Ebner and colleagues [1] described the clinical and laboratory features of a six-member family with Graves disease and encouraged reports of other clusters.

Patient 1

A 27-year-old man developed symptoms of hyperthyroidism in December 1987, and on presentation in May 1988 he had a small (40-g), diffuse goiter. He had elevated T4 (251 nmol/L) and T3 (6.7 nmol/L) levels and homogeneous and elevated uptake on thyroid scan (88% at 6 hours and 80% at 24 hours). Thyrotropin-binding inhibitory immunoglobulins (TBII) were present at a low titer (12%; normal, < 10%). He was started on tapazole, 30 mg daily, and his thyroid function returned to normal in 2 months. Tapazole was tapered and stopped after 1 year. Several months later, he had a recurrence, and tapazole was restarted and maintained. His family history was negative for thyroid diseases; his HLA haplotype is HLA-A26 A11, HLA-BW22.

Patient 2

A 26-year-old woman, the fiancee of Patient 1 since 1985, developed fatigue and increased frequency of bowel movements in February 1988, 2 months after her boyfriend's symptoms began. In July 1988, she showed signs of hyperthyroidism and a diffuse nontender 60-g goiter with a faint bruit. Total and free plasma thyroid hormones were elevated (T4, 229 nmol/L; T3, 4.6 nmol/L); antithyroglobulin and antithyroid peroxidase antibodies were not detected, but TBII were present (26%). She was treated with tapazole and showed rapid improvement with normalization of thyroid function tests in 3 months. Tapazole was gradually tapered from 30 mg to 5 mg daily and was discontinued in October 1990; although she still has a goiter, she remains in remission. Her HLA haplotype is HLA-A9, HLA-B14 B35, HLA-CW4. A sister and two uncles had unspecified thyroid diseases.

Both patients were tested for Yersinia enterocolitica infection in February 1990; stool cultures were negative and only Patient 1 showed a low titer of serum antibodies.

We could not determine any factor that triggered Graves disease or goiter (for example, exposure to iodine or a specific stressful event). Their HLA haplotypes are not those associated with an increased risk for Graves disease.

Applying the methods suggested by Ebner [1], we estimate the number of affected couples living together in Italy to be from 7 to 550 of 19 million and the chance of developing Graves disease within 2 months of each other to be less than 1 in 1 million. It seems likely that environmental factors play an important role in some cases of Graves disease.