FELINE GOITEROUS CONGENITAL HYPOTHYROISISM

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。先天性甲状腺功能减退症可能是由甲状腺形态发育不良（发育不全或发育不全）或甲状腺肿相关的激素生成障碍引起的。甲状腺生成障碍包括甲状腺不能浓缩碘、甲状腺球蛋白缺乏和由甲状腺过氧化物酶缺乏引起的器官形成缺陷。先天性甲状腺功能减退症在人类和动物中均有描述，包括零星的猫科病例。 我们研究了一个患有原发性先天性甲状腺功能减退症的家猫家族的临床特征、内分泌和生化异常、病理结果以及育种研究。一个月大的雄性和雌性同窝仔未能茁壮成长，面部特征粗糙，生长发育迟缓，体长缩短，出现便秘和迟钝。骨生长明显延迟的年龄的动物。根据血清T3和T4浓度低以及对甲状腺素治疗的反应，诊断为甲状腺功能减退症。受影响的雄性和母亲繁殖，导致受影响的小猫，而当与健康的无关动物杂交时，没有产生受影响的小猫。繁殖两个健康的后代的受影响的猫也产生了受影响的小猫。所有受影响的小猫都有先天性甲状腺肿，原始受影响猫的甲状腺每个测量为5 x 2 x 2 cm，尽管治疗2年，但重量为6.6和5.72 g。甲状腺明显细胞过多，显示很少开放卵泡和极少量胶体产生。免疫组化结果与甲状腺滤泡上皮细胞增生一致。与健康猫相比，受影响猫的血清T3、游离T4和总T4浓度始终较低/不可测量，而血清促甲状腺激素（TSH）水平从出生后第一天开始就较高。在患病猫的甲状腺组织中没有甲状腺过氧化物酶活性，而正常甲状腺显示碘氧化活性为1.04 <$0.59 U/mg蛋白。在这个家庭的家猫，先天性甲状腺功能减退症与甲状腺肿是由一个完整的甲状腺过氧化物酶缺乏症，并作为一个常染色体隐性遗传性状。分子研究正在进行中，以确定这种猫科动物模型中疾病的遗传基础。临床和病理特征，内分泌基础和遗传方式与人类和犬中观察到的疾病相似。这种疾病模型可能提供机会，以评估甲状腺激素，基因转移到甲状腺和干细胞治疗的子宫内的影响。 我们还研究了两个侏儒，弱智金毛猎犬与甲状腺功能减退症由于TSH缺乏提示脑垂体缺陷。这些额外的疾病模型可能会提供一个更好的了解整个内分泌轴的甲状腺激素在这个物种。

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.