Permanent congenital hypothyroidism (ORPHA:226292)
Permanent congenital hypothyroidism is a type of congenital hypothyroidism (CH; see this term), a thyroid hormone deficiency present from birth.
Epidemiology
Incidence of permanent CH varies widely with geographic location with reported incidences between 1/800 and 1/10,000 live births and an average incidence of 1/3,000 live births.
Clinical description
The clinical manifestations are often subtle, probably as a result of trans-placental passage of some maternal thyroid hormone or due to the fact that many infants have some thyroid production of their own.More specific symptoms and signs often 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 CH results in severe intellectual deficit and short stature.
Etiology
Permanent CH has a variety of primary, secondary and peripheral causes and may occur as part of a syndrome (primary, secondary, peripheral or syndromic hypothyroidism; see these terms). Primary causes include defects in thyroid gland development (thyroid dysgenesis; see this term), deficiencies in thyroid hormone production (thyroid dyshormonogenesis; see this term), or defects of thyroid-stimulating hormone (TSH) binding or signal transduction (due to TSH receptor mutations; see this term). Secondary or central CH is most commonly due to a pituitary defect. Other causes include isolated TSH deficiency (see this term), which is transmitted in an autosomal recessive manner and is caused by mutations in the TSH beta subunit gene (1p13), by thyrotropin releasing hormone (TRH) resistance (see this term), which results from mutations in the TRH receptor gene (TRHR; 8q23), or by mutations in genes regulating pituitary gland development (see this term) including HESX1, LHX3, LHX4, POU1F1 and PROP1 (3p21.2-p21.1, 9q34.3, 1q25, 3p11 and 5q). Peripheral CH (see this term) may be caused by peripheral resistance to the action of thyroid hormone (see this term), of which 90% of cases are due to dominantly inherited mutations in genes encoding for thyroid hormone receptor beta. The majority of these individuals have normal thyroid function but some hypothyroid individuals have been described. Peripheral hypothyroidism may also be caused by defects in thyroid hormone transport, such as in Allan-Herndon-Dudley syndrome (see this term) where X-linked peripheral hypothyroidism is associated with intellectual deficiency and neurologic abnormalities including quadriplegia. Permanent CH may also be associated with a syndrome such as Pendred or Bamforth syndromes among others (see these terms).
Management and treatment
Recombinant human TSH (rhTSH) may be of use in the future confirmation of permanent CH. If at any time after the first 6 months of age, the serum TSH rises above 20mU/L due to undertreatment, permanent CH is assumed. If permanent CH has not been established by 2-3 years of age a 30 day trial off l-thyroxine therapy is recommended. If serum or free T4 is low and TSH elevated, permanent CH is confirmed and the patient is restarted on therapy.

                            Last update: 
                            August 2010


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