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AIP-Related Familial Isolated Pituitary Adenomas

, MD, PhD and , MD.

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Summary

Clinical characteristics.

AIP-related isolated familial pituitary adenoma (AIP-related 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 non-functioning pituitary adenomas (NFPA). Rarely TSH- or ACTH-secreting adenomas (thyrotropinoma and corticotropinoma) 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-related FIPA is around 20-24 years (age range: 6-66 years).

Diagnosis/testing.

The diagnosis of AIP-related FIPA relies on identification of characteristic pituitary adenomas based on hormone secretion, pituitary MRI, and histologic findings, and identification of a heterozygous AIP pathogenic variant in an affected family member.

Management.

Treatment of manifestations: Pituitary adenomas identified in those with AIP-related FIPA are treated in the same manner as pituitary adenomas of unknown cause: they can be treated by surgery, medical therapy (somatostatin analogs, growth hormone receptor antagonists, and dopamine agonists), and/or radiotherapy. Although surgery is usually performed in persons with AIP-related 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.

Surveillance: Persons with AIP-related FIPA who have had a pituitary adenoma need to be followed for both recurrence of a treated adenoma and development of new adenomas. No specific guidelines exist; the authors' recommendations are:

  • Yearly clinical assessment and pituitary function tests (IGF-1, spot GH, prolactin, LH/FSH, estradiol/testosterone, TSH, fT4, and morning cortisol);
  • Dynamic testing to evaluate for hormone excess or deficiency (e.g., glucose tolerance test, insulin tolerance test) as needed; and
  • Follow-up 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) are necessary.

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

Genetic counseling.

AIP-related FIPA is inherited in an autosomal dominant manner. Each child of an individual with AIP-related FIPA has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the AIP pathogenic variant of an affected family member has been identified; however, requests for prenatal testing for conditions which (like FIPA) do not affect intellect and have some treatment available are rare. Furthermore, as AIP-related FIPA demonstrates reduced penetrance, the finding of a AIP pathogenic variant prenatally does not allow accurate prediction of whether a tumor will develop, the adenoma type, age of onset, prognosis, availability of and/or outcome of treatment.

Diagnosis

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

The pituitary adenomas can be:

  • Growth hormone-secreting (somatotropinoma)
  • Prolactin-secreting (prolactinoma)
  • Growth hormone and prolactin co-secreting (somatomammotropinoma)
  • Non-functioning pituitary adenoma (NFPA)
  • TSH- or ACTH-secreting (thyrotropinoma and corticotropinoma).
  • Note: These are rare; thyrotropinoma has been observed in one person with an AIP pathogenic variant.
  • Multihormonal (i.e., secreting more than one pituitary hormone)

Testing

Pituitary adenomas can be categorized by cell-type origin, hormone secreting activity, and/or size. Tumors smaller than 10 mm in diameter are considered microadenomas; tumors larger than 10 mm in diameter are considered macroadenomas. Virtually all pituitary tumors are benign adenomas; pituitary carcinomas are very rare. Despite the benign histologic nature of the pituitary adenomas they can cause morbidity through hormone dysfunction and/or mass effects (i.e., the tumor compression syndrome).

The diagnostic changes in hormone secretion, findings on imaging, and histology of each tumor type are reviewed in Endocrinology [De Groot & Jameson 2010]. The following is a brief summary.

Somatotropinoma

  • Growth hormone (GH) secretion. The diagnostic test for somatotropinoma is an oral glucose tolerance test (oGTT) using 75 mg glucose. Controls fully suppress GH secretion to undetectable levels, whereas persons with a somatotropinoma fail to suppress growth hormone below 1 mU/L; some show a paradoxic increase in growth hormone concentration [Katznelson et al 2011].
    Note: (1) IGF-1 levels are invariably high in individuals with severe untreated somatotropinoma; however, divergent GH and IGF-I values may be seen in up to 30% of patients: the most common discrepancy is an elevated IGF-I level with a normal GH value, thought to reflect earlier disease. Of note, age-related IGF-1 normal ranges need to be used to interpret test results. (2) The diagnosis of somatotropinoma can be difficult to establish in adolescents: during peak growth velocity GH levels can be high and not fully suppressed during oGTT; IGF-1 levels range widely and can vary by stage of puberty. False-positive responses to the oGTT may also be seen in patients with diabetes mellitus, liver disease, renal disease, or anorexia nervosa. (3) About half of GH-secreting pituitary adenomas with pathogenic variants in AIP co-secrete prolactin, which may be due to co-secretion and/or the "stalk effect" (i.e., high hormone levels that result from compression of the pituitary stalk and decreased inhibitory dopaminergic input). (4) Deficiency of other pituitary hormones is often seen in macroadenomas.
  • Imaging. Contrast-enhanced pituitary MRI is the imaging modality of choice. By the time they cause symptoms and biochemical abnormalities, the overwhelming majority of somatotropinomas are macroadenomas and are sufficiently large to be detected by MRI; however, tumors may not be detectable in their early stages. Note: With modern imaging techniques and contrast agents, tumors as small as 2 mm can be identified.
  • Histology. Immunostaining for growth hormone is usually positive in somatotropinomas. Immunostaining for prolactin is often positive with or without clinical or biochemical hyperprolactinemia. In somatomammotropinomas both GH and PRL staining are positive.
    Somatotropinomas can be classified into sparsely and densely granulated adenomas using electron microscopy or a cytokeratin stain (e.g., Cam5.2 or CK8). Persons with AIP-related FIPA often have sparsely granulated adenomas.
    Somatotroph (growth hormone-secreting) cell hyperplasia has been described in a few cases of AIP-related FIPA and acromegaly. Note: Somatotroph cell hyperplasia can be distinguished from somatotropinoma by reticulin staining.

Prolactinoma

  • Prolactin (PRL) secretion. PRL concentration can be assessed from a random serum sample.
    Note: (1) Due to common interference of assays for prolactin with macroprolactin, it is important for the laboratory to perform PEG (polyethylene glycol) precipitation at the initial assessment. (2) Macroprolactinomas can be associated with paradoxically normal or only slightly elevated levels of prolactin as a result of the hook effect (i.e., falsely low values on the prolactin immunoassay in the presence of an overwhelming amount of antigen [prolactin] that affects the binding capacity of the added antibody). (3) Some of the numerous causes of hyperprolactinemia without pituitary adenoma include: pregnancy, lactation, exercise, stress, certain drugs, and polycystic ovary syndrome. Pituitary lesions that do not produce prolactin can also cause high prolactin levels due to the stalk effect. (4) About half of the AIP-mutation positive GH-secreting pituitary adenomas co-secrete prolactin.
  • Imaging. Contrast-enhanced pituitary MRI is the imaging modality of choice. Sometimes pituitary microadenomas too small to be detected on MRI can cause elevated serum concentrations of prolactin. With modern imaging techniques and contrast agent, tumors as small as 2 mm can be identified.
    The overwhelming majority of prolactinomas in persons with a germline AIP pathogenic variant are macroadenomas.
  • Histology. Immunostaining for prolactin is usually positive. In somatomammotropinomas both GH and PRL staining are positive.

Non-functioning pituitary adenoma (NFPA)

  • Hormone secretion. By definition, no clinically relevant increase in hormone secretion is observed; however, low-level increases in FSH secretion can be observed.
  • Imaging. Contrast-enhanced pituitary MRI detects clinically relevant NFPAs.
  • Histology. More than 95% of NFPAs are of gonadotroph origin; immunostaining for LH/FSH can be observed in scattered cells.
    • "Null" adenomas are those in which no immunostaining for any pituitary hormones is evident.
    • "Silent" ACTH, GH, or GH and PRL adenomas (i.e., non-functioning adenomas in which immunostaining is positive for ACTH, GH, or PRL) have been described in persons with a germline AIP pathogenic variant.

Thyrotropinoma

  • TSH secretion. Serum concentrations of TSH are normal or high in the presence of elevated total and/or free thyroid hormone concentrations. Note: Measurement of markers of peripheral thyroid hormone action and dynamic tests of thyroid function may distinguish a thyrotropinoma from the syndrome of resistance to thyroid hormone.
  • Imaging. Contrast-enhanced pituitary MRI is the imaging modality of choice. Thyrotropinomas are often, but not always, macroadenomas.

Corticotropinoma

  • ACTH secretion. The diagnosis of Cushing disease can be difficult and may require dynamic testing, abnormal circadian rhythm, and sometimes petrosal sampling.
  • Imaging. Contrast-enhanced pituitary MRI is the imaging modality of choice.
  • Histology. Immunostaining for ACTH is observed in most cases; Crook's change (hyalinization) can be observed in some.

Molecular Genetic Testing

Gene. By definition AIP is the only gene in which pathogenic variants cause AIP-related familial isolated pituitary adenomas.

Table 1.

Molecular Genetic Testing Used in AIP-Related Familial Isolated Pituitary Adenomas

Gene 1Test MethodAllelic Variants Detected 2Mutation Detection Frequency by Test Method 1
AIPSequence analysis 4Sequence variants 5~90% 6
Deletion/duplication analysis 7, 8Exon or whole-gene deletions~10%
1.
2.

See Molecular Genetics for information on allelic variants.

3.

The ability of the test method used to detect a pathogenic variant that is present in the indicated gene

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. 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.

5.

One promoter variant has been reported. See Table 4 (pdf).

6.
7.

Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

8.

If laboratories are using commercial MLPA kits, the probes for AIP are typically combined with the probes for MEN1 (see Multiple Endocrine Neoplasia Type 1); such kits can detect deletions or duplications in both genes.

Testing Strategy

To confirm/establish the diagnosis of AIP-related FIPA in a proband. Individuals with a pituitary adenoma in whom molecular genetic testing for an AIP germline pathogenic variant should be considered are those who do not have a clinical diagnosis or features of a recognized syndrome or a pathogenic variant in one of the genes known to cause multiple endocrine neoplasia type 1 or type 4 (MEN1 or MEN4) or Carney complex, and who have one or more of the following [Korbonits et al 2012]:

The molecular genetic testing strategy for AIP germline pathogenic variants:

1.

Perform sequence analysis.

2.

If no pathogenic variant is identified by sequence analysis, perform deletion/duplication testing.

Predictive testing for at-risk asymptomatic family members requires prior identification of the pathogenic variant in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variant in the family.

Clinical Characteristics

Clinical Description

The most common pituitary adenomas observed in AIP-related familial isolated pituitary adenoma (AIP-related FIPA) are somatotropinoma (growth hormone-secreting), followed by somatomammotropinoma (growth hormone- and prolactin-secreting) and prolactinoma (prolactin-secreting) [Vierimaa et al 2006, Daly et al 2007, Leontiou et al 2008]. Clinically non-functioning pituitary adenomas (NFPAs) are also identified. Rarely, TSH-secreting or ACTH-secreting adenomas have been identified.

In the Daly et al [2007] cohort, 36% had a GH adenoma, 42% had a PRL adenoma, 14% had NFPA, and 8% had an ACTH-, TSH- or FSH-oma. In the Igreja et al [2010] study, 68% had a GH or mixed GH/PRL adenoma, 20% had PRL adenoma, 11% had NFPA, and 1% had ACTH-, TSH-, or FSH-oma. Of note, within the same family different relatives with the same AIP pathogenic variant can have different types of adenomas.

The following is true of AIP-related FIPA as well as all types of pituitary adenomas. Histologically, pituitary adenomas are benign; however, because of their hormonal activity, location, size, and proximity to important structures, the prognosis depends on the stage of the tumor at diagnosis; the morbidity of tumors diagnosed at an advanced stage (i.e., with invasion of surrounding structures) tends to be high.

The median age of diagnosis of AIP-related FIPA is 23 years. The earliest age of diagnosis of a pituitary tumor in a person with an AIP pathogenic variant is six years; the oldest is 78 years [Daly et al 2010, Chahal et al 2011].

  • In 20 families with an AIP pathogenic variant, 16 had at least one member with pituitary gigantism (i.e., childhood-onset somatotropinoma) and/or disease onset before age 18 years, while only three of the 44 families with FIPA who did not have an AIP pathogenic variant had a member with pituitary gigantism and/or disease onset before age 18 years [Igreja et al 2010].
  • Of 75 persons who had an AIP germline pathogenic variant, over 52% had childhood- or adolescent-onset somatotropinoma; 4% of persons who were simplex cases without an AIP pathogenic variant had a somatotropinoma [Daly et al 2010].

Hormone Dysfunction

Somatotropinoma (growth hormone-secreting pituitary adenoma)

  • Acromegaly. Approximately 80%-85% of persons with AIP-related FIPA have acromegaly. Persons with acromegaly have excess growth hormone secretion resulting in enlargement of the hands and feet, and coarse facial appearance with prognathism and malocclusion of the teeth. They may have headaches, joint pain, carpal tunnel syndrome, sleeping difficulties, excessive sweating, hypertension, diabetes mellitus, and muscle weakness. 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 (see following).
  • Pituitary gigantism. Excessive growth hormone secretion before the fusion of the growth plates results in pituitary gigantism. Exceptionally tall stature results from a combination of high GH 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 persons with an AIP mutation-positive GH-secreting adenoma have pituitary gigantism [Daly et al 2010].

Prolactinomas. Approximately 10%-15% 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]. In contrast, prolactinomas in affected families without an AIP pathogenic variant can be both macro- and microadenomas

Non-functioning 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. Distinguishing NFPA from prolactinomas can occasionally be difficult due to the stalk effect.

In AIP-related FIPA NFPAs are often (but not always) silent somatotroph or lactotroph adenomas [Igreja et al 2010, Villa et al 2011]. In families with AIP-related FIPA, NFPAs are identified at a younger age than NFPAs in persons without a germline pathogenic variant [Daly et al 2010].

Note: NFPAs are more common in families with FIPA without an AIP pathogenic variant than in families with AIP-related FIPA. NFPAs in families with FIPA who do not have an AIP pathogenic variant are most often silent gonadotroph adenomas.

TSH-secreting adenomas (causing hyperthyroidism) and ACTH-secreting adenomas (causing Cushing disease) are rarely seen in FIPA.

A single individual with AIP-related FIPA and a thyrotropinoma, and a single individual with FIPA, a thyrotropinoma, and no pathogenic variant in AIP have been described [Daly et al 2007, Daly et al 2010].

Two simplex cases with AIP-related FIPA with Cushing disease have been described. Of 74 children with Cushing disease, the one child found to harbor an AIP pathogenic variant had an aggressive tumor [Stratakis et al 2010]. Another individual with Cushing disease was described by Georgitsi et al [2007a].

Note: A few families with homogeneous pituitary adenoma phenotypes (i.e., pituitary tumors of the same type) and heterogeneous phenotypes (i.e., pituitary tumors of different types) with FIPA without an AIP pathogenic variant with Cushing disease have been described [Daly et al 2007, Igreja et al 2010].

Other. Subfertility is common in persons with pituitary tumors. No data are available specifically regarding subfertility in AIP-related 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 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-related FIPA [Chahal et al 2011].

Pituitary carcinoma. To date pituitary carcinoma has not been described in an individual with AIP-related FIPA.

Other, non-pituitary tumors have been observed in some families with AIP-related 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.

Genotype-Phenotype Correlations

The question of genotype-phenotype correlation in AIP-related FIPA is controversial. The majority (70%) of AIP variants result in a truncated protein.

  • Some have suggested that individuals with an AIP pathogenic variant resulting in a truncated protein manifest symptoms at a significantly younger age than those with a pathogenic variant that preserves the structure of the C-terminal end of the protein (22.7 +/- 9.6 vs. 29.8 +/- 10.9 years, respectively) [Cazabat et al 2009]; however, data from the two largest cohorts of those with AIP-related FIPA do not support this finding [Cain et al 2010, Daly et al 2010].
  • Penetrance was no higher in persons with a pathogenic truncating variant than in those with a non-truncating variant [Cain et al 2010, Igreja et al 2010].

Penetrance

Studies on large families with AIP pathogenic variants show a clinical penetrance of pituitary tumors of approximately 15%-30% [Vierimaa et al 2006, Naves et al 2007, Chahal et al 2011]. Although some families with AIP-related 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 [Khoo et al 2009].

Anticipation

Genetic anticipation is not observed in AIP-related FIPA. However, affected second- or third-generation family members may be diagnosed earlier than members of the first generation because of greater awareness of the disorder and, thus, earlier recognition of the significance of adenoma-related symptoms [Daly et al 2006].

Nomenclature

Pituitary adenoma predisposition (PAP) syndrome is used to refer to those individuals who have an AIP pathogenic variant. See Figure 1.

Figure 1.

Figure 1.

Relationship between terms used in the past for familial isolated pituitary adenomas (FIPA) PAP = pituitary adenoma predisposition syndrome

Prevalence

The exact prevalence of AIP-related FIPA is not known. To date, about 50 families and about 50 simplex cases (i.e., a single occurrence in a family) of AIP-related FIPA have been identified [Chahal et al 2010, Daly et al 2010].

Differential Diagnosis

Familial Isolated Pituitary Adenoma (FIPA)

FIPA is defined as more than one member of a family with a pituitary adenoma and no other features of a syndrome known to be associated with pituitary adenomas. Except for those with pathogenic variants in AIP, a genetic cause has not yet been determined for the remainder of families with FIPA.

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 [Chahal et al 2010] (see Table 2).

Table 2.

Comparison of Findings in Persons with Pituitary Adenomas by Family History and Presence/Absence of a Germline AIP Pathogenic Variant

AIP-Related FIPANon-AIP Related
FIPASimplex somatotropinoma 1
Clinical featuresAge of onset 218-24 years40 years43 years
Average number affected family members 33-42-3N/A
Male to female ratio 42:11:11:1
Adenoma featuresSomatotropinomas / somatomammotropinomas70%-80%~50%N/A
SizeMacroadenomas in vast majorityN/ASmaller
AggressivenessMoreN/ALess
Response to treatmentPoorerN/ABetter

Other Causes of Pituitary Tumors

In children more often than in adults, pituitary tumors may be a manifestation of a genetic condition. In addition to familial isolated pituitary adenoma, genetic conditions are multiple endocrine neoplasia type 1 and type 4, Carney complex, and McCune-Albright syndrome [Keil & Stratakis 2008].

  • Multiple endocrine neoplasia type 1 (MEN1) includes varying combinations of more than 20 endocrine and non-endocrine tumors. Clinical diagnostic criteria for MEN1 include the presence of two endocrine tumors that are parathyroid, pituitary, or gastro-entero-pancreatic (GEP) tract tumors. The most common endocrine tumor in MEN1 is parathyroid adenoma, with nearly all affected individuals developing hypercalcemia by age 50 years. Pituitary tumors occur in about 40% of persons with MEN1, most often prolactinomas. Mutation of MEN1 is causative; inheritance is autosomal dominant.
  • MEN1-like syndrome caused by mutation of CDKN1B (encoding cyclin dependent kinase inhibitor 1B), also known as MEN4. The clinical findings are similar to those of MEN1. This syndrome has been reported in five families to date [Pellegata et al 2006, Georgitsi et al 2007b, Agarwal et al 2009].
  • Carney complex is characterized by skin pigmentary abnormalities, myxomas of the heart and other organs, endocrine tumors or overactivity, and schwannomas. Primary pigmented nodular adrenocortical disease (PPNAD), which causes Cushing syndrome, is the most frequently observed endocrine tumor in Carney complex, occurring in approximately 25% of affected individuals. Large-cell calcifying Sertoli cell tumors (LCCSCTs) are observed in one third of affected males within the first decade and in almost all adult males. Up to 75% of individuals with Carney complex have multiple thyroid nodules. Although many affected individuals have somatotroph cell hyperplasia, true adenomas do not develop. Acromegaly has been reported in approximately 10% of adults. About 60% of Carney complex results from mutation of PRKAR1A (encoding protein kinase A1A regulatory subunit); inheritance is autosomal dominant.
  • McCune-Albright syndrome is characterized by polyostotic fibrous dysplasia, café au lait patches, and multiple endocrine disorders (e.g., multinodular goiters, multinodular adrenal hyperplasia, precocious puberty, and pituitary adenomas). Increased secretion of growth hormone and prolactin is common in persons with this disorder because of growth hormone-producing adenomas and nodular and diffuse hyperplasia of somatomammotroph cells, respectively [Horvath & Stratakis 2008]. Somatic mosaicism for pathogenic gain-of-function variants in GNAS (encoding guanine nucleotide-binding protein G(s) subunit alpha isoforms short) is causative; no familial cases have been reported.

Sporadic pituitary tumors. The incidence of symptomatic pituitary tumor in the general population is estimated at 1:1000 to 1:1300 [Daly et al 2006, Fernandez et al 2010]. Autopsy and radiologic studies suggest that 14%-22% of the population may harbor a pituitary tumor, most of these being asymptomatic [Ezzat et al 2004]. Thus, it is possible for two pituitary tumors, especially prolactinomas, to occur in a family by chance. Instances of phenocopies in families with an AIP pathogenic variant have been documented [Vierimaa et al 2006, Igreja et al 2010].

Other. 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.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual with AIP-related FIPA, the following evaluations are recommended (for details see Katznelson et al [2011]; full text). Note: The evaluation may have to be individualized depending on the presentation.

  • Detailed personal history, including findings that may be consistent with the following:
    • A growth hormone-secreting tumor (stature in relation to the rest of the family, change in facial appearance, change in shoe size, problems with ring sizes, headache, excessive sweating, joint pains, carpal tunnel syndrome)
    • A prolactinoma (menstrual history, galactorrhea, infertility, low libido, impotence)
    • A non-functioning pituitary adenoma and mass effects (headache, lack of other pituitary hormones, visual field problems)
    • Thyrotropinoma (hyperthyroidism with non-suppressed TSH)
    • Corticotropinoma with Cushing disease (truncal obesity, striae, muscle weakness, thin skin, diabetes mellitus, hypertension)
  • Review of serial photographs over time to help identify the onset of acromegalic or cushingoid changes if present at the time of diagnosis
  • Measurement of parental heights
  • Clinical examination including measurement of height and documentation of presence or absence of features consistent with the endocrine disorders acromegaly, pituitary gigantism, Cushing disease, thyrotoxicosis
  • Visual field evaluation
  • Basal pituitary function including: spot GH, IGF-1; prolactin; LH, FSH, testosterone/estradiol; TSH, fT4; 9 a.m. cortisol
  • Glucose tolerance test (GTT) in persons with findings of acromegaly to identify abnormal GH dynamics. In addition, about 25% of persons with acromegaly have a diabetic GTT. Assess ACTH reserve if necessary.
  • In adults with acromegaly, colonoscopy at age 40 years with further surveillance at three- to ten-year intervals depending on the presence/absence of adenomas in the initial colonoscopy and IGF-1 levels [Cairns et al 2010]
  • Pituitary MRI to detect the size and extent of a tumor, if one is suspected
  • Consultation with specialists in endocrinology
  • Consultation with specialists in clinical genetics to obtain detailed family history (of possible pituitary problems, unusual stature, fertility problems, and/or early death)

Treatment of Manifestations

While there is experience with treating pituitary adenomas in symptomatic persons with FIPA, there is little experience in the management and treatment of persons identified prospectively through clinical screening due to family history of FIPA and/or presence of a heterozygous AIP germline pathogenic variant. The following recommendations are based on those of Biller et al [2008], Jaffe [2006], Katznelson et al [2011], and Melmed et al [2011].

Pituitary adenomas can be treated by surgery, medical therapy, and/or radiotherapy.

Adenomas in persons with FIPA, especially those with AIP-related FIPA, are aggressive. Surgery is usually performed, but often does not fully control the tumor. Transsphenoidal surgery has been performed for large adenomas, while microadenomas with normal clinical and biochemistry findings are monitored closely [Chahal et al 2011]. Large tumors, especially those recurring after surgery, may require radiotherapy when the tumor invades neighboring anatomic structures (such as the cavernous sinus).

Somatotropinomas, particularly in persons with a germline AIP pathogenic variant, often do not respond to medical therapy with somatostatin analogs. Daly et al [2010] showed no tumor shrinkage in AIP-related adenomas and significantly lower reductions in GH secretion (40% vs 75%) and IGF-1 secretion (47% and 56%); in these instances growth hormone receptor antagonist therapy could be initiated [Leontiou et al 2008, Daly et al 2010].

Radiotherapy (conventional or radiosurgery) is an option for treating growing adenomas, for which repeat surgery is unlikely to control hormone levels.

Prolactinomas are usually treated with dopamine agonist therapy (cabergoline being the drug of choice), which can result in tumor regression or in some cases disappearance of detectable lesions. No data suggest that FIPA-associated prolactinomas would respond less favorably to dopamine agonist therapy than do sporadic tumors; however, Daly et al [2010] suggested that prolactinomas in AIP-related FIPA appear to be aggressive and difficult to treat. Persons with AIP-related FIPA and a macroprolactinoma (diameter >10 mm) often undergo surgery.

NFPAs are treated with surgery and, if necessary, radiotherapy. They usually do not respond to traditional somatostatin analogs despite the presence of somatostatin receptors and an often good response in vitro. Dopamine agonist therapy has been tried in some cases. Timely diagnosis, prediction of long-term outcome, and treatment of NFPAs remain a challenge for endocrinologists [Korbonits & Carlsen 2009].

Temozolomide has been successfully used for the treatment of a few aggressive pituitary adenomas; however, there is no experience with its use in persons with AIP-related FIPA.

The increased burden of GH secretion and IGF-1 secretion (defined as the level and duration of increased hormone levels) observed in those with acromegaly is associated with an increased risk for cardiovascular, cerebrovascular, and metabolic complications [Jayasena et al 2011]. Individuals with long-standing acromegaly often have cardiovascular and rheumatologic/orthopedic complications, which need to be treated accordingly.

Prevention of Secondary Complications

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

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

Surveillance

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

Persons with AIP-related FIPA who have had a pituitary adenoma. The following are recommended to monitor for recurrence of the previous adenoma and development of new adenomas.

  • Yearly clinical assessment and basal pituitary function (IGF-1, spot GH, prolactin, LH/FSH, estradiol/testosterone, TSH, fT4, morning cortisol) and if necessary dynamic testing (e.g., glucose tolerance test, insulin tolerance test) to evaluate for hormone excess or deficiency
  • Repeat pituitary MRI. Note: Frequency depends on clinical status, previous extent of the tumor, and treatment modality.

Persons with acromegaly. Follow established guidelines regarding clinical monitoring for related complications including diabetes mellitus, hypertension, osteoarthritis, and colon cancer.

Persons with hypogonadism. Follow established guidelines. Because long-standing untreated hypogonadism may result in the early onset of osteoporosis, bone density needs to be assessed at baseline and if necessary monitored with DEXA scanning.

Persons with an AIP pathogenic variant and no history of pituitary adenomas. Recommendations follow. Note, however, that long-term experience with asymptomatic AIP heterozygotes is limited; more data are needed to develop appropriate future guidelines.

In a family in which an AIP pathogenic variant has been identified, relatives who have the family-specific AIP pathogenic variant or who have not been tested:

Adults

  • Baseline. Clinical assessment, pituitary function tests (IGF-1, prolactin, estradiol/testosterone, LH, FSH, and fT4), and pituitary MRI
  • Thereafter
    • Perform annual clinical assessment and pituitary function tests.
    • Consider repeating a pituitary MRI every five years if clinical findings and pituitary function tests remain normal.
    • Consider discontinuing monitoring about age 50 years, after which the likelihood of developing new pituitary adenomas is low.

Children

  • Yearly beginning at age four years
    • Measure height and weight with calculation of height velocity. Document pubertal development, Tanner stages
    • Perform pituitary function tests (as for adults).
  • Perform baseline pituitary MRI at about age ten years.
  • Consider repeating the pituitary MRI every five years if clinical and pituitary function tests remain normal.

Evaluation of Relatives at Risk

It is appropriate to offer molecular genetic testing to at-risk relatives if the pathogenic variant has been identified in an affected family member so that morbidity and mortality can be reduced by early diagnosis and treatment.

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.

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-related FIPA and acromegaly and pituitary gigantism [Goldenberg et al 2008; Author, personal observation]. 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].

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

AIP-related familial isolated pituitary adenoma (AIP-related 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-related FIPA have a parent who is also heterozygous for the AIP pathogenic variant [Chahal et al 2010, Stratakis et al 2010]. Because of reduced penetrance, the parent may not be affected.
  • If the disease-predisposing variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo pathogenic variant in the proband, assuming paternity is as stated. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • As not all simplex AIP-related FIPA cases (i.e., a single occurrence in a family) have been evaluated sufficiently to determine if the pathogenic variant was de novo, the proportion of AIP-related FIPA resulting from a de novo AIP pathogenic variant is unknown. However, this is likely to be low: to date, only one case of proven de novo mutation has been reported in an individual with a childhood-onset corticotroph adenoma [Stratakis et al 2010].
  • Recommendations for the evaluation of parents of a proband with AIP-related FIPA include molecular genetic testing for the AIP pathogenic variant identified in the proband.
    Evaluation of parents may determine that one is heterozygous for an AIP pathogenic variant but has escaped previous diagnosis because of a milder phenotypic presentation or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Sibs of a proband

  • If a parent of the proband is affected or has an AIP pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%.
  • The sibs of a proband with clinically unaffected parents are still at increased risk of inheriting the pathogenic variant because of the possibility of reduced penetrance in a parent.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism. No instances of germline mosaicism have been reported to date.

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

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant, it is possible that mutation occurred de novo in the proband. However, possible non-medical explanations include alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could be considered.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal 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 Diagnosis

Once the AIP pathogenic variant has been identified in the family, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for FIPA are possible.

As AIP-related 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 of and/or outcome of treatment.

Requests for prenatal testing for conditions which (like familial isolated pituitary adenomas) do not affect intellect and have some treatment available are rare. In addition, the penetrance, though not yet adequately studied, is thought to be reduced in most families. 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 decisions regarding prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • FIPA Patients
    Familial Isolated Pituitary Adenoma
    Email: info@fipapatients.org
  • AMEND Research Registry
    The Warehouse
    Draper Street
    Tunbridge Wells Kent TN4 0PG
    United Kingdom
    Phone: +44 1892 516076
    Email: jo.grey@amend.org.uk
  • FIPA Consortium Registry
    Patients with familial pituitary adenoma or childhood onset pituitary disease and their families are encouraged to contact the registry.
    Email: info@fipapatients.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

AIP-Related Familial Isolated Pituitary Adenomas : Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
AIP11q13​.2AH receptor-interacting proteinAIP Gene Mutations
AIP database
AIPAIP

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for AIP-Related Familial Isolated Pituitary Adenomas (View All in OMIM)

102200PITUITARY ADENOMA 1, MULTIPLE TYPES; PITA1
219090PITUITARY ADENOMA 4, ACTH-SECRETING; PITA4
600634PITUITARY ADENOMA, PROLACTIN-SECRETING
605555ARYL HYDROCARBON RECEPTOR-INTERACTING PROTEIN; AIP

Gene structure. AIP comprises six exons encoding a 330-amino acid protein. For a detailed summary of gene and protein information, see Table A, Gene.

Variants of uncertain significance. The variant c.47G>A (p.Arg16His), identified in a few simplex cases of acromegaly (including some childhood-onset cases), was also found in three of 360 controls [Cazabat et al 2007, Daly et al 2007, Georgitsi et al 2007a, Tichomirowa et al 2011]. It was identified in 0.3% of European Americans and 0.08% of African Americans in the general population. An in vitro functional study of loss of binding to one of the partners of AIP (phosphodiesterase [PDE] subtype 4A5) did not show a significant functional change [Igreja et al 2010]. Furthermore, in a family with FIPA the c.47G>A (p.Arg16His) variant did not segregate with pituitary adenomas [Guaraldi & Salvatori 2011].

The variant c.145G>A (p.Val49Met), reported in one simplex case of gigantism, did not show loss of heterozygosity [Iwata et al 2007] or loss of binding to one of the partners of AIP (phosphodiesterase [PDE] subtype 4A5) [Igreja et al 2010]. Of note, loss of in vitro PDE binding does not necesserily correspond to clinically important loss of function; however, few functional tests for AIP are currently available and none has proven clinical relevance.

The variant c.896C>T (p.Ala299Val) was reported in a simplex case of acromegaly [Georgitsi et al 2007a] and in compound heterozygous asymptomatic persons whose other AIP allele has the p.Arg304Ter pathogenic truncating variant. The c.896C>T variant is unlikely to reduce the function of the AIP protein significantly, as biallelic inactivation of AIP in humans may be an embryonic lethal event, as was demonstrated in mice with a complete Aip knockout.

Pathogenic variants. About 50 different AIP pathogenic variants have been reported, including nonsense, missense, frame shift, and splice site variants, intragenic deletions and insertions, and deletions of one or more exons. See Table 3, Table 4 (pdf).

Most pathogenic missense variants affect the TPR (tetratricopeptide repeat) (see Normal gene product) domains or the C-terminal alpha-helix. This supports the earlier evidence that the TPR domains and the last five C-terminal amino acids are important for the activity of AIP [Petrulis & Perdew 2002].

Recurrent AIP pathogenic variants include:

  • p.Arg304Ter or p.Arg304Gln in several independent families and several simplex cases. Out of the several individuals with the p.Arg304Ter variant, two independent clusters (in Ireland and Italy) were shown result from a founder effect [Occhi et al 2010, Chahal et al 2011].
  • p.Arg81Ter in two families
  • p.Arg271Trp in two families and a simplex case of pituitary gigantism
  • c.807C>T in one family and three simplex cases
  • c.805_825dup (p.Phe269_His275dup) segmental duplication, identified in five apparently independent families (Note: This duplication is detectable by sequence analysis.)
  • p.Gln14Ter in a few families and several simplex cases from Finland, suggesting the presence of a founder variant

Table 3.

Selected AIP Variants

Variant
Classification
DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
Uncertain
significance
c.47G>Ap.Arg16HisNM_003977​.2
NP_003968​.2
c.145G>Ap.Val49Met
c.896C>Tp.Ala299Val
Pathogenicc.40C>Tp.Gln14Ter
c.241C>Tp.Arg81Ter
c.807C>Tp.= 1
c.721A>Gp.Lys241Glu
c.805_825dupp.Phe269_His275dup
c.811C>Tp.Arg271Trp
c.911G>Ap.Arg304Gln
c.910C>Tp.Arg304Ter

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

p.= designates that protein has not been analyzed, but no change is expected.

Normal gene product. AIP is a tumor suppressor gene [Leontiou et al 2008]. Its protein product, 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].

Abnormal gene product. The majority (70%) of AIP 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.

References

Published Guidelines / Consensus Statements

  • Katznelson L, Atkinson JL, Cook DM, Ezzat SZ, Hamrahian AH, Miller KK. American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of acromegaly--2011 update. Available online (pdf). 2011. Accessed 8-3-18. [PubMed: 21846616]

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Chapter Notes

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:otliam.

Acknowledgments

We are grateful to referring colleagues and patients for providing information on this disease. We are grateful for the expert help of Giampaolo Trivellin in the compilation of Table 4.

Revision History

  • 21 June 2012 (me) Review posted live
  • 3 February 2011 (mk) Original submission
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