Clinical characteristics.

AIP familial isolated pituitary adenoma (AIP-FIPA) is defined as the presence of an AIP germline pathogenic variant in an individual with a pituitary adenoma (regardless of family history).

The most commonly occurring pituitary adenomas in this disorder are growth hormone-secreting adenomas (somatotropinoma), followed by prolactin-secreting adenomas (prolactinoma), growth hormone and prolactin co-secreting adenomas (somatomammotropinoma), and nonfunctioning pituitary adenomas (NFPA). Rarely TSH-secreting adenomas (thyrotropinomas) are observed. Clinical findings result from excess hormone secretion, lack of hormone secretion, and/or mass effects (e.g., headaches, visual field loss). Within the same family, pituitary adenomas can be of the same or different type. Age of onset in AIP-FIPA is usually in the second or third decade.

Diagnosis/testing.

The diagnosis of AIP-FIPA is established in a proband with a pituitary adenoma by identification of a heterozygous germline pathogenic variant in AIP by molecular genetic testing.

Management.

Treatment of manifestations: Pituitary adenomas identified in those with AIP-FIPA are generally treated in the same manner as pituitary adenomas of unknown cause: they can be treated by medical therapy (somatostatin analogs, growth hormone receptor antagonists, and dopamine agonists), surgery, and/or radiotherapy. Although surgery is usually performed in persons with AIP-FIPA, it often does not fully control the tumor; thus, medical therapy and radiotherapy following surgery may be required to control hormone output and tumor growth. AIP-FIPA adenomas often do not respond well to first-generation somatostatin analog, while data suggest that they may respond better to second-generation multi-ligand agonists. Prolactinomas are treated with dopamine agonist therapy or surgery and can be aggressive and difficult to treat. NFPA is treated with surgery and if necessary radiotherapy.

Prevention of secondary complications: Expert management for hypopituitarism which can be due to tumor size, surgery, or radiotherapy. Persons on glucocorticoid replacement therapy need to increase their steroid dose when ill or stressed.

Surveillance: In asymptomatic individuals: annual growth assessment and evaluation for signs/symptoms of pituitary adenoma and pubertal development from age four years until adulthood. Continue annual evaluation for signs and symptoms of pituitary adenoma until age 30 years and then every five years between ages 30 and 50 years. Annual pituitary function tests (serum IGF-1, prolactin, estradiol/testosterone, LH, FSH, TSH, free T4) beginning at age four years until age 30; pituitary MRI at age ten years and repeated (every 5 years has been suggested) or as necessary based on clinical and biochemical parameters until age 30 years. Starting at age 30 to 50 years surveillance can be relaxed.

In symptomatic individuals: annual clinical assessment and pituitary function tests (serum IGF-1, spot growth hormone, prolactin, estradiol/testosterone, LH, FSH, TSH, free T4, and morning cortisol); if indicated annual dynamic testing to evaluate for hormone excess or deficiency (e.g., glucose tolerance test, insulin tolerance test); pituitary MRI with frequency depending on clinical status, previous extent of the tumor, and treatment modality. Clinical monitoring of secondary complications of the tumor and/or its treatment (e.g., diabetes mellitus, hypertension, osteoarthritis, hypogonadism, osteoporosis); in those with acromegaly, colonoscopy at age 40 years and repeated every three to ten years depending on the number of colorectal lesions and IGF-1 levels.

Evaluation of relatives at risk: Family members at risk for AIP-FIPA warrant molecular genetic testing for the family-specific pathogenic variant to identify those who harbor the variant and thus require surveillance for pituitary adenomas.

Genetic counseling.

AIP-FIPA is inherited in an autosomal dominant manner. Each child of an individual with AIP-FIPA has a 50% chance of inheriting the pathogenic variant. Prenatal testing for a pregnancy at increased risk is possible if the AIP pathogenic variant of an affected family member has been identified; however, because AIP-FIPA demonstrates reduced penetrance, the finding of an AIP pathogenic variant prenatally does not allow accurate prediction of whether a tumor will develop, or the type of adenoma, age of onset, prognosis, or availability and/or outcome of treatment.

Suggestive Findings

AIP familial isolated pituitary adenoma (AIP-FIPA) should be suspected in individuals with the following:

• A pituitary adenoma diagnosed before age 18 years, especially a growth hormone-secreting pituitary adenoma, regardless of family history
• A pituitary macroadenoma (tumor >10 mm in diameter) diagnosed before age 30 years, especially a growth hormone-secreting pituitary adenoma, regardless of family history
• A prolactin-secreting pituitary macroadenoma (tumor >10 mm in diameter) diagnosed before age 30 years, regardless of family history
  Note: (1) A germline AIP pathogenic variant is identified in approximately 20% of simplex cases of childhood-onset growth hormone-secreting pituitary adenomas [Chahal et al 2010, Cazabat et al 2011, Tichomirowa et al 2011]. (2) A germline AIP pathogenic variant is identified in 11% of simplex cases of young-onset (age <30 years) pituitary macroadenomas [Tichomirowa et al 2011].
• A family history of more than one individual with a pituitary adenoma
  Note: (1) A germline AIP pathogenic variant is identified in approximately 20% of families with FIPA [Chahal et al 2010] and in 40% of families in which somatotropinomas are the only tumor type observed. (2) To date, AIP pathogenic variants have not been identified in families with two adults with microprolactinomas (prolactin secreting tumors <10 mm in diameter); therefore, the probability of identifying an AIP pathogenic variant in such a family is low.
• Absence of clinical features of other disorders associated with pituitary adenomas such as multiple endocrine neoplasia type 1 or type 4 (MEN1 or MEN4) or Carney complex

The pituitary adenomas in individuals with AIP-FIPA can include:

• Growth hormone-secreting (somatotropinoma)
  Note: Somatotroph (growth hormone-secreting) cell hyperplasia has also been described in individuals with AIP-FIPA, although it is extremely rare.
• Prolactin-secreting (prolactinoma)
• Growth hormone and prolactin co-secreting (somatomammotropinoma)
• Nonfunctioning pituitary adenoma (NFPA)
  Note: Most AIP-related NFPAs show growth hormone and/or prolactin immunostaining in tumor tissue.
• Thyrotropinoma (TSH-secreting) (rare; 1 thyrotropinoma described)
• Multihormonal (i.e., secreting >1 pituitary hormone) (extremely rare apart from tumors secreting growth hormone and prolactin)

No unequivocal cases of corticotropinomas have been described.

Establishing the Diagnosis

The diagnosis of AIP-FIPA is established in a proband with a pituitary adenoma(s) by identification of a heterozygous germline pathogenic variant in AIP by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of AIP-FIPA can occur with other disorders, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from other inherited disorders with pituitary tumors are more likely to be diagnosed using comprehensive genomic testing (see Option 2).

Clinical Description

To date, more than 300 individuals with a germline pathogenic variant in AIP have been identified [Beckers et al 2013, Hernández-Ramírez et al 2015]. The following description of the phenotypic features associated with this condition is based on these reports.

The median age of diagnosis of AIP familial isolated pituitary adenoma (AIP-FIPA) is 23 years. The earliest age of diagnosis of a pituitary adenoma in a person with an AIP pathogenic variant is four years [Dutta et al 2019].

Genotype-Phenotype Correlations

Individuals with AIP truncating pathogenic variants may have a slightly earlier age of onset and diagnosis compared to those with non-truncating pathogenic variants [Hernández-Ramírez et al 2015].

Penetrance

Studies on large families with AIP pathogenic variants show a clinical penetrance of pituitary adenomas of approximately 23% (range 15%-30%) [Vierimaa et al 2006, Naves et al 2007, Williams et al 2014, Hernández-Ramírez et al 2015]. Although some families with AIP-FIPA can show high penetrance, the higher levels of penetrance initially reported in some families is probably ascertainment bias due to insufficient information on all at-risk family members (e.g., lack of medical records, information on pituitary hormone testing, and/or imaging studies) [Daly et al 2007, Leontiou et al 2008].

The factors influencing penetrance are not known; the possibility of a second locus has been investigated but not confirmed [Khoo et al 2009, Hernández-Ramírez et al 2015].

Nomenclature

Previously, pituitary adenoma predisposition (PAP) syndrome was used to refer to individuals who had an AIP pathogenic variant; the term is not used widely.

Prevalence

The exact prevalence of AIP-FIPA is not known. To date, about 150 families and about 150 simplex cases (i.e., a single occurrence in a family) of AIP-FIPA have been identified [Daly et al 2010, Hernández-Ramírez et al 2015, Caimari et al 2018].

Familial Isolated Pituitary Adenomas (FIPA)

FIPA is defined as a hereditary condition associated with pituitary adenomas and no other features of a syndrome known to be associated with pituitary adenomas.

X-linked acrogigantism (XLAG), a second genetically characterized type of FIPA, is caused by duplication of GPR101. XLAG, a highly penetrant disorder, is associated with pituitary hyperplasia or adenoma resulting in growth hormone excess with onset in infancy, usually with associated hyperprolactinemia [Trivellin et al 2014]. Most individuals with XLAG have a de novo somatic mosaic genetic alteration not inherited from a parent.

Families with FIPA of known or unknown cause can have homogeneous pituitary adenoma phenotypes (i.e., pituitary tumors of the same type) or heterogeneous phenotypes (i.e., pituitary tumors of different types).

Aspects of FIPA that tend to differ between families in which a germline AIP pathogenic variant has been identified and those in which no germline AIP pathogenic variant has been identified include: age of onset, number of persons affected in the family, male-to-female ratio, and typical adenoma types. Tumor variables may also include: size, aggressiveness, and response to treatment [Hernández-Ramírez et al 2015] (see Table 3).

Syndromes Associated with Pituitary Tumors

Note: Autopsy and radiologic studies suggest that 14%-22% of the population may harbor a pituitary adenoma, most of these being asymptomatic [Ezzat et al 2004]. Thus, it is possible for two pituitary adenomas, especially prolactinomas, to occur sporadically in a family by chance.

Other Space-Occupying Lesions

In addition to pituitary adenomas, numerous space-occupying lesions can occur in the pituitary fossa [Saeger et al 2007]. The most common space-occupying lesions after pituitary adenomas are craniopharyngiomas, which cause symptoms by compressing the normal pituitary, resulting in hormonal deficiencies and mass effects on the surrounding tissues and brain [Zacharia et al 2012].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual with AIP familial isolated pituitary adenoma (AIP-FIPA), the evaluations in Table 5 are recommended (for details see Katznelson et al [2011]).

Treatment of Manifestations

While there is experience with treating pituitary adenomas in symptomatic persons with FIPA, the experience of management and treatment of persons identified prospectively through clinical screening due to family history of FIPA and/or presence of a heterozygous germline AIP pathogenic variant is relatively recent. However, the age of detection in the AIP-FIPA is earlier and the prognosis generally better. Given the prevalence of incidental pituitary adenomas, it is important to remember that such a tumor may arise in an individual with an AIP pathogenic variant, completely by chance. The following recommendations are based on those of Katznelson et al [2011], Melmed et al [2011], Williams et al [2014], and Hernández-Ramírez et al [2015].

Prevention of Secondary Complications

Tumor size, surgery, and/or radiotherapy can cause hypopituitarism, which requires careful expert follow up.

Persons on glucocorticoid replacement therapy need to increase their steroid dose when ill or stressed.

Surveillance

No formal guidelines regarding surveillance of persons with AIP-FIPA have been established. The following recommendations are based on expert opinion from the literature and on the authors' personal experience with more than 200 persons with symptomatic or asymptomatic AIP-FIPA.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual by molecular genetic testing for the familial AIP pathogenic variant so that morbidity and mortality can be reduced by early diagnosis and treatment. Identification of at-risk family members may also reduce the need for costly screening procedures in those family members who have not inherited a pathogenic variant.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancy may increase the size of a growth hormone-secreting adenoma or a prolactin-secreting adenoma (especially macroadenomas); thus, a pregnant woman with pituitary macroadenoma is at risk of developing visual field defects. In each trimester it is appropriate to inquire about headaches and perform visual field testing. Medical therapies are stopped during pregnancy.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

A study that is actively ascertaining individuals with FIPA or childhood-onset pituitary adenoma is listed in ClinicalTrials.gov.

Growth hormone receptor antagonists block the action of endogenous growth hormone, thereby controlling disease manifestations such as headaches, soft tissue enlargement, diabetes mellitus, hypertension, and high IGF-1 levels. A growth hormone receptor antagonist has been used successfully in persons with AIP-FIPA and acromegaly and pituitary gigantism [Goldenberg et al 2008]. In two individuals with AIP-related pituitary tumors resistant to treatment with first-generation somatostatin analogs, pasireotide, a second-generation multi-ligand somatostatin analog with affinity to multiple somatostatin receptors, was shown to achieve long-term control of disease [Daly et al 2019]. Although growth hormone receptor antagonists are currently not licensed for pediatric use, several case reports have shown their effectiveness, especially when IGF-1 levels need to be reduced immediately to prevent abnormally rapid growth [Higham et al 2010, Dutta et al 2019].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

AIP familial isolated pituitary adenoma (AIP-FIPA) is inherited in an autosomal dominant manner with reduced penetrance.

Risk to Family Members

Parents of a proband

• Almost all individuals reported to date with AIP-FIPA have a parent who is also heterozygous for the AIP pathogenic variant [Hernández-Ramírez et al 2015]. Because of reduced penetrance, the parent may or may not be affected.
• Reports of unequivocally de novo pathogenic variants are rare [Ramírez-Rentería et al 2016]. As not all simplex AIP-FIPA cases (i.e., a single occurrence in a family) have been evaluated sufficiently to determine if the pathogenic variant occurred de novo in the proband, the proportion of AIP-FIPA resulting from a de novo AIP pathogenic variant is unknown.
• Molecular genetic testing is recommended for the parents of a proband with an apparently negative family history of the disease and a pathogenic AIP variant.
• If the AIP pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent.* Although no instances of germline mosaicism have been reported, it remains a possibility.
  * Misattributed parentage can also be explored as an alternative explanation for an apparent de novo pathogenic variant.
• The family history of some individuals diagnosed with AIP-FIPA may appear to be negative because of failure to recognize the disorder in family members due to a milder phenotypic presentation or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected or is known to have the AIP pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. Because the clinical penetrance of pituitary tumors in AIP-FIPA is approximately 15%-30%, sibs who inherit an AIP pathogenic variant may or may not develop a pituitary adenoma (see Penetrance).
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• The sibs of a proband with clinically unaffected parents are still at increased risk of inheriting the AIP pathogenic variant because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual heterozygous for an AIP pathogenic variant has a 50% chance of inheriting the AIP pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents; if a parent is heterozygous for an AIP pathogenic variant, his or her family members may be at risk for AIP-FIPA.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the AIP pathogenic variant has been identified in the family, prenatal and preimplantation genetic testing for AIP-FIPA are possible. As AIP-FIPA demonstrates reduced penetrance, the finding of a pathogenic variant in AIP prenatally does not allow accurate prediction of a tumor, the adenoma type, age of onset, prognosis, or availability and/or outcome of treatment.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While use of prenatal testing is a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

AIP encodes AIP, a co-chaperone with several interacting partners. In the context of pituitary adenomas, AIP behaves as a tumor suppressor gene [Leontiou et al 2008]. AIP, previously known as hepatitis B virus (HBV) X-associated protein (XAP2) or aryl hydrocarbon receptor (AhR)-associated protein (ARA9), is a 330-amino acid 37-kd protein [Kuzhandaivelu et al 1996, Carver & Bradfield 1997]. The C-terminal end of the protein has three tetratricopeptide repeats (TPRs) and a final alpha-helix. The three TPR domains are degenerate sequences of 34 amino acids comprising two antiparallel helices that play a crucial role in mediating the protein-protein interactions of AIP [Kazlauskas et al 2002].

Mechanism of disease causation. The majority (75%) of AIP pathogenic variants result in, or predict, a truncated protein. Many of the pathogenic missense variants affect structurally important conserved amino acids of the TPR structure [Vargiolu et al 2009, Igreja et al 2010, Cai et al 2011]. Clinical data and functional studies both indicate a tumor suppressor role for AIP.

Of note, truncating variants have been reported throughout the protein. Some are predicted to cause nonsense-mediated decay, while others lose the functionally important C-terminal alpha helix. In addition, truncating variants may result in protein with a shortened half-life. Shortened protein half-life has also been shown for many of the pathogenic missense variants [Hernández-Ramírez et al 2016].

Published Guidelines / Consensus Statements

• Katznelson L, Atkinson JL, Cook DM, Ezzat SZ, Hamrahian AH, Miller KK, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of acromegaly--2011 update. Endocr Pract. 2011;17 Suppl 4:1–44. [PubMed: 21846616]

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Author Notes

Website: www.fipapatients.org

The FIPA Patients website, established by Dr Korbonits in collaboration with the FIPA Consortium, is an information resource for patients and families with familial isolated pituitary adenoma. It also provides general information for medical professionals on research in the field of FIPA, including links to relevant publications.

The authors welcome comments and inquiries: gro.stneitapapif@ofni.

Acknowledgments

We are grateful to referring colleagues and patients for providing information on this disease.

Revision History

• 16 April 2020 (sw) Comprehensive update posted live
• 21 June 2012 (me) Review posted live
• 3 February 2011 (mk) Original submission