Presentation: Child with suspected hypophosphatasia

A three-year-old boy has an unusual gait with bowed legs and premature loss of his baby incisors (with the roots attached when they fell out). The family has a healthy lifestyle, and he takes over-the-counter oral vitamin D supplements.

Genomic testing should be considered if:

• laboratory findings include anomalies such as reduced alkaline phosphatase activity and hypercalciuria (plasma calcium and phosphate levels may be normal or elevated);
• radiographic features, such as infantile rickets or defective mineralisation of bone and/or teeth, or pathological fractures are identified; and/or
• clinical features of hypophosphatasia (HPP) are identified.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria, which provides information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • For those working within NHS Wales, please consult the All Wales Medical Genomics Service website for information on how to arrange testing.
• To find out which genes are included on different gene panels, you can access the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• Decide which of the panels best suits the needs of your patient and/or their family.
• • A number of gene panels contain the ALPL gene, variants in which cause HPP.
• • Which panel you should choose depends on the scenario. If you are confident that the diagnosis is HPP, it is better to opt for a smaller panel to avoid unclear or incidental findings – an example is the R154 Hypophosphataemia or rickets panel, which includes a small gene panel and detection of copy number variants. Please note that hypophosphataemia is a different genetic condition to HPP, but the R154 panel does also contain the ALPL gene.
• • If the predominant presenting feature is craniosynostosis and the differential is other craniosynostosis syndromes, R100 Craniosynostosis would be most appropriate.
• • If the clinical features only somewhat resemble HPP and could be attributed to one of many alternative skeletal dysplasia conditions, you could select R104 Skeletal dysplasia. See Child with suspected skeletal dysplasia for more information.
• • There are several other panels that contain the ALPL gene. See the National Genomic Test Directory for more information.
• For tests that are undertaken using whole genome sequencing (WGS), such as R100.3 and R104.3, you will need to:
• • complete an NHS GMS test order form with details of the affected child (proband) and their parents, including details of the phenotype (using human phenotype ontology (HPO) terms) and the appropriate panel name(s) with associated R number (see How to complete a test order form for WGS for support in completing WGS-specific forms);
• • complete an NHS GMS record of discussion (RoD) form for each person being tested – for example, if you are undertaking trio testing of an affected child and their parents, you will need three RoD forms (see How to complete a record of discussion form for support); and
• • submit parental samples alongside the child’s sample (this is trio testing) to aid interpretation, especially for the larger WGS panels (where this is not possible, for example because the child is in care or the parents are unavailable for testing, the child may be submitted as a singleton).
• For tests that do not include WGS:
• • you can use your local Genomic Laboratory Hub test order and consent (RoD) forms; and
• • parental samples may be needed for interpretation of the child’s result. Parental samples can be taken alongside that of the child, and their DNA stored, or can be requested at a later date if needed.
• The majority of tests are DNA based, and an EDTA sample (purple-topped tube) is required. Exceptions include karyotype testing and DNA repair defect testing (for chromosome breakage), which require lithium heparin (green-topped tube).
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• GeneReviews: Hypophosphatasia
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory
• Skeletal Dysplasia Management Consortium: List of publications

References:

• Firth HV and Hurst JA. ‘Oxford Desk Reference: Clinical Genetics and Genomics, second edition’. Oxford University Press, 2017. ISBN: 9780199557509
• Rush ET. ‘Childhood hypophosphatasia: To treat or not to treat’. Orphanet Journal of Rare Diseases 2018: volume 13, article 116. DOI: 1186/s13023-018-0866-7
• Vogt M, Girschick H, Schweitzer T and others. ‘Pediatric hypophosphatasia: lessons learned from a retrospective single-center chart review of 50 children’. Orphanet Journal of Rare Diseases 2020: volume 15, article 212. DOI: 10.1186/s13023-020-01500-x

For patients

• Soft Bones UK