Thyroid dyshormonogenesis 5

Mendelian MONDO:0010137 Pathograph 7 Show in embeddings browser hereditary disease

Thyroid dyshormonogenesis 5 (TDH5) is autosomal recessive congenital hypothyroidism caused by biallelic pathogenic variants in DUOXA2. Thyroid hormone synthesis requires hydrogen peroxide at the apical membrane of the follicular cell, where thyroid peroxidase uses it to iodinate thyroglobulin. That peroxide is generated by DUOX2, which cannot fold, exit the endoplasmic reticulum or reach the plasma membrane on its own: it depends on the ER-resident maturation factor DUOXA2, encoded head-to-head with DUOX2 and co-expressed with it. Loss of DUOXA2 therefore strands DUOX2 in the ER and starves the apical membrane of peroxide, producing a partial iodine organification defect and goitrous congenital hypothyroidism. TDH5 is mechanistically a chaperone/maturation-factor deficiency rather than a defect in a hormone-synthesizing enzyme itself, and its phenotype tends to be milder than biallelic DUOX2 nonsense disease because the paralogous factor DUOXA1 can partially substitute. Course is variable and frequently transient: on re-evaluation at 2-3 years most DUOXA2-associated congenital hypothyroidism resolves, and severity does not track genotype, so a DUOXA2 result predicts neither permanence nor severity.

Ask OpenScientist

Ask a research question about Thyroid dyshormonogenesis 5. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
6
Pathophys.
4
Phenotypes
3
Gaps
7
Pathograph
1
Genes
2
Medical Actions
9
References
🏷

Classifications

Harrison's Part
ENDOCRINOLOGY METABOLISM GENETICS ENVIRONMENT DISEASE
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
TDH5 requires biallelic DUOXA2 variants. Recessive inheritance was established in the index pedigree by showing that heterozygous carriers had normal thyroid function and normal neonatal TSH screening, and has been reproduced in later cohorts where parents heterozygous for DUOX2 or DUOXA2 variants were euthyroid.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:18042646 SUPPORT Human Clinical
"Pedigree analysis demonstrated recessive inheritance, because heterozygous carriers had normal thyroid function including negative results in neonatal TSH screening."
Direct pedigree demonstration that a single DUOXA2 allele is not sufficient to cause disease.
PMID:33310921 SUPPORT Human Clinical
"Thyroid function tests of most parents with heterozygous state of DUOX2 and DUOXA2 variants were normal."
Independent cohort confirmation that heterozygous carriers are generally euthyroid.
PMID:29650690 SUPPORT Human Clinical
"Autosomal recessive inheritance of CH caused by mutations in DUOX2, DUOXA2, TG and TPO was confirmed by analysis of 22 family pedigrees."
Pedigree analysis across 22 families confirms recessive inheritance for the dyshormonogenesis genes including DUOXA2.
?

Discussions and Knowledge Gaps

3
Does DUOXA1-mediated compensation actually account for the milder phenotype of DUOXA2 disease in patients, or is the severity difference explained by residual allele function and cohort ascertainment?
KNOWLEDGE GAP OPEN tdh5_duoxa1_compensation_untested_in_patients
Attached to
pathophysiology#Partial Compensation by DUOXA1
The compensation model is attractive and mechanistically plausible — DUOXA1 is a paralogue with the same maturation function for DUOX1 — but the evidence is a functional study plus a severity comparison anchored on a single DUOXA2 proband against DUOX2-nonsense patients. That comparison cannot separate paralogue compensation from allele-specific residual function or from the ascertainment route, since the DUOXA2 patient was found by screening a partial-organification-defect cohort, which selects against the most severe presentations. The question matters because DUOXA1 compensation, if real and modifiable, is a therapeutic target in a disease otherwise managed only by hormone replacement.
Proposed experiments
DUOXA1 and DUOX1 expression in DUOXA2-deficient thyroid tissue
exp_tdh5_duoxa1_expression_in_patient_thyroid
Quantify DUOXA1 and DUOX1 transcript and protein in thyroid tissue or thyrocyte models from DUOXA2-deficient patients versus controls, testing whether compensation is accompanied by measurable paralogue upregulation.
Genotype-stratified severity comparison across dyshormonogenesis genes
exp_tdh5_genotype_severity_cohort
Assemble reported DUOXA2, DUOX2 and TPO patients and compare severity measures ascertained the same way, to test whether the DUOXA2 milder-course claim survives control for ascertainment.
Why does DUOXA2 genotype fail to predict whether congenital hypothyroidism is transient or permanent, or how severe it is?
KNOWLEDGE GAP OPEN tdh5_no_genotype_phenotype_correlation
Attached to
pathophysiology#DUOXA2 Loss of Function pathophysiology#Goitrous Congenital Hypothyroidism
The absence of a correlation is stated directly rather than merely unobserved, which makes it a finding rather than a gap in ascertainment. The same homozygous p.Tyr246Ter genotype produced transient disease in one child and mild permanent disease in another; monoallelic carriers ranged from typical permanent CH to transient. Several explanations are open and none tested: variable DUOXA1 compensation between individuals, dietary iodine sufficiency modifying how much residual peroxide output suffices, oligogenic contributions from the other dyshormonogenesis genes (digenic and triallelic DUOX2/DUOXA2 combinations are common in cohort series), or a developmental window after which the demand for hormone synthesis falls. Distinguishing them matters because it determines whether a trial off levothyroxine can be predicted rather than simply attempted. Monoallelic reports are recorded here rather than as phenotypes, deliberately. A dizygotic twin pair (PMID:27349010) is often cited to illustrate genotype-independence, and it cannot do that work for this entry: the twins each carried a SINGLE heterozygous variant, and in different genes - the boy a DUOXA2 p.Tyr246Ter, the girl a DUOX2 p.Arg885Gln. So the pair says nothing about DUOXA2 genotype-phenotype independence, and the boy's thyroid imaging cannot be curated as a TDH5 phenotype without contradicting this entry's own `inheritance` evidence that heterozygous carriers are euthyroid with negative neonatal screening. The wider question of why monoallelic DUOXA2 carriers are reported with CH at all - whether through an undetected second hit, an oligogenic contribution, or ascertainment - is part of this gap, not a settled phenotype.
Proposed experiments
Genotype-stratified re-evaluation cohort with iodine status
exp_tdh5_transient_vs_permanent_cohort
Reassess DUOXA2 patients off treatment at a uniform age while recording full dyshormonogenesis-gene genotype, DUOXA1 variants and iodine status, to test whether apparent genotype-independence survives control for oligogenic burden and environmental iodine.
Residual peroxide output as a predictor of course
exp_tdh5_residual_h2o2_vs_outcome
Measure H2O2 generation for each reported DUOXA2 allele in a common reconstitution system and test whether residual output, rather than allele identity, correlates with transient versus permanent disease.
Should the gene-anchored thyroid dyshormonogenesis entities be curated as standalone entries, as here, or folded into the Congenital_Hypothyroidism entry's Dyshormonogenesis subtype?
KNOWLEDGE GAP OPEN tdh5_boundary_with_congenital_hypothyroidism_entry
Attached to
pathophysiology#DUOXA2 Loss of Function
This is a curation-boundary question, recorded so the decision is auditable rather than implicit. Congenital_Hypothyroidism already carries a Dyshormonogenesis has_subtypes entry bound to MONDO:0010132, which is the direct MONDO parent of this entry's MONDO:0010137. That subtype names DUOXA2 in prose but carries no per-gene mechanism, and a lumped subtype cannot represent a maturation-factor defect distinctly from a defect in a hormone-synthesizing enzyme — the distinction that makes TDH5 mechanistically interesting. A standalone entry was therefore curated. The repository has precedent both ways (Central_Congenital_Hypothyroidism is standalone alongside a Central subtype), and an active reconciliation of exactly this pattern is under way for Loeys-Dietz, so the convention may change.
⚙

Pathophysiology

6
DUOXA2 Loss of Function
Biallelic DUOXA2 variants abolish or severely reduce the function of the dual oxidase maturation factor 2 protein. The index allele, homozygous p.Tyr246Ter, truncates the protein before transmembrane helix 5 and the C-terminal cytoplasmic domain, and the truncated product was shown to be inactive when tested for its ability to reconstitute DUOX2.
Thyroid follicular cell CL:0002258 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Thyroid follicular cell (CL:0002258). CL:0002258 is a cell type from the Cell Ontology.
DUOXA2 hgnc:32698 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves DUOXA2 (hgnc:32698). hgnc:32698 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
The index genotype is a homozygous germline nonsense allele in a non-consanguineous Chinese family. Loss of function was demonstrated functionally, not merely predicted from the truncation.
endoplasmic reticulum membrane GO:0005789 Gene Ontology (GO) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in endoplasmic reticulum membrane (GO:0005789). GO:0005789 is an anatomical location from the Gene Ontology.
Downstream
Failure of DUOX2 Maturation and Apical Trafficking
Show evidence (3 references)
PMID:18042646 SUPPORT Human Clinical
"One Chinese patient born to nonconsanguineous parents was homozygous for a nonsense mutation (p.Y246X), producing a truncated DUOXA2 protein lacking transmembrane helix 5 and the C-terminal cytoplasmic domain."
Identifies the index allele and the protein domains it removes.
PMID:18042646 SUPPORT In Vitro
"The mutant protein was inactive in reconstituting DUOX2 in vitro."
Functional demonstration that the patient allele is loss-of-function for the protein's defining activity.
PMID:25675383 SUPPORT In Vitro
"In vitro experiments showed that the mutant I26M protein expression levels did not differ from those of wild-type DUOXA2 but that mutant I26M resulted in a complete deficiency of H2O2 generation."
Shows the lesion can be purely functional: a DUOXA2 allele may be expressed at normal levels and still abolish peroxide generation, so protein abundance is not a valid readout of pathogenicity here.
Failure of DUOX2 Maturation and Apical Trafficking
DUOX2 cannot mature or leave the endoplasmic reticulum unaided. DUOXA2 is an ER-resident transmembrane protein whose co-expression permits ER-to-Golgi transition, maturation and translocation of functional DUOX2 to the plasma membrane; this was the activity by which DUOXA2 was originally identified, resolving the long-standing failure to reconstitute a functional DUOX-based NADPH oxidase at the cell surface. Without DUOXA2, DUOX2 is retained in the ER and never reaches its site of action.
Thyroid follicular cell CL:0002258 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Thyroid follicular cell (CL:0002258). CL:0002258 is a cell type from the Cell Ontology.
endoplasmic reticulum to Golgi vesicle-mediated transport GO:0006888 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased endoplasmic reticulum to Golgi vesicle-mediated transport (GO:0006888). GO:0006888 is a biological process from the Gene Ontology. ↓ DECREASED
endoplasmic reticulum membrane GO:0005789 Gene Ontology (GO) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in endoplasmic reticulum membrane (GO:0005789). GO:0005789 is an anatomical location from the Gene Ontology.
Downstream
Deficient Apical Hydrogen Peroxide Generation
Show evidence (2 references)
PMID:16651268 SUPPORT In Vitro
"We demonstrate that co-expression of DUOXA2, an ER-resident transmembrane protein, allows ER-to-Golgi transition, maturation, and translocation to the plasma membrane of functional DUOX2 in a heterologous system."
Establishes the maturation and trafficking function of DUOXA2 that is lost in TDH5.
PMID:16651268 SUPPORT In Vitro
"It has been proposed that DUOX retention in the endoplasmatic reticulum (ER) of heterologous systems is due to the lack of an unidentified component required for functional maturation of the enzyme."
States the ER-retention phenotype that DUOXA2 deficiency reproduces.
Deficient Apical Hydrogen Peroxide Generation
DUOX2 is the catalytic core of the thyroid hydrogen peroxide generator, an NADPH:O2 oxidoreductase flavoprotein that supplies peroxide at the apical membrane of the follicular cell. With DUOX2 stranded in the ER, apical peroxide generation falls and the oxidant required for the iodination reaction is no longer available in the follicular lumen.
Thyroid follicular cell CL:0002258 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Thyroid follicular cell (CL:0002258). CL:0002258 is a cell type from the Cell Ontology.
Downstream
Partial Iodine Organification Defect
Show evidence (2 references)
PMID:16651268 SUPPORT In Vitro
"Dual oxidase 2 (DUOX2), an NADPH:O(2) oxidoreductase flavoprotein, is a component of the thyroid H(2)O(2) generator crucial for hormone synthesis at the apical membrane."
Identifies DUOX2 as the apical peroxide-generating enzyme whose delivery DUOXA2 controls.
PMID:18042646 SUPPORT Other
"Dual oxidase 2 (DUOX2) is the catalytic core of the H(2)O(2) generator crucial for the iodination of thyroglobulin in thyroid hormone synthesis."
Links apical peroxide generation directly to thyroglobulin iodination, the next step in the chain.
Partial Iodine Organification Defect
Thyroid peroxidase requires hydrogen peroxide to organify iodide onto thyroglobulin tyrosyl residues. Peroxide limitation therefore presents as an organification defect, demonstrable on perchlorate discharge testing. It is characteristically partial rather than total — the index cohort was assembled specifically from patients with a partial iodine organification defect — which is consistent with residual peroxide supply from DUOXA1-supported DUOX1.
thyroid hormone generation GO:0006590 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased thyroid hormone generation (GO:0006590). GO:0006590 is a biological process from the Gene Ontology. ↓ DECREASED
thyroid gland UBERON:0002046 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in thyroid gland (UBERON:0002046). UBERON:0002046 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Goitrous Congenital Hypothyroidism
Show evidence (2 references)
PMID:18042646 SUPPORT Human Clinical
"Subjects included 11 CH patients with partial iodine organification defect but negative for other known genetic causes of partial iodine organification defect."
Establishes the partial organification defect as the biochemical phenotype in which DUOXA2 disease was found.
PMID:25231445 SUPPORT Other
"Mutations in 7 genes are well described causing iodine transport defect (SLC5A5), iodine organification defect (TPO, DUOX2, DUOXA2, SLC26A4), thyroglobulin (TG) synthesis or transport defect or iodotyrosine deiodinase (IYD/DEHAL1) deficiency."
Classifies DUOXA2 disease specifically as an iodine organification defect.
Goitrous Congenital Hypothyroidism
Reduced hormone output releases the pituitary from negative feedback; the resulting TSH drive both raises TSH on newborn screening and produces goitrous enlargement of a structurally normal, eutopic gland. Reported DUOXA2 disease spans transient and permanent congenital hypothyroidism, with severity variable and generally milder than biallelic DUOX2 nonsense disease.
thyroid hormone metabolic process GO:0042403 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased thyroid hormone metabolic process (GO:0042403). GO:0042403 is a biological process from the Gene Ontology. ↓ DECREASED
Show evidence (3 references)
PMID:18042646 SUPPORT Human Clinical
"We report the first mutation in DUOXA2, identified in a patient with CH and dyshormonogenic goiter."
Documents the goitrous congenital hypothyroidism phenotype in the index patient.
PMID:18042646 SUPPORT Human Clinical
"Biallelic DUOXA2 mutations are a novel genetic event in permanent CH."
The index report's classification as permanent CH; marked PARTIAL because a later series with re-evaluation at 2-3 years found most DUOXA2-associated CH to be transient.
PMID:28100324 SUPPORT Human Clinical
"DUOXA2 gene mutation is a common molecular pathogenic basis for CH children with suspected thyroid dyshormonogenesis in Guangzhou, and most of them are manifested as transient CH."
Establishes that most DUOXA2-associated congenital hypothyroidism in this series was transient, correcting the permanent-only reading. The series majority is carried by monoallelic heterozygotes, so it bounds the permanent-only claim rather than fixing a rate for biallelic disease.
Partial Compensation by DUOXA1
DUOXA2 has a paralogue, DUOXA1, arranged head-to-head with DUOX1 in the same way DUOXA2 is with DUOX2. Functional studies indicate DUOXA1 can partially substitute for missing DUOXA2, which is the proposed reason the index DUOXA2 patient had a milder phenotype than patients carrying biallelic DUOX2 nonsense alleles. This node is a severity modifier rather than a step in the causal chain, and the supporting evidence is in-vitro plus a single-patient clinical correlation, so it is curated as PROVISIONAL.
DUOXA1 hgnc:26507 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves DUOXA1 (hgnc:26507). hgnc:26507 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Partial Iodine Organification Defect
Show evidence (1 reference)
PMID:18042646 SUPPORT In Vitro
"Functional studies suggest that the DUOXA2 paralog (DUOXA1) can partially compensate DUOXA2 deficiency, consistent with the proband having a milder CH phenotype than patients with biallelic DUOX2 nonsense mutations."
The sole evidence for the compensation model and for its proposed clinical consequence, both carried here at PROVISIONAL confidence.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Thyroid dyshormonogenesis 5 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

4
Endocrine 1
Dyshormonogenic Goiter HP:0000853 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Goiter (HP:0000853). HP:0000853 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18042646 SUPPORT Human Clinical
"We report the first mutation in DUOXA2, identified in a patient with CH and dyshormonogenic goiter."
Documents dyshormonogenic goiter in the index patient.
Other 3
Congenital Hypothyroidism HP:0000851 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital hypothyroidism (HP:0000851). HP:0000851 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18042646 SUPPORT Human Clinical
"Biallelic DUOXA2 mutations are a novel genetic event in permanent CH."
The index report's classification as permanent CH; marked PARTIAL because a later series with re-evaluation at 2-3 years found most DUOXA2-associated CH to be transient. Graded the same way as the identical quote on the pathophysiology node, so one sentence is not scored two ways in one file.
Transient Congenital Hypothyroidism HP:0000851 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital hypothyroidism (HP:0000851), qualified as temporality transient. HP:0000851 is a phenotype from the Human Phenotype Ontology.
Temporal: TRANSIENT
Show evidence (1 reference)
PMID:28100324 SUPPORT Human Clinical
"DUOXA2 gene mutation is a common molecular pathogenic basis for CH children with suspected thyroid dyshormonogenesis in Guangzhou, and most of them are manifested as transient CH."
Establishes transient CH as the predominant DUOXA2 outcome on re-evaluation.
Variable Severity Independent of Genotype Congenital hypothyroidism HP:0000851 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital hypothyroidism (HP:0000851). HP:0000851 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28100324 SUPPORT Human Clinical
"There is no association between DUOXA2 genotypes and phenotypes."
Direct statement that genotype does not predict phenotype in DUOXA2 disease.
🧬

Genetic Associations

1
DUOXA2
Gene: DUOXA2 hgnc:32698 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DUOXA2 (hgnc:32698). hgnc:32698 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:18042646 SUPPORT Human Clinical
"One heterozygous carrier of Y246X was identified in unrelated Chinese controls (n = 92) but not in Caucasian or Japanese controls, indicating that homozygosity for Y246X could be a frequent cause of CH in Chinese."
Supports population enrichment of the index allele in Chinese populations.
PMID:33310921 SUPPORT Human Clinical
"Of 45 variants, 7 genes were involved (DUOX2, DUOXA2, TG, TPO, SLC5A5, PAX8 and TSHR)."
Confirms DUOXA2 recurs as a causative gene in an independent congenital hypothyroidism cohort.
💊

Medical Actions

2
Levothyroxine Replacement
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: levothyroxine NCIT:C62080 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses levothyroxine (NCIT:C62080). NCIT:C62080 is a therapeutic agent from the NCI Thesaurus.
Thyroid hormone replacement is the standard treatment for permanent congenital hypothyroidism from any dyshormonogenesis gene. It corrects the hormone deficit; it does not address the DUOXA2 maturation defect.
Show evidence (1 reference)
PMID:21543982 SUPPORT Other
"A definite molecular diagnosis of thyroid dyshormonogenesis allows genetic counseling and has prognostic value in differentiating transient from permanent congenital hypothyroidism and predicting the response of patients to iodine supplementation as adjunct or alternative treatment to L-T4 replacement."
Names L-T4 replacement as the reference treatment against which iodine supplementation is positioned.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Recessive inheritance carries a 25% recurrence risk for siblings, and current consensus guidance recommends counselling for every family with an affected child. Counselling also identifies asymptomatic carriers.
Show evidence (1 reference)
PMID:25231445 SUPPORT Other
"The new consensus guidelines for CH recommend genetic counseling for each family with an affected child."
States the guideline recommendation for genetic counselling in congenital hypothyroidism.
🔬

Biochemical Markers

1
Partial Iodine Organification Defect on Perchlorate Discharge (PRESENT)
Show evidence (1 reference)
PMID:18042646 SUPPORT Human Clinical
"Subjects included 11 CH patients with partial iodine organification defect but negative for other known genetic causes of partial iodine organification defect."
Defines the biochemical selection criterion that identified DUOXA2 disease.
🔬

Diagnosis

2
Newborn TSH Screening
TDH5 is ascertained through routine neonatal congenital hypothyroidism screening. Screening does not distinguish dyshormonogenesis from dysgenesis; that requires imaging of a eutopic gland plus, ideally, molecular diagnosis.
Show evidence (1 reference)
PMID:18042646 SUPPORT Human Clinical
"Pedigree analysis demonstrated recessive inheritance, because heterozygous carriers had normal thyroid function including negative results in neonatal TSH screening."
Establishes neonatal TSH screening as the ascertainment route and shows carriers screen negative.
Molecular Diagnosis of the Dyshormonogenesis Gene
Identifying the specific gene has prognostic value beyond confirming the diagnosis: it distinguishes transient from permanent congenital hypothyroidism, informs genetic counselling, and predicts whether iodine supplementation may serve as an adjunct or alternative to levothyroxine.
Show evidence (1 reference)
PMID:21543982 SUPPORT Other
"A definite molecular diagnosis of thyroid dyshormonogenesis allows genetic counseling and has prognostic value in differentiating transient from permanent congenital hypothyroidism and predicting the response of patients to iodine supplementation as adjunct or alternative treatment to L-T4 replacement."
States the specific clinical value of establishing the molecular diagnosis.
{ }

Source YAML

click to show 
name: Thyroid dyshormonogenesis 5
creation_date: "2026-08-22T00:00:00Z"
description: >-
  Thyroid dyshormonogenesis 5 (TDH5) is autosomal recessive congenital
  hypothyroidism caused by biallelic pathogenic variants in DUOXA2. Thyroid
  hormone synthesis requires hydrogen peroxide at the apical membrane of the
  follicular cell, where thyroid peroxidase uses it to iodinate thyroglobulin.
  That peroxide is generated by DUOX2, which cannot fold, exit the endoplasmic
  reticulum or reach the plasma membrane on its own: it depends on the
  ER-resident maturation factor DUOXA2, encoded head-to-head with DUOX2 and
  co-expressed with it. Loss of DUOXA2 therefore strands DUOX2 in the ER and
  starves the apical membrane of peroxide, producing a partial iodine
  organification defect and goitrous congenital hypothyroidism. TDH5 is
  mechanistically a chaperone/maturation-factor deficiency rather than a defect
  in a hormone-synthesizing enzyme itself, and its phenotype tends to be milder
  than biallelic DUOX2 nonsense disease because the paralogous factor DUOXA1
  can partially substitute. Course is variable and frequently transient: on
  re-evaluation at 2-3 years most DUOXA2-associated congenital hypothyroidism
  resolves, and severity does not track genotype, so a DUOXA2 result predicts
  neither permanence nor severity.
category: Mendelian
parents:
- hereditary disease
synonyms:
- TDH5
- DUOXA2 deficiency
- congenital hypothyroidism due to DUOXA2 deficiency
- thyroid dyshormonogenesis type 5
- dual oxidase maturation factor 2 deficiency
disease_term:
  preferred_term: Thyroid dyshormonogenesis 5
  term:
    id: MONDO:0010137
    label: thyroid dyshormonogenesis 5
classifications:
  harrisons_chapter:
  - classification_value: ENDOCRINOLOGY_METABOLISM
    evidence:
    - reference: PMID:21543982
      reference_title: "Genetic causes of congenital hypothyroidism due to dyshormonogenesis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        These include defects in iodide trapping (NIS), in the facilitated iodide
        efflux across the apical membrane (PDS), the organification of iodide
        within the follicular lumen (thyroid peroxidase, DUOX2, DUOXA2), the
        substrate for thyroid hormone synthesis (thyroglobulin) and the ability to
        recover and retain intrathyroidal iodine (iodotyrosine deiodinase).
      explanation: >-
        Places DUOXA2 defects within the thyroid hormone biosynthesis disorders,
        an endocrine disease class.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:18042646
      reference_title: "Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Biallelic DUOXA2 mutations are a novel genetic event in permanent CH.
      explanation: >-
        Establishes TDH5 as a single-gene recessive Mendelian disorder.
references:
- reference: PMID:16651268
  title: "Identification of the maturation factor for dual oxidase. Evolution of an eukaryotic operon equivalent."
- reference: PMID:18042646
  title: "Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism."
- reference: PMID:21543982
  title: "Genetic causes of congenital hypothyroidism due to dyshormonogenesis."
- reference: PMID:25231445
  title: "Clinical genetics of congenital hypothyroidism."
- reference: PMID:33310921
  title: "DUOX2 variants are a frequent cause of congenital primary hypothyroidism in Thai patients."
- reference: PMID:29650690
  title: "The genetic characteristics of congenital hypothyroidism in China by comprehensive screening of 21 candidate genes."
- reference: PMID:28100324
  title: "[Characteristics of DUOXA2 gene mutation in children with congenital hypothyroidism]."
- reference: PMID:25675383
  title: "A novel missense mutation (I26M) in DUOXA2 causing congenital goiter hypothyroidism impairs NADPH oxidase activity but not protein expression."
- reference: PMID:27349010
  title: "Heterozygous Mutations of the DUOXA2 and DUOX2 Genes in Dizygotic Twins with Congenital Hypothyroidism."
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    TDH5 requires biallelic DUOXA2 variants. Recessive inheritance was
    established in the index pedigree by showing that heterozygous carriers had
    normal thyroid function and normal neonatal TSH screening, and has been
    reproduced in later cohorts where parents heterozygous for DUOX2 or DUOXA2
    variants were euthyroid.
  evidence:
  - reference: PMID:18042646
    reference_title: "Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pedigree analysis demonstrated recessive inheritance, because heterozygous
      carriers had normal thyroid function including negative results in neonatal
      TSH screening.
    explanation: >-
      Direct pedigree demonstration that a single DUOXA2 allele is not sufficient
      to cause disease.
  - reference: PMID:33310921
    reference_title: "DUOX2 variants are a frequent cause of congenital primary hypothyroidism in Thai patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thyroid function tests of most parents with heterozygous state of DUOX2 and
      DUOXA2 variants were normal.
    explanation: >-
      Independent cohort confirmation that heterozygous carriers are generally
      euthyroid.
  - reference: PMID:29650690
    reference_title: "The genetic characteristics of congenital hypothyroidism in China by comprehensive screening of 21 candidate genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autosomal recessive inheritance of CH caused by mutations in DUOX2,
      DUOXA2, TG and TPO was confirmed by analysis of 22 family pedigrees.
    explanation: >-
      Pedigree analysis across 22 families confirms recessive inheritance for the
      dyshormonogenesis genes including DUOXA2.
pathophysiology:
- name: DUOXA2 Loss of Function
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: ESTABLISHED
  description: >-
    Biallelic DUOXA2 variants abolish or severely reduce the function of the dual
    oxidase maturation factor 2 protein. The index allele, homozygous p.Tyr246Ter,
    truncates the protein before transmembrane helix 5 and the C-terminal
    cytoplasmic domain, and the truncated product was shown to be inactive when
    tested for its ability to reconstitute DUOX2.
  genes:
  - preferred_term: DUOXA2
    term:
      id: hgnc:32698
      label: DUOXA2
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    description: >-
      The index genotype is a homozygous germline nonsense allele in a
      non-consanguineous Chinese family. Loss of function was demonstrated
      functionally, not merely predicted from the truncation.
  locations:
  - preferred_term: endoplasmic reticulum membrane
    term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
  cell_types:
  - preferred_term: Thyroid follicular cell
    term:
      id: CL:0002258
      label: thyroid follicular cell
  evidence:
  - reference: PMID:18042646
    reference_title: "Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One Chinese patient born to nonconsanguineous parents was homozygous for a
      nonsense mutation (p.Y246X), producing a truncated DUOXA2 protein lacking
      transmembrane helix 5 and the C-terminal cytoplasmic domain.
    explanation: >-
      Identifies the index allele and the protein domains it removes.
  - reference: PMID:18042646
    reference_title: "Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The mutant protein was inactive in reconstituting DUOX2 in vitro.
    explanation: >-
      Functional demonstration that the patient allele is loss-of-function for the
      protein's defining activity.
  - reference: PMID:25675383
    reference_title: "A novel missense mutation (I26M) in DUOXA2 causing congenital goiter hypothyroidism impairs NADPH oxidase activity but not protein expression."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro experiments showed that the mutant I26M protein expression levels
      did not differ from those of wild-type DUOXA2 but that mutant I26M resulted
      in a complete deficiency of H2O2 generation.
    explanation: >-
      Shows the lesion can be purely functional: a DUOXA2 allele may be expressed
      at normal levels and still abolish peroxide generation, so protein abundance
      is not a valid readout of pathogenicity here.
  downstream:
  - target: Failure of DUOX2 Maturation and Apical Trafficking
- name: Failure of DUOX2 Maturation and Apical Trafficking
  biological_scale: MOLECULAR
  role: central_effector
  mechanism_confidence: ESTABLISHED
  description: >-
    DUOX2 cannot mature or leave the endoplasmic reticulum unaided. DUOXA2 is an
    ER-resident transmembrane protein whose co-expression permits ER-to-Golgi
    transition, maturation and translocation of functional DUOX2 to the plasma
    membrane; this was the activity by which DUOXA2 was originally identified,
    resolving the long-standing failure to reconstitute a functional DUOX-based
    NADPH oxidase at the cell surface. Without DUOXA2, DUOX2 is retained in the
    ER and never reaches its site of action.
  biological_processes:
  - preferred_term: endoplasmic reticulum to Golgi vesicle-mediated transport
    modifier: DECREASED
    term:
      id: GO:0006888
      label: endoplasmic reticulum to Golgi vesicle-mediated transport
  locations:
  - preferred_term: endoplasmic reticulum membrane
    term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
  cell_types:
  - preferred_term: Thyroid follicular cell
    term:
      id: CL:0002258
      label: thyroid follicular cell
  evidence:
  - reference: PMID:16651268
    reference_title: "Identification of the maturation factor for dual oxidase. Evolution of an eukaryotic operon equivalent."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We demonstrate that co-expression of DUOXA2, an ER-resident transmembrane
      protein, allows ER-to-Golgi transition, maturation, and translocation to the
      plasma membrane of functional DUOX2 in a heterologous system.
    explanation: >-
      Establishes the maturation and trafficking function of DUOXA2 that is lost
      in TDH5.
  - reference: PMID:16651268
    reference_title: "Identification of the maturation factor for dual oxidase. Evolution of an eukaryotic operon equivalent."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      It has been proposed that DUOX retention in the endoplasmatic reticulum (ER)
      of heterologous systems is due to the lack of an unidentified component
      required for functional maturation of the enzyme.
    explanation: >-
      States the ER-retention phenotype that DUOXA2 deficiency reproduces.
  downstream:
  - target: Deficient Apical Hydrogen Peroxide Generation
- name: Deficient Apical Hydrogen Peroxide Generation
  biological_scale: CELLULAR
  role: central_effector
  mechanism_confidence: ESTABLISHED
  description: >-
    DUOX2 is the catalytic core of the thyroid hydrogen peroxide generator, an
    NADPH:O2 oxidoreductase flavoprotein that supplies peroxide at the apical
    membrane of the follicular cell. With DUOX2 stranded in the ER, apical
    peroxide generation falls and the oxidant required for the iodination
    reaction is no longer available in the follicular lumen.
  cell_types:
  - preferred_term: Thyroid follicular cell
    term:
      id: CL:0002258
      label: thyroid follicular cell
  evidence:
  - reference: PMID:16651268
    reference_title: "Identification of the maturation factor for dual oxidase. Evolution of an eukaryotic operon equivalent."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Dual oxidase 2 (DUOX2), an NADPH:O(2) oxidoreductase flavoprotein, is a
      component of the thyroid H(2)O(2) generator crucial for hormone synthesis at
      the apical membrane.
    explanation: >-
      Identifies DUOX2 as the apical peroxide-generating enzyme whose delivery
      DUOXA2 controls.
  - reference: PMID:18042646
    reference_title: "Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Dual oxidase 2 (DUOX2) is the catalytic core of the H(2)O(2) generator
      crucial for the iodination of thyroglobulin in thyroid hormone synthesis.
    explanation: >-
      Links apical peroxide generation directly to thyroglobulin iodination, the
      next step in the chain.
  downstream:
  - target: Partial Iodine Organification Defect
- name: Partial Iodine Organification Defect
  biological_scale: TISSUE
  role: central_effector
  mechanism_confidence: ESTABLISHED
  description: >-
    Thyroid peroxidase requires hydrogen peroxide to organify iodide onto
    thyroglobulin tyrosyl residues. Peroxide limitation therefore presents as an
    organification defect, demonstrable on perchlorate discharge testing. It is
    characteristically partial rather than total — the index cohort was assembled
    specifically from patients with a partial iodine organification defect — which
    is consistent with residual peroxide supply from DUOXA1-supported DUOX1.
  biological_processes:
  - preferred_term: thyroid hormone generation
    modifier: DECREASED
    term:
      id: GO:0006590
      label: thyroid hormone generation
  locations:
  - preferred_term: thyroid gland
    term:
      id: UBERON:0002046
      label: thyroid gland
  evidence:
  - reference: PMID:18042646
    reference_title: "Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Subjects included 11 CH patients with partial iodine organification defect
      but negative for other known genetic causes of partial iodine organification
      defect.
    explanation: >-
      Establishes the partial organification defect as the biochemical phenotype
      in which DUOXA2 disease was found.
  - reference: PMID:25231445
    reference_title: "Clinical genetics of congenital hypothyroidism."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mutations in 7 genes are well described causing iodine transport defect
      (SLC5A5), iodine organification defect (TPO, DUOX2, DUOXA2, SLC26A4),
      thyroglobulin (TG) synthesis or transport defect or iodotyrosine deiodinase
      (IYD/DEHAL1) deficiency.
    explanation: >-
      Classifies DUOXA2 disease specifically as an iodine organification defect.
  downstream:
  - target: Goitrous Congenital Hypothyroidism
- name: Goitrous Congenital Hypothyroidism
  biological_scale: ORGANISM
  role: consequence
  mechanism_confidence: ESTABLISHED
  description: >-
    Reduced hormone output releases the pituitary from negative feedback; the
    resulting TSH drive both raises TSH on newborn screening and produces
    goitrous enlargement of a structurally normal, eutopic gland. Reported
    DUOXA2 disease spans transient and permanent congenital hypothyroidism,
    with severity variable and generally milder than biallelic DUOX2
    nonsense disease.
  biological_processes:
  - preferred_term: thyroid hormone metabolic process
    modifier: DECREASED
    term:
      id: GO:0042403
      label: thyroid hormone metabolic process
  evidence:
  - reference: PMID:18042646
    reference_title: "Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report the first mutation in DUOXA2, identified in a patient with CH and
      dyshormonogenic goiter.
    explanation: >-
      Documents the goitrous congenital hypothyroidism phenotype in the index
      patient.
  - reference: PMID:18042646
    reference_title: "Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic DUOXA2 mutations are a novel genetic event in permanent CH.
    explanation: >-
      The index report's classification as permanent CH; marked PARTIAL because a
      later series with re-evaluation at 2-3 years found most DUOXA2-associated CH
      to be transient.
  - reference: PMID:28100324
    reference_title: "[Characteristics of DUOXA2 gene mutation in children with congenital hypothyroidism]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DUOXA2 gene mutation is a common molecular pathogenic basis for CH children
      with suspected thyroid dyshormonogenesis in Guangzhou, and most of them are
      manifested as transient CH.
    explanation: >-
      Establishes that most DUOXA2-associated congenital hypothyroidism in this
      series was transient, correcting the permanent-only reading. The series
      majority is carried by monoallelic heterozygotes, so it bounds the
      permanent-only claim rather than fixing a rate for biallelic disease.
- name: Partial Compensation by DUOXA1
  biological_scale: MOLECULAR
  role: modifier
  mechanism_confidence: PROVISIONAL
  description: >-
    DUOXA2 has a paralogue, DUOXA1, arranged head-to-head with DUOX1 in the same
    way DUOXA2 is with DUOX2. Functional studies indicate DUOXA1 can partially
    substitute for missing DUOXA2, which is the proposed reason the index DUOXA2
    patient had a milder phenotype than patients carrying biallelic DUOX2
    nonsense alleles. This node is a severity modifier rather than a step in the
    causal chain, and the supporting evidence is in-vitro plus a single-patient
    clinical correlation, so it is curated as PROVISIONAL.
  genes:
  - preferred_term: DUOXA1
    term:
      id: hgnc:26507
      label: DUOXA1
  evidence:
  - reference: PMID:18042646
    reference_title: "Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional studies suggest that the DUOXA2 paralog (DUOXA1) can partially
      compensate DUOXA2 deficiency, consistent with the proband having a milder CH
      phenotype than patients with biallelic DUOX2 nonsense mutations.
    explanation: >-
      The sole evidence for the compensation model and for its proposed clinical
      consequence, both carried here at PROVISIONAL confidence.
  downstream:
  - target: Partial Iodine Organification Defect
phenotypes:
- category: Endocrine
  name: Congenital Hypothyroidism
  description: >-
    Primary congenital hypothyroidism detected on newborn TSH screening,
    arising from a hormone-synthesis defect in a structurally normal gland
    rather than from thyroid dysgenesis. Permanence is not assumed: see the
    Transient Congenital Hypothyroidism phenotype for the resolving arm.
  phenotype_term:
    preferred_term: Congenital hypothyroidism
    term:
      id: HP:0000851
      label: Congenital hypothyroidism
  evidence:
  - reference: PMID:18042646
    reference_title: "Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic DUOXA2 mutations are a novel genetic event in permanent CH.
    explanation: >-
      The index report's classification as permanent CH; marked PARTIAL because a
      later series with re-evaluation at 2-3 years found most DUOXA2-associated CH
      to be transient. Graded the same way as the identical quote on the
      pathophysiology node, so one sentence is not scored two ways in one file.
- category: Endocrine
  name: Dyshormonogenic Goiter
  description: >-
    Sustained TSH stimulation of a gland that cannot make hormone efficiently
    produces goitrous enlargement. The gland is eutopic and structurally normal,
    which distinguishes dyshormonogenesis from thyroid dysgenesis on imaging.
  phenotype_term:
    preferred_term: Goiter
    term:
      id: HP:0000853
      label: Goiter
  evidence:
  - reference: PMID:18042646
    reference_title: "Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report the first mutation in DUOXA2, identified in a patient with CH and
      dyshormonogenic goiter.
    explanation: >-
      Documents dyshormonogenic goiter in the index patient.
- category: Endocrine
  name: Transient Congenital Hypothyroidism
  description: >-
    Hypothyroidism that resolves on re-evaluation off treatment. A Guangzhou
    series that reassessed children at 2-3 years found most DUOXA2-associated CH
    to be transient, which refutes a permanent-only reading; the denominator
    warrants care, because that majority (4 of 6) is carried by monoallelic
    heterozygotes, and the two p.Tyr246Ter homozygotes split one transient and
    one mild permanent. For biallelic disease as defined here the balance is
    therefore unresolved on n=2. The practical consequence either way is that a
    DUOXA2 diagnosis warrants a planned trial off levothyroxine rather than an
    assumption of lifelong replacement.
  phenotype_term:
    preferred_term: Congenital hypothyroidism
    term:
      id: HP:0000851
      label: Congenital hypothyroidism
    temporality: TRANSIENT
  evidence:
  - reference: PMID:28100324
    reference_title: "[Characteristics of DUOXA2 gene mutation in children with congenital hypothyroidism]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DUOXA2 gene mutation is a common molecular pathogenic basis for CH children
      with suspected thyroid dyshormonogenesis in Guangzhou, and most of them are
      manifested as transient CH.
    explanation: >-
      Establishes transient CH as the predominant DUOXA2 outcome on re-evaluation.
- category: Endocrine
  name: Variable Severity Independent of Genotype
  description: >-
    Severity does not track the DUOXA2 genotype. The Guangzhou series states
    directly that there is no genotype-phenotype association, and homozygous
    p.Tyr246Ter produced transient disease in one child and mild permanent
    disease in another. Genotype therefore cannot be used to predict course,
    which is an unusual and clinically important negative.
  phenotype_term:
    preferred_term: Congenital hypothyroidism
    term:
      id: HP:0000851
      label: Congenital hypothyroidism
  evidence:
  - reference: PMID:28100324
    reference_title: "[Characteristics of DUOXA2 gene mutation in children with congenital hypothyroidism]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There is no association between DUOXA2 genotypes and phenotypes.
    explanation: >-
      Direct statement that genotype does not predict phenotype in DUOXA2 disease.
biochemical:
- name: Partial Iodine Organification Defect on Perchlorate Discharge
  presence: PRESENT
  notes: >-
    The discriminating biochemical phenotype. A perchlorate discharge test
    demonstrates that trapped iodide has not been organified onto thyroglobulin.
    In DUOXA2 disease the defect is partial rather than total, and the original
    DUOXA2 patient was found precisely by screening a cohort selected for partial
    organification defect with no other identified genetic cause.
  evidence:
  - reference: PMID:18042646
    reference_title: "Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Subjects included 11 CH patients with partial iodine organification defect
      but negative for other known genetic causes of partial iodine organification
      defect.
    explanation: >-
      Defines the biochemical selection criterion that identified DUOXA2 disease.
genetic:
- name: DUOXA2
  gene_term:
    preferred_term: DUOXA2
    term:
      id: hgnc:32698
      label: DUOXA2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  frequency: >-
    Biallelic in the index families that define TDH5; cohort sequencing also
    reports monoallelic DUOXA2 carriers with congenital hypothyroidism (4 of 6
    in one Guangzhou series), whose sufficiency is unresolved
  notes: >-
    DUOXA2 (15q21.1) is transcribed head-to-head with DUOX2 from a shared
    bidirectional promoter region, an arrangement the discovering authors likened
    to a eukaryotic operon equivalent and which can be traced back before the
    divergence of echinoderms. The index pathogenic allele is the nonsense
    c.738C>G (p.Tyr246Ter). That allele appears to be population-enriched: one
    heterozygous carrier was found among 92 unrelated Chinese controls but none
    among Caucasian or Japanese controls.
  evidence:
  - reference: PMID:18042646
    reference_title: "Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One heterozygous carrier of Y246X was identified in unrelated Chinese
      controls (n = 92) but not in Caucasian or Japanese controls, indicating that
      homozygosity for Y246X could be a frequent cause of CH in Chinese.
    explanation: >-
      Supports population enrichment of the index allele in Chinese populations.
  - reference: PMID:33310921
    reference_title: "DUOX2 variants are a frequent cause of congenital primary hypothyroidism in Thai patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of 45 variants, 7 genes were involved (DUOX2, DUOXA2, TG, TPO, SLC5A5, PAX8
      and TSHR).
    explanation: >-
      Confirms DUOXA2 recurs as a causative gene in an independent congenital
      hypothyroidism cohort.
diagnosis:
- name: Newborn TSH Screening
  description: >-
    TDH5 is ascertained through routine neonatal congenital hypothyroidism
    screening. Screening does not distinguish dyshormonogenesis from dysgenesis;
    that requires imaging of a eutopic gland plus, ideally, molecular diagnosis.
  evidence:
  - reference: PMID:18042646
    reference_title: "Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pedigree analysis demonstrated recessive inheritance, because heterozygous
      carriers had normal thyroid function including negative results in neonatal
      TSH screening.
    explanation: >-
      Establishes neonatal TSH screening as the ascertainment route and shows
      carriers screen negative.
- name: Molecular Diagnosis of the Dyshormonogenesis Gene
  description: >-
    Identifying the specific gene has prognostic value beyond confirming the
    diagnosis: it distinguishes transient from permanent congenital
    hypothyroidism, informs genetic counselling, and predicts whether iodine
    supplementation may serve as an adjunct or alternative to levothyroxine.
  evidence:
  - reference: PMID:21543982
    reference_title: "Genetic causes of congenital hypothyroidism due to dyshormonogenesis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A definite molecular diagnosis of thyroid dyshormonogenesis allows genetic
      counseling and has prognostic value in differentiating transient from
      permanent congenital hypothyroidism and predicting the response of patients
      to iodine supplementation as adjunct or alternative treatment to L-T4
      replacement.
    explanation: >-
      States the specific clinical value of establishing the molecular diagnosis.
treatments:
- name: Levothyroxine Replacement
  description: >-
    Thyroid hormone replacement is the standard treatment for permanent
    congenital hypothyroidism from any dyshormonogenesis gene. It corrects the
    hormone deficit; it does not address the DUOXA2 maturation defect.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levothyroxine
      term:
        id: NCIT:C62080
        label: Levothyroxine
  evidence:
  - reference: PMID:21543982
    reference_title: "Genetic causes of congenital hypothyroidism due to dyshormonogenesis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A definite molecular diagnosis of thyroid dyshormonogenesis allows genetic
      counseling and has prognostic value in differentiating transient from
      permanent congenital hypothyroidism and predicting the response of patients
      to iodine supplementation as adjunct or alternative treatment to L-T4
      replacement.
    explanation: >-
      Names L-T4 replacement as the reference treatment against which iodine
      supplementation is positioned.
- name: Genetic Counseling
  description: >-
    Recessive inheritance carries a 25% recurrence risk for siblings, and current
    consensus guidance recommends counselling for every family with an affected
    child. Counselling also identifies asymptomatic carriers.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:25231445
    reference_title: "Clinical genetics of congenital hypothyroidism."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The new consensus guidelines for CH recommend genetic counseling for each
      family with an affected child.
    explanation: >-
      States the guideline recommendation for genetic counselling in congenital
      hypothyroidism.
discussions:
- discussion_id: tdh5_duoxa1_compensation_untested_in_patients
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does DUOXA1-mediated compensation actually account for the milder phenotype
    of DUOXA2 disease in patients, or is the severity difference explained by
    residual allele function and cohort ascertainment?
  attaches_to:
  - "pathophysiology#Partial Compensation by DUOXA1"
  rationale: >-
    The compensation model is attractive and mechanistically plausible — DUOXA1
    is a paralogue with the same maturation function for DUOX1 — but the evidence
    is a functional study plus a severity comparison anchored on a single DUOXA2
    proband against DUOX2-nonsense patients. That comparison cannot separate
    paralogue compensation from allele-specific residual function or from the
    ascertainment route, since the DUOXA2 patient was found by screening a
    partial-organification-defect cohort, which selects against the most severe
    presentations. The question matters because DUOXA1 compensation, if real and
    modifiable, is a therapeutic target in a disease otherwise managed only by
    hormone replacement.
  proposed_experiments:
  - experiment_id: exp_tdh5_duoxa1_expression_in_patient_thyroid
    name: DUOXA1 and DUOX1 expression in DUOXA2-deficient thyroid tissue
    description: >-
      Quantify DUOXA1 and DUOX1 transcript and protein in thyroid tissue or
      thyrocyte models from DUOXA2-deficient patients versus controls, testing
      whether compensation is accompanied by measurable paralogue upregulation.
  - experiment_id: exp_tdh5_genotype_severity_cohort
    name: Genotype-stratified severity comparison across dyshormonogenesis genes
    description: >-
      Assemble reported DUOXA2, DUOX2 and TPO patients and compare severity
      measures ascertained the same way, to test whether the DUOXA2 milder-course
      claim survives control for ascertainment.
- discussion_id: tdh5_no_genotype_phenotype_correlation
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why does DUOXA2 genotype fail to predict whether congenital hypothyroidism is
    transient or permanent, or how severe it is?
  attaches_to:
  - "pathophysiology#DUOXA2 Loss of Function"
  - "pathophysiology#Goitrous Congenital Hypothyroidism"
  rationale: >-
    The absence of a correlation is stated directly rather than merely
    unobserved, which makes it a finding rather than a gap in ascertainment. The
    same homozygous p.Tyr246Ter genotype produced transient disease in one child
    and mild permanent disease in another; monoallelic carriers ranged from
    typical permanent CH to transient. Several explanations are open and none
    tested: variable DUOXA1 compensation between individuals, dietary iodine
    sufficiency modifying how much residual peroxide output suffices, oligogenic
    contributions from the other dyshormonogenesis genes (digenic and triallelic
    DUOX2/DUOXA2 combinations are common in cohort series), or a developmental
    window after which the demand for hormone synthesis falls. Distinguishing
    them matters because it determines whether a trial off levothyroxine can be
    predicted rather than simply attempted.

    Monoallelic reports are recorded here rather than as phenotypes, deliberately.
    A dizygotic twin pair (PMID:27349010) is often cited to illustrate
    genotype-independence, and it cannot do that work for this entry: the twins
    each carried a SINGLE heterozygous variant, and in different genes - the boy
    a DUOXA2 p.Tyr246Ter, the girl a DUOX2 p.Arg885Gln. So the pair says nothing
    about DUOXA2 genotype-phenotype independence, and the boy's thyroid imaging
    cannot be curated as a TDH5 phenotype without contradicting this entry's own
    `inheritance` evidence that heterozygous carriers are euthyroid with negative
    neonatal screening. The wider question of why monoallelic DUOXA2 carriers are
    reported with CH at all - whether through an undetected second hit, an
    oligogenic contribution, or ascertainment - is part of this gap, not a
    settled phenotype.
  proposed_experiments:
  - experiment_id: exp_tdh5_transient_vs_permanent_cohort
    name: Genotype-stratified re-evaluation cohort with iodine status
    description: >-
      Reassess DUOXA2 patients off treatment at a uniform age while recording
      full dyshormonogenesis-gene genotype, DUOXA1 variants and iodine status, to
      test whether apparent genotype-independence survives control for oligogenic
      burden and environmental iodine.
  - experiment_id: exp_tdh5_residual_h2o2_vs_outcome
    name: Residual peroxide output as a predictor of course
    description: >-
      Measure H2O2 generation for each reported DUOXA2 allele in a common
      reconstitution system and test whether residual output, rather than allele
      identity, correlates with transient versus permanent disease.
- discussion_id: tdh5_boundary_with_congenital_hypothyroidism_entry
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Should the gene-anchored thyroid dyshormonogenesis entities be curated as
    standalone entries, as here, or folded into the Congenital_Hypothyroidism
    entry's Dyshormonogenesis subtype?
  attaches_to:
  - "pathophysiology#DUOXA2 Loss of Function"
  rationale: >-
    This is a curation-boundary question, recorded so the decision is auditable
    rather than implicit. Congenital_Hypothyroidism already carries a
    Dyshormonogenesis has_subtypes entry bound to MONDO:0010132, which is the
    direct MONDO parent of this entry's MONDO:0010137. That subtype names DUOXA2
    in prose but carries no per-gene mechanism, and a lumped subtype cannot
    represent a maturation-factor defect distinctly from a defect in a
    hormone-synthesizing enzyme — the distinction that makes TDH5 mechanistically
    interesting. A standalone entry was therefore curated. The repository has
    precedent both ways (Central_Congenital_Hypothyroidism is standalone
    alongside a Central subtype), and an active reconciliation of exactly this
    pattern is under way for Loeys-Dietz, so the convention may change.
notes: >-
  Scope and boundaries. This entry covers TDH5 specifically — the DUOXA2-anchored
  member of the thyroid dyshormonogenesis series (MONDO:0010137). It deliberately
  does not restate the general congenital hypothyroidism picture, which is curated
  in Congenital_Hypothyroidism, nor the DUOX2-anchored disease, which is a
  distinct entity. See the tdh5_boundary_with_congenital_hypothyroidism_entry
  discussion for why a standalone entry was created rather than a has_subtypes
  entry, and revisit it if the repository settles a different convention.

  What makes this entity mechanistically distinct. Most dyshormonogenesis genes
  encode enzymes or transporters that act directly in hormone synthesis (TPO, TG,
  SLC5A5, SLC26A4, IYD). DUOXA2 does not: it is a maturation factor whose only
  role is to get another protein folded, out of the ER and onto the apical
  membrane. TDH5 is therefore a trafficking/chaperone disease presenting as an
  organification defect, and the pathograph is curated to keep that distinction
  visible rather than collapsing it to "impaired hormone synthesis".

  A correction worth preserving. The index report classified biallelic DUOXA2
  disease as permanent congenital hypothyroidism, and that framing propagated.
  A later series that actually re-evaluated children off treatment at 2-3 years
  found most DUOXA2-associated CH to be transient, including in a p.Tyr246Ter
  homozygote. The entry now carries both, with the index claim marked PARTIAL.
  Note the denominator: that series' transient majority is carried by
  monoallelic heterozygotes, and its two homozygotes split one transient and one
  mild permanent, so it refutes permanent-only without establishing a rate for
  biallelic disease.
  Do not restore a permanent-only reading: the clinical consequence is that a
  DUOXA2 diagnosis warrants a planned trial off levothyroxine rather than an
  assumption of lifelong replacement.

  Protein abundance is not a pathogenicity readout here. The I26M allele is
  expressed at wild-type levels and still abolishes H2O2 generation entirely, so
  a normal Western blot does not exclude a damaging DUOXA2 variant.

  Evidence base. Small. The gene's function rests on the 2006 identification
  paper, and the disease on the 2008 index patient plus subsequent cohort
  sequencing studies in which DUOXA2 recurs as a minority cause alongside the
  much more common DUOX2. Severity claims should stay hedged accordingly.
📚

References & Deep Research

References

9
PMID:16651268
Identification of the maturation factor for dual oxidase. Evolution of an eukaryotic operon equivalent.
No top-level findings curated for this source.
PMID:18042646
Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism.
No top-level findings curated for this source.
PMID:21543982
Genetic causes of congenital hypothyroidism due to dyshormonogenesis.
No top-level findings curated for this source.
PMID:25231445
Clinical genetics of congenital hypothyroidism.
No top-level findings curated for this source.
PMID:33310921
DUOX2 variants are a frequent cause of congenital primary hypothyroidism in Thai patients.
No top-level findings curated for this source.
PMID:29650690
The genetic characteristics of congenital hypothyroidism in China by comprehensive screening of 21 candidate genes.
No top-level findings curated for this source.
PMID:28100324
[Characteristics of DUOXA2 gene mutation in children with congenital hypothyroidism].
No top-level findings curated for this source.
PMID:25675383
A novel missense mutation (I26M) in DUOXA2 causing congenital goiter hypothyroidism impairs NADPH oxidase activity but not protein expression.
No top-level findings curated for this source.
PMID:27349010
Heterozygous Mutations of the DUOXA2 and DUOX2 Genes in Dizygotic Twins with Congenital Hypothyroidism.
No top-level findings curated for this source.