Aip Familial Isolated Pituitary Adenomas
Summary
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 pregnancies 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.
Diagnosis
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 historyNote: (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 adenomaNote: (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).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of AIP-FIPA, molecular genetic testing approaches can include single-gene testing (or concurrent or serial single-gene testing) or use of a multigene panel:
- Single-gene testing. Sequence analysis of AIP detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
- A multigene panel that includes AIP and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the phenotype is indistinguishable from other inherited disorders characterized by pituitary tumors, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is a possible option. Exome sequencing is most commonly used; genome sequencing is also possible.
If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in AIP-FIPA
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| AIP | Sequence analysis 3 | ~95% 4, 5 |
| Gene-targeted deletion/duplication analysis 6 | ~5% 7 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Georgitsi et al [2008]; Igreja et al [2010]; Hernández-Ramírez et al [2015]; Author, personal observation
- 5.
One promoter variant has been reported (see Molecular Genetics).
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 7.
To date, four individuals/families with exon or multiexon deletions and two families with whole-gene deletions have been identified [Georgitsi et al 2008, Igreja et al 2010, Hernández-Ramírez et al 2015, Marques et al 2020].
Clinical Characteristics
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.
Table 2.
Pituitary Adenomas in Individuals with AIP-FIPA
| Type of Pituitary Adenoma | % of Persons w/Type of Adenoma | Reference |
|---|---|---|
| Somatotropinoma (growth hormone-secreting) | 70% | Hernández-Ramírez et al [2015] |
| Somatomammotropinoma (growth hormone- and prolactin-secreting) | 10% | |
| Prolactinoma | 10% | |
| Nonfunctioning pituitary adenoma | 8% | |
| Thyrotropinoma (TSH-secreting) | Rare |
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].
Hormone Dysfunction
Somatotropinoma (growth hormone-secreting pituitary adenoma)
- Acromegaly. Approximately 80% of persons with AIP-FIPA have acromegaly. Persons with acromegaly have excess growth hormone secretion resulting in enlargement of hands and feet, and coarse facial appearance with prognathism and malocclusion of teeth. They may have headaches, joint pain, carpal tunnel syndrome, sleeping difficulties, excessive sweating, hypertension, diabetes mellitus, and muscle weakness. Individuals with longstanding acromegaly often have cardiovascular and rheumatologic/orthopedic complications, which need to be treated accordingly. Individuals with acromegaly of any cause are at increased risk for colon cancer.If acromegaly starts in childhood/adolescence it can lead to pituitary gigantism.
- Pituitary gigantism. Excessive growth hormone secretion before fusion of the growth plates results in pituitary gigantism. Exceptionally tall stature results from a combination of high growth hormone levels and delayed onset of puberty due to suppression of LH/FSH secretion by mass effect of the tumor and/or, when present, the direct effect of high prolactin levels.One third of all individuals with a germline AIP pathogenic variant and 40%-50% of individuals with AIP-FIPA with a somatotropinoma have pituitary gigantism [Daly et al 2010].
Prolactinomas. Approximately 10% of persons with an AIP pathogenic variant have a prolactinoma [Daly et al 2010, Igreja et al 2010]. Prolactinomas result in signs and symptoms of prolactin excess (i.e., amenorrhea, sexual problems, galactorrhea, and infertility) and can also cause mass effects (e.g., visual field defects, headaches).
Almost all AIP-related prolactinomas are macroadenomas with male predominance [Daly et al 2010, Igreja et al 2010].
Nonfunctioning pituitary adenomas (NFPAs). NFPAs are seen in 4%-7% of persons with an AIP pathogenic variant.
NFPAs are usually diagnosed due to the local effects of the tumor, such as bitemporal hemianopia or hypogonadism. It is unclear why these silent adenomas do not release hormones at a clinically recognizable level; however, there is likely to be a continuum between fully functional and completely silent adenomas [Drummond et al 2019]. Distinguishing NFPA from prolactinomas can occasionally be difficult due to the stalk effect (pituitary stalk compression resulting in increased prolactin levels in the absence of a prolactin-secreting adenoma).
In AIP-FIPA, NFPAs that have been resected are often (but not always) silent somatotropinoma or lactotroph adenomas [Igreja et al 2010, Villa et al 2011]. In families with AIP-FIPA, NFPAs are identified at a younger age than NFPAs in persons without a germline pathogenic variant [Daly et al 2010]. Screening of clinically unaffected AIP heterozygotes can identify small nonfunctioning pituitary lesions, equivalent to incidentalomas in the general population [Caimari et al 2018].
Thyrotropinomas (TSH-secreting adenomas causing hyperthyroidism) are rarely seen in AIP-FIPA.
A single individual with AIP-FIPA and a thyrotropinoma has been described [Daly et al 2007].
AIP-FIPA does not appear to increase the risk of corticotropinoma. The individuals with FIPA previously reported with Cushing disease were subsequently found to have likely benign variants in AIP, variants of uncertain significance [Beckers et al 2013], or no loss of heterozygosity identified in the tumor [Cazabat et al 2012].
Subfertility is common in persons with pituitary tumors. No data are available specifically regarding subfertility in AIP-FIPA.
Mass effects. Large pituitary adenomas can be associated with deficiencies of other pituitary hormones that result in subfertility, hypothyroidism, hypoadrenalism, low levels of growth hormone, and panhypopituitarism.
Macroadenomas (>10 mm in diameter) may also press on the optic chiasm and optic tracts, causing bitemporal hemianopia. The tumor may invade the adjacent cavernous sinus. Headache can be present in any type of adenoma but is especially common in acromegaly; the mechanism for the increased frequency is unknown.
Larger pituitary tumors may autoinfarct, resulting in pituitary apoplexy (sudden-onset severe headache, visual disturbance, cranial nerve palsies, hypoglycemia, and hypotensive shock). Pituitary apoplexy has been described in individuals with AIP-FIPA [Chahal et al 2011].
Pituitary carcinoma. To date pituitary carcinoma has not been described in an individual with AIP-FIPA.
Other, non-pituitary tumors have been observed in some families with AIP-FIPA; however, because the background population risk for tumors is fairly high and because no consistent pattern has been observed, at present there is no conclusive evidence that an AIP germline pathogenic variant increases the risk for any other tumors. In addition, non-pituitary tumors from AIP heterozygotes have been analyzed for loss of heterozygosity at the AIP locus, and no abnormality was found [Hernández-Ramírez et al 2015].
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].
Differential Diagnosis
In children more often than in adults, pituitary adenomas may be a manifestation of a genetic condition. Pituitary adenomas of genetic origin can be divided into isolated and syndromic categories.
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).
Table 3.
Comparison of Findings in Persons with Isolated Pituitary Adenomas by Family History and Presence/Absence of a Germline AIP Pathogenic Variant
| Characteristics | Familial Isolated Pituitary Adenoma | Simplex Somatotropinoma 1 | |||
|---|---|---|---|---|---|
| AIP-FIPA | XLAG | FIPA of unknown cause | |||
| Clinical features | Age of onset 2 | 4-24 yrs | Infancy / early childhood | 40 yrs | 43 yrs |
| Average # of affected family members 3 | 3-4 | 1 | 2-3 | n/a | |
| Male-to-female ratio 4 | 1:1 to 2:1 | 1:2 | 1:1 | 1:1 | |
| Adenoma features | Somatotropinomas / somatomammotropinomas | 70%-80% | ~100% | ~50% | n/a |
| Size | Macroadenomas in vast majority | Pituitary hyperplasia-macroadenoma | Majority macroadenoma 5 | Smaller | |
| Aggressiveness | More | Variable | More | Less | |
| Response to treatment | Poorer | Poorer | Poorer | Better | |
FIPA = familial isolated pituitary adenoma
- 1.
Simplex case = a single occurrence in a family
- 2.
Daly et al [2010], Igreja et al [2010], Hernández-Ramírez et al [2015], Daly et al [2016]
- 3.
Igreja et al [2010]
- 4.
Cazabat et al [2009], Daly et al [2010], Igreja et al [2010]
- 5.
Marques et al [2020]
Syndromes Associated with Pituitary Tumors
Table 4.
Syndromes Associated with Pituitary Tumors
| Gene(s) | Disorder | MOI | Pituitary Tumor Features | Other Features |
|---|---|---|---|---|
| MEN1 | Multiple endocrine neoplasia type 1 (MEN1) | AD | Pituitary tumors occur in ~40% of affected individuals, most often prolactinomas |
|
| CDKN1A CDKN1B CDKN2B CDKN2C | MEN1-like syndrome 1 | AD | Pituitary tumors occur in ~40% of affected individuals, most often somatotropinomas |
|
| PRKAR1A PRKACB 2 | Carney complex | AD | ~80% of affected individuals have somatotroph cell hyperplasia or small pituitary adenoma |
|
| GNAS | McCune-Albright syndrome | n/a (somatic) |
|
|
| MAX SDHA SDHB SDHC SDHD RET | Hereditary paraganglioma-pheochromocytoma syndromes | AD |
|
|
| DICER1 | DICER1 syndrome | AD |
| Manifests before age 2 yrs |
| MSH2 MSH6 MLH1 ?PMS2 | Lynch syndrome | AD |
| Colorectal, endometrial, ovarian, & other carcinomas |
| USP8 | Pituitary adenoma 4 (OMIM 219090) | AD | 1 individual w/pituitary adenoma | Developmental delay |
AD = autosomal dominant; GIST = gastrointestinal stromal tumor; MEN1 = multiple endocrine neoplasia type 1; MOI = mode of inheritance
- 1.
Agarwal et al [2009]
- 2.
One individual with Carney complex (<1% of families with Carney complex) had a germline rearrangement resulting in four copies of PRKACB [Forlino et al 2014]. PRKACB encodes the catalytic subunit Cβ of the cyclic AMP-dependent protein kinase A (PKA). Levels of Cβ and PKA activity were increased in the individual's lymphoblasts and fibroblasts; the authors propose that this is a Carney complex-causing gain-of-function variant.
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].
Management
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]).
Table 5.
Recommended Evaluations Following Initial Diagnosis in Individuals with AIP-FIPA
| System/Concern | Evaluation |
|---|