Constitutively active germline mutation of the thyrotropin receptor gene as a cause of congenital hyperthyroidism☆,☆☆,★,★★
Section snippets
Case Report
The family history was uneventful with respect to thyroid diseases (Fig. 1) except for two children and their mother, a 24-year-old woman, who received antithyroid medications since she was 3 years old. With the suspected diagnosis of Graves' disease, a partial thyroidectomy was performed, but a recurrent multinodular goiter developed, which was treated by further surgery. Thyroid autoantibodies were never detected (Table I). The mother experienced a third recurrence with clinical signs of
Methods
Lymphocytes from 10 ml heparinized blood were obtained from all family members and separated using a ficoll gradient (Ficoll-paque, Pharmacia, Germany). DNA was extracted from lymphocytes as follows: Cells were lysed overnight at 53° C in a lysis buffer (400 mmol/L NaCl, 10 mmol/L Tris, pH 8.2, 2 mmol/L EDTA, 0.2 mg/ml protease K, and 0.5% sodium dodecylsulfate). Proteins were subsequently removed using phenol/chloroform and genomic DNA was resuspended in Tris (10 mmol/L)/EDTA (1 mmol/L) buffer
Results
The levels of thyroxine, triiodothyronine, and TSH of all family members are shown in Table I. No member of the family had measurable antibody levels against the thyroid-specific antigens thyroglobulin, thyroid peroxidase, and the TSH receptor. Furthermore, stimulating TSH receptor antibodies or cytotoxic antibodies were absent. The elevation of thyroglobulin autoantibodies in the father and grandfather had no clinical relevance as shown by further investigations.
Sequence analysis of the
Discussion
The TSH receptor is a member of the large group of G protein coupled receptors characterized by seven transmembrane helices connected by three extracellular and three intracellular loops. Like two other members of the glycoprotein hormone receptors, the luteinizing hormone/human chorionic–gonadotropin receptor and the human follicle–stimulating hormone receptor, the TSH receptor has a long extracellular aminoterminal domain that has been shown to play a role in specific hormone recognition.
Acknowledgements
We acknowledge Dr. Anette Grüters, MD, Berlin, Germany, for measuring cytotoxic antibodies and Dr. Rendl, MD, Würzburg, Germany, for performing standard thyroid function tests.
References (30)
- et al.
Familial hyperthyroidism including two siblings with neonatal Graves’ disease
J Pediatr
(1971) - et al.
Molecular cloning, sequence and functional expression of the cDNA for the human thyrotropin receptor
Biochem Biophys Res Com
(1989) Molecular mechanisms of membrane receptor desensitization
Biochim Biophys Acta
(1993)- et al.
Dual activation by thyrotropin of the phospholipase C and cyclic AMP cascades in human thyroid
Mol Cell Endocrinol
(1987) - et al.
Constitutive activation of the alpha 1B-adrenergic receptor by all amino acid substitutions at a single site: evidence for a region which constrains receptor activation
J Biol Chem
(1992) Pathogenesis and therapy of neonatal Graves’ disease
Am J Dis Child
(1976)- et al.
Fetal and neonatal hyperthyroidism and hypothyroidism due to maternal TSH receptor antibodies
Thyroid
(1992) - et al.
Hereditary aspects of Graves’ disease in infancy and childhood
J Pediatr
(1972) - et al.
Congenital Graves’ disease
Am J Dis Child
(1976) - et al.
Familial hyperthyroidism without evidence of autoimmunity
Acta Endocrinol
(1982)
Behavior of thyroid tissue from patients with Graves’ disease in nude mice
J Clin Endocrinol Metab
Germline mutations in the thyrotropin receptor gene cause non-autoimmune autosomal dominant hyperthyroidism
Nat Genet
A neomutation of the thyroid-stimulating hormone receptor in a severe neonatal hyperthyroidism
J Clin Endocrinol Metab
Brief report: congenital hyperthyroidism caused by a mutation in the thyrotropin-receptor gene
N Engl J Med
Functional characteristics of three new germline mutations of the thyrotropin receptor gene causing autosomal dominant toxic thyroid hyperplasia
J Clin Endocrinol Metab
Cited by (54)
A Case of Familial Nonautoimmune Hyperthyroidism During Pregnancy
2020, AACE Clinical Case ReportsCitation Excerpt :This indicated that the patient would have already had hyperthyroidism at 35 weeks of gestation. In addition, 10 cases had been reported to have been diagnosed up to 1 year after the birth in families with FNAH (7,9–15). Symptoms leading to the diagnosis of hyperthyroidism included diarrhea, loss of body weight, and tachycardia.
Receptor Transduction Pathways Mediating Hormone Action
2020, Sperling Pediatric Endocrinology: Expert Consult - Online and PrintInheritable and sporadic non-autoimmune hyperthyroidism
2017, Best Practice and Research: Clinical Endocrinology and MetabolismCitation Excerpt :Probably hyperthyroidism running in families is sometimes misdiagnosed as Graves disease. Until the last update from the TSH Receptor Mutation Database, 28 families with FNAH [22–49] and 16 cases with PSNAH [8,50–64] have been published. Women are affected slightly more frequently by the familial form (83 women compared to 69 men), but not by the sporadic form.
Receptor transduction pathways mediating hormone action
2014, Pediatric Endocrinology: Fourth EditionGenetics and phenomics of inherited and sporadic non-autoimmune hyperthyroidism
2010, Molecular and Cellular EndocrinologyConstitutive activation of G protein-coupled receptors and diseases: Insights into mechanisms of activation and therapeutics
2008, Pharmacology and Therapeutics
- ☆
From the Institute for Pharmacology and Toxicology and Children's Hospital of the University of Wuerzburg, University Clinic of Internal Medicine, Bochum, Germany
- ☆☆
The study was supported by grants of the Deutsche Forschungsgemeinschaft (DFG) to KOS (Schw 573 /1-1 and 1-2) and to MD (De 407/ 7-1) and by Forum Schilddrüse.
- ★
Reprint requests: K.O. Schwab, MD, Department of Pediatrics, University of Freiburg, Mathildenstr. 1, D-79106 Freiburg, Germany.
- ★★
9/21/81915