This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Congenital hypothyroidism may either be caused by dysmorphogenesis of the thyroid gland (hypo- or aplasia) or by dyshormonogenesis associated with a goiter. Disorders in hormonogenesis include the inability of the thyroid to concentrate iodide, thyroglobulin deficiency, and organification defects caused by thyroid peroxidase deficiency. Congenital hypothyroidism has been described in humans and animals, including sporadic feline cases. We have studied the clinical features, endocrine and biochemical abnormalities, pathologic findings, and breeding studies of a family of domestic shorthair cats with primary congenital hypothyroidism. Month-old male and female littermates failed to thrive, had coarse facial features, stunted growth with shortened body length, and appeared constipated and dull. Bone growth was markedly delayed for the age of the animals. A diagnosis of hypothyroidism was reached based upon low serum T3 and T4 concentrations and a response to thyroxin treatment. The affected male and mother were bred which resulted in affected kittens, whereas, when out-crossed to healthy unrelated animals no affected kittens were produced. Breeding two healthy offspring of the affected cat also produced affected kittens. All affected kittens had a congenital goiter with thyroid glands of the original affected cat measuring 5 x 2 x 2 cm each and weighing 6.6 and 5.72 g despite 2 years of treatment The thyroid glands were markedly hypercellular revealing few open follicles and minimal colloid production. Immunohistochemistry was consistent with thyroid hyperplasia of follicular epithelial cells. Serum T3, free, and total T4 concentrations of affected cats were consistently low/unmeasurable, whereas serum thyroid stimulating hormone (TSH) levels were high from the first days of life when compared to healthy cats. There was no thyroid peroxidase activity in thyroid tissue from affected cats, whereas normal thyroids showed iodide oxidation activity of 1.04 0.59 U/mg protein. In this family of domestic shorthair cats, congenital hypothyroidism with goiter was caused by a complete thyroid peroxidase deficiency and is inherited as an autosomal recessive trait. Molecular studies are underway to determine the genetic basis for the disease in this feline model. The clinical and pathologic features, endocrine basis, and mode of inheritance are homologues to the disorder seen in humans and dogs. This disease model may offer opportunities to assess the intrauterine effects of thyroid hormone, gene transfer to the thyroid gland and stem cell therapy. We are also studying two dwarf, retarded Golden retriever littermates with hypothyroidism due to a TSH deficiency suggestive of a pituitary defect. These additional disease models may offer a better understanding of the entire endocrine axis for the thyroid hormone in this species.
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