Screening for hypophosphatasia: does biochemistry lead the way?

Area of Science:

• Biochemistry
• Pediatric Endocrinology
• Genetics

Background:

• Childhood hypophosphatasia (HPP) presents with nonspecific symptoms, complicating early diagnosis.
• Low serum alkaline phosphatase (AP) activity is a key indicator of HPP.
• Identifying mild HPP forms is crucial for timely intervention and management.

Purpose of the Study:

• To develop and validate a laboratory screening strategy for identifying mild childhood HPP.
• To utilize decreased AP activity as a primary screening marker in a pediatric population.
• To confirm HPP diagnosis through further biochemical and genetic testing.

Main Methods:

• Retrospective hospital-based data screening of pediatric AP activity levels.
• Defined age- and sex-specific thresholds for low AP activity.
• Further diagnostic workup included AP re-testing, PLP, PEA, and inorganic pyrophosphate levels, followed by ALPL gene sequencing.

Main Results:

• 14,913 samples from 6,731 patients were screened, identifying 393 screening-positive cases.
• After excluding other causes of low AP, 30 patients underwent further diagnostics.
• Three patients showed decreased AP with elevated PLP and PEA; two were identified as ALPL mutation carriers, one diagnosed with childhood HPP and initiated on enzyme replacement therapy.

Conclusions:

• A diagnostic algorithm based on decreased AP activity effectively identifies potential HPP cases.
• Exclusion of differential diagnoses and confirmation with elevated AP substrates are essential.
• This approach aids in detecting ALPL mutations and diagnosing HPP in pediatric patients.