UMMS Affiliation

Department of Pediatrics, Division of Endocrinology

Publication Date


Document Type



Adolescent; Base Sequence; Cell Line; Cyclic AMP; DNA Mutational Analysis; Family Health; Female; *Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Hyperthyroidism; Male; Molecular Sequence Data; *Mutation; Protein Structure, Tertiary; Receptors, Thyrotropin


Endocrinology, Diabetes, and Metabolism | Pediatrics


Constitutively-activating germline mutations of the thyrotropin receptor (TSHR) gene are very rare and are considered the cause of hereditary nonautoimmune hyperthyroidism. We describe four affected individuals from a Caucasian family: a mother and her three children, and an unaffected father. The mother and her first two children presented in a similar manner: lifelong histories of heat intolerance, hyperactivity, fast heart rate, reduced energy, increased appetite, and scrawny build. They all developed goiter in childhood and showed a suppressed TSH and elevated thyroxine (T(4)). The last child, a 12-year-old female, presented with no clinical symptoms or palpable neck mass, but with a suppressed TSH, elevated T(4) and thyromegaly detected by ultrasound. Mutation analysis of the TSHR gene in all family members revealed a novel heterozygous germline mutation resulting in the substitution of phenylalanine (TTC) by serine (TCC) at codon 631 in transmembrane helix 6 in the mother and all three children. Functional characterization of this germline mutation showed constitutive activation of the G(s)-mediated cyclic adenosine monophosphate (cAMP) pathway, which controls thyroid hormone production and thyroid growth. Molecular characterization of F631S demonstrates that this activating mutation plays a key role in the development of hereditary hyperthyroidism in this family although the timing of onset of clinical manifestations in the subjects may depend on other, as yet unidentified, factors.

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This is a copy of an article published in Thyroid © 2006 copyright Mary Ann Liebert, Inc.; Thyroid is available online at:

DOI of Published Version



Benjamin U. Nwosu, Loukas Gourgiotis, Marvin C. Gershengorn and Susanne Neumann. Thyroid. May 2006, 16(5): 505-512. doi:10.1089/thy.2006.16.505. Link to article on publisher's site

Journal/Book/Conference Title

Thyroid : official journal of the American Thyroid Association

Related Resources

Link to Article in PubMed

PubMed ID