Hypophosphatasia (HPP), a rare inherited metabolic disorder affecting bone and tooth development, remains significantly underdiagnosed in Korea. With only approximately 30 diagnosed patients across all age groups, the country faces substantial challenges in identifying and managing this complex condition.

The primary obstacles to HPP diagnosis in Korea stem from limited awareness of low alkaline phosphatase (ALP) levels as a diagnostic clue, non-specific symptoms that can be mistaken for other conditions like rickets or cerebral palsy, and fragmented care across multiple specialties, including pediatrics, dentistry, and orthopedics.

This disconnect often leads to diagnostic delays and missed opportunities for early intervention.

Dr. Eric T. Rush, a clinical genetics specialist at the University of Kansas Medical Center and Children's Mercy Hospital, recently sat down with Korea Biomedical Review to discuss the complexities of HPP, current diagnostic and treatment challenges in Korea, and how global clinical strategies are evolving to serve patients with this rare metabolic disorder better.

With over 15 years of dedicated research in skeletal disorders, Rush has been at the forefront of advancing HPP understanding and treatment approaches.

Understanding the complexity of HPP

HPP presents unique characteristics that distinguish it from conventional skeletal disorders.

As Rush explains, the condition results from loss-of-function mutations in the ALPL gene, which produces tissue-nonspecific alkaline phosphatase (TNSALP).

“Unlike typical bone diseases, HPP is a systemic metabolic condition with far-reaching effects beyond the skeletal system,” he said. “The disease can impact various bodily functions, making it fundamentally different from localized bone disorders.”

The variability in HPP presentation is remarkable among metabolic diseases.

Some patients face severe complications from infancy, including rickets, seizures, and pulmonary disease, while others may live into adulthood experiencing only dental-related issues.

This spectrum of severity creates additional diagnostic challenges, as symptoms can range from life-threatening complications to seemingly minor dental problems.

As a result, the age of onset plays a crucial role in determining disease severity and clinical presentation.

“The age of onset significantly influences disease severity,” Dr. Rush emphasizes. “In infants, the most serious complications are respiratory failure and severe rickets. School-age children typically experience growth disorders, motor dysfunction, pain, and sleep disturbances. Adults often face chronic, non-healing fractures and debilitating pain that severely impacts their quality of life.”

Diagnostic challenges and clinical recognition

In Korea, physicians typically identify HPP after a patient presents with nonspecific symptoms -- such as growth delay, gait disturbances, or frequent fractures -- that prompt blood testing.

A notably low alkaline phosphatase (ALP) level often leads to further radiographic evaluation and confirmatory genetic testing via next-generation sequencing (NGS).

However, the path to diagnosis remains fragmented, with most patients bouncing between pediatrics, orthopedics, and dentistry departments without a clear diagnostic route.

Age-related variations in ALP levels add another layer of complexity to diagnosis.

"ALP levels vary significantly with age, with higher levels being normal during growth periods," Dr. Rush notes. "While adults typically have normal ranges around 40 units per liter, children and adolescents have higher normal values.”

Rush stressed that gender differences may appear temporarily during puberty as girls typically enter puberty earlier with rapidly rising ALP levels, while boys start puberty later but achieve higher peak levels.

Rush noted that Korea’s low diagnosis rate may stem from a critical lack of awareness among frontline clinicians.

“ALP is usually flagged when elevated, but few doctors understand that low ALP levels -- especially in the absence of liver disease or malnutrition -- should raise suspicion for HPP,” he said. “Another missed clue is early loss of baby teeth, especially before the age of five, without root resorption.”

Dentists could be key to catching these cases earlier, he added.

Rush stressed that the diagnostic accuracy of ALP screening can be enhanced through additional biomarkers.

"Low ALP doesn't automatically indicate HPP, as nutritional deficiencies or liver dysfunction can also cause decreased levels, requiring differential diagnosis," Rush explains. "For instance, HPP patients tend to have elevated vitamin B6 levels, so the combination of low ALP and high vitamin B6 strongly suggests HPP.”

Genetic testing for ALPL gene mutations can also improve screening accuracy and considering both biochemical markers and genetic information together enhances diagnostic precision, he added.

When asked if HPP can be diagnosed prenatally, Rush stressed that the potential for prenatal diagnosis represents an exciting frontier in HPP management.

"Prenatal ultrasound can significantly aid early HPP diagnosis," Rush said. "Japan has successfully diagnosed HPP during fetal development and initiated treatment immediately after birth.”

While prenatal treatment isn't yet technically feasible, the ability to diagnose before birth is very encouraging, he added.

Treatment evolution and current approaches

When asked about the treatment landscape for HPP, Rush explained that the field has undergone a dramatic transformation over the past decade.

"HPP was first described in the 1940s by a Canadian pediatrician, but received little attention for over 60 years," Rush recalls. "Before Strensiq (ingredient: asfotase alfa), no disease-specific treatments existed, with care limited to symptom management and supportive measures.”

Strensiq, developed by Alexion Pharmaceuticals, a subsidiary of AstraZeneca, and approved in the U.S. in 2015, remains the only enzyme replacement therapy for HPP.

It provides recombinant alkaline phosphatase to correct the underlying enzyme deficiency, improving bone mineralization and systemic health.

“Children who would have died in infancy are now surviving, walking, and thriving thanks to Strensiq,” Rush said. “Real-world outcomes have mirrored clinical trial data, with gradual but meaningful improvements in respiratory function, growth trajectories, and bone integrity.”

In several cases, ventilator-dependent infants have transitioned to independent breathing after months of therapy.

However, Rush stressed that Strensiq is not a cure and the treatment must be tailored to individual patient needs, with careful consideration of disease severity, functional impairment, and quality of life.

In milder cases, the decision to initiate therapy is more nuanced. “We often say, ‘We’re not treating the disease -- we’re treating the patient,’” Dr. Rush added.

Duration of therapy remains open-ended, as while overall patient satisfaction is high, some pediatric patients resist frequent injections, and logistical burdens remain. Families also face anxiety over long-term access and treatment affordability -- especially in regions with restrictive reimbursement policies.

“I don’t tell families this will be lifelong treatment, but I do tell them we don’t yet know how long is enough,” he said. “We reassess based on how the patient is doing.”

Korean policy gaps and global contrasts

In Korea, the drug was approved by the Ministry of Food and Drug Safety (MFDS) on Feb. 12, 2016, with both 40 mg/mL and 100 mg/mL formulations. Since June 2020, Strensiq has been reimbursed under the national health insurance system, but only for patients with pediatric-onset HPP diagnosed before age 19.

This cutoff has left many patients untreated or facing out-of-pocket costs that are prohibitively high.

Rush acknowledged similar diagnostic delays in the U.S., but noted that insurance coverage is more flexible.

“If a patient is diagnosed at 45 but clearly had symptoms since childhood, we can classify them as juvenile-onset,” he explained. “The key is recognizing that age at diagnosis doesn’t always match age at onset.”

Toward better systems and solutions

In the U.S., multidisciplinary rare disease teams have become a cornerstone of early diagnosis. Rheumatologists, orthopedic surgeons, pediatricians, and dentists work alongside geneticists to coordinate care and streamline referrals.

National medical conferences and specialty symposia serve as platforms for clinician education and knowledge exchange.

Online resources and patient advocacy organizations like Soft Bones also help raise awareness, provide educational materials, and empower families to advocate for themselves.

“Social media platforms, especially TikTok, have unexpectedly emerged as hubs for patient communication and disease discovery among adolescents,” Rush said.

As genomic medicine evolves, future prospects for HPP include earlier family-based screening, improved biomarker strategies, and novel therapeutic approaches beyond enzyme replacement.

“Eventually, we hope to move beyond symptom management to actual disease modification—or even a cure,” Rush said.

Until then, he urges both clinicians and patients in Korea to stay engaged and proactive.

“HPP may be rare, but patients are not alone,” he said. “There is a global community working to advance diagnosis, treatment, and understanding. The more we share and learn from each other, the better outcomes we can achieve.”