Four new cases of congenital secondary hypothyroidism due to a splice site mutation in the thyrotropin-beta gene: phenotypic variability and founder effect.
Isolated TSH deficiency is a rare cause of congenital hypothyroidism. We here report four children from two consanguineous Turkish families with isolated TSH deficiency. Affected children who were screened at newborn age had an unremarkable TSH result and a low serum TSH level at diagnosis. Age at diagnosis and clinical phenotype were variable. All affected children carried an identical homozygous splice site mutation (IVS2 + 5 G--> A) in the TSHbeta gene. This mutation leads to skipping of exon 2 and a loss of the translational start codon without ability to produce a TSH-like protein. However, using specific monoclonal antibodies, we detected a very low concentration of authentic, heterodimeric TSH in serum, indicating the production of a small amount of correctly spliced TSH mRNA. By genotyping all family members with polymorphic markers at the TSHbeta locus, we show that the mutation arose on a common ancestral haplotype in three unrelated Turkish families indicating a founder mutation in the Turkish population. These results suggest that this TSHbeta mutation is among the more common TSHbeta gene mutations and stress the need for a biochemical and molecular genetic workup in children with symptoms suggestive of congenital hypothyroidism, even when the neonatal TSH screening is normal.
Borck
Guntram
G
Children's Hospital of the Johannes Gutenberg University, Mainz, Germany.
Topaloglu
A Kemal
AK
Korsch
Eckhard
E
Martiné
Ursula
U
Wildhardt
Gabriele
G
Onenli-Mungan
Neslihan
N
Yuksel
Bilgin
B
Aumann
Ulrich
U
Koch
Gerhard
G
Ozer
Guler
G
Pfäffle
Roland
R
Scherberg
Neal H
NH
Refetoff
Samuel
S
Pohlenz
Joachim
J
D000225:Adenine; D002648:Child; D002675:Child, Preschool; D003409:Congenital Hypothyroidism; D005260:Female; D018703:Founder Effect; D006147:Guanine; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D007037:Hypothyroidism / Q000097:blood / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D007438:Introns; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D013972:Thyrotropin / Q000097:blood; D037322:Thyrotropin, beta Subunit / Q000235:genetics*
D037322:Thyrotropin, beta Subunit; D006147:Guanine; D013972:Thyrotropin; D000225:Adenine