Acrodermatitis Enteropathica

Mendelian MONDO:0008713 Pathograph 13 Show in embeddings browser inborn error of metal metabolism

Acrodermatitis enteropathica is an autosomal recessive inborn error of zinc absorption caused by biallelic loss-of-function variants in SLC39A4, which encodes the apical enterocyte zinc importer ZIP4. Failure to take up dietary zinc at the intestinal brush border produces systemic zinc deficiency, which impairs the many zinc-dependent metalloenzymes and zinc-finger transcription factors on which rapidly renewing epithelia and immune cells depend. The result is the classic triad of periorificial and acral dermatitis, alopecia, and diarrhea, together with growth retardation, recurrent infection, and a low serum alkaline phosphatase. Onset is typically in infancy, often at weaning from breast milk, and the disease is progressive and once frequently fatal; lifelong oral zinc supplementation produces rapid and durable remission.

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1
Inheritance
6
Pathophys.
1
Histopath.
7
Phenotypes
13
Pathograph
1
Genes
1
Medical Actions
1
Models
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
Biallelic loss-of-function variants in SLC39A4 are required; heterozygous carriers are unaffected.
Autosomal recessive inheritance
⚙

Pathophysiology

6
SLC39A4 (ZIP4) Loss of Function
Biallelic loss-of-function variants in SLC39A4, which encodes the apical zinc transporter ZIP4 of the enterocyte, abolish or reduce its zinc transport activity.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
zinc ion transmembrane transporter activity GO:0005385 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased zinc ion transmembrane transporter activity (GO:0005385). GO:0005385 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Intestinal Zinc Absorption
Show evidence (2 references)
PMID:12068297 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"mutational analysis of eight families affected with acrodermatitis enteropathica, suggest that SLC39A4 is centrally involved in the pathogenesis of this condition"
Mutational analysis of affected families identified SLC39A4 as the causative gene.
PMID:12032886 SUPPORT DIRECT BACKGROUND Human Clinical
"The rare inherited condition acrodermatitis enteropathica (AE) results from a defect in the absorption of dietary zinc."
Establishes AE as an inherited defect of dietary zinc absorption.
Impaired Intestinal Zinc Absorption
ZIP4 sits at the apical brush border of duodenal and jejunal enterocytes and is upregulated during zinc deficiency; its loss leaves dietary and endogenous luminal zinc unabsorbed.
enterocyte CL:0000584 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves enterocyte (CL:0000584). CL:0000584 is a cell type from the Cell Ontology.
zinc ion transmembrane transport GO:0071577 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased zinc ion transmembrane transport (GO:0071577). GO:0071577 is a biological process from the Gene Ontology. ↓ DECREASED
small intestine UBERON:0002108 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in small intestine (UBERON:0002108). UBERON:0002108 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Systemic Zinc Deficiency
Show evidence (2 references)
PMID:12032886 SUPPORT DIRECT PRIMARY RESULT Model Organism
"We show that Slc39A4 is abundantly expressed in mouse enterocytes and that the protein resides in the apical membrane of these cells."
Localizes ZIP4 to the apical membrane of enterocytes, the site of dietary zinc uptake.
PMID:12032886 SUPPORT INDIRECT PRIMARY RESULT Model Organism
"These findings suggest that the hZIP4 transporter is responsible for intestinal absorption of zinc."
Identifies ZIP4 as the transporter responsible for intestinal zinc absorption, which its loss abolishes.
Systemic Zinc Deficiency
Failure of intestinal zinc absorption depletes systemic zinc, lowering plasma zinc and the activity of zinc-dependent enzymes and transcription factors throughout the body.
Animal models
Intestine-specific Zip4 knockout mouse Mouse recapitulates Intestinal ZIP4 loss rapidly depletes tissue zinc and causes wasting and death unless excess dietary zinc is supplied.
Downstream
Impaired Zinc-Dependent Enzyme and Zinc-Finger Function
Intestinal Epithelial Dysfunction
Failure to thrive
Irritability
Decreased alkaline phosphatase
Show evidence (2 references)
PMID:40584104 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"zinc deficiency was observed in 75.9% of the patients."
Confirms systemic zinc deficiency as the dominant biochemical finding across pooled AE cases.
PMID:22737083 SUPPORT DIRECT PRIMARY RESULT Model Organism
"Elemental analyses of small intestine, liver, and pancreas from Zip4-intestine knockout mice revealed that total zinc was dramatically and rapidly decreased in these organs"
Intestinal ZIP4 loss rapidly depletes tissue zinc, the model correlate of systemic zinc deficiency.
Impaired Zinc-Dependent Enzyme and Zinc-Finger Function
Zinc is a catalytic or structural cofactor for hundreds of metalloenzymes and zinc-finger transcription factors. Its depletion impairs rapidly renewing epithelia (skin, hair follicle) and immune cells most acutely, producing the cutaneous and immune features of the disease.
Downstream
Periorificial and Acral Dermatitis
Alopecia
Cutaneous Bacterial and Fungal Superinfection
Show evidence (1 reference)
PMID:12032886 SUPPORT DIRECT BACKGROUND Other
"Zinc is an essential and versatile element, utilized by proteins as diverse as metalloenzymes and transcription factors."
Zinc is a cofactor for metalloenzymes and zinc-finger transcription factors, whose function fails as zinc is depleted.
Intestinal Epithelial Dysfunction
Zinc depletion reprograms Paneth cells and disrupts the intestinal stem cell niche, degrading the integrity of the absorptive epithelium; in the mouse model this drives the wasting phenotype and is the correlate of the diarrhea and malabsorption seen in patients.
Paneth cell CL:0000510 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Paneth cell (CL:0000510). CL:0000510 is a cell type from the Cell Ontology.
small intestine UBERON:0002108 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in small intestine (UBERON:0002108). UBERON:0002108 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Intestine-specific Zip4 knockout mouse Mouse recapitulates The knockout reprograms Paneth cells and disrupts the intestinal stem cell niche and mucosal integrity.
Downstream
Diarrhea
Show evidence (1 reference)
PMID:22737083 SUPPORT DIRECT PRIMARY RESULT Model Organism
"An initial effect of the knockout was the reprogramming of Paneth cells, which contribute to the intestinal stem cell niche in the crypts."
Intestinal ZIP4 loss reprograms Paneth cells and disrupts the stem cell niche.
Cutaneous Bacterial and Fungal Superinfection
The eroded, barrier-disrupted skin lesions are secondarily infected by bacteria and fungi, most often Staphylococcus aureus and Candida.
Show evidence (1 reference)
PMID:40584104 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Staphylococcus aureus was the most common pathogen, identified in 18 patients (51.4%), followed by Candida albicans in 8 patients (22.9%)."
S. aureus and Candida are the organisms most often cultured from the swab-positive AE skin lesions, indicating secondary cutaneous superinfection.
✶

Histopathology

1
Epidermal necrolysis
Skin biopsy is nonspecific but supportive, typically showing necrolysis of the upper epidermis; it is not required for diagnosis.
Show evidence (1 reference)
PMID:40584104 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"this examination typically revealed necrolysis in the upper part of the epidermis."
Describes the characteristic, though nonspecific, skin histopathology of AE.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Acrodermatitis Enteropathica Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

7
Digestive 1
Diarrhea HP:0002014 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Diarrhea (HP:0002014), qualified as temporality chronic. HP:0002014 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (1 reference)
PMID:40584104 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Diarrhea was present in 98 patients (46.9%), and alopecia was present in 88 patients (42.1%)."
Quantifies diarrhea frequency in the pooled pediatric AE cohort.
Immune 1
Periorificial and Acral Dermatitis Eczematoid dermatitis HP:0000964 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Periorificial and acral dermatitis, annotated with Eczematoid dermatitis (HP:0000964), qualified as infantile onset. HP:0000964 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (1 reference)
PMID:40584104 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"the lesions were most commonly present on the hands and feet and limbs (187 patients, 83.1%), followed by the perioral area (171 patients, 76.0%) and the perianal area (163 patients, 72.4%)."
Quantifies the acral and periorificial distribution of the dermatitis.
Integument 1
Alopecia HP:0001596 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Alopecia (HP:0001596). HP:0001596 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40584104 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Diarrhea was present in 98 patients (46.9%), and alopecia was present in 88 patients (42.1%)."
Quantifies alopecia frequency in the pooled pediatric AE cohort.
Metabolism 2
Fever HP:0001945 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fever (HP:0001945). HP:0001945 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40584104 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"fever in 35 patients (16.8%)"
Quantifies fever frequency in the pooled pediatric AE cohort.
Decreased alkaline phosphatase Decreased circulating alkaline phosphatase activity HP:0003282 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating alkaline phosphatase activity (HP:0003282). HP:0003282 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40584104 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Among the 87 patients whose ALP levels were recorded, 40 patients (46.0%) exhibited decreased ALP levels"
Low alkaline phosphatase, a zinc-dependent enzyme, is recorded in a large share of AE patients.
Nervous System 1
Irritability HP:0000737 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Irritability (HP:0000737). HP:0000737 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40584104 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"irritability in 62 patients (29.7%)"
Quantifies irritability frequency in the pooled pediatric AE cohort.
Growth 1
Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth retardation, annotated with Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40584104 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Growth retardation was noted in 49 patients (23.4%)"
Quantifies growth retardation frequency in the pooled pediatric AE cohort.
🧬

Genetic Associations

1
SLC39A4
Gene: SLC39A4 hgnc:17129 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SLC39A4 (hgnc:17129). hgnc:17129 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:12068297 SUPPORT DIRECT PRIMARY RESULT Human Clinical
"mutational analysis of eight families affected with acrodermatitis enteropathica, suggest that SLC39A4 is centrally involved in the pathogenesis of this condition"
Identifies SLC39A4 as the causative gene from affected families.
💊

Medical Actions

1
Zinc Supplementation
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: zinc sulfate CHEBI:35176 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses zinc sulfate (CHEBI:35176). CHEBI:35176 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Lifelong oral elemental zinc (given as the sulfate, gluconate, or acetate salt) corrects the deficiency and reverses the clinical features, with 1-3 mg/kg/day the most commonly used effective dose. Excess zinc can cause copper deficiency, so copper is monitored.
Show evidence (1 reference)
PMID:40584104 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Among the 174 AE patients who received zinc supplementation at various dosages, 159 (91.4%) demonstrated therapeutic efficacy, with 1-3 mg/kg/day as the most commonly used effective dosage."
Quantifies the high therapeutic response to zinc supplementation and the usual effective dose.
🔬

Biochemical Markers

1
Serum zinc (DECREASED)
Show evidence (1 reference)
PMID:40584104 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"Among 191 patients, 145 (75.9%) had zinc deficiency"
Low blood zinc is the principal laboratory abnormality and was present in a majority of patients.
🔬

Diagnosis

1
Zinc, alkaline phosphatase, and SLC39A4 sequencing
Diagnosis rests on a low plasma or serum zinc (interpreted with care, as infection and low albumin lower it), a supportive low alkaline phosphatase, and biallelic pathogenic SLC39A4 variants on sequencing with deletion/duplication analysis. A prompt response to zinc supports the diagnosis but does not distinguish inherited from acquired deficiency. The main differential is acquired zinc deficiency, especially transient neonatal zinc deficiency from low breast-milk zinc caused by maternal SLC30A2 (ZnT2) variants.
Show evidence (1 reference)
PMID:40584104 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical
"mutations in the SLC39A4 gene were confirmed in 32 of these individuals"
SLC39A4 sequencing confirms the diagnosis in genetically characterized cases.
📊

Prevalence

1
Worldwide
Unknown 0.2 per 100,000 1–9 per 1,000,000
Commonly cited frequency of approximately 1 in 500,000; the measure type is not specified by the source.
Show evidence (1 reference)
PMID:22737083 SUPPORT DIRECT BACKGROUND Human Clinical
"AE occurs at a frequency 1 in 500,000"
States the commonly cited frequency of AE.
🐁

Animal Models

1
Intestine-specific Zip4 knockout mouse
A tamoxifen-inducible, enterocyte-specific Slc39a4 (Zip4) knockout that reproduces the zinc-malabsorption phenotype of AE.
Species
Mouse
Genotype
villin-ErtCre; Slc39a4 (Zip4) floxed, tamoxifen-induced enterocyte knockout
Publication
PMID:22737083
Pathograph links
Systemic Zinc Deficiency recapitulates fidelity: moderate observes: organism Intestinal ZIP4 loss rapidly depletes tissue zinc and causes wasting and death unless excess dietary zinc is supplied.
Limitations: The global Zip4 knockout is embryonic lethal, unlike human AE where residual function is retained, and the intestine-specific model is an acute, complete-loss model that does not reproduce the skin phenotype.
Readouts
Total tissue zinc
Direction: DECREASED
Interpretation: Elemental analysis shows rapid zinc depletion in intestine, liver, and pancreas.
Show evidence (1 reference)
PMID:22737083 SUPPORT PRIMARY RESULT Model Organism
"Elemental analyses of small intestine, liver, and pancreas from Zip4-intestine knockout mice revealed that total zinc was dramatically and rapidly decreased in these organs"
Measures the tissue zinc depletion that defines the model.
Show evidence (1 reference)
PMID:22737083 SUPPORT PRIMARY RESULT Model Organism
"We created a tamoxifen-inducible, enterocyte-specific knockout of this gene in mice which mimics this human disorder."
Establishes the model as informative for the zinc-deficiency mechanism of AE.
Intestinal Epithelial Dysfunction recapitulates fidelity: moderate observes: tissue The knockout reprograms Paneth cells and disrupts the intestinal stem cell niche and mucosal integrity.
Limitations: An acute, complete-loss intestinal model rather than the chronic partial-loss state of most human patients.
Readouts
Paneth cell reprogramming
Direction: ALTERED
Interpretation: Loss of Paneth cell labile zinc with downstream stem-niche disruption.
Show evidence (1 reference)
PMID:22737083 SUPPORT PRIMARY RESULT Model Organism
"An initial effect of the knockout was the reprogramming of Paneth cells, which contribute to the intestinal stem cell niche in the crypts."
Measures the Paneth cell and stem-niche disruption in the model.
Show evidence (1 reference)
PMID:22737083 SUPPORT PRIMARY RESULT Model Organism
"These studies strongly suggest that wasting and lethality in acrodermatitis enteropathica patients reflects the loss-of-function of the intestine zinc transporter ZIP4, which leads to abnormal Paneth cell gene expression, disruption of the intestinal stem cell niche, and diminished function of..."
Links intestinal ZIP4 loss to Paneth cell and stem-niche dysfunction as the basis of the phenotype.
{ }

Source YAML

click to show 
name: Acrodermatitis Enteropathica
creation_date: "2026-10-04T00:00:00Z"
category: Mendelian
synonyms:
- AE
- AEZ
- acrodermatitis enteropathica, zinc deficiency type
- inherited zinc deficiency
- congenital zinc malabsorption
- Danbolt-Closs syndrome
description: >-
  Acrodermatitis enteropathica is an autosomal recessive inborn error of zinc
  absorption caused by biallelic loss-of-function variants in SLC39A4, which
  encodes the apical enterocyte zinc importer ZIP4. Failure to take up dietary
  zinc at the intestinal brush border produces systemic zinc deficiency, which
  impairs the many zinc-dependent metalloenzymes and zinc-finger transcription
  factors on which rapidly renewing epithelia and immune cells depend. The
  result is the classic triad of periorificial and acral dermatitis, alopecia,
  and diarrhea, together with growth retardation, recurrent infection, and a low
  serum alkaline phosphatase. Onset is typically in infancy, often at weaning
  from breast milk, and the disease is progressive and once frequently fatal;
  lifelong oral zinc supplementation produces rapid and durable remission.
notes: >-
  The pooled phenotype, laboratory, and treatment frequencies cited from
  PMID:40584104 come from a 231-patient pediatric review that mixed inherited
  (SLC39A4 confirmed in 32), acquired, and metabolic-disorder AE, so those
  percentages describe AE broadly and are not specific to the inherited
  SLC39A4 disease this entry is scoped to.
disease_term:
  preferred_term: acrodermatitis enteropathica
  term:
    id: MONDO:0008713
    label: acrodermatitis enteropathica
parents:
- inborn error of metal metabolism
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic loss-of-function variants in SLC39A4 are required; heterozygous
    carriers are unaffected.
pathophysiology:
- name: SLC39A4 (ZIP4) Loss of Function
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    Biallelic loss-of-function variants in SLC39A4, which encodes the apical
    zinc transporter ZIP4 of the enterocyte, abolish or reduce its zinc
    transport activity.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: zinc ion transmembrane transporter activity
    modifier: DECREASED
    term:
      id: GO:0005385
      label: zinc ion transmembrane transporter activity
  evidence:
  - reference: PMID:12068297
    reference_title: "Identification of SLC39A4, a gene involved in acrodermatitis enteropathica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: "mutational analysis of eight families affected with acrodermatitis enteropathica, suggest that SLC39A4 is centrally involved in the pathogenesis of this condition"
    explanation: Mutational analysis of affected families identified SLC39A4 as the causative gene.
  - reference: PMID:12032886
    reference_title: "A novel member of a zinc transporter family is defective in acrodermatitis enteropathica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: "The rare inherited condition acrodermatitis enteropathica (AE) results from a defect in the absorption of dietary zinc."
    explanation: Establishes AE as an inherited defect of dietary zinc absorption.
  downstream:
  - target: Impaired Intestinal Zinc Absorption
    causal_link_type: DIRECT
- name: Impaired Intestinal Zinc Absorption
  role: amplifier
  biological_scale: CELLULAR
  description: >-
    ZIP4 sits at the apical brush border of duodenal and jejunal enterocytes and
    is upregulated during zinc deficiency; its loss leaves dietary and
    endogenous luminal zinc unabsorbed.
  cell_types:
  - preferred_term: enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  biological_processes:
  - preferred_term: zinc ion transmembrane transport
    modifier: DECREASED
    term:
      id: GO:0071577
      label: zinc ion transmembrane transport
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  evidence:
  - reference: PMID:12032886
    reference_title: "A novel member of a zinc transporter family is defective in acrodermatitis enteropathica."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: "We show that Slc39A4 is abundantly expressed in mouse enterocytes and that the protein resides in the apical membrane of these cells."
    explanation: Localizes ZIP4 to the apical membrane of enterocytes, the site of dietary zinc uptake.
  - reference: PMID:12032886
    reference_title: "A novel member of a zinc transporter family is defective in acrodermatitis enteropathica."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: "These findings suggest that the hZIP4 transporter is responsible for intestinal absorption of zinc."
    explanation: Identifies ZIP4 as the transporter responsible for intestinal zinc absorption, which its loss abolishes.
  downstream:
  - target: Systemic Zinc Deficiency
    causal_link_type: DIRECT
- name: Systemic Zinc Deficiency
  role: central_effector
  biological_scale: ORGANISM
  description: >-
    Failure of intestinal zinc absorption depletes systemic zinc, lowering
    plasma zinc and the activity of zinc-dependent enzymes and transcription
    factors throughout the body.
  evidence:
  - reference: PMID:40584104
    reference_title: "Acrodermatitis enteropathica in the pediatric population: a literature review of real-world studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "zinc deficiency was observed in 75.9% of the patients."
    explanation: Confirms systemic zinc deficiency as the dominant biochemical finding across pooled AE cases.
  - reference: PMID:22737083
    reference_title: "A mouse model of acrodermatitis enteropathica: loss of intestine zinc transporter ZIP4 (Slc39a4) disrupts the stem cell niche and intestine integrity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: "Elemental analyses of small intestine, liver, and pancreas from Zip4-intestine knockout mice revealed that total zinc was dramatically and rapidly decreased in these organs"
    explanation: Intestinal ZIP4 loss rapidly depletes tissue zinc, the model correlate of systemic zinc deficiency.
  downstream:
  - target: Impaired Zinc-Dependent Enzyme and Zinc-Finger Function
    causal_link_type: DIRECT
  - target: Intestinal Epithelial Dysfunction
    causal_link_type: DIRECT
  - target: Failure to thrive
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Irritability
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Decreased alkaline phosphatase
    causal_link_type: DIRECT
- name: Impaired Zinc-Dependent Enzyme and Zinc-Finger Function
  role: effector
  biological_scale: MOLECULAR
  description: >-
    Zinc is a catalytic or structural cofactor for hundreds of metalloenzymes
    and zinc-finger transcription factors. Its depletion impairs rapidly
    renewing epithelia (skin, hair follicle) and immune cells most acutely,
    producing the cutaneous and immune features of the disease.
  evidence:
  - reference: PMID:12032886
    reference_title: "A novel member of a zinc transporter family is defective in acrodermatitis enteropathica."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: "Zinc is an essential and versatile element, utilized by proteins as diverse as metalloenzymes and transcription factors."
    explanation: Zinc is a cofactor for metalloenzymes and zinc-finger transcription factors, whose function fails as zinc is depleted.
  downstream:
  - target: Periorificial and Acral Dermatitis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Alopecia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Cutaneous Bacterial and Fungal Superinfection
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Intestinal Epithelial Dysfunction
  role: effector
  biological_scale: TISSUE
  description: >-
    Zinc depletion reprograms Paneth cells and disrupts the intestinal stem cell
    niche, degrading the integrity of the absorptive epithelium; in the mouse
    model this drives the wasting phenotype and is the correlate of the diarrhea
    and malabsorption seen in patients.
  cell_types:
  - preferred_term: Paneth cell
    term:
      id: CL:0000510
      label: paneth cell
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  evidence:
  - reference: PMID:22737083
    reference_title: "A mouse model of acrodermatitis enteropathica: loss of intestine zinc transporter ZIP4 (Slc39a4) disrupts the stem cell niche and intestine integrity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: "An initial effect of the knockout was the reprogramming of Paneth cells, which contribute to the intestinal stem cell niche in the crypts."
    explanation: Intestinal ZIP4 loss reprograms Paneth cells and disrupts the stem cell niche.
  downstream:
  - target: Diarrhea
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Cutaneous Bacterial and Fungal Superinfection
  role: consequence
  biological_scale: TISSUE
  description: >-
    The eroded, barrier-disrupted skin lesions are secondarily infected by
    bacteria and fungi, most often Staphylococcus aureus and Candida.
  evidence:
  - reference: PMID:40584104
    reference_title: "Acrodermatitis enteropathica in the pediatric population: a literature review of real-world studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Staphylococcus aureus was the most common pathogen, identified in 18 patients (51.4%), followed by Candida albicans in 8 patients (22.9%)."
    explanation: S. aureus and Candida are the organisms most often cultured from the swab-positive AE skin lesions, indicating secondary cutaneous superinfection.
phenotypes:
- name: Periorificial and Acral Dermatitis
  description: >-
    Erythematous, scaly, vesiculobullous or psoriasiform dermatitis distributed
    acrally (hands, feet, limbs) and around the mouth, anus, and perineum.
  phenotype_term:
    preferred_term: Periorificial and acral dermatitis
    term:
      id: HP:0000964
      label: Eczematoid dermatitis
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:40584104
    reference_title: "Acrodermatitis enteropathica in the pediatric population: a literature review of real-world studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "the lesions were most commonly present on the hands and feet and limbs (187 patients, 83.1%), followed by the perioral area (171 patients, 76.0%) and the perianal area (163 patients, 72.4%)."
    explanation: Quantifies the acral and periorificial distribution of the dermatitis.
- name: Alopecia
  phenotype_term:
    preferred_term: Alopecia
    term:
      id: HP:0001596
      label: Alopecia
  evidence:
  - reference: PMID:40584104
    reference_title: "Acrodermatitis enteropathica in the pediatric population: a literature review of real-world studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Diarrhea was present in 98 patients (46.9%), and alopecia was present in 88 patients (42.1%)."
    explanation: Quantifies alopecia frequency in the pooled pediatric AE cohort.
- name: Diarrhea
  phenotype_term:
    preferred_term: Diarrhea
    term:
      id: HP:0002014
      label: Diarrhea
    temporality: CHRONIC
  evidence:
  - reference: PMID:40584104
    reference_title: "Acrodermatitis enteropathica in the pediatric population: a literature review of real-world studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Diarrhea was present in 98 patients (46.9%), and alopecia was present in 88 patients (42.1%)."
    explanation: Quantifies diarrhea frequency in the pooled pediatric AE cohort.
- name: Failure to thrive
  description: >-
    Growth retardation, more likely with delayed diagnosis.
  phenotype_term:
    preferred_term: Growth retardation
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:40584104
    reference_title: "Acrodermatitis enteropathica in the pediatric population: a literature review of real-world studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Growth retardation was noted in 49 patients (23.4%)"
    explanation: Quantifies growth retardation frequency in the pooled pediatric AE cohort.
- name: Irritability
  phenotype_term:
    preferred_term: Irritability
    term:
      id: HP:0000737
      label: Irritability
  evidence:
  - reference: PMID:40584104
    reference_title: "Acrodermatitis enteropathica in the pediatric population: a literature review of real-world studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "irritability in 62 patients (29.7%)"
    explanation: Quantifies irritability frequency in the pooled pediatric AE cohort.
- name: Fever
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:40584104
    reference_title: "Acrodermatitis enteropathica in the pediatric population: a literature review of real-world studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "fever in 35 patients (16.8%)"
    explanation: Quantifies fever frequency in the pooled pediatric AE cohort.
- name: Decreased alkaline phosphatase
  description: >-
    Low serum alkaline phosphatase, a zinc metalloenzyme, is a supportive
    laboratory marker of zinc deficiency.
  phenotype_term:
    preferred_term: Decreased circulating alkaline phosphatase activity
    term:
      id: HP:0003282
      label: Decreased circulating alkaline phosphatase activity
  evidence:
  - reference: PMID:40584104
    reference_title: "Acrodermatitis enteropathica in the pediatric population: a literature review of real-world studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Among the 87 patients whose ALP levels were recorded, 40 patients (46.0%) exhibited decreased ALP levels"
    explanation: Low alkaline phosphatase, a zinc-dependent enzyme, is recorded in a large share of AE patients.
genetic:
- name: SLC39A4
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: SLC39A4
    term:
      id: hgnc:17129
      label: SLC39A4
  evidence:
  - reference: PMID:12068297
    reference_title: "Identification of SLC39A4, a gene involved in acrodermatitis enteropathica."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: "mutational analysis of eight families affected with acrodermatitis enteropathica, suggest that SLC39A4 is centrally involved in the pathogenesis of this condition"
    explanation: Identifies SLC39A4 as the causative gene from affected families.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.2
  notes: Commonly cited frequency of approximately 1 in 500,000; the measure type is not specified by the source.
  evidence:
  - reference: PMID:22737083
    reference_title: "A mouse model of acrodermatitis enteropathica: loss of intestine zinc transporter ZIP4 (Slc39a4) disrupts the stem cell niche and intestine integrity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: DIRECT
    snippet: "AE occurs at a frequency 1 in 500,000"
    explanation: States the commonly cited frequency of AE.
diagnosis:
- name: Zinc, alkaline phosphatase, and SLC39A4 sequencing
  description: >-
    Diagnosis rests on a low plasma or serum zinc (interpreted with care, as
    infection and low albumin lower it), a supportive low alkaline phosphatase,
    and biallelic pathogenic SLC39A4 variants on sequencing with
    deletion/duplication analysis. A prompt response to zinc supports the
    diagnosis but does not distinguish inherited from acquired deficiency. The
    main differential is acquired zinc deficiency, especially transient neonatal
    zinc deficiency from low breast-milk zinc caused by maternal SLC30A2 (ZnT2)
    variants.
  evidence:
  - reference: PMID:40584104
    reference_title: "Acrodermatitis enteropathica in the pediatric population: a literature review of real-world studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "mutations in the SLC39A4 gene were confirmed in 32 of these individuals"
    explanation: SLC39A4 sequencing confirms the diagnosis in genetically characterized cases.
histopathology:
- name: Epidermal necrolysis
  description: >-
    Skin biopsy is nonspecific but supportive, typically showing necrolysis of
    the upper epidermis; it is not required for diagnosis.
  evidence:
  - reference: PMID:40584104
    reference_title: "Acrodermatitis enteropathica in the pediatric population: a literature review of real-world studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "this examination typically revealed necrolysis in the upper part of the epidermis."
    explanation: Describes the characteristic, though nonspecific, skin histopathology of AE.
biochemical:
- name: Serum zinc
  presence: DECREASED
  biomarker_term:
    preferred_term: serum zinc
    term:
      id: CHEBI:29105
      label: zinc(2+)
  evidence:
  - reference: PMID:40584104
    reference_title: "Acrodermatitis enteropathica in the pediatric population: a literature review of real-world studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Among 191 patients, 145 (75.9%) had zinc deficiency"
    explanation: Low blood zinc is the principal laboratory abnormality and was present in a majority of patients.
treatments:
- name: Zinc Supplementation
  description: >-
    Lifelong oral elemental zinc (given as the sulfate, gluconate, or acetate
    salt) corrects the deficiency and reverses the clinical features, with
    1-3 mg/kg/day the most commonly used effective dose. Excess zinc can cause
    copper deficiency, so copper is monitored.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: zinc sulfate
      term:
        id: CHEBI:35176
        label: zinc sulfate
  evidence:
  - reference: PMID:40584104
    reference_title: "Acrodermatitis enteropathica in the pediatric population: a literature review of real-world studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: "Among the 174 AE patients who received zinc supplementation at various dosages, 159 (91.4%) demonstrated therapeutic efficacy, with 1-3 mg/kg/day as the most commonly used effective dosage."
    explanation: Quantifies the high therapeutic response to zinc supplementation and the usual effective dose.
animal_models:
- name: Intestine-specific Zip4 knockout mouse
  species: Mouse
  genotype: villin-ErtCre; Slc39a4 (Zip4) floxed, tamoxifen-induced enterocyte knockout
  publication: PMID:22737083
  description: >-
    A tamoxifen-inducible, enterocyte-specific Slc39a4 (Zip4) knockout that
    reproduces the zinc-malabsorption phenotype of AE.
  modeled_mechanisms:
  - target: Systemic Zinc Deficiency
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Intestinal ZIP4 loss rapidly depletes tissue zinc and causes wasting and
      death unless excess dietary zinc is supplied.
    limitations: >-
      The global Zip4 knockout is embryonic lethal, unlike human AE where
      residual function is retained, and the intestine-specific model is an
      acute, complete-loss model that does not reproduce the skin phenotype.
    readouts:
    - name: Total tissue zinc
      target: Systemic Zinc Deficiency
      direction: DECREASED
      interpretation: Elemental analysis shows rapid zinc depletion in intestine, liver, and pancreas.
      evidence:
      - reference: PMID:22737083
        reference_title: "A mouse model of acrodermatitis enteropathica: loss of intestine zinc transporter ZIP4 (Slc39a4) disrupts the stem cell niche and intestine integrity."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        snippet: "Elemental analyses of small intestine, liver, and pancreas from Zip4-intestine knockout mice revealed that total zinc was dramatically and rapidly decreased in these organs"
        explanation: Measures the tissue zinc depletion that defines the model.
    evidence:
    - reference: PMID:22737083
      reference_title: "A mouse model of acrodermatitis enteropathica: loss of intestine zinc transporter ZIP4 (Slc39a4) disrupts the stem cell niche and intestine integrity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "We created a tamoxifen-inducible, enterocyte-specific knockout of this gene in mice which mimics this human disorder."
      explanation: Establishes the model as informative for the zinc-deficiency mechanism of AE.
  - target: Intestinal Epithelial Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      The knockout reprograms Paneth cells and disrupts the intestinal stem
      cell niche and mucosal integrity.
    limitations: >-
      An acute, complete-loss intestinal model rather than the chronic
      partial-loss state of most human patients.
    readouts:
    - name: Paneth cell reprogramming
      target: Intestinal Epithelial Dysfunction
      direction: ALTERED
      interpretation: Loss of Paneth cell labile zinc with downstream stem-niche disruption.
      evidence:
      - reference: PMID:22737083
        reference_title: "A mouse model of acrodermatitis enteropathica: loss of intestine zinc transporter ZIP4 (Slc39a4) disrupts the stem cell niche and intestine integrity."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        snippet: "An initial effect of the knockout was the reprogramming of Paneth cells, which contribute to the intestinal stem cell niche in the crypts."
        explanation: Measures the Paneth cell and stem-niche disruption in the model.
    evidence:
    - reference: PMID:22737083
      reference_title: "A mouse model of acrodermatitis enteropathica: loss of intestine zinc transporter ZIP4 (Slc39a4) disrupts the stem cell niche and intestine integrity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "These studies strongly suggest that wasting and lethality in acrodermatitis enteropathica patients reflects the loss-of-function of the intestine zinc transporter ZIP4, which leads to abnormal Paneth cell gene expression, disruption of the intestinal stem cell niche, and diminished function of the intestinal mucosa."
      explanation: Links intestinal ZIP4 loss to Paneth cell and stem-niche dysfunction as the basis of the phenotype.
datasets:
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Acrodermatitis Enteropathica · 2026-10-04T02:33:27Z · View source

New Mendelian entry for acrodermatitis enteropathica (AE), MONDO:0008713, SLC39A4/ZIP4. Curated de novo after confirming no KB entry, no stub-collision, and no competing claim issue (distinct from the matentzn-claimed hereditary folate malabsorption). Deep research via the claude_code provider (web-grounded; report was lead-only with no verbatim quotes and CURIEs flagged, so all snippets were taken from freshly fetched cache). preflight-dr PASS (SLC39A4 x7, OMIM 201100 match). Modeled the transporter-loss causal chain: SLC39A4/ZIP4 loss of function -> impaired apical intestinal zinc absorption -> systemic zinc deficiency -> (impaired zinc-dependent enzyme/zinc-finger function -> dermatitis, alopecia, immune dysfunction; intestinal epithelial/Paneth-cell dysfunction -> diarrhea; growth retardation; low alkaline phosphatase). Seven causally wired phenotypes. Evidence anchored on the two 2002 gene-discovery papers (Kury PMID:12068297 Nat Genet, abstract-only; Wang PMID:12032886 Am J Hum Genet, ZIP4 apical enterocyte localization), the Geiser 2012 PLoS Genet intestine-specific Zip4 knockout mouse (PMID:22737083, two modeled_mechanisms, scale-ALIGNED) and the Frontiers 2025 pediatric real-world review (PMID:40584104) for clinical frequencies and treatment response (91.4% respond, 1-3 mg/kg/day). Autosomal recessive inheritance block, zinc-supplementation treatment (zinc sulfate CHEBI:35176), prevalence ~1/500,000, diagnosis and histopathology. GeneReviews NO_CHAPTER (no chapter exists; StatPearls is never a baseline). The Acta Derm Venereol case report PMID:26351177 cached with no quotable text and is not cited. 25/25 snippets verified; all terms validated; full gate suite green. A pre-PR red-team review (fresh-context subagent) found no blocking defects; its quality fixes were folded in before the first push: the zinc-dependent-function node's snippet was swapped from the clinical-triad sentence to Wang's metalloenzyme/transcription-factor statement (which actually supports the molecular claim), a top-level notes caveat was added that the pooled PMID:40584104 frequencies are not SLC39A4-specific, the over-narrow HOMOZYGOUS zygosity was dropped (AE is often compound heterozygous; biallelic is captured in the inheritance block), and the isolated Irritability phenotype was wired downstream of systemic zinc deficiency.

Claude Code ▸
Acrodermatitis Enteropathica (AE), Research Report
claude-haiku-4-5-20251001, claude-sonnet-5-5 10 citations 2026-10-04T02:19:10.039043

Acrodermatitis Enteropathica (AE), Research Report

Scope and verification status. - I ran three web searches. They confirmed the gene–disease link, the mouse model, and the existence of recent reviews. - Search results returned PMC IDs and URLs, not PMIDs. I did not verify any PMID or snippet against references_cache/. - Every PMC link below is a lead. Before use, run just fetch-reference PMC… or just fetch-reference PMID:… and quote snippets only from the cached text. - Ontology CURIEs marked † were written from memory. Per the CLAUDE.md rule, confirm each with runoak or just validate-terms before binding. - I give no direct quotes, because none were retrieved verbatim.

1. Disease Information

Overview. - AE is an autosomal recessive disorder of intestinal zinc uptake. - It presents as a triad: periorificial and acral dermatitis, alopecia, and diarrhea. - Onset is typically in infancy, often at weaning from breast milk. - Without zinc it is progressive and can be fatal. - Lifelong zinc supplementation produces rapid remission.

Identifiers. - MONDO:0008713 (given in the template). - OMIM #201100.† OMIM is not reachable here, so check the number. - NCBI Gene 55630 (SLC39A4) appeared in the search results. - hgnc:17129† (lowercase prefix per repo convention). - UniProt Q6P5W5† (ZIP4). - Orphanet, ICD-10 (E83.2 "Disorders of zinc metabolism")† and ICD-11 codes were not checked. Use ORPHA: via just fetch-reference for citable rows.

Synonyms. Danbolt–Closs syndrome, hereditary zinc deficiency, congenital zinc malabsorption.

Individual vs aggregate data. This report draws on aggregate disease-level literature and reviews, not EHR data.

Entry-granularity note. Distinguish this entry from acquired or transient zinc deficiency that mimics AE: - breast milk with low zinc, from maternal SLC30A2 (ZnT2) variants causing transient neonatal zinc deficiency; - parenteral nutrition; - malabsorption.

These phenocopies are not AE. Several recent reviews conflate them, so keep the scope explicit.

Key reviews (leads). - 2025 systematic review (190 articles, 231 patients; Frontiers in Nutrition): https://www.frontiersin.org/articles/10.3389/fnut.2025.1590075/full - Pediatric literature review of real-world studies: https://pmc.ncbi.nlm.nih.gov/articles/PMC12202354 - StatPearls chapter: https://www.ncbi.nlm.nih.gov/books/NBK441835/ (point-of-care source; do not treat as a baseline). - Acta Dermato-Venereologica 96(3) (DOI 10.2340/00015555-2240): https://medicaljournals.se/acta/download/10.2340/00015555-2240 - A GeneReviews chapter may not exist. Check with just check-genereviews kb/disorders/Acrodermatitis_Enteropathica.yaml before saying so in notes.

2. Etiology

Causal factor. - Biallelic loss-of-function variants in SLC39A4 (8q24.3) impair the apical enterocyte zinc importer ZIP4. - Wang et al. (2001) mapped the locus by homozygosity mapping. - Küry et al. (2002) and Wang et al. (2002) identified SLC39A4 independently. - Source for the timeline: https://pmc.ncbi.nlm.nih.gov/articles/PMC419995/ and https://pmc.ncbi.nlm.nih.gov/articles/PMC2995241.

Genetic risk and modifiers. - Most cases are monogenic. - A search result noted that standard zinc supplementation can fail in some cases, and that failure is frequent in AE-like presentations tied to metabolic disorders (Frontiers 2025 review above). I did not confirm the mechanism. - Residual-function alleles may influence the age at presentation and the required zinc dose. This is inferred and needs a source.

Environmental risk factors. - Dietary zinc intake interacts with the genotype. - Breast milk contains bioavailable zinc, so symptoms often appear at weaning. Confirm with a primary source. - Infection, diarrhea and increased demand (rapid growth) can unmask or worsen deficiency.

Protective factors. Breast feeding is described as delaying onset. High-dose zinc fully controls the disease.

Gene–environment interaction. Genotype sets the absorptive capacity, and dietary zinc availability and demand determine whether tissue zinc falls below threshold. The mouse intestinal knockout fits this: it is rescued by high dietary zinc (see Section 15).

3. Phenotypes

Frequencies were not retrieved. Mark them "not assessed" unless Orphanet's HPO table is cached (ORPHA: rows are quotable).

Phenotype HPO (verify†) Notes
Periorificial dermatitis (eczematous, vesiculobullous, pustular, psoriasiform) HP:0000988 Skin rash† or a more specific dermatitis term Perioral, perianal, genital
Acral dermatitis as above Hands, feet, elbows, knees
Alopecia HP:0001596† Scalp, eyebrows, eyelashes
Diarrhea HP:0002014† Chronic
Failure to thrive HP:0001508†
Irritability and emotional lability – Often described in zinc deficiency
Paronychia, nail dystrophy –
Conjunctivitis, photophobia –
Immunodeficiency and recurrent infection (e.g., Candida) – Zinc-dependent T-cell function
Low plasma or serum zinc, low alkaline phosphatase lab abnormality Alkaline phosphatase is a zinc metalloenzyme; low activity is a known adjunct marker
  • Onset: infancy, typically from weeks to months of age, often at weaning.
  • Course: progressive without treatment.
  • Severity: variable.
  • Quality of life: not assessed.
  • Do not bind a coarse HPO term (e.g., "Abnormality of the skin") without coarse_binding_basis.

4. Genetic/Molecular Information

  • Gene: SLC39A4, ZIP4, a member of the SLC39 (ZIP) family.
  • Variants: about 30 variants were reported in the search summary. They affect the extracellular zinc-binding domain or one of eight transmembrane domains. Types include missense, nonsense, frameshift and splice-site variants, plus deletions.
  • Functional consequence: loss of function and reduced zinc uptake.
  • ClinVar/ClinGen: not queried. A ClinGen gene–disease validity assertion may exist. Check cache/ for CGGV: records and copy the tier only from the source (see "Gene-Disease Validity Is Copied, Never Assigned").
  • Allele frequencies and founder variants: not retrieved. Founder effects are reported in some populations (e.g., Middle Eastern and consanguineous families) but need a source.
  • Epigenetic and chromosomal abnormalities: none known. Not applicable.

5. Environmental Information

  • Dietary zinc: supply of zinc, and its bioavailability. Phytate-rich diets lower absorption.
  • Lifestyle: not applicable beyond diet.
  • Infectious agents: none causal. Secondary Candida and bacterial superinfection of skin lesions are common.
  • ECTO binding: use exposure to terms only after searching ECTO. An unrecorded search is not a justification for omitting the binding.

6. Mechanism / Pathophysiology

Ordered causal chain. 1. Biallelic SLC39A4 loss-of-function variants lead to absent or defective ZIP4. This is demonstrated by genetics. 2. Loss of ZIP4 at the apical brush border of duodenal and jejunal enterocytes reduces uptake of dietary and endogenous luminal zinc. This is inferred from ZIP4's localization and function; the mouse model supports it. 3. Reduced absorption leads to systemic zinc depletion, with low plasma zinc and low alkaline phosphatase. In mice, zinc falls rapidly in intestine, liver and pancreas. 4. In the gut, zinc loss reprograms Paneth cells and disrupts the intestinal stem cell niche. Sox9 and lysozyme fall, mucin accumulates, and epithelial integrity fails. This is demonstrated in mice (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3380849/). It is a plausible contributor to human diarrhea and malabsorption, but not shown in humans. 5. Zinc is a cofactor for many enzymes and transcription factors (zinc-finger proteins). Rapidly renewing epithelia (skin, hair follicle, gut) and immune cells are most sensitive. This leads to dermatitis, alopecia and immune dysfunction. The skin and hair link is inferred from general zinc biology. 6. Gut barrier damage and diarrhea increase zinc loss and malabsorption of other nutrients. This makes a feed-forward loop and leads to failure to thrive. This step is inferred. 7. Zinc supplementation at pharmacological doses lets passive or ZIP4-independent uptake restore zinc, and the cycle reverses. The exact alternative uptake route is not established here.

Branch. Skin and hair disease (steps 5) and gut disease (steps 4 and 6) arise in parallel from step 3. Immune dysfunction is a third branch from step 5.

Candidate annotations (verify†). - GO: zinc ion transport / zinc ion import across plasma membrane (GO:0071577†); cellular zinc ion homeostasis (GO:0006882†). - CL: enterocyte of small intestine (CL:0002254†); Paneth cell (CL:0000510†); keratinocyte (CL:0000312†). - CHEBI: zinc(2+) (CHEBI:29105†). - Omics, single-cell and CRISPR-screen data for AE: none located. Do not claim any.

7. Anatomical Structures Affected

  • Primary: small intestine (duodenum, jejunum), the site of zinc absorption.
  • Secondary: skin (periorificial, acral), hair and nails, eyes, immune system, and growth overall. Mice also show losses in liver and pancreas.
  • Cells: enterocytes (apical brush border), Paneth cells and intestinal stem cells, keratinocytes, T cells.
  • Subcellular: apical plasma membrane.
  • Lateralization: bilateral and symmetric.
  • UBERON terms: look up (e.g., duodenum, jejunum, skin of body). Do not write them from memory.

8. Temporal Development

  • Onset: infancy, from days to months after birth and often at weaning. Exclusively breast-fed infants may present later.
  • Pattern: subacute to chronic.
  • Progression: progressive and potentially fatal without zinc. With treatment, the course is stable.
  • Duration: lifelong. Treatment is lifelong. A claim that treatment can be stopped later in life should be treated with caution; the search results did not address it.
  • Remission: treatment-induced and rapid. Diarrhea and irritability improve within days, skin lesions within weeks. This is a commonly stated figure and needs a citation.
  • Critical periods: infancy and weaning.

9. Inheritance and Population

  • Inheritance: autosomal recessive (HP:0000007†).
  • Prevalence: approximately 1 per 500,000 live births is the figure usually quoted, with no known ethnic predilection. I did not verify this. Use the Orphanet epidemiology row (ORPHA: cache) and the structured Prevalence slots, with measure_type: BIRTH_PREVALENCE if the source supports it.
  • Penetrance and expressivity: high penetrance, with variable expressivity.
  • Consanguinity: enriches homozygous cases.
  • Carrier frequency, founder effects, anticipation, mosaicism: not retrieved.
  • Sex ratio: reported as equal, unverified.
  • Geographic distribution: worldwide.

10. Diagnostics

  • Laboratory: low plasma or serum zinc (interpret with care; infection and low albumin affect the level). Low alkaline phosphatase is supportive. Check that the sample was collected in a zinc-free tube.
  • Genetic: sequencing of SLC39A4, with deletion/duplication analysis. A panel for skin or immunodeficiency disorders, or exome sequencing, is an alternative. Biallelic pathogenic variants confirm the diagnosis.
  • Histopathology: nonspecific, with pallor of the upper epidermis, keratinocyte necrosis and psoriasiform hyperplasia. A skin biopsy is not required.
  • Differential diagnosis:
  • acquired zinc deficiency;
  • transient neonatal zinc deficiency from low zinc in maternal milk (SLC30A2 variants);
  • cystic fibrosis;
  • biotin or multiple-carboxylase deficiency;
  • organic acidemias;
  • essential fatty acid deficiency;
  • candidiasis;
  • atopic or seborrheic dermatitis;
  • psoriasis;
  • Langerhans cell histiocytosis.
  • Therapeutic trial: a prompt response to zinc supports the diagnosis but does not distinguish AE from acquired deficiency.
  • Screening: there is no newborn screening. Prenatal or carrier testing is possible in known families.

11. Outcome/Prognosis

  • Treated: excellent. Growth and development are normal with adherence.
  • Untreated: the older literature describes high mortality from infection and malnutrition. Obtain a primary citation before using a number.
  • Complications: failure to thrive, infections, and, with delayed treatment, residual growth and developmental effects.
  • Prognostic factors: early diagnosis and adherence. Stopping zinc leads to relapse.
  • QoL: not assessed.

12. Treatment

  • Zinc supplementation: elemental zinc, given as sulfate, gluconate or acetate (zinc acetate has been proposed for better tolerance). The systematic review (Frontiers 2025, linked above) reports that 159 of 174 patients (91.4%) responded. The most common effective dose was 1–3 mg/kg/day of elemental zinc. The optimal dose is not agreed upon.
  • Monitoring: plasma zinc and alkaline phosphatase. Adjust dose for growth, and for increased needs during illness.
  • Refractory cases: zinc supplementation was frequently ineffective in AE-like disease associated with metabolic disorders (same review). Re-examine the diagnosis in these patients.
  • Adverse effects: gastric irritation and nausea. Excess zinc can cause copper deficiency, so monitor copper.
  • Surgical, gene and cell therapy: none. No clinical trials were identified. Search ClinicalTrials.gov before stating that none exist.
  • Preclinical: clioquinol augmented the zinc rescue in the mouse model (https://findanexpert.unimelb.edu.au/scholarlywork/587933-clioquinol-synergistically-augments-rescue-by-zinc-supplementation-in-a-mouse-model-of-acrodermatitis-enteropathica).
  • Historical: diiodohydroxyquin was used before zinc. This is historical background and I did not confirm it.
  • NCIT annotation:
  • treatment_term: NCIT:C15986 (Pharmacotherapy). It is listed in CLAUDE.md.
  • therapeutic_agent: a CHEBI term for zinc sulfate or zinc acetate, verified by lookup.
  • therapeutic_modality: SMALL_MOLECULE.
  • Do not bind Nutritional Support (NCIT:C15433) as BEHAVIORAL.

13. Prevention

  • Primary: none for the genotype. Genetic counseling for families.
  • Secondary: early recognition in infants with a family history, and prompt zinc supplementation.
  • Tertiary: lifelong zinc, with monitoring and extra dosing during illness.
  • Prenatal and preimplantation testing: possible when the familial variants are known.
  • Vaccination: not applicable.

14. Other Species / Natural Disease

  • Lethal trait A46 in cattle (Friesian and Holstein) is a naturally occurring zinc-malabsorption disease resembling AE. It is reported to arise from a different gene (SLC39A4 not implicated in my recollection; the causal gene is DGAT1-unrelated and I could not confirm it). Check OMIA before curating, and do not assert the gene.
  • Bull terrier lethal acrodermatitis is a canine disorder with a similar skin phenotype. Its gene was not confirmed here, so check OMIA.
  • No zoonotic aspects.
  • Mouse Slc39a4 orthologue: confirm the NCBI Gene ID by lookup.

15. Model Organisms

Model Findings Source
Global Slc39a4 (Zip4) knockout mouse Embryonic lethal, with death during early morphogenesis. Dufner-Beattie et al. (see https://pmc.ncbi.nlm.nih.gov/articles/PMC2634863; I did not confirm that this PMC ID is that paper)
Inducible, intestine-specific knockout (villin-ErtCre, floxed Zip4) Wasting and death unless the mice are nursed or fed excess dietary zinc. Zinc falls rapidly in small intestine, liver and pancreas. Paneth cells are reprogrammed (labile zinc lost, then Sox9 and lysozyme fall, mucin accumulates). The stem cell niche and intestinal integrity are disrupted. Geiser et al., PLoS Genet 2012: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3380849/
Same model with clioquinol plus zinc Synergistic rescue. Link in Section 12
Heterozygous Zip4 mice Reported mild effects on embryonic zinc handling. Unverified. –
  • Limitations: the global knockout is not viable, which does not match the human disease, where residual function appears to be retained. The intestine-specific model is an acquired and acute model of complete loss and does not reproduce the skin phenotype in the sources I saw. Record fidelity and limitations accordingly. Use animal_models: with modeled_mechanisms targeting the zinc depletion and Paneth cell nodes. Evidence source for all of this is MODEL_ORGANISM.
  • Other models: zebrafish, Drosophila and cell lines expressing ZIP4 variants exist. I did not search for them.

Gaps and recommended next steps

  1. Fetch and cache the primary references: Wang 2001 and 2002, Küry 2002, Geiser 2012, the 2025 systematic review, and the Orphanet record (ORPHA:). Take all quotes from the cache.
  2. Verify every CURIE marked † and every OMIM, ICD and UniProt identifier.
  3. Check ClinGen (CGGV:), the Bookshelf index (just check-genereviews), and ClinicalTrials.gov.
  4. Resolve open items: epidemiology, untreated mortality, the bovine and canine gene assignments, and the mechanism of zinc-refractory cases.
  5. Add an ECTO search for zinc exposure, recording the exact query and result in notes.

Sources

  • https://pmc.ncbi.nlm.nih.gov/articles/PMC419995/
  • https://pmc.ncbi.nlm.nih.gov/articles/PMC2995241
  • https://pmc.ncbi.nlm.nih.gov/articles/PMC2634863
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3380849/
  • https://pmc.ncbi.nlm.nih.gov/articles/PMC12202354
  • https://www.frontiersin.org/articles/10.3389/fnut.2025.1590075/full
  • https://www.ncbi.nlm.nih.gov/books/NBK441835/
  • https://medicaljournals.se/acta/download/10.2340/00015555-2240
  • https://findanexpert.unimelb.edu.au/scholarlywork/587933-clioquinol-synergistically-augments-rescue-by-zinc-supplementation-in-a-mouse-model-of-acrodermatitis-enteropathica
  • https://www.disgenet.org/browser/0/1/1/C0221036/source__ALL/_b./

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Outcome Count
References checked 7
Resolved 7
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 7
On topic 6
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 14
Resolved 14
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 3
Terms named correctly 1
Terms named as a different term 1
Terms whose name is worth a second look 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0008713 (1 mention) - the report calls it "given in the template"; MONDO calls it acrodermatitis enteropathica

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • NCIT:C15433 (1 mention) - the report calls it "Do not bind Nutritional Support"; NCIT calls it Nutritional Support