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Conditions

Hypoparathyroidism

Hypoparathyroidism is a rare condition in which the parathyroid glands produce too little parathyroid hormone. It can present as a condition by itself, or as part of a broader genetic syndrome.

Overview

Hypoparathyroidism is a rare disease characterised by hypocalcaemia due to deficiency of parathyroid hormone (PTH), usually following surgical removal or damage to the parathyroid glands. It may also have a genetic cause, occurring either as an isolated manifestation or as part of a broader genetic syndrome.

Clinical features

Clinical features of hypoparathyroidism include:

  • hypocalcaemia, classically (but not invariably) with hyperphosphataemia, in the presence of low or inappropriately normal serum PTH levels;
  • classical hypocalcaemic symptoms such as parasthaesia, muscular cramps and tetany leading to carpopedal spasm or stridor, cardiac conduction disturbance, seizure and coma; and
  • non-classical hypocalcaemic symptoms, which may include low mood, fatigue, low quality of life, low energy levels and altered mentation (‘brain fog’).

Depending on the specific cause, patients may also present with:

  • cardiac anomalies;
  • renal dysfunction;
  • deafness;
  • immunodeficiencies; and
  • basal ganglia calcification.

There are different types of genetic hypoparathyroidism, all of which have variable clinical features and different modes of inheritance, and all of which are caused by variations in a range of genes, as shown in table 1.

Table 1: Types of genetic hypoparathyroidism by clinical features, inheritance pattern and affected gene

 

Name (OMIM reference) Gene Inheritance Mechanism
22q11.2 deletion syndrome, also known as DiGeorge syndrome (188400) Chromosome 22q11 deletion, including TBX1 Autosomal dominant The phenotype is variable, but classically involves cardiac anomalies, facial features, immunodeficiency associated with thymic aplasia and hypoparathyroidism.

The TBX1 gene is included in the deletion. TBX1 is a transcription factor involved in parathyroid development and is thought to be the gene responsible for the hypoparathyroidism.

In most cases the deletion is relatively consistent; some variability has been reported, however, with the full range of deletions varying between 1.5Mb and 3Mb.

The name velocardiofacial syndrome (VCFS) is also used, but this classically describes a more extensive phenotype, including 22q11.2 deletion syndrome features, facial developmental anomalies, cleft lip and intellectual disability.
Velocardiofacial syndrome (VCFS) (192430) Chromosome 22q11 deletion Autosomal dominant See above.

VCFS causes a more extensive phenotype, including 22q11.2 deletion syndrome features, facial developmental anomalies, cleft lip and intellectual disability.
22q11.2 deletion syndrome or VCFS complex 2 (601362) Chromosome 10p14-p13 deletion Uncertain The phenotype is similar to classical 22q11.2 deletion syndrome and VCFS.

The NEBL gene has been proposed as a candidate in the 10p14-p13 region, but appears to be inconsistently implicated.
Hypoparathyroidism, deafness, renal dysplasia (HDR) syndrome, also known as Barakat syndrome (146255) GATA3 Autosomal dominant GATA3 is a transcription factor and developmental gene involved in parathyroid gland development.

The phenotype can be variable, including hypoparathyroidism, sensorineural deafness and/or renal dysplasia (which may present as mild renal impairment only, and may not even be detectable at all).
Autoimmune polyglandular syndrome type 1, also known as autoimmune polyglandular-endocrinopathy-candidiasis-ectodermal dystrophy (240300) AIRE Autosomal dominant, autosomal recessive The phenotype is described in the long form of the name.

The polyglandular endocrinopathy is variable, but often includes hypoparathyroidism and variably includes type 1 diabetes, Addison disease and premature ovarian failure.

The candidiasis is mucocutaneous and results from a cell-mediated immunity defect.

The ectodermal dystrophy is variable, but may extend to alopecia totalis, dystrophy of dental enamel, nail dystrophy and lens opacities in severe cases.

The AIRE gene encodes a transcriptional regulator involved in thymic induction if immunologic self-tolerance.
Autosomal dominant hypocalcaemia type 1 (ADH1) (601198) CASR Autosomal dominant Caused by activating variants in the calcium-sensing receptor gene.

Can be conceptualised as an ‘opposite’ phenotype of familial hypocalciuric hypercalcaemia, which arises due to inactivating variations of the CASR gene.

Hypercalciuria is a prominent feature of ADH1, and is associated with nephrolithiasis, nephrocalcinosis and impairment of renal function.
Autosomal dominant hypocalcaemia type 2 (ADH2) (615361) GNA11 Autosomal dominant Caused by gain-of-function variations in GNA11, part of the signal transduction pathway for the calcium-sensing receptor.

Produces a very similar phenotype to ADH1.
Familial isolated hypoparathyroidism type 1 (168450) PTH Autosomal dominant, autosomal recessive This condition is caused by a variety of PTH gene variants that can lead to aberrant processing or secretion of the hormone or a less biologically active hormone.
Familial isolated hypoparathyroidism type 2 (618883) GCM2 Autosomal dominant, autosomal recessive This condition is caused by homozygous loss-of-function or heterozygous dominant negative variants in GCM2, a transcription factor gene that functions as a developmental gene for the parathyroid glands. These variants lead to absence of parathyroid gland development.
X-linked hypoparathyroidism (307700) SOX3

 

 X-linked This condition is caused by a complex deletion-insertion near the SOX3 gene, which is a transcription factor involved in parathyroid gland development.

The condition presents with isolated parathyroid gland agenesis.

Genetics

Although hypoparathyroidism can have a wide variety of potential genetic causes, as outlined in the table above, 22q11.2 deletion syndrome is probably the most common.

If you are requesting genomic testing for hypoparathyroidism in the UK, the usual test provided will be R153.1 Familial hypoparathyroidism, which is a small gene panel test.

The latest version of this panel (February 2020) includes the GATA3, AIRE, PTH, GCM2, CASR, GNA11 and TBCE genes, but not the TBX1 gene.

The appropriate test to request for suspected 22q11.2 deletion syndrome is cytogenetic analysis (array CGH) or fluorescent in situ hybridisation (FISH), which will detect the 22q11 microdeletion typical of 22q11.2 deletion syndrome and VCFS complex (see table 1).

For information about testing, see Presentation: Patient with possible familial hypoparathyroidism.

Inheritance and genomic counselling

Inheritance patterns vary according to the genetic cause – see table 1.

Management

Management of patients with hypoparathyroidism is complex and should be undertaken by a multidisciplinary team. At the very least, it is essential that hypoparathyroidism patients receive care from an accredited adult and/or paediatric endocrinologist.

Conventionally, treatment of hypoparathyroidism has involved oral calcium supplements and activated vitamin D metabolites (calcitriol or alfacalcidol). However, these treatments are imperfect, often associated with poor quality-of-life scores, ongoing symptomatology, elevated risk of unscheduled hospital attendance or admission and increased risk of development of nephrocalcinosis, nephrolithiasis and impaired renal function. In some regions globally, therapy with recombinant human full-length PTH (rhPTH1-84) is now licensed, although in practice, availability is limited due to licensing, reimbursement and supply difficulties.

Ongoing gene-directed therapies and trials are investigating the use of rhPTH1-84, rhPTH1-34 and other novel PTH analogues, as well as possible gene therapy for PTH replacement.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 13/07/2023
  • Next review due: 13/07/2025
  • Authors: Dr Jeremy Turner
  • Reviewers: Dr Emile Hendriks, Dr Louise Izatt, Professor Márta Korbonits