Congenital Central Isolated Hypothyroidism Caused by a Homozygous Mutation in the TSH-β Subunit Gene

Abstract

We report a Belgian girl born in 1983 with isolated thyrotropin (TSH) deficiency. Hypothyroidism without goiter was diagnosed at the age of 2 months, with extremely low total thyroxine (T4) at 0.3 microg/dL (4 nmol/L; N[normal]: 5.6-11.4 microg/dL). Basal TSH, only moderately elevated at 14.8 mU/L (N: 0-5.3; competitive radioimmunoassay, RIA), increased to 18.2 mU/L after thyrotropin-releasing hormone (TRH) stimulation, whereas prolactin increased normally. At age 15 years, after withdrawal of levothyroxine (LT4) therapy for 6 weeks, TRH stimulation slightly increased serum TSH using two immunometric assays, from less than 0.03 to 0.07 and from 0.2 to 0.3 (a monoclonal and polyclonal antibody), and from 1.9 to 4.1 mU/L using a polyclonal TSH antibody and iodinated recombinant TSH. Sequencing of the TSH-beta subunit gene revealed a homozygous single nucleotide deletion in codon 105 producing a frame shift that results in a truncated TSH-beta with nonhomologous 9 carboxyterminal amino acids and a loss of the 5 terminal residues. This mutation was previously reported in one Brazilian and two German families. The abnormal, and presumably biologically inactive, TSH can be detected in serum using appropriate antibodies. Its relatively small amount in serum is due to either reduced secretion or rapid degradation. The occurrence of the same mutation in three families of different ethnic origin suggests that this mutation may be prevalent in the population. Common ancestry or de novo mutations in a hot spot cannot be excluded. Finally, we must be aware that neonatal screening of congenital hypothyroidism based on blood spot TSH measurement will not detect this rare but severe genetic defect.

Thyrostimulin, but Not Thyroid-stimulating Hormone (TSH), Acts as a Paracrine Regulator to Activate the TSH Receptor in Mammalian Ovary

“…However, its exact roles are still unknown. Patients with lost-of-function mutations of TSH␤ exhibit congenital central hypothyroidism (33,34), whereas Gpb5-null mice show no overt thyroid-related phenotype (8,35). Distinct from TSH expressed in thyrotrophs, thyrostimulin expression in the anterior pituitary is located at the corticotrophs, where its release has been demonstrated not to be in response to thyrotropin-releasing hormone (8,9).…”

Thyrostimulin, a heterodimer of two new human glycoprotein hormone subunits, activates the thyroid-stimulating hormone receptor

“…Although thyrostimulin was found to be a potent stimulator of thyroid cell functions in vitro and in vivo, its exact role in thyroid physiology is still unknown. TSH-β loss-of-function mutations have been found in patients with congenital central hypothyroidism (21)(22)(23)(24). Because these patients exhibited defective thyroid functions, it is unlikely that thyrostimulin participates in the TRH-TSH-T4 feedback loop to substitute the thyroid action of TSH in adult life.…”

The C105fs114X Is the Prevalent Thyrotropin Beta-Subunit Gene Mutation in Argentinean Patients with Congenital Central Hypothyroidism

“…Congenital isolated thyrotropin (TSH) deficiency is an unusual condition, with a prevalence from 1/30,000 to 1/50,000 newborns, characterized by low levels of both thyroid hormones and TSH and usually presenting early typical signs of severe hypothyroidism [1, 2, 3, 4, 5, 6, 7, 8, 9, 10]. Patients with this disorder are not detected by neonatal screening programs based on TSH measurements, which is frequently in the low to normal range.…”

“…Five different β-TSH mutations have been described so far: (1) a missense G29R mutation in exon 2, in 5 Japanese consanguineous families [12], (2) a nonsense mutation at codon 12 (E12X) in exon 2, in 2 consanguineous Greek families [4], (3) a nonsense mutation at codon 49 (Q49X) in exon 2, in an Egyptian consanguineous patient [3]and in 2 consanguineous Turkish siblings [5], (4) a mutation in the donor splice site of intron 2 of the β-TSH gene (IVS2 +5; G>A), in a consanguineous German family [6], and (5) a single base pair deletion in exon 3 (822delT) resulting in the substitution of cysteine 105 for valine and a frameshift with the appearance of a premature stop codon at position 114 (C105fs114X). This last mutation is the most frequently reported, is less geographically restricted and has been described in 2 consanguineous Brazilian families [2], 1 Belgian family [7], 3 unrelated German families with 5 affected individuals [8, 9], 2 brothers from the USA [13]and in 2 unrelated Swiss families [10]. …”