Multisystemic Impact of HPP in Your Patients

Image is not of an actual patient.

Multisystemic Symptoms

Understanding the multisystemic impact of hypophosphatasia (HPP) is important for proper diagnosis^1,2

Patients may be diagnosed with^3-13:

osteoporosis
arthritis
fibromyalgia
pseudogout
other rheumatic conditions

Identifying HPP requires comprehensive assessment. It’s important to perform a complete evaluation of your patients for all possible HPP signs and symptoms.^3,14

As we've learned more about HPP, as we know more about this condition, we are truly understanding that it is a multisystemic disease and not just a skeletal disease.

— Dr Eric Rush, Clinical Geneticist

Patients with HPP can have structural (skeletal) and functional (muscle and CNS) manifestations that contribute to disease burden^7,15-17

Click regions to view information

Use the arrows to cycle through regions to view information

Diagram outlines symptoms seen in infants, children, and adults.

This is not an exhaustive list of HPP signs and symptoms in each region.

Neurologic^18,21-24

•Brain fog
•Headache
•Sleep disturbance
•Neuropathy
•Anxiety and depression
•Hearing loss
•Balance issues/vertigo
•Behavioral health
•ADHD (pediatric patients)
•Seizures (in infants)

Dental^9,10,18,28

• Premature loss of deciduous and permanent teeth
• Dental caries
• Poor or abnormal dentition
• Periodontal disease

Growth/Development
(in children)^10,18

• Failure to thrive
• Poor weight
• Short stature
• Delayed or missed motor milestones
• Premature loss of teeth with roots intact
• Rickets

Respiratory (in infants)^10,18,29,30

• Respiratory failure
• Pneumonia
• Improper development of ribs and chest deformities

Muscular^10,18-20

•Pain
•Weakness
•Hypotonia
•Reduced grip force
•History of abnormal gait
•Reduced mobility
•Tendon calcification

Gastrointestinal¹⁴

• Nausea, vomiting, and feeding difficulties (in infants)
• Gastrointestinal dysfunction (in adults)

Renal^18,20,23,32

•Hypercalcemia
•Hyperphosphatemia
•Nephrolithiasis
•Nephrocalcinosis

Rheumatic^10,18,20,31

•Calcific periarthritis
•Chondrocalcinosis
•Pain
•Pseudogout
•Osteoarthropathy

Skeletal/
Craniosynostosis^{9,10,18,20,23,25-27}

•Fractures
•Delay in fracture healing
•Pseudofractures
•Rickets (in children)
•Osteomalacia
•Hypomineralization
•Bone/joint pain
•Bone deformities

Diagram outlines symptoms seen in infants, children, and adults.

This is not an exhaustive list of HPP signs and symptoms in each region.

*HPP is a rare disease; the true prevalence is unknown.³³

^†Based on the Global HPP Registry, an observational, prospective, multinational study of 269 patients with a confirmed diagnosis of HPP (children, n=121; adults, n=148).²⁰

Some of the things that I was experiencing—like the muscle pain all these years, all the joint issues, the fine little breaks in the ankle and things like this that were happening to me throughout all these years—these were all parts of HPP.

— CAROL, LIVING WITH HPP

Adults

Male, severe chronic pain and muscle weakness, fatigue, abnormal gait, and headaches

64-year-old with chronic pain, fatigue, and no history of fractures. Has family presenting with similar progressive symptoms; suffering from abnormal gait and headaches.

Current and Historical Clinical/Lab/Imaging Results

Low ALP activity at 28 U/L (reference range: 47 U/L-123 UL)
Elevated vitamin B₆ (PLP) at 112 mg/mL (reference range: 5 ng/mL-50 ng/mL)
PLP (1 year prior): 98 ng/mL (reference range: 5 ng/mL-50 ng/mL)
No genetic tests performed
No fracture found on current hip imaging (performed due to difficulty walking and hip pain)

Current Symptoms Impacting Daily Life

Pain and fatigue have occasionally led to consecutive days bedridden
Abnormal gait
Missing out on social activities with grandchildren

Family History

Father: arthritis and suffers from anxiety
Sister: diagnosed with osteoporosis, history of bisphosphonate use, and atypical femoral fracture

Medical History

Missed early motor milestones as infant/toddler
Chronic joint pain, muscle weakness, fatigue, and headaches
Age 54: diagnosed with fibromyalgia
Reports self-medicating daily with NSAIDs

Interaction With HCPs

Primary care referred to rheumatologist due to chronic joint pain
Rheumatologist identified low ALP and consulted with an endocrinologist on further management
Currently seeing endocrinologist, who suspects HPP

Female, history of multiple fractures and broken bones

54-year-old with history of slow-healing fractures. Recently had to reduce her hours as a chef due to multiple, recurrent lower extremity fractures, constant fatigue, and foot pain.

Current and Historical Clinical/Lab/Imaging Results

Low ALP activity at 32 U/L (reference range: 49 U/L-135 U/L)
ALPL genetic test: variant of uncertain significance (VUS) identified

Current Symptoms Impacting Daily Life

Current nontraumatic hairline fracture of the tibia
Progressive bone pain in back and thigh, hindering movement

Family History

Mother: osteoporosis, suspected due to fractures; hypertension

Medical History

Early nontraumatic loss of primary teeth
Forced to quit sports team at 13 due to inability to keep up
Multiple nontraumatic metatarsal fractures starting in her 20s and a femoral fracture at age 48
Age 50: kidney stones
Recent diagnosis of pseudogout

Interaction With HCPs

First seen by an internist, who referred to a rheumatologist and was diagnosed with pseudogout
Followed for years by an orthopedic surgeon for poorly healing fractures, who recently referred her to an endocrinologist for an evaluation

Children

Male, chronic pain and muscle weakness, and difficulty sleeping

12-year-old with significant “growing pains,” including in wrist and ankles. Progressively struggling to keep up with peers in sports and taking a long time to recover after physical activity. Missing school and becoming more withdrawn and isolated from friends.

Current and Historical Clinical/Lab/Imaging Results

Low ALP activity at 121 U/L (age- and sex-adjusted reference range: 141 U/L-460 U/L)
Positive for ALPL, the likely pathogenic gene variant. Subsequently, father also tested positive for the likely pathogenic ALPL variant
Vitamin B₆ (PLP) elevated at 145 ng/mL (reference range: 5 ng/mL-50 ng/mL)

Current Symptoms Impacting Daily Life

Increased musculoskeletal pain
Struggling to keep up with peers in sports
Feeling tired and missing school for the past few months. Some difficulty sleeping
Struggling with maintaining friendships and becoming more isolated

Family History

Father: chronic pain

Medical History

Delay in walking milestones
Age 12: started presenting with joint aches, including in wrists and ankles

Interaction With HCPs

Was recently seen by pediatric rheumatologist for wrist and ankle pains, who suspects juvenile arthritis. (No ALP testing conducted)
Caregiver seeks second opinion with a pediatric endocrinologist who performed ALP testing, followed by genetic and B₆ tests. Suspects HPP

Female, rickets (soft, curved bones) and prone to bone deformities

4-year-old with bowed legs and rickets, prone to bone deformities, having trouble keeping up with peers in sports and outdoor activities due to difficulty running.

Current and Historical Clinical/Lab/Imaging Results

Presence of rickets on radiograph (metaphyseal flaring and physeal widening)
Normal vitamin D level
Low ALP activity at 75 U/L (age- and sex-adjusted reference range: 156 U/L-369 U/L)

Current Symptoms Impacting Daily Life

Not keeping up with peers in sports due to difficulty running
Delayed walking milestone

Family History

Mother: diagnosed with fibromyalgia

Medical History

Poor weight gain
Delayed walking and other motor milestones
Premature loss of primary teeth 3 months ago

Interaction With HCPs

Pediatrician identified rickets on X-ray (metaphyseal flaring and physeal widening) and suspected vitamin D deficiency, but vitamin D level was normal; notices tooth loss. Refers to an endocrinologist
Pediatric endocrinologist notices low ALP and suspects HPP

Infants

Female, life-threatening HPP

Female with life-threatening HPP.

Early Onset Issues

Generalized tonic-clonic seizure with cyanosis
Feeding tube
Respiratory distress requiring endotracheal intubation and mechanical ventilation
Generalized osteopenia, thin ribs, and a tongue-like protrusion of radiolucency on the metaphyses of the long bones (femur, tibia, and radius)

Diagnostic Features

Low ALP activity at 18 U/L (age- and sex-adjusted reference range: 134 U/L-518 U/L)
Low PTH at 6 pg/mL (reference range: ~15 pg/mL-65 pg/mL)
Elevated PLP at 320 ng/mL (reference range: 5 ng/mL-50 ng/mL)
Generalized osteopenia, thin ribs, and tongues of radiolucency on the metaphyses of long bones

Perinatal lethal HPP, confirmed with sequencing of *ALPL**

*While a positive ALPL genetic test may help to confirm if your patient has HPP, it is NOT required for diagnosis, and a negative test does not rule out HPP.³⁴

Profiles and images are based on hypothetical patient cases. Please note, individual patient experience and outcomes may vary.

See how HPP may impact patients’ quality of life and daily activities, including their ability to work and learn

Life Impact

See important diagnostic criteria

Diagnosing HPP

CONTACT A REP

Villa-Suárez JM, García-Fontana C, Andújar-Vera F, et al. Int J Mol Sci. 2021;22(9):4303.

Conti F, Ciullini L, Pugliese G. Clin Cases Miner Bone Metab. 2017;14(2):230-234.

Injean P, Tan J, Lee S, Downey C. ACR Open Rheumatol. 2023;5(10):524-528.

Tsang T, Raghuwanshi MP. J Endocr Soc. 2021;5(suppl 1):A201-A202.

Yoshida H, Murakami T, Ogawa A, et al. Endocrinol Diabetes Metab Case Rep. 2025;2025(1):e240121.

Feurstein J, Behanova M, Haschka J, et al. Orphanet J Rare Dis. 2022;17(1):435.

Szabo SM, Tomazos IC, Petryk A, et al. Orphanet J Rare Dis. 2019;14(1):85.

Bangura A, Wright L, Shuler T. Cureus. 2020;12(6):e8594.

Nunes ME. In: Adam MP, Mirzaa GM, Pagon RA, et al, eds. GeneReviews^®. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1150/

Rockman-Greenberg C. Pediatr Endocrinol Rev. 2013;10(suppl 2):380-388.

Mornet E, et al. In: Pagon et al, eds. GeneReviews. Accessed April 21, 2026. http://www.ncbi.nlm.nih.gov/books/NBK1150

Lefever E, Witters P, Gielen E, et al. J Clin Densitom. 2020;23(3):340-348.

Rodziewicz M, Moss K. Rheumatol Adv Pract. 2018;2(suppl 1):rky034.042.

Seefried L, Genest F, Hofmann C, Brandi ML, Rush E. Calcif Tissue Int. 2025;116(1):46.

Dahir KM, Seefried L, Kishnani PS, et al. Orphanet J Rare Dis. 2022;17(1):277.

Dahir KM, Kishnani PS, Martos-Moreno GÁ, et al. Front Endocrinol (Lausanne). 2023;14:1138599.

Martos-Moreno GÁ, Rockman-Greenberg C, Ozono K, et al. Horm Res Paediatr. 2024;97(3):233-242.

Kishnani PS, Rush ET, Arundel P, et al. Mol Genet Metab. 2017;122(1-2):4-17.

Jandl NM, Schmidt T, Rolvien T, et al. Calcif Tissue Int. 2021;108(3):288-301.

Högler W, Langman C, Gomes da Silva H, et al. BMC Musculoskelet Disord. 2019;20(1):80.

Colazo JM, Hu JR, Dahir KM, Simmons JH. Osteoporos Int. 2019;30(2):469-480.

Kim I, Noh ES, Kim MS, et al. Medicine (Baltimore). 2023;102(6):e32800.

Bianchi ML, Bishop NJ, Guañabens N, et al. Osteoporos Int. 2020;31(8):1445-1460.

Pierpont EI, Simmons JH, Spurlock KJ, Shanley R, Sarafoglou KM. Orphanet J Rare Dis. 2021;16(1):80.

Shapiro JR, Lewiecki EM. J Bone Miner Res. 2017;32(10):1977-1980.

Hypophosphatasia. NORD. Updated February 16, 2021. Accessed April 21, 2026. https://rarediseases.org/rare-diseases/hypophosphatasia/

Whyte MP. Hypophosphatasia. In: Bilezikian JP, et al, eds. Principles of Bone Biology. 3rd ed. Academic Press; 2008:1573-1598.

Bloch-Zupan A. Int J Paediatr Dent. 2016;26(6):426-438.

Whyte MP, Leung E, Wilcox WR, et al. J Pediatr. 2019;209:116-124.e4.

Bishop N, Munns CF, Ozono K. Arch Dis Child. 2016;101(6):514-515.

Brandi ML, Khan AA, Rush ET, et al. Osteoporos Int. 2024;35(3):439-449.

Weber TJ, Sawyer EK, Moseley S, Odrljin T, Kishnani PS. Metabolism. 2016;65(10):1522-1530.

Kishnani PS, Seefried L, Ozono K, et al. Orphanet J Rare Dis. 2025;20(1):626.

Khan AA, Brandi ML, Rush ET, et al. Osteoporos Int. 2024;35(3):431-438.

Neurologic18,21-24

Dental9,10,18,28

Growth/Development(in children)10,18

Respiratory (in infants)10,18,29,30

Muscular10,18-20

Gastrointestinal14

Renal18,20,23,32

Rheumatic10,18,20,31

Skeletal/Craniosynostosis9,10,18,20,23,25-27

See how HPP may impact patients’ quality of life and daily activities, including their ability to work and learn

See important diagnostic criteria

Neurologic^18,21-24

Dental^9,10,18,28

Growth/Development
(in children)^10,18

Respiratory (in infants)^10,18,29,30

Muscular^10,18-20

Gastrointestinal¹⁴

Renal^18,20,23,32

Rheumatic^10,18,20,31

Skeletal/
Craniosynostosis^{9,10,18,20,23,25-27}