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AIP – risk management

In this document the terms ‘male’ and ‘female’ refer to sex assigned at birth. For more information about providing individualised care refer to Resources to assist in the care of transgender individuals referred to a clinical genetics service or familial cancer centre

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Pathogenic variants in the AIP gene are inherited in an autosomal dominant manner. These variants predispose to familial isolated pituitary adenoma (FIPA). The pituitary adenomas are nearly always benign, but individuals with AIP pathogenic variants are often younger, male, demonstrate growth hormone excess, have larger and more invasive tumours, and more often require multi-modal treatment compared to individuals with pituitary adenomas and no AIP pathogenic variants.

The care of an individual who has developed a related tumour or cancer should be individualised based on their clinical situation, their family history and the monitoring they need as part of their treatment and post-treatment follow-up.

The risk management of an individual with a pathogenic variant in two or more genes that confer a predisposition to cancer should also be individualised.

  • Unaffected known or obligate AIP pathogenic variant carrier.
  • Individuals at 50% risk of inheriting an AIP pathogenic variant.

Exclusion criteria

  • Familial isolated pituitary adenoma (FIPA) where no AIP pathogenic variant has been identified.
  • Individuals with a pathogenic variant in another endocrine tumour predisposition gene (e.g. MEN1, CDKN1B, PRKAR1A, SDHA, SDHB, SDHC, SDHD, SDHAF2).
  • Individuals with a variant of uncertain significance.
Cancer/tumour type AIP pathogenic variant carrier* General population risk 
Pituitary adenoma 20-23% by age 30 yearsr

Clinically significant pituitary adenoma 0.1%r 

Any pituitary adenoma ~10% (MRI/autopsy studies)

*If no disease present at age 30 years, risk of development of disease after this age is very low

The choice of risk management strategy should take into account current age, other health issues and age-related cancer risk. Risks and benefits of interventions should be discussed with an experienced medical professional.

The impact of lifestyle on cancer risk should be discussed e.g. exercise most days for at least 30 minutes at moderate or strenuous intensity, maintain a healthy weight, have a healthy diet, limit alcohol intake, do not smoke and avoid excess sun exposure.

Cancer/tumour type Recommendations
Pituitary adenoma Surveillance Age Strategy and frequency
From age 4 years
  • Annual clinical examination and growth assessment
  • Annual biochemical assessment with prolactin and IGF-1 
From age 10 years
  • Annual history and clinical examination
  • Annual visual field testing by confrontation*
  • Annual biochemical assessment with prolactin and IGF-1 
  • Baseline high resolution pituitary MRI. Repeat every 5 years
From age 30 years
  • Patients diagnosed over age 30 years should have baseline high resolution pituitary MRI and a biochemical assessment with prolactin and IGF-1
  • If no pituitary pathology detected by age 30 years (or at the time of the initial assessment if over age 30 years), surveillance could be reduced or discontinued

*any visual field defects that are detected on confrontation should be followed up with pituitary MRI to assess for a pituitary mass causing optic chiasm compression, and computerised perimetry.

Screening cessation

For individuals who reach age 30 years with no AIP-related abnormalities detected, the surveillance frequency could be reduced and consideration could be given to cessation of regular surveillance. There appears to be a very low probability of developing pituitary disease beyond this age, and there is some evidence in the literature that small non-functioning tumours detected at an older age may be pituitary incidentalomas rather than representing AIP-related disease.

Individuals with AIP pathogenic variants have disease onset less than age 18 years in 65% and less than age 30 years in 87% of cases, with the youngest reported case at age 4 years.r Most individuals with clinical features have symptom onset before age 30 years. In the largest study on the FIPA consortium cohort there were no cases with a normal full pituitary assessment at age 30 years who later developed a pituitary adenoma.r The use of biochemical testing and MRI imaging will accurately detect all clinically relevant cases of pituitary disease, allowing for early treatment.  There is evidence to support the significant benefit of clinical screening in familial isolated and young-onset pituitary tumours.r FIPA kindreds can share the same pituitary adenoma subtype (homogeneous FIPA) or different pituitary adenoma subtypes can occur within the one family (heterogeneous FIPA).

Individuals with AIP-mutated tumours are more frequently male, are 8 years younger at first symptom onset and 6 years younger at diagnosis than the comparison cohort with AIP negative FIPA/pituitary adenoma. Individuals with AIP-associated pituitary adenoma have higher rates of pituitary apoplexy, suprasellar extension and requirement for multimodal therapy including external beam radiation therapy. They are more likely to have clinical and biochemical growth hormone excess (often gigantism). Tumours are often refractory to medical therapy with first generation somatostatin analogues but may respond to second generation agents.r 

There is evidence to support offering predictive testing before the age of 5 years due to reports of disease onset at age 4 years in the setting of AIP pathogenic variants. Clinical assessment in children with AIP pathogenic variants should include height and weight, growth velocity, pubertal development, and baseline pituitary function tests. Most clinically relevant pituitary adenomas reported prior to age 10 years are growth-hormone or prolactin secreting. MRI pituitary prior to the age of 10 years may require general anaesthesia. Therefore, in children less than age 10 years with normal growth and no clinical or biochemical features of hormone excess, consideration could be given to commencing MRI surveillance at age 10 years when this can be performed without general anaesthesia. MRI could be performed prior to age 10 years if indicated by hormonal abnormality or accelerated growth.

First degree blood relatives (parents/brothers/sisters/children) are at up to 50% risk of having inherited the pathogenic variant. More distant relatives may also be at risk of inheriting the pathogenic variant. Genetic relatives should be referred to a clinical genetics service or familial cancer centre to discuss predictive genetic testing.

Informing family members about hereditary cancer

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Version 2

Date Summary of changes
15/09/2023

New eviQ cancer genetics risk management template changes applied - PDF of changes.

Version number changed to V.2.

Version 1

Date Summary of changes
25/01/2023 Discussed at October 20, 2022 reference committee meeting and approved for publication. Review in 1 year.

The information contained in this document is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to care or treatment. Any clinician seeking to apply or consult this document is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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https://www.eviq.org.au/p/4188

04 Dec 2023