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With hypophosphatasia still being frequently overlooked and misdiagnosed, the primary aim of this prospective observational study is to determine the prevalence of hypophosphatasia in adult patients in rheumatology, and beyond that to establish an algorithm that promotes early hypophosphatasia detection in clinical practice.
Hypophosphatasia (HPP) is a rare genetic disorder (1-3/300,000 severe cases in Europe) caused by one or more mutations in the alkaline phosphatase (ALP) gene. Hypomineralization results in symptoms such as arthralgias, insufficiency fractures, and poor dental status beginning in childhood. A fatal outcome is conceivable in circumstances of early infancy first presentation. In consistency with the musculoskeletal complaint pattern, HPP is far more common in the rheumatology patient population than in the general population.
However, HPP is still frequently misdiagnosed as some other form of bone disease (e.g., rickets, osteomalacia, or osteoporosis). Therefore, implementation of a clinically applicable algorithm for early hypophosphatasia detection is needed.
The primary aim of this prospective observational study is to determine the prevalence of hypophosphatasia in adult patients in rheumatology. Moreover, a further goal is to establish an algorithm that reliably separates adult HPP patients from other, rheumatologic and bone diseases.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Persistant hypophosphatasemia | Patients with persistant hypophosphatasemia are highly suspicious for hypophosphatasia, and as such are the main focus of this study. In case of persistently low alkaline phosphatase (2nd measurement, 2-4 weeks after the 1st measurement) with normal serum calcium and phosphate values (exclusion of secondary hypophosphatemia due to e.g. rickets or malnutrition) and exclusion of other causes of secondary hypophosphatemia, genetic testing for a pathological ALP gene is performed as part of routine diagnostics. This study involves the structured recording of specific symptoms, the entire course of the disease since childhood, laboratory parameters and genetic testing. |
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| Transient hypophosphatasemia (Control group without hypophosphatasia) | In patients, in which the initial hypophosphatasemia does not confirm with the second ALP testing, the former suspicion of hypophosphatasia must be discarded. With the exclusion of a hypophosphatasia (characterized by a persistant hypophosphatasemia among other criteria) this group of patients qualifies as a control group of patients without hypophosphatasia. Data from this control group will be analyzed in order to investigate patient historical, clinical and laboratory features that may help in the discrimination of hypophosphatasia patients against healthy individuals. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Second alkaline phosphatase measurement | Diagnostic Test | (2-4 weeks after the 1st measurement) |
|
| Measure | Description | Time Frame |
|---|---|---|
| Prevalence of hypophosphatasia in adult patients in rheumatology | The primary aim of this prospective observational study is to determine the prevalence of hypophosphatasia in adult patients presenting with musculoskeletal symptoms in rheumatology. | 24 months |
| Measure | Description | Time Frame |
|---|---|---|
| Frequency of musculoskeletal pathology in hypophosphatasia patients in comparison with normal controls. | Frequency of musculoskeletal pathology in people with biochemistry suggestive of hypophosphatasia and positive ALP gene test as compared with normal controls. | 24 months |
| Health-related quality of life: Short Form-36 |
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Inclusion Criteria:
Exclusion Criteria:
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Any adult patient presenting at the University Hospital Bonn's rheumatology department with musculoskeletal complaints within the timeframe of the study conduct.
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Valentin S. Schäfer, Dr. med. | Contact | +49 228 287-17000 | rheumatologie@ukbonn.de |
| Name | Affiliation | Role |
|---|---|---|
| Valentin S. Schäfer, Dr. med. | University Hospital of Bonn | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Clinic of Internal Medicine III, Department of Oncology, Haematology, Rheumatology and Clinical Immunology, University Hospital Bonn | Recruiting | Bonn | North Rhine-Westphalia | 53127 | Germany |
Data will be available upon reasonable request
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| Extended laboratory diagnostics | Diagnostic Test | Laboratory testing investigating features that support the diagnosis of hypophosphatasia or exclude it by indicating secondary hypophosphatasemia for other reasons (including parameters such as serum calcium, inorganic serum phosphate, vitamin B6, vitamin B12, folic acid, bone-specific alkaline phosphatase, vitamin D3, and more). |
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| Symptom and clinical findings checklist for hypophosphatasia | Diagnostic Test | Checklist including numerous symptoms and clinical findings regarding the musculoskeletal system and non-musculoskeletal body parts |
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| SF-36 | Diagnostic Test | Quality of life questionnaire |
|
| Short physical performance battery (SPPB) score | Diagnostic Test | The short physical performance battery is a group of measures that combines the results of the gait speed, chair stand and balance tests. It has been used as a predictive tool for possible disability and can aid in the monitoring of function in older or disease-affected people. The scores range from 0 (worst performance) to 12 (best performance). The SPPB has been shown to have predictive validity showing a gradient of risk for mortality, nursing home admission, and disability. |
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| Physical examination | Diagnostic Test | A full rheumatological examination will be performed. |
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| Recording of vital signs | Diagnostic Test | (including body temperature, blood pressure, heart rate) |
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| Bioelectrical Impedance Analysis | Diagnostic Test | A body composition measurement by BIA (Bioelectrical Impedance Analysis [proportional mass of muscle, water and fat in kg]) will be performed. |
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| Genetic testing of the alkaline phosphatase gene | Diagnostic Test | Investigation of mutations regarding the alkaline phosphatase gene |
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The possible score ranges from 0 to 100 points, where 0 points represent the greatest possible health limitation, while 100 points represent no health limitation at all. |
| 24 months |
| Frequency of specific symptoms and clinical findings in patients with hypophosphatasia | This will be derived from the symptom and clinical findings checklist. | 24 months |
| Frequency of specific patient history findings and the occurence of hypophosphatasia | Data will be derived from the medical history of hypophosphatasia patients (patient clinical data will be collected regarding the diagnosis, onset, progression, treatment course and outcome for patients with hypophosphatasia) | 24 months |
| Correlation between physical performance abnormalities and hypophosphatasia | Physical performance is determined by standardized "short physical performance battery" | 24 months |
| Correlation between body composition abnormalities and hypophosphatasia | Body composition is determined by bioelectrical impedance analysis. | 24 months |
|
| ID | Term |
|---|---|
| D007014 | Hypophosphatasia |
| D035583 | Rare Diseases |
| D030342 | Genetic Diseases, Inborn |
| D012216 | Rheumatic Diseases |
| D001851 | Bone Diseases, Metabolic |
| ID | Term |
|---|---|
| D008664 | Metal Metabolism, Inborn Errors |
| D008661 | Metabolism, Inborn Errors |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D009140 | Musculoskeletal Diseases |
| D003240 | Connective Tissue Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D001847 | Bone Diseases |
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| ID | Term |
|---|---|
| D010808 | Physical Examination |
| ID | Term |
|---|---|
| D019937 | Diagnostic Techniques and Procedures |
| D003933 | Diagnosis |
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