Shumei Meng, MD, PhD, from the Baylor University Medical Center and the Texas A&M School of Medicine, discusses a remarkable case study from JCEM Case Reports detailing how endocrinologists may have discovered a new syndromic association that may have saved a pregnant patient’s life.
By Kelly Horvath
Sometimes in medicine, everything aligns, and patients with unusual presentations who might otherwise experience negative outcomes beat the odds. That serendipity starts with the medical team and their use of expert clinical reasoning. In “An Unusual Case of Pheochromocytoma Associated with von Hippel-Lindau Disease and Lynch Syndrome During Pregnancy,” published in June in JCEM Case Reports, Shumei Meng, MD, PhD, clinical associate professor at the Texas A&M School of Medicine, in Bryan, Texas, and the chief of endocrinology at the Baylor University Medical Center in Dallas, shares just such a story.
Case History
In 2023, Meng and her team at Baylor University Medical Center were referred a 25-year-old patient who was 22 weeks’ pregnant with suspected preeclampsia from an outside hospital — a decision that likely saved the patient’s life. At just nine weeks of pregnancy, she began experiencing hypertension, dizziness, nausea, and vomiting, common symptoms of pregnancy. Although these symptoms initially improved with medication, they later progressed. At 20 weeks, symptoms concerning for preeclampsia appeared, including tongue swelling, weakness, and vision loss in addition to higher blood pressure, and she was started on preeclampsia medications. When magnetic resonance imaging (MRI) revealed a mass in the medulla of her brain, the hospital swiftly transferred her to Baylor University Medical Center and endocrinology was consulted.
“For this case, she was so symptomatic at the outside hospital,” explains Meng. “When a young pregnant patient presents all of a sudden with vision changes and higher blood pressure, they may think about common pregnancy complications, like gestational diabetes and preeclampsia. But preeclampsia is highly unusual at nine weeks. With that initial brain MRI, they realized it’s more complicated, so they were able to transfer her to us.”
There, further imaging revealed pancreatic cysts, a renal cyst, and hemangioblastoma in the brainstem with associated syrinx formation in the thoracic spine, raising the suspicion for von Hippel–Lindau (VHL) disease. Initial genetic testing with next-generation sequencing was negative, but the team continued to pursue VHL on the differential due to high clinical suspicion.
Laboratory testing with fractionated serum metanephrines provided additional clues in the form of more than twofold higher normetanephrine levels, suggesting the presence of pheochromocytomas (PCCs) and paragangliomas (PGLs), which had not initially been identified on imaging. But the team then considered that some subtypes of VHL predispose to PCCs and PGLs, prompting further treatment in lieu of certain tests that are harmful in pregnancy. Meng credits the radiologists’ expertise here for seeing the possibility of something atypical, potentially VHL, and wanting the “whole picture.” “Generally speaking,” she says, “PCCs and PGLs are rare, and if they are not diagnosed before pregnancy, they can lead to very catastrophic outcomes.”
“Gene mutations don’t typically change over time, but the methods we use to detect them do evolve. Some of the genetic methods we use check only a few genes and maybe even miss some the deletions and duplications, but nowadays we have much better screening and technology to pick up things we missed using the older methods.” — Shumei Meng, MD, PhD, clinical associate professor, Texas A&M School of Medicine, Bryan; chief of endocrinology, Baylor University Medical Center, Dallas, Texas
Management consists of first an a-blocker (e.g., doxazosin) then a b-blocker (e.g., labetalol in pregnancy) and volume expansion to control symptoms (a sequence Meng emphasizes is important to follow to negate first vasoconstriction then effect heart rate control), followed by postpartum surgery. Because this patient’s condition was not diagnosed prior to pregnancy, and, in fact, pregnancy potentiated her symptoms (possibly due to the known interaction of VHL with female hormones, which pregnancy would amplify), her management was adjusted to allow for antepartum surgery to avoid an adrenergic crisis. At 24 weeks, the hemangioblastoma was resected, but she experienced respiratory failure from aspiration, a common postoperative complication, especially in someone so ill, requiring emergent management. Her pregnancy consequently ended at 27 weeks. After a three-month hospital stay, she was discharged to inpatient rehabilitation, which she has subsequently successfully completed and returned to normal life, but with some caveats.
Outcomes and Implications
Meng says: “For this young patient who was completely healthy, recently married, and then pregnant, we would expect a happy outcome. Then, all of a sudden something like this happens. I think she is traumatized not just from the loss of the pregnancy, but also in terms of how long she was in the hospital. She also has anxiety, probably from not being able to breathe when she developed respiratory failure. In terms of future pregnancy, she is also concerned about genetic defects.”
It turns out, during follow-up, the team performed RNA analysis, a type of genetic testing with better sensitivity, and that this time was positive for both VHL disease and Lynch syndrome, the latter of which was unexpected. “Gene mutations don’t typically change over time, but the methods we use to detect them do evolve,” Meng says. “Some of the genetic methods we use check only few genes and maybe even miss some the deletions and duplications, but nowadays we have much better screening and technology to pick up things we missed using the older methods.” In other words, the team was connecting the dots between the patient’s cysts and her neuroendocrine tumor, which pointed them to VHL disease, despite the first negative genetic test.
“PCCs and PGLs can be a common phenotype of VHL, and there are several different subtypes,” Meng says. “Some subtypes are more correlated with big adrenal PCCs, some are more associated with PGLs, either sympathetic or parasympathetic gangliomas, and some have less risk for either. However, the Lynch syndrome was a surprising finding. Its gene is a DNA mismatch repair gene, so if a mutation happens, you can have other tumors. With the typical Lynch phenotype, we think about gastrointestinal and uterine endometrium malignancies, which this patient did not exhibit at present.”
It’s important to note here that the team had only half of the patient’s family history to guess her genetic makeup — her father’s information is unknown. That they continued pursuing VHL disease and arrived at the diagnosis attests to their clinical acumen. They do not know whether these two genetic syndromes may have been inherited from which parent, but they do know that the two conditions occurring together is exceedingly rare, and this patient endured a very heavy clinical burden as a result. It’s also rare that either condition is diagnosed during pregnancy.
“The question is, is the VHL associated with the Lynch syndrome or not?” Meng says. “We don’t really know for sure because there are not many cases reported — if at all — so we’re trying to accumulate data, and maybe over time we start putting things together. Maybe this association is a new discovery.”
Takeaways and Future Impacts
Meng and team have three key points to make for clinicians: awareness, surveillance, and referral. “The number one is awareness of the possibility of this co-occurrence because early diagnosis can result in much better outcomes,” Meng says. “It’s not hard to screen for them, but if you don’t know about or think about them, you wouldn’t screen for them.” Secondly, Meng emphasizes that newer genetic tests helped the team screen for other things. “For future follow-ups, I definitely keep eyes on what could develop over time with more targeted surveillance,” she says. Finally, Meng’s advice for the general practitioner or obstetrician/gynecologist is: “If something looks very unusual, refer the patient to a bigger, more specialized center.”
Indeed, while the patient in Meng’s team’s care was unfortunate to have two genetic syndromes that combined to make her very ill, she was simultaneously very fortunate to have been referred to Meng and team and receive the exceptional care that facilitated her recovery. The patient herself expressed as much to Meng. The multidisciplinary makeup of the team was also critical, with one specialist after the next making the right call and ensuring steady progress to diagnosis and treatment. They continue to stand behind her, seeing her for follow-up in clinic as well as supporting her efforts also for emotional recovery from her ordeal. They want the best for her in all ways.
“For any scientist or physician, I don’t think at any moment we feel like we know enough. But the point of scientific curiosity and research is bringing that knowledge to patient care. It’s making an impact on patients’ lives. That’s exactly what the Society has done. You have to link the research to the clinical practice to make that impact.” — Shumei Meng, MD, PhD, clinical associate professor, Texas A&M School of Medicine, Bryan; chief of endocrinology, Baylor University Medical Center, Dallas, Texas
Meng also appreciates the Endocrine Society for providing resources and support within the field. She attended ENDO 2024 and enjoyed it very much for not just “elevating her knowledge level,” but also for delivering both sides of the knowledge coin. “For any scientist or physician, I don’t think at any moment we feel like we know enough. But the point of scientific curiosity and research is bringing that knowledge to patient care. It’s making an impact on patients’ lives. That’s exactly what the Society has done. You have to link the research to the clinical practice to make that impact.” This patient’s case may well be an exemplar of that synergy.
Horvath is a freelance writer based in Baltimore, Md. In the September issue, she wrote about some of the women’s health research presented at ENDO 2024 in Boston.
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