319	NM_130849.4(SLC39A4):c.1224del (p.Leu410fs)	SLC39A4	Pathogenic	criteria provided, multiple submitters, no conflicts
3254617	NM_130849.4(SLC39A4):c.14_17delinsCCCCA (p.Val5fs)	SLC39A4	Pathogenic	criteria provided, single submitter
3534	NM_130849.4(SLC39A4):c.1224_1228del (p.Gly409fs)	SLC39A4	Pathogenic	no assertion criteria provided
3535	NM_130849.4(SLC39A4):c.970_973del (p.Ser324fs)	SLC39A4	Pathogenic	criteria provided, multiple submitters, no conflicts
3536	NM_130849.4(SLC39A4):c.475-19G>A	SLC39A4	Pathogenic	no assertion criteria provided
3537	NM_130849.4(SLC39A4):c.599C>T (p.Pro200Leu)	SLC39A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3538	NM_130849.4(SLC39A4):c.1576G>A (p.Gly526Arg)	SLC39A4	Pathogenic	no assertion criteria provided
3540	NM_130849.4(SLC39A4):c.318C>A (p.Asn106Lys)	SLC39A4	Pathogenic	no assertion criteria provided
3541	SLC39A4, 2-KB DEL, UPSTREAM REGION	SLC39A4	Pathogenic	no assertion criteria provided
3542	NM_130849.4(SLC39A4):c.989G>A (p.Gly330Asp)	SLC39A4	Pathogenic	no assertion criteria provided
3543	NM_130849.4(SLC39A4):c.1018_1070dup (p.Thr357_His358insAlaArgSerLeuAlaSerCysCysTer)	SLC39A4	Pathogenic	no assertion criteria provided
3544	NM_130849.4(SLC39A4):c.283C>T (p.Arg95Cys)	SLC39A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3545	NM_130849.4(SLC39A4):c.909G>C (p.Gln303His)	SLC39A4	Pathogenic	no assertion criteria provided
3896408	NM_130849.4(SLC39A4):c.1109dup (p.Ala371fs)	SLC39A4	Pathogenic	criteria provided, single submitter
390605	NM_130849.4(SLC39A4):c.493C>T (p.Gln165Ter)	SLC39A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4533375	NM_130849.4(SLC39A4):c.1288-1G>C	SLC39A4	Pathogenic	criteria provided, single submitter
4816454	NM_130849.4(SLC39A4):c.143T>G (p.Leu48Ter)	SLC39A4	Pathogenic	criteria provided, single submitter
810336	NM_130849.4(SLC39A4):c.295G>A (p.Ala99Thr)	SLC39A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
952106	NM_130849.4(SLC39A4):c.89_99del (p.Ser30fs)	SLC39A4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
SLC39A4	Definitive	Autosomal recessive	acrodermatitis enteropathica	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC39A4	Orphanet:37	Acrodermatitis enteropathica

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC39A4	HGNC:17129	ENSG00000147804	Q6P5W5	Zinc transporter ZIP4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC39A4	Zinc transporter ZIP4	Selective transporter that mediates the uptake of Zn(2+).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Transporter	1	77.8×	0.013

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC39A4	Transporter	yes		ZIP, ZIP4_N, ZIP4_12_EF-hand

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)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
duodenum	1
small intestine	1
small intestine Peyer’s patch	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC39A4	134	ubiquitous	marker	duodenum, small intestine Peyer’s patch, small intestine

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC39A4	1,382

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC39A4	Q6P5W5	75.05

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 1 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
Defective SLC39A4 causes acrodermatitis enteropathica, zinc-deficiency type (AEZ)	1	11420.0×	9e-04	SLC39A4
Zinc transporters	1	1142.0×	0.003	SLC39A4
Zinc influx into cells by the SLC39 gene family	1	1142.0×	0.003	SLC39A4
Metal ion SLC transporters	1	601.0×	0.004	SLC39A4
SLC transporter disorders	1	203.9×	0.009	SLC39A4
R-HSA-425366	1	181.3×	0.009	SLC39A4
Disorders of transmembrane transporters	1	139.3×	0.010	SLC39A4
SLC-mediated transmembrane transport	1	59.2×	0.021	SLC39A4
Transport of small molecules	1	25.1×	0.044	SLC39A4
Disease	1	13.1×	0.076	SLC39A4

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
cellular response to zinc ion starvation	1	2407.4×	0.001	SLC39A4
zinc ion import across plasma membrane	1	1685.2×	0.001	SLC39A4
intracellular monoatomic cation homeostasis	1	1123.5×	0.001	SLC39A4
zinc ion transmembrane transport	1	702.2×	0.002	SLC39A4
intracellular zinc ion homeostasis	1	481.5×	0.002	SLC39A4

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC39A4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
D	Druggable family + AlphaFold only, no drug	1	SLC39A4
E	Difficult family or no structure, no drug	0

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)
SLC39A4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT02870166	Not specified	COMPLETED	Genetic Study of Severe Zinc Deficiencies