X-linked hypophosphatemia can remain undiagnosed across generations when symptoms are mistaken for normal childhood development or ordinary family traits. Here, we look at diagnostic barriers, the importance of testing and genetic counseling, and how identifying one patient can prompt a cascade of family diagnoses.
When Emily’s seven-month-old daughter Ila began pulling herself up to stand, Emily noticed that her legs were significantly bowed. “You always hear that some bowing under age two is normal,” Emily says, “but it just seemed very pronounced.”
For the next several months, Emily raised her concerns at Ila’s well-child visits, but the pediatrician did not detect anything amiss, telling her that some bowing occurs in up to 95% of children and that Ila would grow out of it. “I thought, maybe I’m blowing this out of proportion,” Emily recalls. But by the 15-month appointment, Ila had been walking for a few months, and the bowing was more, not less, prominent. “I really pushed at that visit for more answers,” she says, and her persistence finally produced a pediatric orthopedic referral.
During the following nearly two-month wait for the referral appointment, Emily took matters into her own hands, researching online what might explain Ila’s condition as well as reaching out to a specialist who studies metabolic bone diseases. “I discovered hypophosphatemia and felt pretty certain that was it,” she says. She thought back to her own active childhood and the musculoskeletal issues she experienced. For example, after soccer practice, she would become so stiff during the car ride home that she would have to warm up just to be able to walk into her house. She also experienced frequent kneecap dislocations and seemed to walk and run at a slower pace than her peers. “I just thought that was my normal,” she recalls. “I didn’t know that wasn’t normal.”
When the time came to attend the orthopedic appointment, she was prepared. “I’d found four or five generations of family members who’d had surgeries and knee problems with their joints,” she explains. Even with that level of support for her hunch, however, the orthopedist reiterated that Ila’s bowing was physiologic, an opinion that Emily says “did not hold water for her.” Fortunately, just the day before, the specialist she had contacted called and arranged to see Emily and Ila. Emily’s instincts were correct, and the diagnosis of X-linked hypophosphatemia (XLH) was confirmed.
Emily calls the whole process her family’s “diagnostic odyssey,” an unfortunate though certainly apt phrase. According to Mark Eugene Nunes, MD, medical director of Genetics, Genomics, and Metabolism at Intermountain Children’s Health in Las Vegas, Nev., having to undertake such an odyssey is far more common than we would like.
Challenges in Diagnosis and Care
Nunes specializes in metabolic bone diseases and offers an important perspective on why identifying these conditions is critical. He uses pouring a driveway as an analogy for understanding the underlying mechanism. “Collagen is like the rebar, the metal grid, and calcium and phosphorus are like the concrete poured over top. If you have no collagen, you’re going to have brittle bones; if you have faulty calcium or phosphorus, you’re going to have soft bones.” Thus, identifying individuals who have low phosphorus, which is necessary for bones and for numerous other biologic functions is very important. “It’s extremely important in children,” Nunes continues, “because phosphorus is fundamental for normal growth and development, and it’s important in adults because the bone issues go undiagnosed and unrecognized as well as for the other benefits that correcting abnormally low phosphorus has for a person’s health.”
“The things you’re not looking for are the things you miss. For a primary care doctor, if you’re not obtaining a serum phosphorus, you’re not going to recognize a low one. For endocrinologists, who are obtaining phosphorus routinely and are more likely to recognize the diagnosis, don’t be afraid to ‘phone a friend’ and ask a genetic counselor for help in making a difference in the lives of four, five, or six relatives who are also at risk.”
Mark Eugene Nunes, MD, medical director, Genetics, Genomics, and Metabolism, Intermountain Children’s Health, Las Vegas, Nev.
Yet Emily’s early experience — concern raised, dismissed, raised again — fits a pattern Nunes sees regularly. Part of the problem, he explains, is that routine bloodwork panels will not catch it. Sodium, bicarbonate, and calcium levels are all measured using the same electrode that measures pH, but it cannot measure phosphorus, which requires a special, extra test that adds cost and steps. This means that, “unless you’re checking the serum phosphorus, you’re not going to know it needs correcting,” says Nunes. Unfortunately, primary care clinicians may not even be aware that phosphorus is not on the panel, so educating them is vital: “If they see someone with a high alkaline phosphatase level, which is an indicator of rickets or osteomalacia, one of the tests they should order separately is a serum phosphorus, in addition to the chemistry panel,” he explains.
Another problem contributing to underdiagnosis is mistaking other conditions for XLH, like vitamin D deficiency, which affects a third of the population. It can take a while to see that replacing the vitamin D is not resolving all of a patient’s issues (“the disease process in XLH doesn’t allow conversion of inactive vitamin D into active vitamin D,” explains Nunes) and getting to the root of the problem. Another is skeletal dysplasia, commonly suspected when x-rays demonstrate abnormal-appearing metaphyses. Here, at least, genetic tests may be done, and “you back into the diagnosis of hypophosphatemia because you find a genetic change in the PHEX gene, which is on those skeletal dysplasia panels,” says Nunes. He also explains that XLH is inherited 80% of the time, while 20% of cases arise from de novo mutations.
Although XLH remains underrecognized, it is nevertheless the most common metabolic bone disease, occurring in about 1 in 20,000 individuals. Nunes says that he sees osteogenesis imperfecta and hypophosphatasia in his clinic more frequently, even though they occur with less frequency within the general population, at 1 in 25,000 and 300,000, respectively.
Nunes also points to a blind spot in how the condition was formerly considered. “We were taught that hypophosphatemia was predominantly a childhood disorder and something you grew out of,” he says. “The idea that there might be adult features of this diagnosis really wasn’t something we understood 20 years ago the way we do now.” These gaps begin to explain why Emily’s own case (and that of some of her relatives) went unrecognized for decades before a specialist connected the dots, and her daughter Ila’s diagnosis brought everything into focus.
Of course, other factors complicate the clinical picture, including transitioning from pediatric to adult care. “Most of the individuals identified in 2026 are children,” explains Nunes, “and they grow up into adults. The old thinking was that treatment stopped once the skeleton was mature. Now we’d like to pass those kids on to an adult practitioner, because the pediatric endocrinologist can’t take care of a 24-year-old with the diagnosis. A lot of the cases coming to an adult endocrinologist are inherited pediatric cases, where the kids have gone through their teenage years and become nonadherent to therapy thinking there aren’t any issues. So, we need a good, warm handoff from the pediatric endocrinologist to the adult endocrinologist for continuity of care.” Nunes cites Vanderbilt University’s Transitions Lab as one that handles this well.
“Domino Effect”
Emily recounts how once Ila was diagnosed, “it was kind of like a domino effect through the family tree. This is more widespread than just the two of us.” Her paternal grandmother had begun building an informal family record that Emily later picked up where she left off, cataloguing symptoms across her four sisters and other relatives. Emily’s great-grandfather was never tested, “but it’s safe to say he had XLH due to his very pronounced leg-bowing,” she says. Despite that one of those great-aunts was even treated for bone problems at a specialist hospital in the early 1940s, the notion that this problem was genetic did not occur to their clinicians, so affected family members remained in the dark.
To begin disseminating her findings, Emily used her extended family’s Facebook group. “It put more information out there for everybody to see,” she explains, “and let each relative decide for themselves whether to get tested.” Roughly two dozen living family members now have a confirmed diagnosis, with others clearly affected but never formally tested. This “domino effect,” as Emily called it, is why Nunes considers XLH a family diagnosis, not just an individual one. “About 80% of cases are inherited,” he explains, “and because it’s X-linked, the pattern is predictable: An affected father passes it to all of his daughters and none of his sons; an affected mother can pass it to sons and daughters alike.”
Thus, a single pediatric diagnosis can flag other family members from the just pedigree structure and lead to a “cascading diagnosis” throughout the family. Interestingly, families tend to consider their symptoms as a family trait rather than a disease process. Nunes describes a family he treated whose great-grandfather had bowed legs, but which did not affect his ability to carry out activities of daily living. This bowing passed, with varying severity, through his daughter, granddaughter, and eventually a great-grandson referred for a suspected skeletal dysplasia. “They didn’t see it as something that stopped mom from working, marrying, or having children. It was just, ‘that’s the way things are in my family’.”
Nevertheless, identifying a heritable diagnosis in one individual may mean being able to make a difference in the lives of the relatives who are also at risk. Recognizing that this sensitive news might be difficult to communicate within some families, Nunes has a suggestion: “I’d say there’s a great role for genetic counselors here; these resources are available to endocrinologists to help sort things out for the family.” He specifically mentions Susan Starling Hughes, MS, CGC, at Children’s Mercy Hospital, Kansas City, in Missouri, who is an active member of the National Society of Genetic Counselors and whose primary clinical focus is skeletal and connective tissue disorders.
You Miss What You Don’t Look For
Emily, who is an ambassador for pharmaceutical company Kyowa Kirin’s XLH Family Outreach Initiative [see sidebar] program, drew on multiple resources, not to mention her own commitment to advocating for her daughter, to eventually have XLH confirmed across four generations in her family. “So many things can be genetic, or more likely to occur within a family, and it’s worth talking about,” Emily says. This also works in reverse, “When the adult endocrinologist makes the diagnosis in an adult patient, even though it might be a brand-new mutation, the patient’s children are certainly at risk. So how do you make sure they get treated?” Nunes says. “There’s a handoff in the opposite direction that I don’t think we usually think about.”
Nunes has additional, actionable advice for both primary care physicians and endocrinologists. “The things you’re not looking for are the things you miss. For a primary care doctor, if you’re not obtaining a serum phosphorus, you’re not going to recognize a low one. For endocrinologists, who are obtaining phosphorus routinely and are more likely to recognize the diagnosis, don’t be afraid to ‘phone a friend’ and ask a genetic counselor for help in making a difference in the lives of four, five, or six relatives who are also at risk.”
Back to her own family, Emily says, “I feel like it could have been figured out sooner if people had been more open to talking about their health with family members.” In their own ways, Emily, Nunes, and Wilson are each working to change that. Meanwhile, Ila is approaching her ninth birthday and doing well, according to Emily. “Having her diagnosis has helped guide our decision-making. For example, instead of soccer, playing a lower-impact sport would be better for her. That’s not to say she can’t ever play soccer, but it helps us think about her health overall. Luckily, she’s not super interested in it anyway.”
Horvath is a freelance writer based in Baltimore, Md. In the September issue, she wrote “Minding the Gaps: What Happens When Pediatric Patients with Pituitary Tumors Become Adults?”
