Congenital Hypothyroidism: Etiologies, Diagnosis, and Management

Abstract

Congenital hypothyroidism is a common preventable cause of mental retardation. The overall incidence is approximately 1:4000; females are affected about twice as often as males. Approximately 85% of cases are sporadic, while 15% are hereditary. The most common sporadic etiology is thyroid dysgenesis, with ectopic glands more common than aplasia or hypoplasia. While the pathogenesis of dysgenesis is largely unknown, some cases are now discovered to be the result of mutations in the transcription factors PAX-8 and TTF-2. Loss of function mutations in the thyrotropin (TSH) receptor have been demonstrated to cause some familial forms of athyreosis. The most common hereditary etiology is the inborn errors of thyroxine (T4) synthesis. Recent mutations have been described in the genes coding for the sodium/iodide symporter, thyroid peroxidase (TPO), and thyroglobulin. Transplacental passage of a maternal thyrotropin receptor blocking antibody (TRB-Ab) causes a transient form of familial congenital hypothyroidism. The vast majority of infants are now diagnosed after detection through newborn screening programs using a primary T4-backup TSH or primary TSH test. Screening test results must be confirmed by serum thyroid function tests. Thyroid scintigraphy, using 99mTc or 123I, is the most accurate diagnostic test to detect thyroid dysgenesis or one of the inborn errors of T4 synthesis. Thyroid sonography is nearly as accurate, but it may miss some cases of ectopic glands. If maternal antibody-mediated hypothyroidism is suspected, measurement of maternal and/or neonatal TRB-Ab will confirm the diagnosis. The goals of treatment are to raise the serum T4 as rapidly as possible into the normal range, adjust the levothyroxine dose with growth to keep the serum T4 (or free T4) in the upper half of the normal range and the TSH normal, and maintain normal growth and development while avoiding overtreatment. An initial starting dose of 10-15 microg/kg per day is recommended; this dose will decrease on a weight basis over time. Serum T4 (or free T4) and TSH should be monitored every 1-2 months in the first year of life and every 2-3 months in the second and third years.

Etiological evaluation of primary congenital hypothyroidism cases

“…The prevalence of PCH is 1/2000-4000 in neonatal screening programs (1-3). The female/male ratio is 1.1-2:1 (3,8,9,(17)(18)(19)(20). In Turkey, the prevalence of PCH was found as 1/650 as a result of screening programs performed between 2008 and 2010 and the female/male ratio was similar (17).…”

“…According to the general opinion, subjects with transient PCH should be treated until the age of 3 years, though there are cases where treatment can be terminated earlier because transient thyroid hormone failure is in question (2). The rate of subjects diagnosed based on clinical findings is 5% because the diagnostic clinical findings in primary congenital hypothyroidism generally appear after the sixth postnatal week (2,7,8). PCH should be diagnosed and thyroxine replacement treatment should be initiated in the first two weeks to prevent mental retardation (1, 9).…”

Kocher-Debre-Semelaigne Syndrome: Response to Thyroxine Replacement Therapy

“…Inherited defects in hormone biosynthesis are rare causes of goitrous hypothyroidism and account for nearly 10-15% of cases. In most instances the defect is transmitted as an autosomal recessive trait [2]. Protean clinical manifestations result from the involvement of multiple systems as a result of deficiency of thyroid hormones.…”

Clinical and laboratory features of children and adolescents with congenital hypothyroidism due to dyshormonogenesis in southern Brazil

“…Several genes have been identified and mu tations have been recognized as causes of CH (1,2). Dyshormonogenesis is usually transmitted in an au tosomal recessive pattern (3). Clinical manifestations of CH caused by dyshormonogenesis are similar to those associated with thyroid dysgenesis, except for a familial incidence and a tendency to develop goi ter during the neonatal period or, more commonly, during childhood or adulthood.…”