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Canine Mendelian disease record

Congenital Hypothyroidism (Discovered in the Toy Fox and Rat Terrier)

Congenital Hypothyroidism (Discovered in the Toy Fox and Rat Terrier). Autosomal recessive. Observed in 6 of 266 breeds tested in the Sniff Atlas, with measured carrier frequencies drawn from 242,617 dogs (Donner 2023). Per-dog phenotype outcome depends on penetrance, modifiers, and environment; the carrier frequencies below describe variant prevalence, not disease incidence.

OMIA identifier
OMIA:000536-9615
Autosomal recessive
Source dataset
Sniff Atlas v1.0.1 / DOI
The human connection

A model of human thyroid dyshormonogenesis 2A

Dogs with this condition carry a change in TPO. In people, changes in the same gene cause thyroid dyshormonogenesis 2A. That makes affected dogs a naturally-occurring model of the human disease, and it is part of why studying dogs moves medicine forward for everyone. It does not mean your dog has the human disease. It means the two share an underlying biology.

In people, the disease is described as: Thyroid peroxidase system defect due to presumed mutation(s) in the TPO gene, resulting in decreased activity of thyroid peroxidase.

In humans it is also called: TDH2A, thyroid dyshormonogenesis type 2A, thyroid hormonogenesis, genetic defect in, 2A, TPO familial thyroid dyshormonogenesis.

MONDO:0010133 OMIM 274500

Mapped from OMIA via the human disease's OMIM entry to the Mondo Disease Ontology (Monarch Initiative, CC-BY 4.0). Sniff renders this as a model-of link; the canine disease remains the subject of this page.

About this disease

From OMIA's curated record

Documented in OMIA (Online Mendelian Inheritance in Animals). This describes the disease as recorded in the published literature, not a prediction for any individual dog. As of 2026-06-03.

Summary

Congenital hypothyroidism (CH) is an endocrine disorder characterized by inadequate T4 levels early in life concurrent with signs of hypothyroidism. Disease can be primary (failure to make T4), which is due to abnormal thyroid development or function. Primary hypothyroidism often presents with goiter but can be due to thyroid dysgenesis. CH can be secondary (failure to make bioactive TSH), which is caused by abnormal pituitary development or function. CH can also be tertiary (failure to make TRH) due to abnormal hypothalamic function. Signs of CH with goiter include growth retardation (dwarfism), epiphyseal dysplasia in the vertebrae and limbs, and delay in maturation changes such as dental eruption, opening of eyes and ear canals, and growth of guard hairs. Other signs include thickened subcutis, lethargy, unresponsiveness, and failure to suckle. The disorder is lethal unless diagnosed and treated early. Goiter, extremely low T4, and increased TSH are signs in Toy Fox Terriers, Rat Terriers, Tenterfield Terriers, and Spanish Water Dogs. In dogs likely causal variants have been described in at least two genes (TPO - described in this entry, and SLC5A5 - see 'OMIA002174-9615 Hypothyroidism, congenital dyshormonogenic, with goiter). Non-genetic forms of the condition are possible and may represent some of the case studies for which references are listed in this entry. The mode of inheritance is autosomal recessive for TPO-related congenital hypothyroidism in dogs. Causative mutations in 3 terrier breeds and the Spanish water dog are all in the gene that codes for thyroid peroxidase (TPO), the enzyme responsible for irreversible binding of iodide to thyroglobulin. This process is known as organification of iodide, and it is a necessary step of thyroid hormone synthesis. If thyroid peroxidase activity is not present, the animal is unable to make T4 and presents with primary hypothyroidism. Goiter develops as thyroid cells undergo hypertrophy and hyperplasia due to unrelenting TSH stimulation. DNA-based tests are available to detect the TPO mutation in all 4 breeds. Breeding of carrier animals to each other is not recommended. If a carrier animal is bred to a homozygous normal animal, testing the offspring is advised. Edited by John C. Fyfe, D.V.M., Ph.D. (edited by IT 22/5/2022)

Clinical features

Signs include growth retardation (dwarfism), epiphyseal dysplasia in the vertebrae and limbs, delayed dental eruption, delayed opening of eyes and ear canals, delayed haircoat maturation, thickened subcutis, lethargy, unresponsiveness, failure to suckle. Goiter, extremely low T4, and increased TSH are signs in Toy Fox Terriers, Rat Terriers, Tenterfield Terriers, and Spanish Water Dogs. Onset of signs is early (less than one week of age) in primary congenital hypothyroidism Clinical signs of iodine toxicosis in fetal and early postnatal life are similar to those of congenital hypothyroidism but the two disorders are distinguished by different thyroid histology.

Molecular genetics

By cloning and sequencing a very likely candidate gene (based on knowledge that the disorder is due to deficiency of thyroid peroxidase), Fyfe et al. (2003) reported that the causative mutation in Toy Fox Terriers is a C to T transition that creates an early stop codon in the gene coding for thyroid peroxidase (c.331C>T; p. Arg111Ter). Pettigrew et al. (2007) discovered the same causal mutation in Rat Terriers. Tenterfield Terriers have a C to T missense mutation (c.1777C>T) predicting a tryptophan substitution for a highly conserved arginine residue (p.R593W)(Dodgson et al., 2012). Fyfe et al. (2013) identified a novel form of TPO mutation in two half-sib Spanish Water Dogs: "A single guanosine insertion was observed in the first exon of the affected-dog TPO cDNA at a site not previously thought to be within the coding sequence. The insertion allele segregated with the deduced disease allele in the SWD breed and was not observed in unrelated dogs of various breeds. Comparison of the insertion site (an 8-nt poly-G tract) with the orthologous sequences of other mammalian reference genomes revealed that the octa-G tract obliterated the intron 1 splice acceptor site and the exon 2 translation initiation codon found at that position in other species. An in-frame ATG in strong Kozak consensus context was observed in the normal dog sequence 12 codons 5' of the usual mammalian start site, suggesting that dogs have lost the noncoding exon 1 demonstrated in human and mouse. A survey of TPO sequences in other carnivore species indicates that the poly-G tract necessitating an alternative translation initiation site is a canid-specific feature." Major et al. (2015) reported a likely causal mutation in the TPO gene in a French Bulldog as a "T>C transition in the +2 position of the intron 12 splice donor site (CFA17:801,598; TPO c.2242 + 2T>C)".

Pathology

Congenital hypothyroidism caused by a mutation in TPO is a form of dyshormonogenesis. Thyroid peroxidase is the enzyme responsible for irreversible binding of iodide to thyroglobulin, a necessary step of thyroid hormone synthesis. If thyroid peroxidase activity is not present, the animal is unable to make thyroid hormones and will present with primary hypothyroidism (Fyfe et al., 2003). Goiter will develop in a few weeks due to unrelenting TSH secretion.

Prevalence

Most hypothyroidism is not congenital – only 3.6% of hypothyroid dogs are less than one year of age (Bojanic et al., 2011). Rat Terriers are thought to have acquired the mutation fairly recently, as a result of interbreeding with Toy Fox Terriers (Pettigrew et al., 2007).

Inheritance

The mode of inheritance is autosomal recessive.

Control

Breeding of carrier animals to each other is not recommended. If a carrier animal is bred to a homozygous normal animal, testing the offspring is advised.

Genetic testing

DNA-based tests are available to detect the mutations in all 4 breeds.

Human analog

OMIA links this condition to its human counterpart in OMIM (Mendelian Inheritance in Man), the place to read across to the deeper human literature for the same biology.

Disease · OMIM 274500 Gene · OMIM 606765

Source: OMIA (Nicholas, Tammen & the Sydney Informatics Hub), entry OMIA:000536-9615, doi:10.25910/2AMR-PV70 (CC-BY 4.0).

Signs & cross-references

How it presents

Catalogued in the Mondo disease ontology (the cross-species disease identity used by the Monarch Initiative) as thyroid dyshormonogenesis 2A (MONDO:0010133).

Phenotype terms: Human Phenotype Ontology + Mammalian Phenotype Ontology; disease terms: Mondo (Monarch Initiative). Cross-references curated by OMIA (doi:10.25910/2AMR-PV70, CC-BY 4.0).

The evidence

Published references

The peer-reviewed papers behind this disease, curated by OMIA. Starred entries are OMIA-designated landmark papers. Showing 6 of 109.

  2. Changes of the salivary and serum proteome in canine hypothyroidism. · Domest Anim Endocrinol · 2023 · PMID 37980820
  3. 2023 AAHA selected endocrinopathies of dogs and cats guidelines. · J Am Anim Hosp Assoc · 2023 · PMID 37167252

References curated by OMIA (Nicholas, Tammen & the Sydney Informatics Hub), doi:10.25910/2AMR-PV70 (CC-BY 4.0). Full list at the OMIA entry.

Predict a litter

Set each parent's status for Congenital Hypothyroidism (Discovered in the Toy Fox and Rat Terrier) and see the odds for their puppies. Single recessive variant, exact Mendelian math.

Parent A
Parent B
NNClear
NmCarrier
NmCarrier
mmAffected
Clear25%
Carrier50%
Affected25%

These are the genetic odds for one known variant, not a promise: a real litter varies around them, and penetrance or other genes can change whether the condition ever appears. Use it to avoid pairing two carriers and to keep a line healthy, not to engineer a dog. Inheritance mode per OMIA.
Your breed

See what Congenital Hypothyroidism (Discovered in the Toy Fox and Rat Terrier) looks like in your dog's breed.
Carrier frequency by breed

Top 5 well-sampled breeds (n ≥ 50)

Maximum per breed across variants in the Donner 2023 cohort, with . The list below is split into well-sampled breeds (n ≥ 50 tested) and small-sample breeds (n < 50, where the Wilson CI typically spans more than 20 percentage points and frequencies should not be compared directly to the well-sampled entries). Frequencies are population-level, not per-litter or per-line.

0%3%5%
Dachshund Miniature Longhaired0.23% · n 213
Chihuahua<0.1% · n 4,273
Beagle<0.1% · n 5,291
Yorkshire Terrier<0.1% · n 8,366
American Staffordshire Terrier<0.1% · n 42,785
n = 60,928 dogs · Donner et al. 2023 carrier-screening cohort · Sniff Atlas
Each bar is one well-sampled breed; the whisker is its Wilson 95% CI, and fainter bars have wider intervals. Frequencies are population-level, not per-litter. Carrier status for Congenital Hypothyroidism (Discovered in the Toy Fox and Rat Terrier) is measured; phenotype outcome depends on penetrance and modifiers.
▸ Full table with Wilson 95% confidence intervals
Breed Carrier frequency n tested
Dachshund Miniature Longhaired 0.23% 213
Chihuahua <0.1% 4,273
Beagle <0.1% 5,291
Yorkshire Terrier <0.1% 8,366
American Staffordshire Terrier <0.1% 42,785
▸ Also observed in 1 small-sample breed (n < 50)

Frequencies in this section are statistical estimates with wide Wilson 95% confidence intervals (typically >20 percentage points). Treat these as "carriers observed but the true population frequency is not yet measurable" rather than as comparable to the well-sampled entries above.

Breed Estimate n tested
Fox Terrier Toy 4.2% 48

260 additional breeds in the Donner 2023 cohort were tested but showed no carriers.

Scope of this record

Scope

This record carries the breed-level carrier frequencies from the Donner 2023 cohort. Penetrance data (the fraction of at-risk dogs that develop the phenotype) is not yet quantified for this disease in the Sniff Atlas v1.0.1. The OMIA entry is the authoritative reference for the clinical phenotype, inheritance pattern, and gene assignment.

Predicted disease relevance at the per-dog level is UNPROVEN. The carrier frequency is measured; phenotype outcome depends on penetrance, environment, and modifier loci. Consult a veterinarian for clinical interpretation.

How to cite this record

Citations

If you use this record in published work, cite the Sniff Atlas (the published dataset that carries the breed-level carrier frequencies) and the upstream sources:

  • Sniff Atlas v1.0.1 for the per-breed carrier frequencies:

    Gehring, M. (2026). Sniff Atlas v1.0.1. Zenodo. https://doi.org/10.5281/zenodo.20566358. CC-BY 4.0.

  • OMIA for the disease definition, inheritance, and gene assignment:

    Nicholas, F. W., & Tammen, I. (2024). OMIA. Sydney Informatics Hub, The University of Sydney. https://doi.org/10.25910/2AMR-PV70. Entry: OMIA:000536-9615.

  • Donner et al. 2023 for the breed × variant carrier-frequency cohort:

    Donner, J., Freyer, J., Davison, S., Anderson, H., Blades, M., Honkanen, L., et al. (2023). Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs. PLOS Genetics, 19(2), e1010651. https://doi.org/10.1371/journal.pgen.1010651.

Full citation formats (BibTeX, RIS, CITATION.cff) at sniff.world/cite.

Related

Related

Last updated
Sources: Sniff Atlas v1.0.1 · OMIA OMIA:000536-9615 · Donner et al. 2023