Compound Heterozygous and Homozygous Mutations of the TSHβ Gene as a Cause of Congenital Central Hypothyroidism in Europe

Abstract

Background: Thyroid hormones are crucial for normal growth and central nervous system development. In recent years, germline variants of the TSHβ subunit gene have been identified as a cause of congenital TSH deficiency. Methods: We performed a genetic and clinical study in children from four European countries diagnosed with congenital isolated central hypothyroidism. Results: TSHβ gene analysis revealed compound heterozygosity for 145C→T (Q49X) and 313delT (C105Vfs114X) in 1 infant and homozygous mutation 313delT (C105Vfs114X) in 5 patients. Although all presented with typical symptoms of hypothyroidism, diagnosis and treatment was delayed until 3–5 months in 5 of 6 patients. In a longitudinal sibpair analysis, thyroxine substitution initiated immediately after birth was effective to prevent developmental delay and growth retardation. Conclusion: Clinical awareness is required to detect hypothyroidism due to TSHβ mutations, which is not identified by TSH-based newborn screening. TSHβ variants C105Vfs114X and Q49X are the most frequent cause of this severe disorder in Europe, now for the first time observed in compound heterozygous state.

A Novel Deletion in the Thyrotropin Beta-Subunit Gene Identified by Array Comparative Genomic Hybridization Analysis Causes Central Congenital Hypothyroidism in a Boy Originating from Turkey

“…So far, more than 30 families with mutations in the TSHβ gene have been described [3,4,5,6,7,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31]. Whereas in many other reported patients, some residual TSH concentration in serum was detectable, our patient had an undetectably low TSH serum concentration, suggesting an absolute lack of TSH.…”

“…In contrast to primary hypothyroidism, patients with ICCH are not identified by the majority of neonatal screening programmes, which are based on the detection of hyperthyrotropinaemia [2]. Thus, most patients with ICCH are diagnosed later in life, which, in some cases, can result in severe growth failure and intellectual disability [3,4,5,6]. Miyai et al [7] were the first to report familial congenital hypothyroidism due to thyrotropin (TSH) deficiency.…”

AMPD1 gene mutations are associated with obesity and diabetes in Polish patients with cardiovascular diseases

“…TSPAN2 encodes a membrane protein classified as one of the tetraspanins, which participate in the transduction of signals controlling cell development, activation, growth, and movement. TSHB encoding the beta subunit of thyrotropic hormone (TSH) is particularly interesting, since its mutations lead to congenital secondary hypothyroidism (Karges et al 2004), while both hypo- and hyperthyroidism are recognized risk factors for cardiovascular diseases. We have not found any reports analyzing the association between polymorphisms of the above-mentioned genes and cardiovascular diseases.…”

Congenital Thyrotropin Deficiency-From Discovery to Molecular Biology, Postgenome and Preventive Medicine-

“…The mutations were homozygous or compound heterozygous. For instance, in the case reported by Karges et al [30], mutations were found at codon 49 in one allele and 105 in the other allele in which cytocine (C) to thymine (T) transition at codon 49 resulted in alteration of glutamine (Gln) (Q) to stop (termination) codon (X) and deletion of one base pair T at codon 105 resulted in alteration of cysteine (Cys) (C) to valine (Val) (V) followed by frameshift (fs) and stop codon (X) at 114. These were described as [Q49X]/ [C105delT (fs 114X)].…”