Researchers Discover Genetic Underpinnings of Inherited Condition Often Misdiagnosed as Hypothyroidism

A newborn undergoes foot prick genetic screen test
Article Summary
  • Dr. Roy Weiss was part of a research team that discovered the genetic explanation for the inherited condition, resistance to TSH.
  • The researchers found genetic changes in the non-coding region of chromosome 15 leads to resistance to TSH.
  • Dr. Weiss believes a greater understanding of these non-coding regions may lead to increased knowledge about other genetic diseases.

Miami cardiologist Cintia Cuperman’s first-born son screened positive for congenital hypothyroidism in 2002. Her family doctor initially thought it was a false positive. Only one in about 4,000 babies are born with a malfunction of the thyroid gland that produces low levels of thyroid hormone and results in high levels of thyroid stimulating hormone (TSH).

“We did some reading ourselves,” Dr. Cuperman said. “My husband and I are both physicians and we could tell there was something going on that we should be concerned about.”

In the first few weeks, before they were referred to an endocrinologist, “we were freaking out,” Dr. Cuperman added.

When the couple had twins, both children had abnormal thyroid screenings, too. They underwent thyroid hormone treatment for years to avoid the associated health risks, including poor growth and neurologic and cognitive impairment.

Dr. Cuperman’s children are adults now and recently found out they no longer need therapy. Roy E. Weiss, M.D., Ph.D., professor and chair of the Department of Medicine at the University of Miami Miller School of Medicine, delivered the good news.

“I was able to convince them and their doctors not to treat them because otherwise they would have been inappropriately treated with thyroid hormone for the rest of their lives,” said Dr. Weiss, also the Rabbi Morris I. Esformes Endowed Chair in Medicine and Endocrinology and the Kathleen & Stanley Glaser Distinguished Chair of Medicine. “Their thyroid tests were not consistent with the type of congenital hypothyroidism that needed treatment.”

Dr. Roy Weiss
Dr. Roy Weiss

In some cases, newborns screened for congenital hypothyroidism have high TSH but have normal levels of thyroxine hormone. Dr. Cuperman’s children have this rare, congenital thyroid condition, known as resistance to TSH.

“The important clinical implication is making the correct diagnosis, as most of these patients do not need any treatment and are misdiagnosed as hypothyroid,” Dr. Weiss said. “The misdiagnosis commits them to a lifetime of thyroid hormone treatment and blood tests that are not needed.”

Resistance to TSH at birth has been a longstanding mystery, until now.

Dr. Weiss and fellow researchers Samuel Refetoff, M.D., from the University of Chicago Medicine, Helmut Grasberger, M.D., from the University of Michigan, and others found a genetic explanation in an unexpected place. They knew for years the genetic variants related to resistance to TSH were on chromosome 15. Recently they identified genetic changes in the non-coding region of this chromosome, a discovery published in the prestigious journal Nature Genetics.

As we better understand the function of the majority of the genome, the noncoding areas, we will learn more not only about how the thyroid functions but the genetics of other diseases.
—Dr. Roy Weiss

Importantly, they found how the non-coding regions resulted in the clinical syndrome. A separate team of researchers in Japan made a similar discovery regarding the molecular mechanism behind this condition and published their work in the same issue of the journal.

Their discovery may lead to finding more genetic changes and helping people with other inherited, or Mendelian, genetic conditions. Dr. Weiss and researchers identified noncoding mutations on a short tandem repeat to be the underlying cause of the condition in all affected individuals.

These mutations occur on primate-specific DNA known as the Alu retrotransposon, also found in gorillas. Previous studies have shown that some gorillas also have high-TSH thyroid tests and normal thyroid hormone, which are similar to resistance to TSH.

“This is the exciting part, as we don’t know how often disease is caused by the 98% of total DNA that is non-coding,” Dr. Weiss said. “As we better understand the function of the majority of the genome, the noncoding areas, we will learn more not only about how the thyroid functions but the genetics of other diseases.”

Most of the genetic discovery took place in Dr. Refetoff’s lab, before Dr. Weiss joined the Miller School faculty in 2014. At the time, he and colleagues at the University of Chicago, along with researchers at University of Washington, used the science to identify affected children and families.

One of the families was Dr. Cuperman’s, whom Dr. Weiss first met in 2012. Two years later, they became his patients in Miami and continue to this day. 

As groundbreaking as this genetic discovery is, questions about treatment linger, Dr. Weiss said. But Dr. Cuperman’s sons are doing well and no longer taking thyroid hormone replacement.

“They are super, super healthy,” she said. “They are both playing soccer in college—you know, thriving.”

Tags: Division of Endocrinology Diabetes and Metabolism, Dr. Roy Weiss, hypothyroidism, resistance to TSH