Non-autoimmune subclinical hypothyroidism due to a mutation in TSH receptor: report on two brothers

Manuela Cerbone,Patrizia Agretti,Nicola Improda,Mariacarolina Salerno,Francesca Santamaria,Massimo Tonacchera,Claudio Pignata,Giuseppina De Marco

doi:10.1186/1824-7288-39-5

Abstract

Subclinical hypothyroidism (SH) is a condition characterized by a mild persistent thyroid failure. The main cause is represented by autoimmune thyroiditis, but mutations in genes encoding proteins involved in TSH pathway are thought to be responsible for SH, particularly in cases arising in familial settings. Patients with the syndrome of TSH unresponsiveness may have compensated or overt hypothyroidism with a wide spectrum of clinical and morphological alterations depending on the degree of impairment of TSH-receptor (TSH-R) function. We describe the case of two brothers with non autoimmune SH carrying the same heterozygous mutation in the extracellular domain of TSH-R and presenting with different clinical, biochemical and morphological features. The first one had only a slight persistent elevation of TSH, a normal thyroid ultrasound and did never require l- thyroxine (L-T4) replacement treatment. The second one had a neonatal persistent moderate TSH levels increase associated with a thyroid gland hypoplasia and was treated with L-T4 since the first months of life.These two cases support the recent association of TSH-R mutations inheritance as an autosomal dominant pattern with variable expressivity and suggest that the decision to start replacement therapy in patients with persistent SH due to TSH resistance should be individualized.

Highlights

Subclinical hypothyroidism (SH) is a biochemical condition characterized by serum levels of TSH above the statistically defined upper limit of reference range, with normal concentrations of thyroid hormones and without severe clinical features of hypothyroidism [1]
The neonatal history was normal, he was not affected by any chronic disease, and was not taking any drugs potentially interfering with thyroid function
The mutation R109Q in the extracellular domain of TSH-xR, found in our two brothers, was first described by Clifton-Bligh et al in a child compound heterozygote for another missense mutation in the fourth transmembrane segment of receptor. This child presented with markedly increased serum TSH concentrations and low normal thyroid hormone levels identified after a positive result on neonatal screening for congenital hypothyroidism (CH), normal thyroid morphology and treated with l- thyroxine (L-T4) since 8 weeks of age [17]

Summary

Background

Subclinical hypothyroidism (SH) is a biochemical condition characterized by serum levels of TSH above the statistically defined upper limit of reference range, with normal concentrations of thyroid hormones and without severe clinical features of hypothyroidism [1]. Autoimmune thyroiditis, morphological anomalies of thyroid gland, iodine deficiency and pseudohypoparathyroidism, were excluded by clinical, biochemical and ultrasound evaluation He was not treated with L-T4 due to the slight elevation of TSH (ranging always between 4.5 and 10 μU/ml) and was closely monitored with clinical and laboratory examinations. At the age of 10 years, because of the persistence of SH and the familiarity for thyroid diseases, molecular analysis for TSH-R was performed. During the follow-up, despite a persistent slight elevation of TSH, he never required L-T4 replacement therapy He always presented a normal growth and bone maturation. TSH levels raised in a month over 10 μU/ml and persisted elevated in the following 3 measurements, ranging between 13 and 18 μU/ml He reported clinical symptoms of hypothyroidism such as fatigue, mood changes and impaired concentration in addition to significant weight gain. The puberty began and progressed regularly but the evaluation of IQ at the age of 16 years was slightly low (IQ 80)

Findings

Discussion

Conclusions