Familial isolated pituitary adenomas (FIPA) and the pituitary adenoma predisposition due to mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene

Abstract

Pituitary adenomas are one of the most frequent intracranial tumors and occur with a prevalence of approximately 1:1000 in the developed world. Pituitary adenomas have a serious disease burden, and their management involves neurosurgery, biological therapies, and radiotherapy. Early diagnosis of pituitary tumors while they are smaller may help increase cure rates. Few genetic predictors of pituitary adenoma development exist. Recent years have seen two separate, complimentary advances in inherited pituitary tumor research. The clinical condition of familial isolated pituitary adenomas (FIPA) has been described, which encompasses the familial occurrence of isolated pituitary adenomas outside of the setting of syndromic conditions like multiple endocrine neoplasia type 1 and Carney complex. FIPA families comprise approximately 2% of pituitary adenomas and represent a clinical entity with homogeneous or heterogeneous pituitary adenoma types occurring within the same kindred. The aryl hydrocarbon receptor interacting protein (AIP) gene has been identified as causing a pituitary adenoma predisposition of variable penetrance that accounts for 20% of FIPA families. Germline AIP mutations have been shown to associate with the occurrence of large pituitary adenomas that occur at a young age, predominantly in children/adolescents and young adults. AIP mutations are usually associated with somatotropinomas, but prolactinomas, nonfunctioning pituitary adenomas, Cushing disease, and other infrequent clinical adenoma types can also occur. Gigantism is a particular feature of AIP mutations and occurs in more than one third of affected somatotropinoma patients. Study of pituitary adenoma patients with AIP mutations has demonstrated that these cases raise clinical challenges to successful treatment. Extensive research on the biology of AIP and new advances in mouse Aip knockout models demonstrate multiple pathways by which AIP may contribute to tumorigenesis. This review assesses the current clinical and therapeutic characteristics of more than 200 FIPA families and addresses research findings among AIP mutation-bearing patients in different populations with pituitary adenomas.

Figure 1.

Pedigree of original Finnish family with pituitary adenoma due to a Q14X founder mutation in AIP. Generations are indicated with Roman numerals. Generation I is from the 18th century. Numbers within diamonds indicate number of children. Circles, Females; squares, males; diagonal line, deceased. Pedigree has been modified for confidentiality.

Figure 2.

Proportions of 211 FIPA kindreds with homogeneous (A) or heterogeneous (B) presentation of pituitary adenomas within the same family. GH, Somatotropinoma (includes also somatolactotrope tumors); PRL, prolactinoma; ACTH, Cushing disease; LH/FSH, gonadotropinomas; TSH, thyrotropinomas.

Figure 3.

A, Percentage of patients with different pituitary adenoma types seen in patients (n = 215) with germline AIP mutations. B, Distribution of AIP mutation-positive pituitary adenoma population by age at diagnosis (divided into 5 yr cohorts).

Figure 4.

Relative resistance to somatostatin analogs in AIP mutation-related somatotropinomas vs. controls. Patients treated with somatostatin analogs for acromegaly who had germline AIP mutations (n = 75) had a statistically significantly lower percentage decrease from baseline in serum GH and serum IGF-I concentration as compared with 232 wild-type AIP control patients that were matched for age, sex, and decade of diagnosis. [Derived from A. F. Daly et al.: Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study. J Clin Endocrinol Metab 95:E373–E383, 2010 (115), with permission. © The Endocrine Society.].

Figure 5.

Aip mouse model phenotype. A, Pituitary adenoma prevalence in heterozygous (Aip+/−) and wild-type (Aip+/+) mice. B, Normal pituitary gland of wild-type mouse. C, Macroadenoma of Aip+/− mouse. Pituitary glands are depicted by white arrows.

Figure 6.

AIP interaction partners. Nodes represent proteins, with their shape indicating the functional class of the protein. The protein-protein interaction network was generated with Ingenuity Pathway Analysis (IPA) software (www.ingenuity.com).

Figure 7.

A schematic figure of the xenobiotic signaling. AHR exists in a dormant state in cytoplasm in association with a complex of HSP90, AIP, and the co-chaperone p23. Upon ligand binding, AHR is activated through conformational change and translocates to the nucleus. It forms a heterodimer with ARNT. The heterodimer binds to the XRE and alters expression of genes involved in the metabolism of xenobiotic agents.

Figure 8.

A, Role of AHR-ARNT heterodimer in transcriptional regulation of xenobiotic, hypoxia, and estrogen signaling. B, Role of AIP in regulation of cAMP signaling via Gα-proteins and C, via PDEs. HRE, Hypoxia response element; ERE, estrogen response element.

Figure 9.

Phenocopy NFPA in the setting of an AIP mutation-positive FIPA kindred with acromegaly.

Figure 10.

Schematic of suggested clinical decision tree to integrate AIP genetic testing into existing testing strategies. The decision tree is based on the presence or absence of typical syndromic features that suggest known diseases such as MEN1, CNC, and McCune Albright syndrome (MAS), which have established genetic testing for known causative genes. Point 1, Established syndromes like MEN1 and CNC are being joined by newer associations of pituitary adenomas with other endocrine tumor types, such as pheochromocytoma in the setting of succinate dehydrogenase subtype gene mutations (250). Ongoing advances in this field will clarify the relative frequency of such associations and the need to integrate testing into standard clinical investigation. Point 2, In CNC, a proportion of patients are negative for PRKAR1A mutations, and another locus on chromosome 2 has been suggested (252). Point 3, MEN4 due to CDKN1B mutations is a rare but emerging condition with pituitary adenomas as part of the spectrum. CDKN1B testing in patients with pituitary adenomas should be limited in the clinical setting to those with associated syndromic features of endocrine or other tumors and negative sequencing for MEN1 mutations (174, 244). Other rare mutations in cyclin-dependent kinases have also been noted infrequently in MEN1-like conditions, but the study of these remains in the research realm (253). Point 4, In the setting of FIPA, the PAP due to AIP germline mutations accounts for about 20% of kindreds. For FIPA kindreds that are AIP mutation negative on sequencing, MLPA should be considered to detect more extensive deletions. To date, other genes have not been identified to cause FIPA. Syndromic conditions like MEN1 and CNC do not frequently present as isolated pituitary adenomas in the absence of other features such as hyperparathyroidism. An exception may be young patients with apparently sporadic pituitary macroadenomas, with recent information from Cuny et al (254) suggesting that MEN1 gene sequencing is a valuable investigation in that population. Therefore, in the verified FIPA setting and in younger patients with aggressive pituitary adenomas, AIP testing may be considered as the first genetic test to be discussed, as long as MEN1 and CNC are ruled out clinically and by simple biochemical testing (e.g., absence of hypercalcemia or cortisol secretion abnormalities).