Categories: Growth / size / body region phene , Homeostasis / metabolism phene , Endocrine / exocrine gland phene (incl mammary gland)

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 188450 (gene) , 274700 (trait)

Single-gene trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2026

Cross-species summary: Please note that this entry is partially overlapping with OMIA:000424 Goitre, familial.

Congenital hypothyroidism (CH) is an endocrine disorder that may cause a range of clinical signs depending on the primary defect, which affects the production of thyroid hormones. Hallmark signs of CH are skeletal abnormalities, resulting in disproportionate dwarfism and developmental delay. Goiter may or may not be present. CH may be the result of a deficiency of, or unresponsiveness to, thyrotropin-releasing hormone (TRH) or thyroid-stimulating hormone (TSH), thyroid dysgenesis, dyshormonogenesis, and iodine deficiency.
CH due to thyroid dyshormonogenesis is a heterogenic disorder that may be caused by loss-of-function variants in any of the genes involved in the individual steps of the thyroid hormone biosynthesis pathway. Eight genes are known to be key players in this pathway and associated with thyroid dyshormonogenesis in humans: SLC5A5 encoding solute carrier family 5 member 5 (also called sodium iodide symporter), SLC26A4 encoding solute carrier family 26 member 4, SLC26A7 encoding solute carrier family 26 member 7, TG encoding thyroglobulin, TPO encoding thyroid peroxidase, DUOX2 encoding dual oxidase 2, DUOXA2 encoding dual oxidase maturation factor 2, and IYD encoding iodotyrosine deiodinase.

Molecular basis: Abitbol et al. (2026) sequenced the genome of an affected Rottweiler at 23x coverage and compared the data to genomes of 1539 genetically diverse other dogs. The "affected dog had 11 homozygous private protein-changing variants, of which only one resided in a functional candidate gene for hypothyroidism" (Abitbol et al. 2026). The identified candidate causal variant was a nonsense variant in TG encoding thyroglobulin (omia.variant:1903). Perfect genotype-phenotype association in a cohort of 6 cases and 87 controls, and correct genotype-phenotype cosegregation in an extended pedigree was observed.

Clinical features: Abitbol et al. (2026) reported on a total of 6 affected dogs with non-goitrous hypothyroidism. Their breeders had noticed delayed growth and development two weeks after birth. Affected dogs had increased thyroid-stimulating hormone (TSH) and decreased total thyroxin (total T4) serum concentrations. The condition can be alleviated by oral thyroxin supplementation. However, even under T4 supplementation, the majority of the affected dogs exhibited pronounced dwarfism and painful orthopedic problems. Two affected dogs died at 9 and 10 months, respectively, despite oral thyroxin supplementation. Two other affected dogs had to be euthanised at 5 months of age due to pain and behavioral changes. Two affected dogs reached adulthood under thyroxin supplementation. They were markedly smaller than their non-affected littermates. Other clinical signs included limb deformities, shortening of the tail, abnormally thick skin, fatigue, and behavioral changes.

Pathology: Abitbol et al. (2026): "Histopathological examination of the thyroid glands of two affected females (cases #4 and #5) revealed diffuse alterations involving the entire gland in both animals. Thyroid follicles were small and irregularly shaped (atrophic), with empty follicular lumina indicating absence of colloid, and were lined by flattened to cuboidal follicular epithelium. Multifocally, normal follicular architecture was replaced by aggregates of parafollicular cells (C cells), consistent with C-cell hyperplasia."

Breed: Rottweiler (Dog) (VBO_0201143).
Breeds in which the phene or likely causal variants have been documented. If a likely causal variant has been documented, see variant-specific breed information in the variant table. (Breed information may be incomplete).

Associated gene: