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).

• 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

• 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.

All extracted references resolved successfully.

Term Validation

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

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