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Conditions

Endocrine neoplasia

Endocrine neoplasia is a condition that causes predisposition to tumours in the endocrine organs. There are several different forms caused by pathogenic variants in several different genes.

Overview

In endocrine neoplasia, tumours develop in the endocrine organs. Depending on the underlying affected gene, different tumours typically cluster together in recognised syndromes. The first tumour may arise in childhood, at which point genomic testing should always be considered. Tumour screening in known carriers of gene variants often starts at a young age.

Clinical features

The clinical features to look out for, as well as inheritance patterns and management considerations, depend on the specific syndrome.

  • Multiple endocrine neoplasia type 1 (MEN1), caused by variants in the MEN1 gene:
    • parathyroid tumours or parathyroid hyperplasia;
    • pituitary tumours;
    • pancreatic neuroendocrine tumours;
    • other endocrine tumours, such as tumours of the gastro-entero-pancreatic tract, adrenocortical tumours and bronchial carcinoid tumours; and
    • other non-endocrine tumours, such as facial angiofibromas, collagenoma and meningioma.
  • Multiple endocrine neoplasia type 2a (MEN2a) and multiple endocrine neoplasia type 2b (MEN2b), caused by variants in the RET gene:
    • medullary thyroid carcinoma;
    • phaeochromocytoma;
    • parathyroid tumours;
    • other non-endocrine manifestations, such as mucosal neuromas; and
    • other non-endocrine manifestations, such as skeletal anomalies (including Marfanoid habitus).
  • Multiple endocrine neoplasia type 4 (MEN4), caused by variants in the CDKN1B gene:
    • pituitary tumours;
    • parathyroid tumours; and
    • endocrine tumours of the gastro-entero-pancreatic tract.
  • von-Hippel-Lindau syndrome, caused by variants in the VHL gene:
    • phaeochromocytoma;
    • paraganglioma;
    • pancreatic neuroendocrine tumours; and
    • other non-endocrine tumours, such as retinal angioma, spinal or cerebellar hemangioblastoma, renal cell carcinoma, endolymphatic sac tumours and papillary cystadenomas of the epididymis or broad ligament.
  • Phaeochromocytoma and paraganglioma, caused by pathogenic variants in the SDHx and NF1 genes:
    • phaeochromocytoma;
    • paraganglioma; and
    • other non-endocrine tumours, such as renal cell carcinoma and gastrointestinal stromal tumours.
  • Familial isolated pituitary adenoma, caused by pathogenic variants in the AIP and GPR101 genes:
    • pituitary tumours.
  • Carney complex, caused by pathogenic variants in the PRKAR1A gene:
    • pituitary hyperplasia and/or adenoma;
    • primary pigmented nodular adrenocortical disease;
    • thyroid carcinoma or benign nodules;
    • gonadal tumours;
    • other non-endocrine tumours, such as cardiac myxomas, dermatological, neurological, breast and musculoskeletal tumours; and
    • other non-endocrine manifestations, such as atypical skin pigmentation (lentigines).
  • McCune-Albright syndrome, caused by somatic mosaicism in the GNAS gene:
    • pituitary tumour and/or hyperplasia causing growth hormone excess;
    • adrenal hyperplasia causing cortisol excess;
    • thyroid enlargement (goitre) and benign nodules causing thyroid hormone excess;
    • other endocrine hyperfunction, such as precocious puberty (common first presentation in children) and FGF-23-mediated phosphaturia; and
    • other non-endocrine manifestations, such as polyostotic fibrous dysplasia and irregular-shaped café-au-lait skin lesions.
  • Pleuropulmonary blastoma-familial tumour and dysplasia syndrome, caused by pathogenic variants in the DICER1 gene:
    • pituitary blastoma causing Cushing syndrome;
    • pineoblastoma;
    • thyroid enlargement (goitre), benign nodules or carcinoma (papillary or follicular);
    • genitourinary or gynaecological neuroendocrine tumours;
    • ovarian embryonal rhabdomyosarcoma;
    • other non-endocrine manifestations, such as childhood pleuropulmonary blastoma or lung cysts, thoracic, uterine or cervical embryonal rhabdomyosarcoma, cystic nephroma, genitourinary sarcoma, ovarian sertoli leydig tumour, gynandroblastoma, ciliary body medulloepithelioma, nasal chondromesenchymal hamartoma and macrocephaly.

Genomics

Many of the above endocrine neoplasia conditions are inherited in an autosomal dominant fashion. Clinicians should refer to the National Genomic Test Directory to assess patient eligibility.

Diagnosis

Diagnosis of endocrine neoplasia is based on clinical, biochemical and radiological features. Genomic testing may establish a molecular diagnosis, guide surveillance and treatment, and identify other family members at risk.

For more information about genomic testing in this context, see: Presentation: Patient with endocrine neoplasia.

Inheritance and genomic counselling

Individuals affected by an autosomal dominant condition have one working copy of the gene, and one with a pathogenic variant. Penetrance is variable, depending upon condition. In the autosomal dominant endocrine neoplasia syndromes, a parent with a pathogenic variant has a 1 in 2 (50%) chance of passing on the variant to their child.

Family planning implications

The Human Fertilisation & Embryology Authority has approved the use of preimplantation genetic testing for monogenic disorders (PGT-M) (previously known as pre-implantation genetic diagnosis) for couples in whom one potential parent is a carrier of a pathogenic variant for many of the endocrine neoplasia syndromes. Clinicians should discuss potential eligibility with the clinical genetics service. It is best practice that discussions regarding PGT-M and other family planning options be undertaken by a specialist genetic counsellor or a clinical geneticist.

Alternative options may include:

  • prenatal testing (invasive, or non-invasive if the intended father is the carrier) with termination of affected embryos;
  • adoption;
  • gamete donation; or
  • natural conception and pregnancy with testing of children at an appropriate age.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 03/09/2025
  • Next review due: 03/09/2027
  • Authors: Professor Márta Korbonits, Dr Ben Loughrey
  • Reviewers: Dr Emile Hendriks, Dr Louise Izatt, Dr Terri McVeigh, Dr Anna Mitchell