Presentation: Patient with possible hereditary hypophosphataemic rickets
Hereditary hypophosphataemic rickets is a genetically heterogeneous condition. It is caused by pathogenic variants in one of several genes involved in phosphate metabolism, and is commonly inherited in an X-linked dominant pattern due to a pathogenic variant in the PHEX gene.
Example clinical scenario
A 22-year-old male is referred to a metabolic bone clinic having presented to his GP complaining of lower limb pain. An initial biochemical evaluation reveals hypophosphataemia, with phosphate levels of 0.46mmol/l (normal range is between 0.8 and 1.2mmol/l), elevated alkaline phosphatase but normal serum calcium (2.25mmol/l) and parathyroid hormone levels. Examination in the clinic reveals short stature (a height of 160cm) with an atypical gait. Plain radiographs of the lower limbs demonstrate mild bowing, femoral pseudo-fractures and osteoarthritis in the hip and knee. Spot urinary calcium, phosphate and creatinine analyses indicate renal phosphate wasting.
When to consider genomic testing
Consider genomic testing for a patient presenting with hypophosphataemia with no identifiable cause, with evidence of decreased renal phosphate reabsorption, which has or could lead to a presentation with rickets.
For further information, see Hereditary hypophosphataemic rickets.
What do you need to do?
- 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 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, see the NHS Genomic Medicine Service (GMS) Signed Off Panels resource.
- For patients who meet the test directory’s eligibility criteria and do not have a personal or family history of a genetic variant in a hereditary hypophosphataemic gene, select the following:
- R154 Hypophosphataemia or rickets. This panel currently comprises the following genes: ALPL, CYP27B1, CYP2R1, DMP1, ENNP1, FAM20C, FGF23, OCRL, PHEX, SLC34A1, SLC34A3 and VDR. It involves small gene panel sequencing and exon-level copy number variant detection by multiplex ligation-dependent probe amplification (MLPA) or equivalent.
- Similar or overlapping tests include:
- R104 Skeletal dysplasia. Patients with clinical features indicative of a likely monogenic skeletal dysplasia should be evaluated via this panel. It includes large gene panel sequencing (of over 400 genes), whole exome sequencing (WES) and whole genome sequencing (WGS).
- For patients presenting with hereditary hypophosphataemia, where a genetic diagnosis in a relevant predisposition gene has been established in another family member, single gene testing for that specific variant should be considered. R240 Diagnostic testing for known mutation(s) could be selected if the pathogenic variant report about the close family member is available and testing was performed in an accredited laboratory.
- For tests that are undertaken using WGS, you will need to:
- complete an NHS Genomic Medicine Service (GMS) test order form. Include details of the phenotype (refer to human phenotype ontology terms) and the appropriate panel name(s) with associated R number (please see our resource on how to complete a test order form for WGS for support); and
- complete an NHS GMS record of discussion form (note that a form is needed for each person being tested – for example, if you are undertaking trio testing of an affected child and their parents, you will need three separate forms). For support, please see our resource on how to complete a record of discussion form.
- For tests that do not include WGS, you should use your local Genomic Laboratory Hub test order and consent (record of discussion) forms.
- These tests are DNA based, and an EDTA sample (purple-topped tube) is required. The sample is best stored at a temperature of four degrees Celsius until it can be posted to the genomic laboratory.
- 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.
Resources
For clinicians
- Genetic and Rare Diseases Information Center: Hypophosphatemic rickets
- NHS England: National Genomic Test Directory