Abstract
Background/Aims
Hypophosphatasia is a metabolic bone disease caused by mutations in the gene encoding tissue-nonspecific alkaline phosphate (TNSALP). Adults present with a variety of manifestations including musculoskeletal pain, calcium pyrophosphate disease (CPPD), dental problems and low trauma fractures. The characteristic finding in hypophosphatasia is a persistently low ALP. Due to the non-specific presentation, hypophosphatasia diagnoses are often delayed and this can result in misdiagnosis and incorrect treatment decisions. This is particularly significant in patients presenting with musculoskeletal pain.
Methods
Here we present 12 adults diagnosed with hypophosphatasia after referral to our general rheumatology clinic with musculoskeletal pain over the past decade. A persistently low ALP was established in all patients. Hypophosphatasia was diagnosed by an elevated fasting vitamin B6 and/or a positive genetic test. All patients had a normal DEXA scan.
Results
11 patients were female and 1 was male.The average age at presentation to rheumatology clinic was 42 years. All patients had a consistently low ALP. This was first documented at the mean age of 39 years. Mean ALP across all patients was 24 U/L (normal range 60-35). ALP range for all patients was <5 to 58 U/L. Descriptions of pain were diverse. Common features included lower limb pain (92%) and pain with flare ups (42%). The average age of pain onset was 26 years. When considering the mean age at diagnosis of 45 years, this gives a mean diagnostic delay of 19 years. Other features of hypophosphatasia were dental symptoms (83%), CPPD (58%), family history (92%) and fractures (42%). P116 Table 1:No.SexAge at diagnosis of HPP (years)Mean ALPu/L[60-350]Age at first documented low ALP (years)Fasted vitamin B6 result µg[5-50]Urine PEA (phospho ethanol amine)ALPL gene mutationsDEXAMSK featuresCPPDFracturesDentalRelevant family history1F5118.539228NegativeHeterozygousNormalTrochanteric bursitis, leg and buttock pain_____________Left ankleRemoved since early 20sLoss of teeth early in life2F5512.542243Not doneHeterozygousNormalBurning in shoulders, knees, arm pain worse on activity with flare upsConfirmed on x ray___________Dentures since early adulthoodFamily history of hypophosphatasia3F324327196Not doneNot doneNormalJoint pain in lower limbs with flare ups, aching in hands, swelling of fingersClinical diagnosis___________Few fillingsGum disease, multiple tooth removals, history of hypophosphatasia4M543050176NegativeHeterozygousNormalTrochanteric bursitis, pain in ankles and wristsClinical diagnosis______________________Dentures5F2516.523415Small peakHeterozygousNormalUpper back pain, pain in knuckles and left wristChondrocalcinosis on US of hand3 toes, 2 fingersfillingsLost teeth, joint pains, osteoporosis6F323521155Not doneNegativeNormalPain in neck, shoulder, lower back, weakness________________________Decay in primary dentitionDental problems, fractures, joint pains7F542152268Small peakheterozygousNormalEarly morning stiffness, skeletal pain in upper arms and lateral thighs_____________Elbow, lower legDecay since age 10Dentures, osteoarthritis, osteoporosis8F6024.555163Not doneheterozygousNormalWeakness, pain in left side worse with activity_____________Vertebral__________Dentures, arthritis, hypermobility9F4517.541287NegativeheterozygousNormalPain in hands, kneesClinical diagnosisLoose teeth in adulthoodOsteoporosis, dentures, gout, joint/muscle pain10F5113.538359Not doneheterozygousNormalPain in legs, backache, leg stiffness________________________Poor teeth since teenage yearsRheumatoid arthritis11F142721126Marginal increaseVariant of uncertain significanceNormalWrist pain worse on use with flare upsClinical diagnosis___________6 teeth removed in childhood_______________12F7037.561195Not doneNot donenormalTrochanteric bursitis, night pain in right knee, back painChondrocalcinosis on x rayL ankle, rib fractures_________________________Mean age at diagnosis - 45 yearsMean ALP - 24 U/LMean age at first documented low ALP - 39 yearsMean fasting vitamin B6 - 235 µg
Conclusion
Our patients experienced a significant diagnostic delay even after the establishment of a persistently low ALP. Various musculoskeletal symptoms were seen and a diagnosis of CPPD was common, affecting 7 of 12 patients (58%).
Patients with hypophosphatasia, presenting to rheumatology clinic with musculoskeletal pain, experience significant diagnostic delay. This can be shortened by considering their pain in conjunction with a persistently low ALP, a history of pain earlier in life, dental problems, fractures, CPPD and a positive family history of dental problems, fractures or arthritis.
Disclosure
A. Rauf: None. K.E. Moss: None.
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