Clinical trial NCT00747760: TSH Receptor Mutations Among a Consanguineous Community
Official title: The Prevalence of TSH Receptor Mutation Among the Arab Population of Israel
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Hypothyroidism
Keywords: TSH Receptor, resistance TSH, Hyperthyrortropinemia
Lead sponsor: HaEmek Medical Center, Israel
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
First posted: 2008-09-05
Enrollment: 209
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Subjects belonging to extended family of the index case

Brief summary: Resistance to thyrotropin (RTSH) is a condition of impaired responsiveness of the thyroid gland to TSH, characterized by elevated TSH, low or normal thyroid hormone levels, and hypoplastic or normal-sized thyroid gland.

The aim of the present study was to evaluate the clinical course over time,the genotype-phenotype association and the frequency of two different TSH-receptor (TSHR) mutations in a highly consanguineous population of the town of Um-El-Fahem.

Detailed description: Resistance to thyrotropin (RTSH) is a syndrome involving reduced sensitivity to TSH. It is characterized by elevated TSH, absence of goiter (normal or hypoplastic thyroid gland) and normal to very low levels of thyroid hormones. The TSH-receptor (TSHR) gene is located on chromosome 14q31 and it consists of extracellular, trans-membrane and intracellular domains. Mutation in the TSHR may cause either gain or loss of function of the receptor. Loss-of-function mutations are autosomal-recessively inherited and lead to a spectrum of phenotypes, ranging from mild euthyroid hyperthyrotropinemia to severe congenital hypothyroidism (CH). Insensitivity to TSH depends on both the severity and location of the TSHR mutations. Since the first report of familial euthyroid hyperthyrotropinemia caused by a TSHR mutation, several cases of loss-of-function mutations of the TSHR have been reported however only a few reports on the outcome of patients affected with TSHR mutations. Whether the condition of euthyroid hyperthyrotropinemia leads to clinical hypothyroidism, remains stable or normalizes over time has yet to be elucidated. We recently described a unique novel TSHR-inactivating mutation located at the third extracellular loop that preferentially affected the inositol phosphate (IP) pathway in three sisters of Arab-Muslim decent that presented with euthyroid hyperthyrotropinemia. Further analysis of the extended family revealed additional members with TSHR syndrome phenotype carrying two different TSHR mutations. All the affected subjects live in the same town. The aim of the present study was to evaluate the clinical course over time, the genotype-phenotype association and the frequency of these two different TSHR mutations among the highly consanguineous population of the town of Um El Fahem.

Eligibility criteria: Inclusion Criteria:

* Subjects belonging to extended family of the index case

Exclusion Criteria:

Primary outcomes:
measure: Two specific TSHR mutations
timeFrame: Finished
Secondary outcomes:
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Samuell Refetoff
state: Illinois
city: Afula
country: Israel
facility: Ha'Emek Medical Center
Study officials:
affiliation: Ha'Emelk Medical Center,Afula, Israel
name: Yardena Tenenbaum-Rakover, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The University of Chicago, Chicago, Il, USA
name: Samuel Refetoff, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Grasberger H, Van Sande J, Hag-Dahood Mahameed A, Tenenbaum-Rakover Y, Refetoff S. A familial thyrotropin (TSH) receptor mutation provides in vivo evidence that the inositol phosphates/Ca2+ cascade mediates TSH action on thyroid hormone synthesis. J Clin Endocrinol Metab. 2007 Jul;92(7):2816-20. doi: 10.1210/jc.2007-0366. Epub 2007 Apr 24.