Variation in phenotypic appearance of Graves' disease: effect of genetic anticipation and duration of complaints.
OBJECTIVE
Both genetic and environmental factors contribute to susceptibility of Graves' disease. In this study, we evaluated whether the duration of symptoms or a positive family history of autoimmune thyroid disease (AITD) are related to specific phenotypes in patients with a first episode of Graves' hyperthyroidism (GH).


METHODS
Cross-sectional multicentre observational study.


METHODS
Two hundred and sixty-three consecutive untreated patients (mean age (+/-s.d.) 42.6+/-12.4 years; range 16-79 years) with a first episode of GH were included. Biochemical and clinical severity of GH was evaluated. Participants were asked to complete questionnaires about environmental factors (smoking behavior, use of estrogens, stress etc.), the duration of symptoms (interval between start of symptoms and date of referral) and family history for AITD. We ascertained the autoimmune nature of thyroid disease in affected relatives. Family history scores (FHS; high score indicating a close genetic relationship and/or a large number of affected relatives) were calculated for patients with a positive family history for AITD.


RESULTS
The peak incidence for the diagnosis of GH was 2-3 months after onset of symptoms (32% of patients). Duration of symptoms was negatively associated with age (P for trend=0.04). A positive family history for AITD was present in 42.6% of patients. Patients with the highest FHS were more often male (P=0.01) while age at onset was lower (P=0.02) compared to patients with a lower FHS. Among patient groups with different FHS, no differences were found in exposure to environmental factors, nor in clinical or biochemical severity of hyperthyroidism.


CONCLUSIONS
Our study does not support the hypothesis that a short duration of thyrotoxic symptoms until diagnosis is related to more severe hyperthyroidism in Graves' disease. We have found supporting evidence for the existence of genetic anticipation in Graves' disease by means of a lower age of onset in the group with the highest FHS.
Department of Endocrinology and Metabolism Laboratory of Endocrinology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. x.g.vos@amc.nl
Xander G
XG
Vos
Natalie
N
Smit
Erik
E
Endert
Jan G P
JG
Tijssen
Wilmar M
WM
Wiersinga
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D020132:Anticipation, Genetic; D004777:Environment; D005192:Family Health; D005260:Female; D006111:Graves Disease / Q000235:genetics* / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012720:Severity of Illness Index; D013967:Thyroiditis, Autoimmune / Q000235:genetics / Q000503:physiopathology; D055815:Young Adult