When Heartache Propels Progress

It wasn’t until Jamie McDonald, MS, as a new mother, started noticing her 4-month-old daughter’s decreased left-side mobility that she began suspecting something much more serious than what her family had always dismissed as the “family bloody-nose thing.”

Hints of the disorder were there all along, some subtle, some not: The frequent bloody noses as a child; the constellation of bright red dots near her mouth; the untimely deaths and mysterious ailments of relatives.

It wasn’t until Jamie McDonald, MS, as a new mother, started noticing her 4-month-old daughter’s decreased left-side mobility that she began suspecting something much more serious than what her family had always dismissed as the “family bloody-nose thing.”  

"Even our family doctors didn’t take it seriously, as they too lacked knowledge about this disorder,” recalls McDonald, a genetic counselor for ARUP and the University of Utah (U of U) and an assistant professor of pathology (clinical).  As a result, her family was never counseled on the associated risks of the disorder, nor advised on what could be done to prevent complications.

The disorder—Hereditary Hemorrhagic Telangiectasia (HHT)—is a genetic disorder of the blood vessels, affecting about 1 in 5,000 people in the United States. If you have a parent or sibling with HHT, there is a 50 percent chance of having the disorder—McDonald’s grandfather and father both inherited it, as did she.

The most deadly, and insidious, aspect of the disorder is the arteriovenous malformations (AVM), which can form in the brain, lungs, and liver.  AVMs are blood vessels which are missing capillaries, resulting in direct artery-to-vein connections that can cause shunting, hemorrhage, and death. Imagine a garden hose gushing water into a balloon and the risk of it rupturing from the rush of water.

“HHT is more common than people appreciate; more common than hemophilia and about as common as cystic fibrosis. Any parent that has it has a 50 percent chance of passing it on.”
Jamie McDonald, MS, ARUP Genetics Counselor, co-founder HHT Center for Excellence

A bigger concern is in the lungs where AVMs are common; the absence of capillaries in blood vessels of the lungs increases the risk that clots and clumps of bacteria won’t be filtered from the bloodstream.  Also concerning are AVMs in the liver, which can significantly increase the volume of blood the heart needs to pump.

“For some of my patients it is as if they are running a marathon yet they are just sitting,” says McDonald.  Eventually all this exhaustive pumping can lead to heart failure.

She Inherited our Blue Eyes and My HHT

Her daughter, Kelsey, would hardly move the left side of her body when engaging with a toy mobile or wiggling around, recalls McDonald. “My pediatrician made me feel like I was just worrying too much,” says McDonald who was living in Los Angeles at the time.

Kelsey’s immobility became more pronounced and at nine-months old, and with insistence from her parents, she finally underwent a brain scan locating a large AVM in her brain. A neurointerventional radiologist treated the AVM with a transcatheter occlusion procedure.

Though McDonald was convinced that her blue-eyed daughter had HHT, the involved neurologists and neurosurgeons were not as persuaded nor were they intent on pursuing what this could mean for Kelsey and her family members.  It is not uncommon for physicians to misdiagnose complications that stem from HHT; these complications can be misleading, appearing as something else unlinked to the disorder.

This was certainly the case in 1987 for the McDonalds when there was no way to test children at a young age to determine whether they had inherited the disorder. Nose bleeds and telangiectases usually don’t show up until after ten years old; though brain and lung AVMs can be present at birth.

Diagnostic testing would remain elusive until 2004, when genetic testing for HHT became possible—ARUP Laboratories becoming one of the first two labs in the nation to conduct HHT genetic testing.

In the depth of a winter night, The McDonalds’ world shattered when 18-month-old Kelsey died from a massive brain hemorrhage. At the time, Jamie was five-months pregnant with her second child, who unbeknownst to her would also have HHT. So would her third. 


“This disorder has lifethreatening complications but if we know the genetics for the patients and their families, then we can be proactive in monitoring and treating them. Identifying it early can save lives.”
Jamie McDonald, MS, ARUP Genetics Counselor, co-founder HHT Center for Excellence

Fueled by Frustration

With two toddlers, McDonald began pushing to have their brains and lungs screened for AVMs despite skeptical doctors. “I wasn’t going to risk losing another child; my attitude was let’s go looking for these before we have a problem.” Both received MRIs, under sedation, in case they had inherited HHT. 

Helping children avoid this invasive medical screening further propelled McDonald down the unpaved path ahead. “This is one of the reasons why Pinar and I worked so hard in the couple years prior to 2004 to develop diagnostic genetic testing for HHT,” recalls McDonald, referring to Pinar Bayrak-Toydemir, MD, PhD, a University of Utah Associate Professor of Pathology and a molecular genetics and genomics medical director at ARUP Laboratories.

At the time a general genetic counselor at the U of U Hospital, McDonald was increasingly frustrated by the lack of medical expertise available for HHT patients. In 1993, McDonald herself was diagnosed with lung AVMs, but noone in the west was fixing lung AVMs or focusing on HHT.” So she headed to the Yale School of Medicine; the only place in the country treating and doing preventive screening for HHT at the time. There, Dr. Robert White, the “grandfather” of HHT, encouraged her to return to Salt Lake City and set up an HHT center. He connected her drive and passion with the expertise of Franklin Miller, MD, a U of U intervention radiologist, to help catalyze such a center.

Today, McDonald is the co-director of the HHT Center of Excellence—the center she helped establish in 1995 to provide expert, multidisciplinary care, follows over 1,200 patients, most from out-of-state. It was the second center in North America to be recognized by the flagship organization, Cure HHT International.

“Despite being a relatively common genetic disorder, most people with this disorder don’t get diagnosed,” says McDonald. “I want to help change that.”

Discovering Answers at Birth to Prevent Death—Testing for HHT

Life with HHT has not prevented Connor and Allison McDonald Kamm from living active, vibrant lives.

The first evaluation for HHT, if it runs in your family, is to test at birth for the family’s HHT genetic mutation to determine if the HHT was inherited. This test involves taking a blood sample from the umbilical cord and sending it to a diagnostic laboratory that specifically provides testing for the multiple genes that can cause HHT.

For newborns who do inherit the family HHT mutation, the risk for a brain AVM at birth is about 15 percent; approximately half of these rupture in early childhood. “That is why it is so important to have access to what Pinar is doing at ARUP,” says McDonald. “In the clinic, I can only look for what is visible—and externally visible signs of HHT often aren’t present in early childhood”.

According to McDonald, most physicians are not advising parents to pursue an early diagnosis for their children, even when one of the parents is known to have HHT. “It is remarkably undiagnosed; only the rare pediatrician will say, let’s figure this out.” The first step, when a child is born to a parent with HHT, is genetic testing.  Most pediatricians are not comfortable ordering or interpreting genetic tests, and typically need to refer a family to a genetics or HHT clinic.

For adults, physicians will typically ask about cancer, strokes, heart attacks, diabetes but not HHT, or its symptoms, in taking a family history. Ninety percent of the U of U’s HHT center’s patients come from out of state because of the lack of expertise available in diagnosing and treating the disorder.

Fatalities from HHT are mostly preventable if AVMs are found and treated early in life before they cause severe complications. After a baby has been determined to carry the HHT gene, the first recommended screening is a brain MRI before six months of age. By late childhood it is important to screen for lung AVMs.

Only one in ten individuals who have HHT have actually been diagnosed, and of those that have been diagnosed, the majority are not receiving routine screening for internal organ AVMs as is recommended by HHT experts.

Fatalities from HHT are preventable if you can identify the AVMs early. After a baby has been determined to carry the HHT gene, then an MRI before six months is recommended (regardless of whether any symptom is present). Externally obvious symptoms might not show up for 20 years, but hidden internal AVMs can be deadly early in life.

At ten-years old, the center screens for AVMS in the lungs; some 30 to 40 percent of children will have them—which can lead to strokes or brain abscesses because blood clots and clumps of bacteria are less likely to be filtered in the lungs that have AVM(s). People with HHT should be evaluated and screened every five years by an HHT center.

“A lot of doctors and genetic counselors take a let’s just wait and watch approach when a baby is born into a family with the disorder,” says McDonald. Adding that by the time symptoms appear, it may be too late. “If you can prove by genetic testing that a child inherited the HHT, your medical management changes at that very moment.”

The Dynamic Trio
The confluence of HHT expertise flowing from each of these three internationally-respected women has established a mecca for those looking for answers and treatment for HHT.

Pinar Bayrak-Toydemir, MD, PhD, a University of Utah Associate Professor of Pathology and a molecular genetics and genomics medical director at ARUP Laboratories; discovered an HHT gene.
Whitney Wooderchak-Donahue, PhD, ARUP, HHT researcher; recipient of the internationally-competitive 2015 Young Scholar Research Grant awarded by Cure HHT; discovered an HHT gene.
Jamie McDonald, Jamie McDonald, ARUP Genetics Counselor; affected with HHT and mother of two children with HHT.

The University of Utah’s HHT Center for Excellence, co-founded by McDonald, is only one of two such centers in the country associated with a genetics lab, ARUP. It is the only lab pursuing HHT research beyond traditional clinical testing, which resulted in the discovery of the fourth gene associated with HHT in 2013.

“ With every discovery, we’re able to increase the sensitivity of the test,” explains Bayrak-Toydemir, who has developed a significant pool of data from identifying mutations in large HHT families over the last ten years. She and her protégé Wooderchak-Donahue have collaborated with researchers in Spain and the United Kingdom to build a data pool of those with HHT but who show no known genetic markers for the disorder.

“By 2004, we could identify mutations for most families but not all of them. Then we realized there could be a whole gene missing or a partial gene,” adds Bayrak-Toydemir, noting that they have discovered different types of HHT along the way.

In 80 percent of families, HHT can be linked to a genetic mutation; in 20 percent who have HHT there is no genetic marker identified. “To figure this out, we are focusing on finding new genes and genetic modifiers that may cause HHT,” explains Wooderchak-Donahue. “We are also looking for novel mutations in regulatory and noncoding regions in the known HHT genes that may have been previously missed in these patients using traditional HHT molecular testing.”

She and Bayrak-Toydemir, created a Next Generation Sequencing (NGS) Panel to look for all four genes and mutations at once for each patient. (NGS technology allows researchers to interrogate multiple genes at once often providing a quicker diagnosis than a gene-by-gene approach.)

If we can find new genetic modifiers or new genes, then we can potentially find novel therapeutics to treat these patients. Whitney Wooderchak-Donahue, PhD

“We complement each other,” admits McDonald, referring to this combination of the medical and molecular expertise. She sends her patient samples to ARUP to be analyzed; some are clear cut HHT, others a subset of HHT or can’t be genetically identified.  If something new is identified, McDonald reaches out to the individual’s extended family to collect more samples for research.

“We have all these pieces of a puzzle and I feel responsible for putting them together,” says Bayrak-Toydemir, admitting she does love a good puzzle. Requests from around the world arrive weekly from physicians who want to enroll patients in ARUP’s HHT data set. She adds, “The fact that we are the only ones with such a large collection of data makes me feel the responsibility that comes with it—it absolutely needs to be used to help others.”