Presentation: Patient with possible familial hypoparathyroidism
Familial hypoparathyroidism may occur as an isolated endocrinopathy or as part of a wider clinical syndrome, including developmental, autoimmune and mitochondrial conditions. Familial forms of hypoparathyroidism can follow autosomal recessive, autosomal dominant and, rarely, X-linked inheritance patterns. Genomic testing can be undertaken if there is a family history, or as part of testing for another condition.
Example clinical scenario
A 36-year-old female presents to her GP with mild paraesthesia. She is found to have a low corrected serum calcium of 1.88mmol/l (normal range 2.1mmol/l to 2.55mmol/l) and an inappropriately low parathyroid hormone (PTH) of 2.0pmol/l (normal range 1.6pmol/l to 6.9pmol/l). She has no history of previous neck surgery (such as thyroidectomy or parathyroidectomy) and no history of autoimmune disease. Her serum magnesium is normal, and she is on no regular medication. She is not aware of any family history of calcium-related problems.
When to consider genomic testing
- Testing should be considered in patients with non-syndromic hypoparathyroidism with low calcium levels and low or inappropriately normal serum PTH, with no detectable cause (no history of previous neck surgery, hypomagnesaemia, culpable drugs such as cinacalcet, no confirmed autoimmune causes).
- Testing of patients who are normocalcaemic may occasionally be appropriate after consultation with an expert in calcium homeostasis.
- Patients with hypoparathyroidism as part of a wider clinical syndrome may be suitable for genomic testing under a different clinical indication, such as autoimmune polyglandular syndrome.
- Where a specific clinical diagnosis is suspected, discussion with the clinical genetics team should be undertaken to determine the optimal testing strategy.
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 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, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
- For patients who meet test directory eligibility criteria and do not have a personal or family history of a genetic variant in a familial hypoparathyroid gene, select the following.
- R153 Familial hypoparathyroidism. This contains the genes AIRE, CASR, GATA3, GCM2, GNA11, PTH and TBCE. Some of these genes are associated with non-syndromic hereditary hypoparathyroidism and hypocalcaemia (CASR, GCM2, GNA11 and PTH), and some are associated with specific syndromes in which hypoparathyroidism is reported (AIRE is associated with autoimmune polyglandular syndrome, GATA3 is associated with hypoparathyroidism, deafness and renal dysplasia syndrome, and TBCE is associated with Kenny-Caffey syndrome type 1). R153 testing involves small gene panel sequencing and exon level copy number variant analysis with multiplex ligation-dependent probe amplification (MLPA) or equivalent.
- Similar or overlapping tests include the below.
- R293 Albright hereditary osteodystrophy pseudohypoparathyroidism, pseudopseudohypoparathyroidism acrodysostosis and osteoma cutis. This test should be used if there is high clinical suspicion of one of these diagnoses.
- R319 Calcium sensing receptor phenotypes. This panel should be employed if there is a high index of suspicion of autosomal dominant hypocalcaemia type 1 due to a pathogenic variant in the CASR gene.
- R155 Autoimmune polyendocrine syndrome type 1. This panel should be employed in the presence of syndromic clinical features (which are caused by pathogenic variants in the AIRE gene).
- R28 Congenital malformation and dysmorphism syndromes – microarray only. This test will detect 22q11.2 deletions. Patients with clinical features of 22q11.2 deletion syndrome (also known as DiGeorge syndrome) should be discussed with the clinical genetics team to determine the most appropriate genomic testing approach. For patients in whom there is a clinical suspicion of 22q11.2 deletion syndrome as well as congenital heart disease, the R137 Congenital heart disease (microarray) test should be requested.
- For patients in whom there is a clinical suspicion of a hereditary cause but no detectable likely pathogenic or pathogenic variant in a hypoparathyroidism predisposition gene, further discussion with the clinical genetics team may identify other genomic testing strategies.
- For patients presenting with hereditary hypoparathyroidism 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.
- These tests do not include whole genome sequencing, so you should use your local Genomic Laboratory Hub test order and consent (record of discussion) forms.
- Most of the tests outlined above (including microarray) 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.