Hypophosphatasia and X-Linked Hypophosphatemia

Phosphate is among the most abundant minerals in the body.¹  It is important for a variety of processes including energy metabolism, protein synthesis, skeletal and tooth development, as well as maintaining bone integrity.¹

Hypophosphatasia and X-linked hypophosphatemia are both genetically inherited conditions that affect phosphate homeostasis and are characterized by abnormal development of bone and teeth.¹  In hypophosphatasia, mineralization is disrupted affecting a number of tissues, including bone and teeth.  With X-linked hypophosphatemia, an inability of the cells in the body to properly process phosphate causes circulating levels of phosphate to be low, resulting in problems with bone and tooth development.¹

Hypophosphatasia is a rare, inherited, progressive metabolic disorder. In its most severe form, it is an ultra-rare disease, occurring in approximately 1 in 100,000 live births and is characterized by defective bone/tooth mineralization, weakness, seizures, respiratory failure, and premature death.² Less-severe forms of the disease occur more frequently, although still uncommonly.³ In a natural history study, infants who had their first symptom of hypophosphatasia within the first 6 months of life had an overall mortality rate of 73% at 5 years, primarily due to respiratory failure.⁴

Hypophosphatasia is caused by loss-of-function mutation(s) in the gene that encodes the tissue-nonspecific isozyme of alkaline phosphatase (TNSALP or TNAP).^{3, 5} Marked reduction in alkaline phosphatase activity results in elevated circulating serum levels of inorganic pyrophosphate (PPi) and pyridoxal-5’-phosphate (PLP; the principal circulating form of vitamin B6), and elevated urine levels of PPi and phosphoethanolamine (PEA), all molecules presumed to be substrates of TNAP.⁶ High extracellular levels of PPi block hydroxyapatite crystal growth, resulting in impaired bone/tooth mineralization and rickets-like symptoms;⁵ severely affected patients can develop hypercalcemia and hyperphosphatemia.⁵ The derangement in vitamin B6 metabolism can result in pyridoxine-responsive seizures.⁵ Hypomineralization of the ribcage (“rachitic chest”) results in hypoinflation of the lungs and respiratory failure.³

Hypophosphatasia can manifest as neonatal death with almost no skeletal mineralization to dental problems in adults without any bone symptoms. The disease has generally been classified according to patient age when the first signs and symptoms manifest; six clinical forms are currently recognized (Table 1). These clinical subtypes can overlap, e.g., infantile and childhood hypophosphatasia share some clinical symptoms, and patients with adult hypophosphatasia often had some clinical symptoms already in childhood.³ Oral manifestations characteristic of various forms of hypophosphatasia can include early loss of deciduous teeth, severe dental caries, improperly formed teeth, and alveolar bone loss.³

Table 1. Clinical Forms of Hypophosphatasia (adapted from Mornet 2007³)

Clinical Form (Inheritance)	Bone/Dental Symptoms
Perinatal lethal (AR)	Bone: hypomineralization osteochondral bone spurs Dental: N/A
Perinatal benign (AD)	Bone: bowing of long bones benign postnatal course Dental: N/A
Infantile (AR; first symptom 6 months of age or younger)	Bone: craniosynostosis hypomineralization rachitic ribs hypercalciuria Dental: premature loss of deciduous teeth
Childhood/Juvenile (AR [frequent] or AD [rare]; first symptom younger than 18 years of age7)	Bone: short stature skeletal deformity waddling gait bone pain/fractures Dental: premature loss of deciduous teeth
Adult (AR or AD)	Bone: Stress fractures: metatarsal, tibia Osteoarthritis Dental: Symptoms may be present or absent
Odontohypophosphatasia (AR or AD)	Bone: loss of alveolar bone Dental: exfoliation (incisors) reduced dentin thickness enlarged pulp chambers caries

^{AD: autosomal dominant; AR: autosomal recessive; N/A: not applicable;}

Oral manifestations characteristic of various forms of hypophosphatasia can include early loss of deciduous teeth, severe dental caries, improperly formed teeth, and alveolar bone loss.^{3, 8, 9}

Enzyme-Replacement Therapy for Hypophosphatasia. Asfotase alfa (Strensiq^®, Alexion Pharmaceuticals, Inc.) is the first agent approved for the treatment of perinatal, infantile, and childhood-onset forms of hypophosphatasia.^{2, 5, 10} A recombinant form of TNAP, asfotase alfa is intended to enhance deficient alkaline phosphatase enzyme activity in patients with these forms of hypophosphatasia.^{2, 10} Safety and efficacy of asfotase alfa were established in patients with perinatal, infantile- or juvenile-onset hypophosphatasia who received treatment for up to 6.5 years during four prospective, open-label studies.^{2, 5, 10} Results showed that patients with perinatal- and infantile-onset hypophosphatasia treated with asfotase alfa had improved overall and ventilator-free survival compared with historical controls; patients with the juvenile form of the disease showed improvements in growth and bone health compared to control patients selected from a natural history database.

Asfotase alfa is administered as a subcutaneous injection (3 to 6 injections per week) in weight-based dosing regimens.¹⁰ Warnings and precautions include hypersensitivity reactions, lipodystrophy at injection sites (i.e., abnormal thickening or thinning of the skin), and ectopic calcifications in the eye and kidneys.¹⁰ The most common adverse reactions occurring in 10% or more of patients include injection site reactions, lipodystrophy, ectopic calcifications, and hypersensitivity reactions.¹⁰

X-linked hypophosphatemia, also known as vitamin D-resistant rickets, is an inherited disorder characterized by low levels of phosphate in the blood due to abnormal processing in the kidney, leading to phosphate wasting and resulting in soft, weak bones (rickets).¹¹  X-linked hypophosphatemia is usually diagnosed in childhood and its features include bowed or bent legs, short stature, bone pain, and severe dental pain, as well as other oral manifestations.¹¹

X-linked hypophosphatemia is caused by mutations in the PHEX gene on the X chromosome; inheritance is X-linked dominant.¹¹  The disease affects approximately 3,000 children and 12,000 adults in the U.S.¹²  The chief characteristic is low serum phosphate levels (hypophosphatemia)¹³ because of impaired processing in the kidney, leading to phosphate wasting and resulting in soft, weak bones (rickets).¹¹  Excess fibroblast growth factor 23 suppresses renal tubular phosphate reabsorption and the renal production of 1,25 dihydroxy vitamin D.¹⁴ The clinical presentation ranges from isolated hypophosphatemia to severe bowing of the lower extremities;¹³ patients may also experience bone/joint pain, impaired growth, hearing loss, and dental pain.¹² Diagnosis of the more severe form is frequently made in the first 2 years of life when lower-extremity bowing becomes evident as the child bears weight in walking; however, because of the extremely variable presentation, the diagnosis is sometimes not made until adulthood.¹³

Individuals with X-linked hypophosphatemia are prone to spontaneous dental abscesses because of structural changes in the dentin: irregular spaces with defective mineralization in the dentin have been described; panoramic imaging reveals enlarged pulp chambers with prominent pulp horns leading to susceptibility to abscess formation.^{13, 15-17}

Pharmacologic treatment focuses on improving pain and correcting bone deformation. Until recently, treatment for most children consisted of oral phosphate administered three to five times daily and high-dose calcitriol, the active form of vitamin D.¹³ In children, treatment generally was initiated at the time of diagnosis and continued until long bone growth was complete.¹³ Because of susceptibility to dental abscesses, which can lead to loss of both deciduous and permanent teeth, dental management consists primarily of prevention with good oral hygiene and regular dental care/examination and fluoride treatments.^{13, 15, 17}

Biologic Antibody Therapy to Suppress Fibroblast Growth Factor 23.  Burosumab-twza (Crysvita™, Ultragenyx Pharmaceuticals, Inc.) is the first biologic agent approved by FDA to specifically address X-linked hypophosphatemia in adults and children older than 1 year.¹²  Burosumab is a monoclonal antibody that binds to and inhibits the activity of excess fibroblast growth factor 23, restoring renal phosphate reabsorption and increasing the serum concentration of 1,25 dihydroxy vitamin D.¹⁴ Safety and efficacy of burosumab were demonstrated in 2 open-label studies in pediatric patients (compared to historical controls) and 2 studies in adult patients: one a randomized, placebo-controlled trial and an open-label extension of that trial.¹⁴ From 94% to up to 100% of patients in the studies on active treatment achieved normal phosphate levels; radiologic findings also improved with active burosumab therapy.

Burosumab is administered as a once-monthly (adults) or every-2-week (children) subcutaneous injection in a weight-based dosing regimen.¹⁴ The most common adverse reactions in adults were back pain, headache, restless leg syndrome, decreased vitamin D, dizziness and constipation, while the most common adverse reactions in children were headache, injection-site reaction, vomiting, decreased vitamin D and fever.¹²

1. Manghat P, Sodi R, Swaminathan R. Phosphate homeostasis and disorders. Ann Clin Biochem 2014;51(Pt 6):631-56.
2. FDA News Release: FDA approves new treatment for rare metabolic disorder. U.S. Food and Drug Administration (FDA) 2015.  Accessed October 26, 2015; archived.
3. Mornet E. Hypophosphatasia. Orphanet J Rare Dis 2007;2:40.
4. Whyte MP, Leung E, Wilcox W. Hypophosphatasia: a retrospective natural history study of the severe perinatal and infantile forms (Abstract 752416). Pediatric Academic Societies and Asian Society for Pediatric Research Joint Meeting. Vancouver, BC, Canada; May 5, 2014.
5. Whyte MP, Greenberg CR, Salman NJ, et al. Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med 2012;366(10):904-13.
6. Millan JL, Plotkin H. Hypophosphatasia - pathophysiology and treatment. Actual Osteol 2012;8(3):164-82.
7. Expanded Access Program for Asfotase Alfa Treatment for Patients With Infantile- or Juvenile-onset Hypophosphatasia (HPP; NCT02496689). ClinicalTrials.gov. Accessed April 18, 2018.
8. Kuklani RM, Supancic JS, Cohen DM, Bhattacharyya I. Improperly Formed Maxillary Teeth. J Am Dent Assoc 2010;141(11):1346-50.
9. McCormick J, Ripa LW. Hypophosphatasia: review and report of case. J Am Dent Assoc 1968;77(3):618-25.
10. Alexion Pharmaceuticals Inc. Strensiq™ (asfotase alfa) injection, for subcutaneous use (rev. 1/2018).  Accessed April 18, 2018.
11. National Institutes of Health Genetic and Rare Diseases Information Center. X-linked hypophosphatemia.  2018.  Accessed April 18, 2018.
12. FDA News Release: FDA approves first therapy for rare inherited form of rickets, x-linked hypophosphatemia. U.S. Food and Drug Administration (FDA) 2018.  Accessed April 18, 2018.
13. Ruppe MD. X-Linked Hypophosphatemia. In: GeneReviews^® [Internet] Seattle (WA): University of Washington, Seattle; 1993-2018 2012 Feb 9 [Updated 2017 Apr 13].  Accessed April 20, 2018.
14. Ultragenyx Pharmaceutical Inc. Crysvita™ (burosumab-twza) injection, for subcutaneous use (rev. 4/2018).  Accessed April 20, 2018.
15. Cohen S, Becker GL. Origin, diagnosis, and treatment of the dental manifestations of vitamin D-resistant rickets: review of the literature and report of case. J Am Dent Assoc 1976;92(1):120-9.
16. Souza MA, Soares Junior LA, Santos MA, Vaisbich MH. Dental abnormalities and oral health in patients with Hypophosphatemic rickets. Clinics (Sao Paulo) 2010;65(10):1023-6.
17. Lee BN, Jung HY, Chang HS, Hwang YC, Oh WM. Dental management of patients with X-linked hypophosphatemia. Restor Dent Endod 2017;42(2):146-51.

ADA Library Services

The National Organization for Rare Disorders (NORD):

• Hypophosphatasia
• Familial Hypophosphatemia

U.S. National Library of Medicine^® Genetics Home Reference:

• Hypophosphatasia
• Hereditary Hypophosphatemic Rickets