3 years ago

Mild TSH resistance: Clinical and hormonal features in childhood and adulthood

Luca Persani, Micol Sonnino, Marianna Di Frenna, Tiziana Filippis, Giulia Gelmini, Maria Cristina Vigone, Giovanna Weber, Marco Bonomi, Silvana Caiulo, Stefano Mora, Fabiana Guizzardi
Objective Mutations in TSH receptor (TSHR) are associated with TSH resistance, a genetic defect characterized by a heterogeneous phenotype ranging from severe hypothyroidism to subclinical hypothyroidism (SCH). We assessed the clinical and hormonal pattern of TSHR variants in a series of pediatric patients, and the long-term outcome of growth, biochemical measurements of metabolism, and neuropsychological functions in TSHR mutations carriers. Design Observational, retrospective study. Patients Thirty four children (age 7 days to 11 years) and 18 adult carriers of TSHR variants. Measurements The TSHR gene was sequenced by PCR-amplified direct sequencing in 111 pediatric patients with slight to moderate elevation of TSH and normal FT4 levels. The study focused on the: auxological and biochemical parameters, thyroid ultrasound, bone age, bone mineral density (BMD), and intellectual outcome (IQ) were collected during the long follow-up (1-15 years). Results Seventeen different TSHR variants (eight novel) were identified in 34 of the 111 pediatric patients, with a high prevalence of familial cases (27/34). Neonatal screening for congenital hypothyroidism was positive in half of the TSHR carriers. Growth, IQ, BMD, and biochemical parameters were normal in all subjects. Twenty patients received L-T4 replacement therapy, in all cases before genetic analysis. After re-evaluation, six patients resumed L-T4 therapy: they were compound heterozygous, or single heterozygous and with associated conditions at risk of thyroid impairment (SGA). No adults presented clinical features consistent with impaired thyroid function. Conclusions Children carriers of TSHR variants, regardless of L-T4 treatment, show regular growth and neuropsychological development, with no evident biochemical and US alterations.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/cen.13387

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