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Summary <p>We evaluated hypophosphatasia diagnostic criteria in adults with low alkaline phosphatase levels and a positive versus negative <i>ALPL</i> genetic test. Performance was optimal with biochemical and genetic data. Without them, sensitivity decreased, though specificity remained. Clinical features alone showed limited discriminative value.</p> Purpose <p>To facilitate early diagnosis of hypophosphatasia (HPP), an international expert group recently proposed standardized diagnostic criteria. This study evaluated the validity and diagnostic utility of the proposed criteria in adults, including scenarios with limited access to tissue-non-specific alkaline phosphatase (TNSALP) substrates and/or genetic assessment.</p> Methods <p>Criteria were applied in adults with persistently low alkaline phosphatase levels (ALP) and a positive genetic test (+ GT) confirming HPP <i>versus</i> those with a negative test (-GT). Diagnostic performance was evaluated by sensitivity, specificity, predictive values and area under the ROC curve (AUC).</p> Results <p>Eighty-three adults were included (47 + GT, 36 -GT). Among + GT individuals, 97.9% met the diagnostic criteria (95.7%, two major; 44.7%, one major and two minor criteria) versus 2.8% of -GT. The two-major criteria arm showed sensitivity of 95.7% and specificity of 100%. The one-major plus two-minor arm had lower sensitivity (44.7%) but high specificity (97.2%). Most discriminative variables were chronic musculoskeletal pain, early tooth loss, and chondrocalcinosis. The criterion based on elevated substrates showed high sensitivity (97.9%) but low specificity (33.3%). In the + GT group, without genetic testing, 51.1% met the criteria (AUC 0.741); without substrate data, 44.7% (AUC 0.71), and with only clinical features, 6.4% (AUC 0.532).</p> Conclusion <p>HPP criteria show high sensitivity and specificity, supporting their clinical utility. Diagnostic performance is optimal when biochemical and genetic data are available. In settings lacking access to genetic testing or substrates, sensitivity is notably reduced despite preserved specificity, and clinical features alone provide limited discriminative value.</p>

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External validation of the proposed diagnostic criteria for hypophosphatasia in adults of a Spanish cohort

  • 期刊论文

  • 发表日期：

    2026年2月16日

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  • C. Tornero,
  • V. Navarro-Compán,
  • K. E. Heath,
  • S. Modamio-Høybjør,
  • A. Buño,
  • S. García-Carazo,
  • I. Monjo,
  • P. Aguado

摘要

Summary

We evaluated hypophosphatasia diagnostic criteria in adults with low alkaline phosphatase levels and a positive versus negative ALPL genetic test. Performance was optimal with biochemical and genetic data. Without them, sensitivity decreased, though specificity remained. Clinical features alone showed limited discriminative value.

Purpose

To facilitate early diagnosis of hypophosphatasia (HPP), an international expert group recently proposed standardized diagnostic criteria. This study evaluated the validity and diagnostic utility of the proposed criteria in adults, including scenarios with limited access to tissue-non-specific alkaline phosphatase (TNSALP) substrates and/or genetic assessment.

Methods

Criteria were applied in adults with persistently low alkaline phosphatase levels (ALP) and a positive genetic test (+ GT) confirming HPP versus those with a negative test (-GT). Diagnostic performance was evaluated by sensitivity, specificity, predictive values and area under the ROC curve (AUC).

Results

Eighty-three adults were included (47 + GT, 36 -GT). Among + GT individuals, 97.9% met the diagnostic criteria (95.7%, two major; 44.7%, one major and two minor criteria) versus 2.8% of -GT. The two-major criteria arm showed sensitivity of 95.7% and specificity of 100%. The one-major plus two-minor arm had lower sensitivity (44.7%) but high specificity (97.2%). Most discriminative variables were chronic musculoskeletal pain, early tooth loss, and chondrocalcinosis. The criterion based on elevated substrates showed high sensitivity (97.9%) but low specificity (33.3%). In the + GT group, without genetic testing, 51.1% met the criteria (AUC 0.741); without substrate data, 44.7% (AUC 0.71), and with only clinical features, 6.4% (AUC 0.532).

Conclusion

HPP criteria show high sensitivity and specificity, supporting their clinical utility. Diagnostic performance is optimal when biochemical and genetic data are available. In settings lacking access to genetic testing or substrates, sensitivity is notably reduced despite preserved specificity, and clinical features alone provide limited discriminative value.