Familial Pituitary Adenomas — Who Should be Tested for AIP Mutations?

Márta Korbonits; Helen Storr; Ajith V. Kumar


Clin Endocrinol. 2012;77(3):351-356. 

In This Article

Abstract and Introduction


Familial Isolated Pituitary Adenomas (FIPA), an autosomal dominant disease with low penetrance is being increasingly recognized. FIPA families can be divided into two distinct groups based on genetic and phenotypic features. Patients with mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are characterized by young-onset somatotroph or lactotroph macroadenomas, while in the other, larger group of FIPA patients with typically adult-onset disease and more varied adenoma types, no causative gene(s) has been identified. Young-onset macroadenoma patients can also be identified with germline AIP mutation without an apparent family history. Further data and longer follow-up are necessary to establish formal guidelines, but the current data suggest genetic screening of the AIP gene in patients with a pituitary adenoma and no other associated features who have (i) a family history of pituitary adenoma, (ii) childhood-onset pituitary adenoma or (iii) a pituitary somatotroph or lactotroph macroadenoma diagnosed before the age of 30 years.


The vast majority of pituitary adenomas occur in adult patients with no family history of pituitary disease. However, patients with a family history are being recognized more frequently,[1,2] and these patients, together with childhood-onset cases, raise the possibility of the presence of an inherited disorder. Pituitary tumours may be a manifestation of a genetic condition such as multiple endocrine neoplasia (MEN) type 1 or type 4, Carney complex, McCune–Albright syndrome and the recently established syndrome of familial isolated pituitary adenoma (FIPA)[2] (Fig. 1). MEN1, MEN4, Carney complex and the FIPA syndrome are dominantly inherited, whereas McCune–Albright syndrome is attributed to a mosaic somatic mutation (see detailed review[3]). In addition, infant-onset ACTH-secreting pituitary blastoma has been recently described with germline DICER1 mutation,[4] and case reports of familial paraganglioma-associated SDH mutations have been described with familial pituitary adenoma, either prolactinoma (SDHB,[5]SDHC,[6]SDHD[7]), non-functioning pituitary adenoma (SDHB[6]) or acromegaly (SDHD).[8]

Figure 1.

Pituitary adenomas can develop as a result of genetic alterations: a somatic activating mutation in the GNAS gene can be found in 30–40% of sporadic somatotroph adenomas. Theoretically, somatic mutations in other genes could also lead to pituitary adenoma development. Mosaic germline-activating mutation of the GNAS gene leads to the McCune–Albright syndrome; some of these patients develop somatotroph hyperplasia or adenoma. Germline mutation in the MEN1 gene or rarely in the CDKN1B (coding for cell cycle regulator protein p27) gene cause MEN1 or MEN4; in a small proportion of affected cases, no gene abnormality can be found. A mutation in the protein kinase A regulatory subunit gene (PRKAR1A) is found in the majority (60%) of patients with the Carney complex; in the remainder, data suggest a causative gene in the 2q16 area. Patients have been described with SDH mutation-related familial paraganglioma/phaeochromocytoma and familial pituitary adenomas.5-8 A mutation in the DICER1 gene, a gene which regulates microRNAs, may cause an ACTH-secreting pituitary blastoma of childhood onset.4 A fifth of families with familial isolated pituitary adenomas cases show a mutation in the AIP gene; in the majority of FIPA families, the causative gene has not yet been identified.

Familial isolated pituitary adenoma is a clinical diagnosis characterized by the presence of a pituitary adenoma in more than one family member without other associated features.[9–12] Typically, the penetrance is incomplete. The commonly occurring adenomas are growth hormone (GH)-secreting, prolactin-secreting and GH and prolactin co-secreting adenomas, followed by nonfunctioning pituitary adenomas (NFPA) (Fig. 2). Rarely TSH- or ACTH-secreting adenomas are observed. Family members with FIPA can have similar or different types of pituitary adenomas within a particular family. Patients with FIPA can be divided to two groups based on their phenotypic and genotypic features.

Figure 2.

Familial isolated pituitary adenoma patient phenotypes in our cohort of families.

AIP Mutation–positive Cases

Approximately 20% of families with FIPA have a heterozygous germline mutation in the aryl hydrocarbon receptor-interacting protein (AIP) gene.[9–11,13] The majority of AIP mutation–positive patients show an onset of symptoms in childhood or young adulthood (mean age of diagnosis around 20–24 years, ranging from 6 years to 74 years).[13,14] A third of all individuals with an AIP mutation and 40–50% of AIP mutation–positive patients with somatotroph adenomas present in childhood, often leading to pituitary gigantism, compared with only 4% of AIP mutation–negative sporadic adenoma patients.[14]AIP mutation–positive patients usually have invasive GH, mixed GH and prolactin or prolactin-secreting macroadenomas (Fig. 2). Occasionally, NFPA and ACTH- or TSH-secreting adenomas have been described.[15,16] Typically, somatotroph adenomas belong to the sparsely granulated subtype and respond poorly to somatostatin analogue therapy.[12–14,17] In addition, they require repeated surgery and radiotherapy more often than AIP mutation–negative sporadic adenomas.[14] Forty per cent of FIPA families with all affected members having acromegaly harbour an AIP mutation. Two-thirds of the AIP mutation–positive adenoma patients are men, but there are no other phenotypic differences between male- and female-affected patients.[14] Large, rapidly growing adenomas may predispose to pituitary apoplexy, and this has been described in several AIP mutation–positive cases[18–21] (and our unpublished observations). Penetrance in AIP mutation–positive families is variable, but averages around 15–30% (range 10–80%).[13,18,22,23] Two or more childhood-onset GH-secreting pituitary adenoma patients within a family are almost invariably caused by an AIP mutation.[13,14,18,24,25]

Germline AIP mutations can be identified in pituitary adenoma patients with no known family history of the disease (so-called simplex cases), in 20% of childhood-onset cases, 11% of young-onset (<30 years) pituitary macroadenomas and 7·2% of micro- or macroadenomas diagnosed <40 years.[14–16,26,27] The apparent absence of a family history could result from reduced penetrance or lack of information about the family. A de novo mutation has been described in one individual so far.[25] The phenotype of simplex cases is not different from the familial cases.

Despite the wide tissue expression profile of AIP, no tumours in other organs have consistently been identified in AIP mutation carrier patients. No somatic AIP mutation (only affecting tumour tissue but not the germline) has been identified to date in pituitary adenomas or any other tumour type.[12,28,29]

AIP has been shown to function as a tumour suppressor gene,[12,13,30] and most (75%) disease-causing mutations lead to a truncated protein. Missense mutations usually affect conserved amino acids in the C-terminal tetratricopeptide repeat domain of the molecule. More than 60 different mutations have been described to date, including a few hotspot mutations (e.g. R304X, R304Q, R271W and R81X). Mutation testing includes sequencing (detects 90% of mutations) of the exons and exon–intron junctions and testing for large deletions/duplications (for example, using MLPA (multiplex ligation-dependent probe amplification), detects 10% of mutations). Promoter mutation has been described in a FIPA family, but promoter sequencing is currently not performed routinely under NHS (UK National Health Service) testing.

False-positive testing: detection of rare sequence variants needs careful assessment (segregation of the variant with the disease, in silico predictions and in vitro functional testing) and genetic counselling. False-negative results: current testing will not identify disease-causing variants in intronic regions. (Of note, in our cohort as well as in the literature, all families with the most characteristic AIP-related phenotype (two or more childhood-onset somatotroph tumours) have a detectable AIP mutation.)

No genotype–phenotype correlation for age of onset, tumour type or level of penetrance has been established to date. A founder effect has been described in Finland, Ireland and Italy, some of these reaching back many centuries.[9,18,31,32]


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