Refetoff Syndrome

Inherited condition resulting in clinical euthyroidism or hypothyroidism in the presence of elevated serum thyroxine levels. End-organ unresponsiveness to thyroid hormone. Other features include congenital deafness, goiter, and exophthalmos.

Thyroid Hormone Unresponsiveness; Thyroid Hormone Resistance.

It has been suggested that both autosomal dominant and recessive forms exist because of different mutations in the same gene. However, mutations that affect the TH receptors are called dominant-negative mutations.

Thyroid Hormone Resistance Syndromes may be classified as Generalized Thyroid Hormone Resistance (GTHR) or Pituitary Thyroid Hormone Resistance (PTHR). Although both GTHR and PTHR result from similar mutations, PTHR is selective in that only the pituitary gland is affected. Mutation of the c-erbA beta gene results in a beta-thyroid hormone receptor that is dominant and has an inhibitory effect on normal beta and alpha thyroid hormone receptors, rendering affected tissues refractory to the effects of thyroxine. The molecular mechanisms of this inhibitory effect are currently under investigation. GTHR is usually heterozygous (one mutant beta allele) The GTHR phenotype is variable and may reflect variable expression of mutant alleles or the presence of other genetic regulatory factors as yet undefined. Refetoff syndrome is caused by complete absence of the beta receptor. A variant in which patients are homozygous for the mutant beta allele (two dominant negative alleles expressed) is also described.

Elevated serum T4 and T3. Normal or moderately elevated serum thyroid-stimulating hormone, which is inappropriate in context of the elevated T4 and T3. Clinically euthyroid or hypothyroid. In PTHR, the clinical picture is of hyperthyroidism.

Goiter is common in GTHR. Delayed speech development, mental retardation, and delayed skeletal maturation represent subtle signs of hypothyroidism. Florid clinical signs and symptoms of hypothyroidism are unusual. Attention deficit disorder is commonly associated with GTHR. GTHR has been erroneously diagnosed as thyrotoxicosis on the basis of laboratory investigations; however, GTHR does not demonstrate depression of thyroid-stimulating hormone levels as is seen in thyrotoxicosis. Treatment is not required for GTHR except in the presence of growth retardation or delayed skeletal maturation. PTHR results in loss of negative feedback to the pituitary with normal peripheral tissue response to thyroxine causing clinical hyperthyroidism which has been treated successfully with d-thyroxine. The condition should be distinguished from a primary pituitary thyroid-stimulating hormone-secreting tumor.

Examine for signs of clinical hypothyroidism (GTHR) and hyperthyroidism (PTHR). Consider ECG in presence of bradycardia or history suggestive of dysrhythmia. Review and continue current drug therapy perioperatively. Review thyroid function.

Euthyroid patients should not cause great concern; however, the possibility of differential resistance to thyroxine between tissues exists. The occurrence of tachydysrhythmias under anesthesia may represent hyperthyroid effects on cardiac muscle requiring beta blockade. Overt clinical hypothyroidism (or hyperthyroidism) should be controlled in consultation with an endocrinologist prior to anesthesia. Regional anesthesia may be useful when the procedure permits.

Esmolol is probably the perioperative beta blocker of choice if signs of hyperthyroidism develop.