title: Long-term outcome of loss-of-function mutations in thyrotropin receptor gene.
abstract: BACKGROUND
  Loss-of-function mutations in the thyrotropin receptor (TSHR) gene lead to resistance to TSH (RTSH) presenting with either congenital hypothyroidism (CH) or subclinical hypothyroidism (SCH). Despite several reports of patients with TSHR mutations, data on the long-term outcome of this condition are limited, and no consensus exists on the need for hormone replacement therapy. The aim of the present study was to assess the long-term outcome in children and adolescents with RTSH due to TSHR mutations.
  
  
  METHODS
  The TSHR gene was sequenced in 94 subjects (aged 3 days-21 years) with either nonautoimmune SCH or CH with RTSH.
  
  
  RESULTS
  Twenty-seven subjects (29%) carried mutations in TSHR. Fifteen infants were identified by neonatal screening, and the other 79 patients were detected in the process of testing for various other conditions or because of family occurrence of thyroid test abnormalities. Six different mutations were identified: c.484C>G (p.P162A), c.202C>T (p.P68S), c.790C>T (p.P264S), c.269A>C (p.Q90P), c.1957C>G (p.L653V), and c.1347C>T (p.R450C). Twelve subjects were homozygous, three were compound heterozygous, and 12 were heterozygous. Mean serum TSH levels at diagnosis and at last visit were significantly higher in patients with TSHR mutations than in those without mutations (29.04 vs. 14.15, p=0.002; 31.73 vs. 6.19, p<0.0001, respectively). Homozygous patients had a more severe phenotype (TSH 53.6 vs. 9.24, p<0.0001). Mean serum free thyroxine (fT4) levels at the last visit were significantly lower than at the first visit in the homozygous individuals (p=0.05) for a follow-up period of as long as 11 years. Heterozygous subjects had only mild hyperthyrotropinemia with stable TSH levels. However, homozygous subjects showed a trend toward increased TSH and decreased fT4 with time.
  
  
  CONCLUSIONS
  SCH in heterozygotes with TSHR mutations is a stable compensated condition with an appropriately adjusted set point for pituitary-thyroid feedback that does not require replacement therapy. However, homozygous subjects, with incompletely compensated SCH, show reduced fT4 levels over time and may require levothyroxine treatment. Replacement therapy should be considered on an individual basis, and long-term follow up is recommended.
authors.affiliation: 1 Pediatric Endocrine Unit, Ha'Emek Medical Center , Afula, Israel .
authors.forename: Yardena
authors.initials: Y
authors.lastname: Tenenbaum-Rakover
authors.forename: Shlomo
authors.initials: S
authors.lastname: Almashanu
authors.forename: Ora
authors.initials: O
authors.lastname: Hess
authors.forename: Osnat
authors.initials: O
authors.lastname: Admoni
authors.forename: Ahmad
authors.initials: A
authors.lastname: Hag-Dahood Mahameed
authors.forename: Naama
authors.initials: N
authors.lastname: Schwartz
authors.forename: Stavit
authors.initials: S
authors.lastname: Allon-Shalev
authors.forename: Dani
authors.initials: D
authors.lastname: Bercovich
authors.forename: Samuell
authors.initials: S
authors.lastname: Refetoff
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003409:Congenital Hypothyroidism / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007037:Hypothyroidism / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D015997:Neonatal Screening; D011989:Receptors, Thyrotropin / Q000235:genetics*; D013960:Thyroid Function Tests; D013961:Thyroid Gland / Q000503:physiopathology; D013972:Thyrotropin / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D011989:Receptors, Thyrotropin; D013972:Thyrotropin