Congenital hypothyroidism, which occurs in approximately 1 in 4,000 births, is a relatively common endocrine disorder of human infants. In contrast, reports of congenital hypothyroidism in dogs are relatively few. Congenital hypothyroidism may be caused by aplasia or hypoplasia of the thyroid gland, thyroid ectopia, dyshormonogenesis, maternal goitrogen ingestion, maternal radioactive iodine treatment, iodine deficiency (endemic goiter), autoimmune thyroiditis, hypopituitarism, isolated thyrotropin deficiency, hypothalamic disease, or isolated TRH deficiency. Of these causes of congenital hypothyroidism in children, only 15% are the result of hypothalamic-pituitary disease. In the dog, congenital or developmental thyrotropin deficiency is usually associated with cystic Rathke's pouch. Neither isolated TSH nor TRH deficiency have been well documented as a cause of central hypothyroidism in dogs.

Congenital hypothyroidism, regardless of cause,results in characteristic clinicopathological features. Both dogs and infants have a history of large prolonged gestation) which is followed by aberrant and delayed growth. In the present study, the first signs of abnormal growth occured as early as 3 weeks after birth. Affected puppies could be distinguished from normal littermates by shortened pinnae, abdominal distenstion, and behavioral abnormalities. abnormal body proportions were evident by 8 weeks of age. This is similar to human infants who are normal at birth, but, if undiagnosed, exhibit characteristic signs by 6-8 weeks of age. Other historical findings in these pupies including lethargy, mental dulness, weak nursing. Delayed dental eruption, and abdominal distension are also observed in hypothytoid children.

Physical features of hypothyroid dwarfism in children include hypotonia, umbilical hernia, skin mottling, large anterior and posterior fontanels, macroglossia, hoarse cry, distended abdomen, dry skin, jaundice, palor, slow deep tendon reflex, delayed dental eruption, and hypothermia. In the dogs described in this report, hypotonia, macroglossia, distended abdomen, dry skin, delayed dental eruption, and hypothermia were identified. In addition, because dogs develop more rapidly and become weight bearing sooner than human infants, gait abnormalities and disproportionate dwarfism were prominent features of hypothyroidism in this study. Midface hypoplasia, broad nose, and a large protruding tongue are some of the sequelae of untreated hypothyroidism in humans. Similar facial features, such as broad maxillas and macroglossia, were observed in affected puppies. In humans, delayed eruption of permanent teeth is observed in untreated congenitally hypothyroid individuals, delayed dental eruption was observed in all dogs but was much more noticeable in the dog (dog 3) treated after 4 months of age. Although abdominal distension was observed in all affected puppies, effusion was evident in only one puppy. In humans, both macroglossia and effusions of the body cavities are the result of myxedematous fluid accumulation. Coarse hair coats were observed in several affected puppies. Similarly, congenitally hypothyroid rats exhibit alterations in hair shaft morphology as a result of thyroid hormone deficiency during development.

Thyroid hormone crucial for proper postnatal development of the nervous system. As a result, a significant number of properly treated and all untreated hypothyroid infants exhibit poor coordination and speech impediments later in life. Delayed treatment often results in low perceptual-motor, visual-spatial, and language scores in children with congenital hypothyroidism. If treatment is delayed beyond 4-6 months, intelligence is irreversibly affected and mental retardation may ensue. Because the bulk of cerebellar development occurs postnatally, Purkinje cell growth is also significantly affected by congenital hypothyroidism. In humans, if treatment is delayed, signs of cerebellar dysfunction, such as ataxia, are observed. In one dog (dog 4), hypermetria has persisted despite treatment of hypothyroidism at 4 months of age.

Skeletal abnormalities are the hallmark of congenital hypothyroidism. Delayed maturation and epiphyseal dygenesis are both recognized features of congenital hythyroidism. Delayed epiphyseal maturation was observed in the vertebral bodies and long bones of affected puppies. Epiphyseal dygenesis, which is characterized by a ragged epiphysis with scattered foci of calcification, is observed in both humans and dogs with untreated congenital hypothyroidism. Normal epiphyseal developement proceeds from a single center; howver, in hypothyroidism, thyroid deficiency leads the development of multiple epiphyseal centers each with its own calcification progression. Disorderly epiphyseal calcification leads to secondary arthropathies in children with untreated congenital hypothyroidism. In the most severely affected dog,(dog 3) in this study, secondary osteoarthritis was evident in several joints.

Clinicopathological features of congenital hypothyroidism include hypercholesterolemia, hypercalcemia, and mild anemia. Hypercholesterolemia develops in both congenital and adult-onset hypothyroidsim because of decreased hepatic metabolism and decreased fecal excretion of cholesterol. Despite a reduction in cholesterol synthesis as a result of thyroid hormone deficiency, clearance of cholesterol is reduced to a greater degree than synthesis. Hypercalcemia is mild, but usually in excess of the mild hypercalcemia associated with growth in young animals. Unlike normal growing puppies, untreated hypothyroid puppies continue to show mild increases in serum calcium during adulthood. Decreased thyroid hormone stimulation of erythropoetic precursors results in mild normocytic, normochromic anemia in some animals with hypothyroidism. Although mild decreases in erythrocytic indices (PCV, RBC count) are often observed in young animals, the puppies described in this report exhibited lower values than normal for dogs 9-12 weeks of age.

In the two dogs of this report that were most thoroughly evaluated, the results of thyroid histology, prolonged TSH testing, and repeat thyroid imaging after multiple injections of TSH were all consistent with secondary or tertiary, rather than primary, hypothyroidism. In primary hypothyroidism, histological examination of a biopsy of the thyroid gland shows loss thyroid follicles resulting from either lymphocytic thyroiditis or thyroidal atrophy. In contrast, with hypothyroidism secondary to TSH deficiency, the thyroid follicles become distended and colloid and the lining epithelial cells become flattened (as in the dogs of this report). The colloid is uniformly dense with complete or nearly complete absence of resoprtion vacuoles at the periphery of the colloid. Grossly, the thyroid glandappears normal to slightly enlarged, because of the accumulation of colloid.

With TSG stimulation testing, primary hypothyroidsim can not consistently be distinguished from secondary or tertiary hypothyroidism using a single dose of TSH. Cases of long-standing pituitary or hypothalmic hypothyroidism with subsequent thyroid atrophy may fail to show a serum T4 response after a single dose of TSJ (like dogs with primary hypothyroidism). When TSH is administered over a period of 2-3 consecutive days, however, the serum thyroid hormone response normalizes in dogs with secondary or tertiary hypothyroidism, but remains blunted in primary hypothyroidism.

Similarly, thyroid imaging before and after prolonged TSH administration is a useful technique to aid in the differentiation between the causes of hypothyroidism. When imaged prior to the administration of TSH, the thyroid image is markedly reduced or virtually absent with either primary or secondary hypothyroidism. Administration of atrophied thyroid tissue will result in a normal thyroid image in dogs with secondary ot tertiary hypothyroidism.

Central hypothyroidism is usually associated with a number of endocrine and neurological abnormalities. Causes of central hypothyroidism include destructive or idiopathic hypothalmic lesions, and tumorous, atrophic, or idiophatic pituitary disorders. Based on clinical signs (lack of permanent or progressive neurologic deficits not attributable to the hypothyroid state) and results of pituitary function testing (adequate reserves of LH, ACTH), pituitary TSH deficiency is the most likely cause of the hypothyroidism, at least in the two dogs most thoroughly evaluated. Individuals with hypothalmic hypothyroidism should have a response to exogenous TRH that results in increased serum TSH and consequently increased serum T4 and T3 concentrations. Since the serum concentrations of T4 and T3 were unchanged in the dogs of this report, the dogs were assumed to have secondary hypothyroidism. Because the pituitary thyrotrophs remain intact with TRH deficiency, human patients with documented hypothalmic hypothyroidism have subnormal serum TSH concentrations but show normal increases in circulating TSH after administration in the dog, it will remain difficult to differentiate putuitary (secondary) from hypothalmic hypothyroidism.

In humans, isolated thyrotropin deficiency has been described in familes with a history of consanguinity, but the mode of inheritance has not been determined. The presence of several affected individuals in the same breed prompted suspicion of a genetic basis for this disorder in Giant Schnauzers. Autosomal recessive inheritance yields an expected ratio of one affected to three nonaffected individuals; however, in the case of censored data (i.e., data collected only from litters with affected individuals), this ratio is usually greater than 1:3. Litter size may also have an effect on the observed ratio of affected to nonafected individuals. Probability functions can be determined for the occurence of 1,2 or more affected individuals per litter and the probability of observing more than one affected individual per litter increases with increasing litter size. The probability of observing one affected individual in two litters of five or six, two affected in two litters of eight and two affected in one litter of 11 is approximately 0.0096. Two litters of five or six with one affected individual, one litter is 11 with two affected individuals, and one litter of eight with one affected individual were observed. The probability of observing this sample with an autosomal recessive segregating allele is 0.0082 or 85.8% as high as the highest probability. This sample, after taking into account both litter size and the censored nature of the data, is clearly consistent with the hypothesis of an autosomal recessive mode of inheritance.