Familial Isolated Pituitary Adenomas (FIPA)

Please click FIPA_AMEND_patient_information_leaflet.pdf [PDF 781KB] for further information regarding FIPA on the Patient Information Leaflet published by the Patient Support Group AMEND.

The pituitary gland is the most important gland in the body. It produces hormones which control all of the other glands in the body. Pituitary adenomas are tiny lumps which grow within the pituitary gland. These can cause problems by producing extra hormones, for example growth hormone resulting in acromegaly, by preventing the normal production of other pituitary hormones, or by squashing other important structures near the pituitary gland, such as the eye nerves. Almost all pituitary tumours are benign, these are called adenomas. This means that they are not cancerous, and do not spread. Most of the time pituitary adenomas grow slowly and it takes years before they get diagnosed. Pituitary adenomas grow for usually 2-10 years before they get diagnosed.

Most pituitary adenomas do not run in families. However, about 1 in 20 pituitary tumours do seem to run in families. These can be split into several groups or syndromes, depending on whether the patients or their family members also have other types of tumours. If the condition only seems to affect the pituitary gland in the family, then the disease is known as Familial Isolated Pituitary Adenoma (FIPA).

Genes are the coded instructions that control the growth and development of our cells. Genes come in pairs; one of each pair is inherited from each parent. Some conditions tend to manifest when one copy of a pair of genes is altered. These are called dominant disorders. Both men and women who have a one copy of an abnormal gene and one copy of the normal gene (a so called 'heterozygote' state) have a 50:50 chance of passing the abnormal gene on to the next generation. However, not all patients who carry the abnormal gene will develop the disease, this is called incomplete penetrance.

Figure 1. Autosomal dominant disease with incomplete penetrance. In this case, the father's abnormal gene was inherited by 2 of his 4 children. Out of the three carriers (the father, one son and one daughter) two patients developed the disease (father and daughter) while the third carries the gene but has not developed the disease. We do not know if this third person (the carrier son in this case) will develop the disease in the future or not, and currently it is not possible to predict this.

Families with pituitary adenomas, FIPA families, can be divided into two groups.

• In about 80% of families the gene causing the disease is unknown. The pituitary tumour types occurring in these families are most commonly growth hormone-secreting adenomas (causing acromegaly or acromegalic gigantism), prolactin-secreting adenomas (prolactinomas) or non-functioning pituitary adenomas (NFPA), very rarely ACTH-secreting adenomas (causing Cushing's disease) or TSH-secreting adenomas. The disease most often starts in adulthood, very rarely in childhood (average age of disease onset in our cohort for AIP negative FIPA patients is 38 years). These families usually only have two or three patients known with the disease.
• In about 20% of families a gene has been identified causing the disease, called Aryl hydrocarbon receptor Interacting Protein, in short AIP (see further information about AIP here). Patients with AIP mutations most often have acromegaly or occasionally prolactinoma, very rarely other types of adenomas. See a typical family tree of a FIPA family with AIP mutation on Figure 2. Often three or more members of the family have been diagnosed with pituitary adenomas. Subjects who carry a mutation in the AIP gene have pituitary adenoma predisposition (PAP). The majority of the patients who carry a mutation in the AIP gene and develop a pituitary adenoma, become diagnosed before the age of 30 years (average age of disease onset in our cohort for AIP mutation positive FIPA patients is 23 years), often in childhood. Forty percent of our AIP mutation positive patients were diagnosed before the age of 18 years. Our youngest AIP mutation positive patient was diagnosed at the age of 6 years with a large adenoma. Interestingly, two third of the patients with AIP mutation positive pituitary adenoma are males. Growth hormone secreting adenomas are often large and not always respond well to somatostatin analogue therapy, while pegvisomant treatment has been applied successfully.

If you carry one abnormal copy of the AIP gene, you do not necesserily develop the disease. Current reports suggest that only a third of those who inherit such a genetic change go on to develop a pituitary tumour (penetrance is only around 30%). If you as a parent have been identified to have the gene, then your future children would have a 50:50 chance of inheriting the genetic changes in the family.

Occasionally patients with childhood or young adult onset pituitary adenomas, most often with acromegaly, carry an AIP mutation, although no known family history of pituitary adenomas is available. Recent data suggest that 15-20% of childhood onset acromegaly patients, with no apparent family history, carry an AIP mutation.

Figure 2. Typical family tree of an AIP mutation positive family showing family members with childhood onset acronegaly (gigantism), adult onset acromegaly, prolactinoma, AIP mutation carrier subjects with no disease and family members who did not inherit the mutation.

Differential diagnosis of FIPA families

If a patient has an other family member with pituitary adenoma we need to think of the following options:

• If the patient or the other family members have other endocrine abnormalities (for example high calcium level in the blood, high pancreas or other gastrointestinal hormone levels) or endocrine tumours (parathyroid adenoma, pancreas adenoma, carcinoid tumour) then the diagnosis of multiple endocrine neoplasia type 1 (MEN1) needs to be considered. See further details here.
• If the patient or the other family members have unusual skin pigmentations, adrenal adenomas, heart tumours, testis adenomas, nerve tumours etc, then the diagnosis of Carney complex needs to be considered. Please note this is an extremely rare disease. See further details here.
• If the patient or the other family members have no other endocrine tumours, only pituitary adenomas, then the diagnosis of familial isolated pituitary adenoma (FIPA) should be considered. The word 'isolated' in the name FIPA refers to the fact that no other endocrine abnormality is associated in this disease as opposed to MEN1 and Carney complex. Testing for AIP mutations is suggested, keeping in mind that about 20% of families harbour an AIP mutation.
• However, we need to be careful that sometimes two diseases can occur in the same person or within the same family without a genetic basis to it. This phenomenon is called phenocopy. Phenocopies have been described in both FIPA families (Viermaa et al., Science, 2006 and Igerja et al., Human Mutation, 2010) and in MEN1 families (Turner et al., Human Mutation, 2010).

What to do next with patients and their family members in FIPA families

• In AIP mutation positive families all relatives with 50% chance to inherit the gene should be screened via a DNA test. This needs a simple blood test and now available via the National Health Service in the UK. The laboratory which performs the test has international accrediation and can process samples from any country as well. Family members with AIP mutations should be seen by an endocrinologist and some blood tests and an MRI scan could help to define if the patient has a pituitary adenoma or not. If these tests were normal then gene carriers can be reviewed once a year. Children could be screened at any age, we suggest not later than 4 years of age.
• In AIP mutation negative families, where one of family members with a pituitary adenoma has been tested negative for AIP mutations, other family members usually do not need to have their AIP gene tested. However, their DNA sample would be very important for studies aiming to identify the disease-causing gene. Family members with 50% chance to inherit the (currently unknown) gene should be seen by an endocrinologist for pituitary hormone testing and MRI. The review of children can be delayed until they are 16 years old.

We have already identified several family members of patients with pituitary adenomas (both in AIP mutation positive and negative families), who were screened due to their family history or AIP mutation carrier status and the presence of a previously unknown pituitary adenoma was identified. These patients benefited from the screening as their disease was identified earlier and this usually improves the chances of treatment.

Conclusions

AIP has been identified as a new tumour suppressor gene involved in the development of FIPA, especially growth hormone- and prolactin-secreting tumours. AIP mutations have been identified in 20% of families with FIPA. Patients with AIP mutations are diagnosed at a younger age and their pituitary tumours tend to be larger, more aggressive and respond less well to somatostatin analogue treatment. If a parent has a mutation in the AIP gene then his or her child has a one in two chance of inheriting the gene. Some people will inherit the gene but never develop the disease. These people are called carriers and while they remain disease free, they can pass the gene down to their children. It appears that one in three carriers of a mutated AIP gene will develop a pituitary tumour. The majority of FIPA families do not carry a mutation in the AIP gene and it is suggested that there might be other gene or genes associated with FIPA that are yet to be identified. FIPA families benefit from prospective screening of family members.

We are actively collecting patients and their families into our study and encourage patients to contact us if they believe they have familial pituitary adenoma or childhood onset pituitary disease. Please click here to contact us. If you have familial pituitary adenoma or have young-onset pituitary adenoma and wish to enter our study we will ask you to read an information sheet and sign a consent form. You also have the opportunity to talk to one of us over the phone to ask further questions and gain more information before you join the study. We may also ask other members of your family, specially other members affected by pituitary disease or carrying the disease-causing gene mutation, to enter the study, if they wish to do so. DNA testing includes a simple blood sample which can be taken at your GP surgery, at the clinic of your endocrinologist or at the clinic of a clinical geneticist doctor. Samples can be sent over the post or with courier at room temperature to the testing laboratory. Genetic testing is available via the National Health Service in the UK. The laboratory which performs the test also has International Accrediation and can process samples from any country as well. Result from the genetic testing are usually available within 8-10 weeks.

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Further Reading

If you would like to read further on this topic, please click Chahal_Patient_journal_2009.pdf [PDF 226KB].

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Further Reading of Medical Literature

• Clinical Reviews
• Original clinical papers
• Original basic science papers