In other species: rock pigeon , chicken , lesser panda , domestic cat , horse , goat , sheep

Categories: Endocrine / exocrine gland phene (incl mammary gland)

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 274500 (trait) , 606765 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0010133: thyroid dyshormonogenesis 2A

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2003

Cross-species summary: Deficiency of thyroid gland activity. Also known as Goiterous congenital hypothyroidism; Congenital hypothyroidism; Thyroid dyshormonogenesis. This disorder can be caused by mutations in different genes, and forms of the disease exist that are not inherited.

Species-specific name: Congenital hypothyroidism with goiter

Species-specific symbol: CHG

Species-specific description: 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)

Inheritance: The mode of inheritance is autosomal recessive.

Mapping: CFA17

Molecular basis: 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)".

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.

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).

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.

Breeds: French Bulldog (Dog) (VBO_0201455), Giant Schnauzer (Dog) (VBO_0200604), Rat Terrier (Dog) (VBO_0201125), Scottish Deerhound (Dog) (VBO_0201195), Spanish Water Dog (Dog) (VBO_0201280), Tenterfield Terrier (Dog) (VBO_0201342), Toy Fox Terrier (Dog) (VBO_0201361).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: