Congenital Hypothyroidism
	Widespread systematic screening for neonatal hypothyroidism has expanded the epidemiology of the various causes of congenital hypothyroidism (table 3). The prevalence of congenital hypothyroidism approximates 1 in 4000 births. Table 3: Causes and mechanisms of congenital hypothyroidism Thyroid dysgenesis: athyreosis hypoplasia ectopia Familial dyshormonogenisis Impaired sensitivity Central-type hypothyroidism: hypothalamic/pituitary TSH deficiency abnormal TSH Severe iodine deficiency Transient congential hypothyroidism: TSH receptor blocking antibodies antithyroid treatment (in the mother) transient hypothyroxinemia transient hyperthyrotropinemia Thyroid hormone resistance syndrome Thyroid dysgenesis The causes of thyroid dysgenesis, which represent 75% of the cases of congenital hypothyroidism are unknown. The involvement of morphogenetic thyroid specific factors is under study. Maternal autoimmune mechanisms have been suspected on the positivity of tests of antithyroid antibody-dependent cell cytotoxicity in 30-40 % of both mothers and hypothyroid children. However, it should be stressed that there is no association, except for the rare instances of transient hypothyroidism due to blocking anti-TSH receptor antibodies, between maternal autoimmune thyroiditis and fetal thyroid dysgenesis. Intensity of hypothyroidism is variable according to the residual functional thyroid mass. Ectopia is usually responsible for the mildest forms of the disease. Familial dyshormonogenesis Altogether, the various types of familial dyshormonogenesis represent 10-15% of the cases of congenital hypothyroidism. They result from inheritable enzymatic deficiencies in the synthesis and secretion of thyroid hormones. Goiter is a characteristic feature but may not be present initially at birth or during early infancy. The classical types of familial thyroid dyshormonogenesis are the following: iodide transport defect: this very rare disease (35 patients reported) is characterized by an absent radioiodide uptake by the thyroid and most probably other tissues with iodide accumulation capacity. This disease is apparently autosomal recessive. The cause of the deffect is not characterized although the recent cloning of the thyroidal membrane Na+/I- symporter should help elucidate its mechanism. defects in thyroglobulin synthesis or coupling: thyroglobulin defects are inherited as autosomal recessive traits. Two mutations have been described, one leading to a deletion of exon 4 which encodes for a thyroxinogenic site, the other to premature termination of the molecule. Other defects are probably to be described, responsible for abnormalities in thyroglobulin structure which could prevent normal coupling of iodotyrosines to form T4 and T3. In one patient, the thyroglobulin synthetic defect resulted from the low expression of the thyroid specific transcription factor TTF1. iodide organification and Pendred's syndrome: this defect may result from abnormalities of either thyroperoxidase or the H2O2 generating system. They are transmitted as autosomal recessive traits. Eight different mutations have been identified in the peroxidase gene leading to a loss of activity of the enzyme. The lack of iodide peroxidation prevents the iodination of the tyrosine residues of thyroglobulin. Very recently a genome-wide linkage search mapped the disease locus on chromosome 7, excluding any abnormality in the thyroglobulin or TPD gene. Most probably a defect in H2O production is the cause of the organification impairment. However, no molecular abnormality of the H2O2 generating system has been characterized, yet. Pendred's syndrome combines a goiter, overt or subclinical hypothyroidism and sensori-neural deafness of variable intensity. The thyroid hormone synthesis defect is usually modest and detected-as the goiter- only in adolescence. This familial autosomal recessive trait affects 1/25000 newborns. The mechanism of hypothyroidism is not completely understood; it is probably not uniform although in many cases evidence of a defect in iodide organification may be demonstrated by a positive perchlorate discharge test. dehalogenase (deiodinase) defect: mono-iodo (MIT) and di-iodotyrosine (DIT) generated by the proteolysis of thyroglobulin during the process of T4 and T3 liberation are normally deiodinated. The iodine thus available is a major source of intrathyroidal iodine for new hormone synthesis. A hereditary disorder of the deiodinating system specific for iodotyrosines, the deshalogenase enzyme, lead to excessive renal loss of iodine as MIT and DIT, responsible for an iodine-deficient hypothyroid state with a goiter of variable size. Inheritance is autosomal recessive. The disease has not been characterized at the molecular level. Peripheral tyrosine desiodinases may or may not be affected. Impaired sensitivity to TSH Familial decreased sensitivity to TSH has recently been shown to be due to a mutation in the extra-cellular TSH binding domain of the TSH receptor. Due to a compensatory increase in TSH secretion, these patients are euthyroid. Impaired TSH responsiveness is also observed in pseudohypoparathyroidism type Ia (Albright's hereditary osteodystrophy), a variably expressed disorder with autosomal dominant inheritance due to a mutation in the Gsa gene. Hypothyroidism is usually marginal, as compared to the other typical and more evident abnormalities characteristic of this syndrome. Central-type hypothyroidism This type of hypothyroidism is observed in 5% of cases. Hypothalamic TRH or pituitary TSH deficiency is rarely isolated. TSH may result from congenital midline central nervous system malformations of the septo-optic dysplasia syndrome, tumors or cysts of the hypothalamo-pituitary area or birth trauma. Congenital TRH deficiency has also been described. Defects in the synthesis of TSH have been reported. Decreased bioactivity of TSH caused by mutations in the TSH b-subunit gene have been described. Also, mutations of the Pit-1 gene coding for the pituitary specific transcription factor, responsible for a selective loss of somatotroph, lactotroph and thyreotroph functions, have been described. Severe iodine deficiency Congenital hypothyroidism may occur because of severe iodine deficiency. This is observed in regions with myxedematous endemic cretinism such as Zaïre, India or Algeria. In Zaïre, 10% of infants aged less than one year are hypothyroid and approximately 50% have a marked delay in bone maturation. Importantly, it has been clearly demonstrated that correction of iodine deficiency in pregnant women by injections of iodized oil results in a normalization of the thyroid function of the newborns. Endemic cretinism appears to correspond to two disctinct clinical presentations, neurologic cretinism on one hand and myxedematous cretinism on the other. Deaf-mutism, mental deficiency, spasticity of gait and motility without hypothyroidism are characteristic of the former, myxedema, growth retardation, bone dystrophy and slow psychomotor activity of the latter. Endemic cretinism results from an insufficient exposure of the developping brain to thyroid hormones. Severe iodine deficiency is responsible for both maternal and fetal hypothyroxinemia. Maternal hypothyroxinemia could impair early brain development in the fetus. Indeed, it is now clear that a substantial amount of thyroxine is transferred from mother to fetus before the onset of significant thyroid function in the fetus (20 weeks). Prevalence of neurologic or myxedematous cretinism appears to be geographically determined. The myxedematous form is explained by co-existing selenium deficiency, that leads to decreased detoxification of H2O2, generated in the thyroid. Excess of H2O2 results in destruction of the thyroid gland. Transient congenital hypothyroidism Although rather unfrequent (10% of cases), transient forms of congenital hypothyroidism should not be overlooked to avoid unnecessary prolonged or even permanent thyroxine treatment. Maternal blocking anti-TSH receptor antibodies transplacentally transferred to the fetus may induce fetal and neo-natal hypothyroidism. This condition should be suspected, and even systematically screened for, when the mother has a history of autoimmune thyroid disease, especially thyroxine-treated primary myxedema. Presence of high titers of blocking anti-TSH receptor antibodies in the mother during pregnancy and in the neonate is confirmatory. Neonatal hypothyroidism usually lasts for 1-4 months according to the initial level and the average 3 week half-life of the maternal antibodies in the infant's circulation. Maternal ingestion of any compound with antithyroid properties might induce iatrogenic congenital hypothyroidism. For this reason, high-dose iodine should be avoided during pregnancy especially near term. Since antithyroid drugs cross the placenta, one of the main concerns in the treatment of Graves' hyperthyroidism in pregnant patients is drug-induced fetal hypothyroidism and goiter. To this end, the rule is to maintain antithyroid drug at the lowest dosage possible and the free T4 in the mother's serum near the upper limit of normal. Administration of high-dose iodine to the newborn may also lead to transient hypothyroidism. Transient hypothyroxinemia, without elevated TSH, is frequent in premature infants. It is thought to represent a stage of hypothalamic immaturity. An important question under current study is to know whether, in this condition, hypothyroxinemia might be deleterious for further brain development. In areas of low iodine intake, premature infants may switch from this central-type hypothyroidism to primary hypothyroidism with low T4 and elevated TSH after one to two weeks of extra-uterine life, because neonatal needs of iodine are not met. Transient neonatal hyperthyrotropinemia is unusual; it has been described mainly in Japan. Assay interferences and the existence of abnormal TSH molecules have been excluded. TSH values normalize in a few months. No satisfactory explanation has been proposed for this abnormality.