“ICSF1 involvement in central hypothyroidism is an important discovery because it creates inroads into our understanding of this rare syndrome, as well as new avenues by which it might be possible one day to control thyroid and testicular function,” said Douglas Forrest, PhD, of the National Institute of Diabetes and Digestive and Kidney Diseases, and Program Co-Chair of the ATA Annual Meeting.

Central hypothyroidism is defined as hypothyroidism—-a state in which the thyroid gland does not make enough thyroid hormone—-due to insufficient stimulation by thyroid stimulating hormone (TSH) of an otherwise normal thyroid gland or in in conjunction with other pituitary hormone deficits. Undetected central hypothyroidism is associated with developmental delay in children and adverse cardiometabolic sequelae in adults. Until now, mutations in the thyrotropin-releasing hormone receptor (TRHR) or TSHb subunit (TSHB) genes had been the only known causes of isolated TSH deficiency.

A team of researchers led by Nadia Schoenmakers, PhD, at the University of Cambridge in the United Kingdom, studied 10 unrelated families with males exhibiting isolated TSH deficiency, testicular enlargement, and variably low serum prolactin levels. Using whole-exome and candidate gene sequencing, they identified nine distinct mutations in the X-linked immunoglobulin superfamily member 1 (IGSF1) gene in affected males.

Their analyses revealed that IGSF1 encodes a pituitary-enriched plasma membrane glycoprotein and that disease-associated mutations block trafficking of IGSF1 from the endoplasmic reticulum to the membrane, consistent with the loss-of-protein function. In addition, the researchers characterized IGSF1-deficient mice and found that adult male IGSF1 null mice have decreased pituitary TSH content and circulating T4 levels and increased body weight and fat mass—characteristics that mimic features of the human disorder. Decreased TRHR mRNA levels in pituitaries from null mice, together with reduced TSH bioactivity in patients with IGSF1 mutations, suggest that impaired TRH signaling may be the basis for the disorder.

About the ATA Annual Meeting 


The 82nd Annual Meeting of the American Thyroid Association is held Sept. 19-23, in Québec City, Québec, Canada. This four-day creative and innovative scientific program, chaired by Elizabeth Pearce, MD, Boston Medical Center, and Douglas Forrest, PhD, National Institute of Diabetes and Digestive and Kidney Diseases, carefully balances clinical and basic science sessions on the latest advances in thyroidology. The ATA meeting is designed to offer continuing education for endocrinologists, internists, surgeons, basic scientists, nuclear medicine scientists, pathologists, endocrine fellows and nurses, physician assistants and other health care professionals. Visit www.thyroid.org for more information.

About the ATA 


The American Thyroid Association (ATA) is the leading worldwide organization dedicated to the advancement, understanding, prevention, diagnosis and treatment of thyroid disorders and thyroid cancer. ATA is an international individual membership organization with over 1,600 members from 43 countries around the world. Celebrating its 89th anniversary, ATA delivers its mission through several key endeavors: the publication of highly regarded monthly journals, THYROID, Clinical Thyroidology and Clinical Thyroidology for Patients; annual scientific meetings; biennial clinical and research symposia; research grant programs for young investigators, support of online professional, public and patient educational programs through www.thyroid.org; and the development of guidelines for clinical management of thyroid disease. Visit www.thyroid.org for more information.

Media Contact
Bobbi Smith 

Executive Director
 of the American Thyroid Association
Email: thyroidexec@thyroid.org 




# # #

“SECISBP2 syndrome has confounded the scientific community. New approaches to study the biological underpinnings of SECISBP2 syndrome are thus critical to truly make progress against this disorder,” said Douglas Forrest, PhD, of the National Institute of Diabetes and Digestive and Kidney Diseases, and Program Co-Chair of the ATA Annual Meeting.

SECISBP2 syndrome is caused by an atypical resistance to thyroid hormone In patients with this disease, aberrant thyroid hormone levels (high T4, low T3, elevated rT3, and high-to-normal TSH) indicate a defect in deiodinase-dependent thyroid hormone metabolism. Findings of reduced concentrations of plasma selenoproteins suggested a generalized defect of selenoprotein biosynthesis and led to the identification of mutations in the SECISBP2 gene. SECISBP2 is thought to play an essential role for selenoprotein biosynthesis. Mutations in the SECISBP2 gene lead to reduced expression of selenoproteins and cause a syndrome with relatively mild to more severe phenotypes.

A team of researchers led by Sandra Seeher at the Institut für Experimentelle Endokrinologie, Charité – Universitätsmedizin Berlin in Berlin, Germany, set out to create mouse models to test whether Secisbp2 is essential for selenoprotein biosynthesis and to study the consequences of Secisbp2 deletion in tissues and the whole organism.
Researchers found that the necessity of Secisbp2, using a constitutional knockout, leads to early embryonic lethality. Nevertheless, Secisbp2 heterozygotes have no obvious phenotype; they are fertile, and their thyroid function tests are normal. Biochemical analysis revealed only minimal changes in selenoprotein expression. Hepatocyte-specific Secisbp2 knockout mice also appear normal, but show a dramatic reduction of hepatic selenoprotein expression. Neuron-specific Secisbp2 knockout mice have a more severe phenotype and survive for approximately three weeks. They are smaller and weigh less than their wild-type littermates, and exhibit a marked movement phenotype with an awkward, broad based, and dystonic gait.

Immunohistochemical stainings demonstrated a specific loss of parvalbumin-positive interneurons in somatosensory cortex and hippocampus. Researchers then compared Secisbp2 mice with similar mouse models lacking tRNA[Ser]Sec. They found that the phenotypes, as well as the consequences on selenoprotein level of our Secisbp2 mice are milder than in tRNA[Ser]Sec knockout mice. Research therefore intend to alternative factors that could compensate for Secisbp2 function.

About the ATA Annual Meeting 


The 82nd Annual Meeting of the American Thyroid Association is held Sept.19-23, in Québec City, Québec, Canada. This four-day creative and innovative scientific program, chaired by Elizabeth Pearce, MD, Boston Medical Center, and Douglas Forrest, PhD, National Institute of Diabetes and Digestive and Kidney Diseases, carefully balances clinical and basic science sessions on the latest advances in thyroidology. The ATA meeting is designed to offer continuing education for endocrinologists, internists, surgeons, basic scientists, nuclear medicine scientists, pathologists, endocrine fellows and nurses, physician assistants and other health care professionals. Visit www.thyroid.org for more information.

About the ATA 


The American Thyroid Association (ATA) is the leading worldwide organization dedicated to the advancement, understanding, prevention, diagnosis and treatment of thyroid disorders and thyroid cancer. ATA is an international individual membership organization with over 1,600 members from 43 countries around the world. Celebrating its 89th anniversary, ATA delivers its mission through several key endeavors: the publication of highly regarded monthly journals, THYROID, Clinical Thyroidology and Clinical Thyroidology for Patients; annual scientific meetings; biennial clinical and research symposia; research grant programs for young investigators, support of online professional, public and patient educational programs through www.thyroid.org; and the development of guidelines for clinical management of thyroid disease. Visit www.thyroid.org for more information.

Media Contact
Bobbi Smith
Executive Director
 of the American Thyroid Association
Email: bsmith@thyroid.org 



# # #

“The ability to detect known mutations linked to thyroid cancer through fine needle aspiration samples is an important advance that may greatly reduce the need for surgery,” said Douglas Forrest, PhD, of at National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health.

FNA is currently the most sensitive method to select suspicious thyroid nodules for surgery but is often limited by indeterminate samples. Genetic sequencing for rearrangements (PAX8/PPARG, RET/PTC) and point mutations (BRAF, NRAS, HRAS, KRAS) has arisen as non-surgical method for the thyroid cancer diagnoses. However, until now, these aberrations have only been detected in fresh FNA samples.

A team of researchers led by Markus Eszlinger, PhD, of the University of Leipzig in Leipzig, Germany, has now shown that the detection of these mutations is feasible using FNA smears. Researchers extracted RNA and DNA from 310 routine air-dried FNA smears (164 indeterminate, 57 malignant, 89 non-neoplastic) and corresponding formalin-fixed paraffin-embedded tissue (FFPE) samples (156 follicular adenomas, 32 follicular thyroid carcinomas, 9 follicular variant papillary thyroid carcinomas, 44 papillary thyroid carcinomas, and 69 goiters). They identified PAX8/PPARG and RET/PTC1 rearrangements using qPCR and BRAF and NRAS and HRAS point mutations using high resolution melting (HRM)-PCR and pyrosequencing.
No KRAS mutations were detected in the FNA samples.

On average, 8% of routine FNA samples did not allow analysis of a point mutation and 3.9% did not allow analysis of a rearrangement. For the 164 indeterminate samples, BRAF mutations were detected in 1 FNA/1 FFPE sample, NRAS mutations in 12 FNA/21 FFPE samples, HRAS mutations in 3 FNA/7 FFPE samples. PAX8/PPARG was detected in 6 FNA/6
FFPE samples, while RET/PTC was not detected in any indeterminate sample.

Molecular FNA screening increased the sensitivity from 67% (cytology alone) to 75% (cytology and molecular FNA screening) in the total set. In the indeterminate set with 19 FTCs the sensitivity of detecting carcinomas and mutation positive adenomas was 48% and specificity was 99%.

About the ATA Annual Meeting 


The 82nd Annual Meeting of the American Thyroid Association will be held Sept. 19-23, in Québec City, Québec, Canada. This four-day creative and innovative scientific program, chaired by Elizabeth Pearce, MD, Boston Medical Center, and Douglas Forrest, PhD, National Institute of Diabetes and Digestive and Kidney Diseases, carefully balances clinical and basic science sessions on the latest advances in thyroidology. The ATA meeting is designed to offer continuing education for endocrinologists, internists, surgeons, basic scientists, nuclear medicine scientists, pathologists, endocrine fellows and nurses, physician assistants and other health care professionals. Visit www.thyroid.org for more information.

About the ATA 


The American Thyroid Association (ATA) is the leading worldwide organization dedicated to the advancement, understanding, prevention, diagnosis and treatment of thyroid disorders and thyroid cancer. ATA is an international individual membership organization with over 1,600 members from 43 countries around the world. Celebrating its 89th anniversary, ATA delivers its mission through several key endeavors: the publication of highly regarded monthly journals, THYROID, Clinical Thyroidology and Clinical Thyroidology for Patients; annual scientific meetings; biennial clinical and research symposia; research grant programs for young investigators, support of online professional, public and patient educational programs through www.thyroid.org; and the development of guidelines for clinical management of thyroid disease. Visit www.thyroid.org for more information.

Media Contact
Bobbi Smith
Executive Director of the American Thyroid Association
Email: thyroidexec@thyroid.org

Current ATA guidelines for well-differentiated thyroid cancer recommend therapeutic neck dissection for clinically involved or metastatic disease and prophylactic central neck dissection for advanced tumors. However, even with established guidelines in place, the surgical management of cervical nodes varies greatly.

A team of researchers led by Katherine Hayes, MD, of Emory University in Atlanta, Ga., reviewed data on 127,192 patients with papillary and follicular thyroid cancer who were treated surgically from 1998 to 2009 to identify disparities in the extent of lymph node dissection during thyroidectomy. Variables examined included patient age, race, gender, insurance status and education level, hospital classification, surgical volume, and size of tumor.

Thyroidectomy alone was performed in 51.1%, while 48.9% also had lymph nodes dissected. Patients with tumors > 1 cm were significantly more likely to have nodes removed during surgery (RR 1.2, CI 1.19–1.22) relative to tumors < 1 cm. Older patients and African Americans were less likely to have any nodes removed (RR 0.75, CI 0.74–0.77 and RR 0.64, CI 0.62–0.66, respectively). Patients treated at National Cancer Institute Designated Centers were more likely (RR 1.13, CI 1.1–1.15) to have > 3 lymph nodes removed, as were patients with tumors > 1 cm (RR 1.25, CI 1.21–1.28). However, women (RR 0.87, CI 0.85–0.88) and African Americans (RR 0.89, CI 0.85–0.93) consistently had fewer lymph nodes removed.

“These new data show that, in spite of existing guidelines, clinician preferences as well as patient characteristics all too often contribute to a number of disparities in the extent of surgery for well-differentiated thyroid cancer,” said Elizabeth Pearce, MD, of the Boston Medical Center and Program Co-Chair of the ATA annual meeting.

About the ATA Annual Meeting 


The 82nd Annual Meeting of the American Thyroid Association is held Sept.19-23, in Québec City, Québec, Canada. This four-day creative and innovative scientific program, chaired by Elizabeth Pearce, MD, Boston Medical Center, and Douglas Forrest, PhD, National Institute of Diabetes and Digestive and Kidney Diseases, carefully balances clinical and basic science sessions on the latest advances in thyroidology. The ATA meeting is designed to offer continuing education for endocrinologists, internists, surgeons, basic scientists, nuclear medicine scientists, pathologists, endocrine fellows and nurses, physician assistants and other health care professionals. Visit www.thyroid.org for more information.

About the ATA
The American Thyroid Association (ATA) is the leading worldwide organization dedicated to the advancement, understanding, prevention, diagnosis and treatment of thyroid disorders and thyroid cancer. ATA is an international individual membership organization with over 1,600 members from 43 countries around the world. Celebrating its 89th anniversary, ATA delivers its mission through several key endeavors: the publication of highly regarded monthly journals, THYROID, Clinical Thyroidology and Clinical Thyroidology for Patients; annual scientific meetings; biennial clinical and research symposia; research grant programs for young investigators, support of online professional, public and patient educational programs through www.thyroid.org; and the development of guidelines for clinical management of thyroid disease. Visit www.thyroid.org for more information.

Media Contact 

Bobbi Smith
Executive Director
 of the American Thyroid Association 

Email: thyroidexec@thyroid.org


# # #