A Pediatric Endocrinologist Explains the Rare Bone Disorder
By Dr. Kelli Davis, Pediatric Endocrinologist & National Bone Expert
Hypophosphatasia (HPP) is a rare, inherited metabolic bone disorder caused by mutations in the ALPL gene. This gene encodes tissue-nonspecific alkaline phosphatase (TNSALP)—an enzyme essential for bone and dental mineralization.
When TNSALP is deficient, key substances such as inorganic pyrophosphate (PPi), pyridoxal 5'-phosphate (PLP), and phosphoethanolamine (PEA) build up in the body. These excess substrates interfere with healthy bone and tooth development, leading to fragile bones, rickets-like features, and sometimes serious systemic complications.
HPP affects children differently depending on severity. Some cases are life-threatening, while others are mild and primarily involve dental changes.
Common features include:
Weak or soft bones resembling rickets
Premature loss of baby teeth, often with roots intact
Delayed walking or motor skill impairment
Craniosynostosis (premature fusion of skull bones)
Chronic musculoskeletal pain
Failure to thrive or poor growth
In severe cases, vitamin B6-dependent seizures caused by high PLP levels
Even children with mild forms—like odonto-HPP (dental-only disease)—require careful evaluation, since misdiagnosis can delay treatment.
Diagnosis requires a combination of laboratory testing, imaging, and genetics:
Low alkaline phosphatase (ALP) for age (a hallmark feature)
Elevated ALP substrates (PLP, PPi, PEA)
Radiographic signs of rickets or abnormal bone mineralization
Genetic confirmation of ALPL mutations
In 2024, the International HPP Working Group established diagnostic criteria for children and adolescents:
Two major criteria (pathogenic ALPL variant, elevated substrates, early tooth loss), or
One major plus two minor criteria (e.g., low bone mineral density, radiographic findings)
Early recognition is essential to avoid missteps—especially since hypophosphatasia can mimic other bone or endocrine conditions.
Management depends on severity:
Enzyme Replacement Therapy (ERT): The drug asfotase alfa is the gold standard for moderate to severe pediatric HPP. Clinical studies show improved survival, stronger bone mineralization, and better motor function.
Supportive care: For milder forms, treatment may involve pain management, dental support, physical therapy, and close monitoring by a pediatric endocrinology team.
Because HPP is lifelong, children often benefit from a multidisciplinary care team—including endocrinologists, geneticists, orthopedists, neurologists, and dentists.
With timely diagnosis and modern therapies, many children with hypophosphatasia can live healthier, more active lives. The key is early recognition and specialized care from experts who understand the nuances of this rare disorder.
At Life Pediatric Endocrinology, we specialize in complex bone diseases like HPP. Families travel from across the U.S. to receive expert diagnosis, treatment, and compassionate care tailored to their child.
If your child has unexplained fractures, premature tooth loss, persistently low alkaline phosphatase, or other concerning bone symptoms, it’s important to seek expert care.
At Life Pediatric Endocrinology, our metabolic bone disease team, led by Dr. Kelli Davis, provides advanced evaluation, personalized treatment, and long-term support for children with rare bone conditions like hypophosphatasia.
👉 Click here to schedule a consultation and learn how we can help your child achieve stronger, healthier growth.
Dr. Kelli Davis is a nationally recognized pediatric endocrinologist specializing in bone disease and complex growth disorders. Dr. Davis completed her fellowship at Vanderbilt University, where she trained under world-renowned pediatric endocrinologist Dr. Jill Simmons, gaining advanced expertise in bone health and rare metabolic disorders and allowing her to help children with rare conditions like hypophosphatasia achieve healthier, more confident lives.
Whyte MP, McAlister WH, Mack KE, Mumm S, Madson KL. Pediatric Hypophosphatasia: Avoid Diagnosis Missteps! J Bone Miner Res. 2024;39(6):655-660. doi:10.1093/jbmr/zjae098.
Rush E, Brandi ML, Khan A, et al. Proposed Diagnostic Criteria for the Diagnosis of Hypophosphatasia in Children and Adolescents: Results From the HPP International Working Group. Osteoporos Int. 2024;35(1):1-10. doi:10.1007/s00198-023-06843-2.
Seefried L, Genest F, Hofmann C, Brandi ML, Rush E. Diagnosis and Treatment of Hypophosphatasia. Calcif Tissue Int. 2025;116(1):46. doi:10.1007/s00223-025-01356-y.