Survey Finds Wide-Ranging Impact of X-Linked Hypophosphatemia (XLH) on Patient Experiences

A Primer on XLH. A rare, lifelong, progressive condition, XLH is characterized by hypophosphatemia (low levels of phosphorus in the blood). This is the result of variants in the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene (found on the X chromosome). The pathogenetic variant produces abnormally high serum levels of a phosphate-regulating hormone called fibroblast growth factor 23 (FGF23), causing excessive renal excretion of phosphate (i.e., “phosphate wasting”), decreasing intestinal absorption of dietary phosphate, and thus low levels of phosphorus in the blood. Though considered a hereditary disorder, affecting up to 1 in 20,000 Americans, up to 30% of cases are the result of de novo variants.

Other than low serum phosphorus levels, the typical signs of the disorder are lower-extremity bowing, rickets, osteomalacia, short stature, and gait abnormalities. Other reported issues include dental caries, bone and joint pain, hearing loss, among other bone and tooth-related symptoms. Adults may suffer excessive fractures or pseudofractures, spinal stenosis, and osteoarthritis.

A Patient Survey to Improve Understanding of XLH. As with many other rare disorders, much of the previous research on the burden associated with XLH focused on physical symptoms. Less is understood about the day-to-day impact of XLH on patients and caregivers.

To better understand the lived experiences and unmet needs of children and adults with XLH, Kyowa Kirin and The XLH Network partnered to conduct a survey of the experiences of patients from around the United States.

The project comprised an online survey and an optional, in-depth phone interview with adult patients (≥ 18 yr) or caregivers of children with XLH. The survey and phone interviews were completed over four months, ending February 2024. A total of 87 online surveys were completed (56 adults, 29 caregivers, and 2 children). Of the adult respondents, their average age was 49.4 years (46 females, 10 males). Of the 29 caregivers and 2 children who responded for themselves, the average age of the child with XLH was 9.0 years (16 females, 14 males, 1 unknown). The average time since their diagnosis was 42.2 years for adult patients and 7.0 years for the children. Fifty-six individuals participated in the optional phone interview (36 adult patients, 20 caregivers).

For the online survey results, 79.3% of the participants were based in urban areas; 85.7% of the adult patients were Caucasian, 8.9% were Latino/Hispanic, and 3.6% identified as Asian, while 0% were Black/African American. Of the children included in the online survey, 67.7% were Caucasian, 12.9% were Latino/Hispanic, 6.5% were Asian, and 6.5% were Black/African American.

Nearly two-thirds of the adults in the online survey (64.3%) reported that other members of their family also had diagnosed XLH. In contrast, approximately two-fifths (37%) of children with XLH and their caregivers indicated that they had other family members with XLH (immediate family members most often mentioned).

Age at Diagnosis, Provider Access and Knowledge of XLH. Patients with XLH can experience a long diagnostic journey, though the age at diagnosis is younger for children with XLH than it is for online survey respondents who are now adults. For the adults participating, their average age at diagnosis was 7.2 years compared with 2.1 years for children with XLH. Challenges cited by respondents in the qualitative interviews included the impression held by the doctor that the child “would grow out of” the symptoms and a delay in genetic testing to confirm a diagnosis. Some respondents reported that genetic testing in children was prompted by a family history or telltale signs requiring further investigation (e.g., bowing legs or lab tests indicating low phosphorus levels). Misdiagnosis was reported by several respondents.

On average, patients in the online survey saw 2.3 healthcare providers before receiving a diagnosis, and one-fifth of adults with XLH reported seeing 5 or more providers before receiving a diagnosis. The diagnosis was most often made by endocrinologists (35.7% of adults, 45.2% of children). Children with XLH were more commonly diagnosed by a geneticist (5.4% of adults, 25.8% of children). For adults surveyed, orthopedic professionals and pediatricians were also cited as making the diagnosis (16.1% and 16.1%, respectively). This likely points to greater knowledge today about XLH and access to genetic testing. The participants rated geneticists as having the greatest knowledge of XLH (8 points out of 10, with 10 = excellent), followed by endocrinologists (7.8), nephrologists (7.4), and primary care (6.8).

In the online survey, 82.1% of adults and 74.2% of children indicated that their current primary XLH healthcare provider is an endocrinologist. However, access is an issue, as they travel on average 90 miles one-way (over 1.5 hours) to see that provider. More than a quarter of adults in the online survey reported seeing at least 10 different healthcare providers since their diagnosis. In addition to their primary care provider, they currently see an average of 4.4 other health professionals (vs. 3.7 providers for children with XLH). Finding knowledgeable healthcare professionals was the most frustrating issue of patients and caregivers surveyed (average rating on a scale of 1–10, with 10 = having experienced significant frustration was 7.9 for adults and 5.7 for children).

Among the 49 adults diagnosed before 18 years of age, 47 (95%) surveyed did not undergo a true transition of care. In follow up interviews, participants cited difficulty in finding a new knowledgeable healthcare provider, misperceptions about the disease process after the patient stopped growing, and lack of their own follow-up as contributing factors.

An Atlas of Symptoms, Physical and Mental Impacts, and Unmet Needs. Adult patients interviewed reported that they experienced a range of physical issues over the years, with pain, stiffness, and lack of energy among the most burdensome physical symptoms reported in the survey.

Partial hearing loss and tinnitus were frequently reported in the qualitative interviews by adult patients (55.6% and 69.4%, respectively). Dental problems were also common, with cavities (83.3%), dental abscesses (75.0%), premature tooth loss (75.0%), and poor enamel (63.9%) among the top complaints. Although children with XLH had a lower incidence of dental issues compared with adults, three-quarters were said to have at least one dental problem. Difficulty falling asleep (69.4% for adults and 30.0% for children) and staying asleep (75.0% and 20.0%, respectively) were also commonly reported by patients with XLH.

Feelings of anxiety, depression, fear, and social isolation are prevalent, especially in the adult population of patients interviewed. Each of these four mental health issues were reported by at least 53% of the responding adult patients. For children, fear and anxiety were each cited by at least half of the respondents. Fourteen percent of adults with XLH reported suicidal thoughts at some point in time. Based on the survey, 83% of adults and 90% of children had at least one mental health concern, but just 13% of adults and 3% of children reported accessing mental health professionals.

Overall, pain was the most burdensome issue reported by interviewees, followed by mental health and the ability to stay asleep. For adults, XLH had a greater impact on their ability to perform daily activities than children, with getting dressed and housework cited as their most common challenges.

The Cost of Care for Patients With XLH. Out-of-pocket costs for respondents to the online survey ranged from 0% to 40% of their annual household income. The costs cited included home modifications, uncovered dental care, and cost sharing for in-network or out-of-network healthcare providers.

Missing work or having to take personal time off for XLH-related reasons were the most commonly cited indirect economic problems associated with the disorder.

Further details about the survey and its results are available from XLHimpact.com.

COR-US-RDS-0145 August 2025