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Conditions

Familial hyperparathyroidism

Familial hyperparathyroidism is a genetic condition that predisposes affected individuals to parathyroid hormone-mediated hypercalcaemia, which presents in varying degrees.

Overview

Familial hyperparathyroidism is a genetic predisposition to parathyroid hormone (PTH)-mediated hypercalcaemia. Primary hyperparathyroidism (PHPT) is a common condition and approximately 1-in-10 cases are caused by a hereditary syndrome. Hereditary forms of PHPT may occur as an isolated endocrinopathy or as part of one of several multiple-tumour syndromes.

Clinical features

  • Familial PHPT results in varying degrees of hypercalcaemia.
  • Hypercalcaemia, particularly when marked, is associated with thirst (polydipsia), polyuria, abdominal pains, acid reflux, constipation, mood disturbance and aches and pains.
  • Hypercalcaemia also increases the risk of renal stone formation and renal impairment, mediated by increased urinary calcium excretion, and fractures mediated by increased bone resorption resulting in osteopenia and osteoporosis.
  • In contrast to sporadic forms of primary hyperparathyroidism, which have a female-to-male predominance of 3:1, hereditary forms of PHPT have an equal sex distribution. Usually, they also have an earlier age of disease onset, often in childhood or young adulthood.

Neonatal severe hyperparathyroidism

  • An extremely rare form of familial hyperparathyroidism is neonatal severe hyperparathyroidism (NSHPT).
  • NSHPT typically presents in the neonatal period with severe hypercalcaemia and high PTH in association with skeletal features (for example, fracture) and respiratory distress.
  • If left untreated, NSHPT is frequently fatal.

Primary hyperparathyroidism or familial hypocalciuric hypercalcaemia?

  • PHPT results in raised serum calcium and PTH levels.
  • PHPT must be differentiated from familial hypocalciuric hypercalcaemia (FHH), an inherited hypercalcaemic autosomal dominant condition that also results in raised serum calcium with normal or raised PTH levels, because the management strategies are different.
  • In a vitamin D replete individual, FHH and PHPT are typically differentiated by the presence or absence of hypocalciuria (urinary calcium-to-creatinine clearance ratio (UCCCR) of less than 0.02 observed in FHH), although overlaps in urinary phenotype may be observed in a minority of patients (such as FHH patients with a UCCCR above the typical threshold).

Genetics

Variants in several genes have been associated with familial PHPT, including CDC73, CDKN1B, GCM2, MEN1, RET and CASR. Each of these are described in more detail below.

CDC73

Constitutional (germline) pathogenic variants in the CDC73 gene have been associated with familial isolated hyperparathyroidism (FIHP), hyperparathyroidism-jaw tumour syndrome and, rarely, with parathyroid carcinoma.

The hyperparathyroidism-jaw tumour syndrome is characterised by PHPT, which may present in childhood or young adulthood, and up to 15% of patients may develop parathyroid carcinoma. Additional clinical features include ossifying fibromas of the jaw and mandible (approximately 30% of cases) and renal and uterine tumours.

Pathogenic CDC73 variants are inherited in an autosomal dominant pattern, with the majority predicting a functional loss of the encoded tumour suppressor protein parafibromin (for example, nonsense, frameshift and splice site variants). Parathyroid tumours in patients with pathogenic constitutional (germline) CDC73 variants typically demonstrate bi-allelic inactivation of the CDC73 gene (loss of heterozygosity is frequently observed). Parafibromin is a nuclear protein implicated in transcriptional regulation and modulation of multiple cell-signalling pathways.

For information about genomic testing, see Presentation: Patient with possible familial hyperparathyroidism and Presentation: Patient with parathyroid carcinoma.

CDKN1B

Pathogenic variants in the CDKN1B gene are associated with a rare form of multiple endocrine neoplasia (MEN) known as MEN type 4 (MEN4), which results in PHPT, pituitary tumours, pancreatic and gastrointestinal neuroendocrine tumours and, less commonly, bronchial and cervical neuroendocrine tumours and adrenal tumours. Pathogenic CDKN1B variants are inherited in an autosomal dominant pattern. CDKN1B encodes the cyclin-dependent kinase inhibitor p27kip, a tumour suppressor gene that acts as a key regulator of the cell cycle.

For information about genomic testing, see Presentation: Patient with endocrine neoplasia.

GCM2

Activating pathogenic variants in GCM2 have been identified in a small number of kindreds with FIHP. Pathogenic GCM2 variants are inherited in an autosomal dominant pattern but have been reported to have such reduced disease penetrance that the value of genomic testing remains uncertain. GCM2 encodes the transcription factor GCMb, which plays a pivotal role in parathyroid gland development. Loss-of-function pathogenic variants in GCM2 are associated with familial hypoparathyroidism.

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

MEN1

PHPT is the most common manifestation of multiple endocrine neoplasia type 1 (MEN1), which is an autosomal dominant endocrine neoplasia syndrome characterised by parathyroid, pituitary and gastropancreatic endocrine tumours. MEN1 results from pathogenic variants in the MEN1 gene, which comprise missense, nonsense, frameshift and splice site variants as well as partial or whole gene deletions. Pathogenic variants in MEN1 are also associated with FIHP; however, MEN panels should be used where there are clinical features of a wider MEN syndrome, either within the individual or within the wider family. The MEN1 gene encodes the tumour suppressor protein menin, which is implicated in multiple cellular activities (for example, transcriptional regulation, epigenetic modifications and cell signalling pathways) through direct and indirect interactions with multiple protein partners.

For information about genomic testing, see Presentation: Patient with possible multiple endocrine neoplasia type 1.

RET

Activating pathogenic variants in the RET gene are associated with multiple endocrine neoplasia type 2a (MEN2A), which is characterised by medullary thyroid carcinoma, phaeochromocytoma and parathyroid tumours. Parathyroid tumours manifesting as PHPT are reported in approximately 30% of MEN2A patients, with the risk directly related to the specific RET variant (for example, the highest frequency of PHPT is found in patients with codon 634 RET variants). Pathogenic RET variants are inherited in an autosomal dominant manner. RET encodes a tyrosine kinase receptor involved in neural crest and enteric nervous system development. MEN panels should be used where there are clinical features of a wider MEN syndrome, either within the individual or within the wider family.

For information about genomic testing, see Presentation: Patient with medullary thyroid carcinoma.

CASR

Although the majority of patients with pathogenic loss-of-function variants in CASR are associated with FHH type 1, a small number of individuals with CASR variants have been reported to have features of primary hyperparathyroidism as part of apparent FIHP. It should be noted that atypical parathyroid histology (for example, hyperplasia) may be observed in patients with FHH.

NSHPT most commonly results from homozygous or compound heterozygous pathogenic variants in the CASR gene.

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

Inheritance and genomic counselling

The above conditions are inherited in an autosomal dominant manner and are typically associated with a high degree of penetrance (with the exception of activating GCM2 variants). For example, over 95% of individuals with MEN1 will develop PHPT over the course of their lifetime.

Management

Individuals with autosomal dominant isolated PHPT are generally managed conventionally with parathyroid surgery. Ongoing follow-up is required to monitor calcium and PTH levels.

Individuals who are identified as having inherited PHPT in the context of one of the MEN syndromes should be managed by clinicians with experience of these complex syndromes, and management of the PHPT itself should be directed by a specialist multidisciplinary team. It is recommended that patients identified as having possible FIHP due to pathogenic variants in one of the genes associated with a wider multiple tumour syndrome (for example, MEN1 or CDC73) are managed as being at risk of the wider clinical syndrome (as such, guidelines for MEN1 and hyperparathyroidism-jaw tumour syndrome should be followed respectively).

Resources

For clinicians

References:

For patients

 

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  • Last reviewed: 18/05/2023
  • Next review due: 18/05/2025
  • Authors: Dr Anna Mitchell, Dr Paul Newey
  • Reviewers: Dr Danielle Bogue, Dr Emile Hendriks, Dr Louise Izatt