The Case of a Tortuous Disorder

What are you dealing with when you see widely-spaced eyes, lax skin, elongated fingers, and arterial vessels that look like the latest thrill ride?

Hal Dietz, M.D.

At home, the infant’s face suddenly turned pale, her lower extremities beet red, and then she started tongue thrusting – all signs of a life-threatening event. The one-month old was rushed to the emergency department of a local hospital, where imaging revealed a congenital hiatal hernia, prompting her swift transfer to Hopkins Children’s neonatal intensive care clinic (NICU). Interestingly, the patient showed signs of hypertension in her upper extremities, while blood pressure in her lower extremities was normal. Even more unusual was what preliminary imaging of the child’s head, neck and chest showed – hairpin turns and pigtail twists in her aortic arch, carotid and pulmonary arteries, which partly explained the hypertension in the upper limbs. Called in to consult, and coupling the girl’s soft skin and small wide-set eyes with the imaging studies, what geneticist Hal Dietz suspected was not so unusual in his experience – a rare vascular disorder he had studied called Arterial Tortuosity Syndrome, or ATS. Indeed, follow-up cardiac catheterization showed severe lengthening, narrowing and twisting of all of the child’s major arteries and severe hypoplasia, or underdevelopment, of the aorta – hallmark signs of ATS that posed risks of aneurysm, infarction or stroke for the young patient.

“Based on this child’s facial features, hernia and some very preliminary vascular imaging studies, we were able to generate a strong hypothesis that ATS was the right diagnosis,” says Dietz. “And it was that hypothesis that led to more extensive vascular imaging for this child that revealed aortic hypoplasia, a known complication of ATS.”

Dietz, a geneticist trained in pediatric cardiology, found his way to ATS through his work with two related vascular disorders – Marfan’s syndrome and Loeys-Dietz syndrome (LDS), the latter characterized by the spiraling arteries, hypertelorism (widely spaced eyes), and aneurysms found in ATS. In studying Marfan’s, Dietz learned that the disease is driven by too much activity of a growth-factor molecule in the body called TGF-beta, which was also found in the vessel walls of patients with LDS, named after Dietz and Belgian physician Bart Loeys. In looking at the vascular tissue in ATS patients who underwent surgery, they also saw a high expression of TGF-beta. More importantly, in studies of Marfan mouse models the researchers found that the hypertension drug Losartan had the ability to decrease the activity of TGF-beta, thereby reducing the risk of aortic aneurysm and other vascular complications seen in infants with ATS.

“Because of the experience with Marfan’s and Loeys-Dietz, we had a reasonable hypothesis that TGF-beta was also involved in ATS,” says Dietz. “Our study of other vascular disorders has provided insight regarding the cause of ATS and at least some ideas for treatments that might prove effective.”

That’s important because therapeutic options are limited for ATS patients. Surgery is complicated in these cases and requires a long time on cardiopulmonary bypass. Recent advances in endovascular techniques have enabled non-surgical treatment of aortic coarctation by balloon dilatation, but these elongated vessels most often tend to be too narrow for stenting. As in this case, physicians typically decide to watch and wait for arteries to grow. But knowing the gene defect for ATS has allowed Dietz and Loeys to screen family members and better understand the clinical spectrum of severity in ATS, opening the door wider to improved outcomes.

“If you pooled the world’s experience with ATS, as recently as three years ago you would have come to the conclusion that this condition is uniformly fatal in infancy or very early childhood,” says Dietz. “Now we can at least offer families hope that their child will be able to survive and have a reasonable quality of life. We still don’t know what the predictors of early death in childhood versus long-term survival are, but with close follow up and aggressive surgical interventions when appropriate, the chances for patients like this child are greatly improved.”

The take-home message for pediatricians? Be wary of the signs of this syndrome but don’t expect to run across it, says Dietz, noting only a couple dozen cases in the medical literature. The important course of action is to promptly steer patients to a center that specializes in treating such vascular disorders. “Because of the focused expertise here,” says Dietz, “we were able to see this child in the NICU and come up with a really definitive diagnosis for a condition that is extraordinarily rare.”