Congenital hypothyroidism due to developmental anomaly (ORPHA:95711)
Thyroid dysgenesis is a type of primary congenital hypothyroidism (see this term), a permanent thyroid hormone deficiency that is present from birth.
Epidemiology
Prevalence is estimated at about 1/4,700. Thyroid dysgenesis causes 85% of permanent congenital hypothyroidism (see this term) in iodine-sufficient countries. Thyroid dysgenesis occurs in three major forms: thyroid ectopy, athyreosis and thyroid hypoplasia (see these terms). Thyroid ectopy causes two-thirds of thyroid dysgenesis while athyreosis and thyroid hypoplasia account for the other third. Thyroid ectopy is twice as common in females as in males.
Clinical description
Clinical manifestations of thyroid dysgenesis are often subtle or not present at birth, probably as a result of trans-placental passage of some maternal thyroid hormone or due to some residual infant thyroid hormone production. Goiter is always absent. More specific symptoms and signs do not develop until several months of age. Common clinical features and signs include decreased activity and increased sleep, feeding difficulty and constipation, prolonged jaundice, myxedematous facies, large fontanels (especially posterior), macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Slow linear growth and developmental delay are usually apparent by 4-6 months of age. Without treatment thyroid dysgenesis results in severe intellectual deficit and short stature. Thyroid ectopy refers to an ectopic location of the thyroid gland, while thyroid athyreosis refers to the complete absence of thyroid tissue and thyroid hypoplasia refers to underdevelopment of the thyroid. Thyroid dysgenesis may also occur as thyroid hemiagenesis (see this term), where half of the gland is missing. In the majority of cases thyroid hemiagenesis is asymptomatic.
Etiology
Around 2% of cases have been shown to be familial and may be caused by mutations in the FOXE1,  NKX2-1, NKX2-5 or PAX8 genes (9q22, 14q13, 5q34 and 2q12-q14). Mutations that result in complete inactivation of the TSHR gene (14q31) can present with athyreosis or thyroid hypoplasia.
Diagnostic methods
In countries with newborn screening programs (with either a primary thyroxine (T4)-follow-up TSH or primary TSH test), infants are diagnosed after detection by screening tests. Diagnosis should be confirmed by elevated serum TSH level and low T4 or free T4 level. The type of thyroid dysgenesis can be determined using thyroid radionuclide uptake and scan and thyroid ultrasonography. Genetic testing can also be used.
Differential diagnosis
Differential diagnoses include other forms of congenital hypothyroidism (see this term), which can be excluded by evidence on imaging studies of the absence or underdevelopment of the thyroid gland.
Antenatal diagnosis
Genetic counseling and antenatal diagnosis can be offered in families where a genetic defect has been identified.
Genetic counseling
Thyroid dysgenesis is generally thought to be sporadic. However, recent evidence points to the possibility of a genetic component.
Management and treatment
It is not necessary to know the underlying etiology when initiating hormone treatment. Levothyroxine is the treatment of choice; the recommended starting dose is 10-15mcg/kg/day. The immediate goals of treatment are to raise the serum T4 above 130 nmol/L (10 ug/dL) as rapidly as possible; with these starting doses, serum TSH usually normalizes in 2-4 weeks. Frequent laboratory monitoring in infancy is essential to ensure optimal neurocognitive outcome. Serum TSH and T4 or free T4 should be measured every 1-2 months in the first 6 months of life, every 3 months between 6 months and 3 years of age, and 4 weeks after any dose change.
Prognosis
The prognosis of infants started on treatment early is excellent, with IQs similar to sibling or classmate controls. Lower neurocognitive outcomes may occur in those infants started after more than 30 days of age, on lower l-thyroxine doses than currently recommended, and in those infants with more severe hypothyroidism.

                            Last update: 
                            August 2010


                            - Expert reviewer(s): 
                            Dr Stephen LAFRANCHI  - Dr Maynika RASTOGI