Familial Isolated Pituitary Adenomas
Apart from familial acromegaly, few studies, none systematic in nature, had been published on other types of familial pituitary tumors unrelated to MEN-1 or CNC. Analyzing the records from our own center beginning in 1999, we noted 27 patients (approximately 1-2% of our total pituitary tumor population) that presented with only pituitary adenomas in a family setting, but without MEN-1 or CNC.[32,33] We termed this clinical condition FIPA, in keeping with naming conventions for other familial endocrine cancers, such as familial isolated hyperparathyroidism (FIHP). In FIPA, kindred tumors of the same type could present in all affected members or, alternatively, different family members could have different tumors; we classified these as homogeneous and heterogeneous presentations, respectively. Between 2000 and 2005, we identified a total of 64 FIPA families among 22 tertiary referral centers. The systematic clinical characterization of FIPA in terms of patient profiles, family presentation, demographics, hormonal and radiological results has been reported.[7,9] In all families, at least one affected member of each kindred had a negative screen for MEN1 mutations, while normal serum calcium and parathyroid hormone levels were demonstrated in FIPA cases. Given that the pituitary presentation of CNC is essentially limited to acromegaly, all homogeneous acromegaly FIPA kindreds underwent PRKAR1A gene screening in one affected member of each family (other relevant clinical profiling, such as cardiac echocardiography for myxomas, was also performed in homogeneous acromegaly FIPA families). Findings within and among FIPA kindreds have been compared with a matched group of patients with sporadic (nonfamilial) pituitary tumors.
To date, FIPA kindreds with up to four affected members (i.e., subjects with pituitary tumors) have been described.[7,9] Females predominate (62%), which is related to the fact that prolactinomas are the most frequent tumor seen in the setting of FIPA and most of these occur in women. The frequencies of the various different tumor types that occur in FIPA are as follows: prolactinoma (41%), somatotropinoma (30%), nonsecreting tumor (13%), somatolactotropinoma (7%), gonadotropinoma (4%), Cushing's disease (4%) and thyrotropinoma (1%). Virtually all FIPA kindreds have at least one prolactinoma, somatotropinoma or somatolactotrope tumor. The FIPA cohort is divided equally between families having the same (homogeneous) or different (heterogeneous) tumor types among affected individuals. A first-degree relationship between affected members within families occurs in approximately three quarters of FIPA families. In the setting of FIPA, patients present with pituitary tumors earlier (approximately 4 years) than their sporadic counterparts, a difference that is mainly due to homogeneous acromegaly kindreds that present more than 10 years earlier than sporadic cases. Interestingly, when families with multiple generations were analyzed, the children/grandchildren presented significantly earlier (on average 20 years) than their parents/grandparents; this factor may be due to earlier recognition in those diagnosed more recently, but genetic causes (e.g., anticipation) cannot be ruled out entirely. Macroadenomas are seen in a majority of cases (63%) in FIPA kindreds. In terms of specific tumor types, prolactinomas in FIPA are mainly microadenomas occurring in women, while males invariably have macroadenomas; this is similar to the characteristics of prolactinomas in general. When they occur in heterogeneous FIPA families, prolactinomas have higher rates of suprasellar extension and cavernous sinus invasion compared with sporadic cases. Apart from FIPA patients with homogeneous acromegaly, 50% of the somatotropinomas occurring in the setting of FIPA are seen in combination with other tumor types. Nonsecreting pituitary tumors occur overwhelmingly in heterogeneous FIPA families and are more aggressive than sporadic nonsecreting tumors (diagnosed 8 years earlier and have a higher rate of involvement of local structures). No specific features of the less frequently seen tumor types occurring in FIPA have been noted, apart from the fact that gonadotropinomas or Cushing's disease can occur in a homogeneous familial setting.
The genealogies of FIPA families reveal that approximately 14% of the total extended family kindreds have a pituitary tumor. Furthermore, the degree of relatedness (or familiality) of FIPA was 0.62, a relatively high number dictated by the fact that nearly 75% of those affected are first-degree relatives of others affected. These data led us to suggest that FIPA involves a genetic inheritance pattern that is autosomal dominant with incomplete penetrance. In 2006, Vierimaa et al. reported the results of a comprehensive genetic study that identified mutations in the AIP gene on chromosome 11q13.3 as being associated with the familial presentation of somatotropinomas, somatolactotrope tumors and prolactinomas. The propensity for developing pituitary adenomas in the setting of an AIP mutation was termed pituitary adenoma predisposition (PAP). The two familial mutations were truncating mutations Q14X and R304X, which occurred in a large Finnish kindred and an Italian family, respectively (a third mutation at the splice acceptor site of exon 4 was seen in a sporadic pituitary tumor patient). Loss of heterozygosity at the AIP locus was seen in tumor samples, which indicated that these tumors had lost the function of the normal allele in a 'second hit'. Other families from Turkey and Germany tested negative. As the chromosomal location of AIP was in an area that had already been linked to IFS, and the presentation of the families appeared to be in keeping with clinical features of FIPA, we undertook a study of our cohort to examine the frequency of AIP mutations in the FIPA setting. Among 73 FIPA families from nine countries, 11 families - 15% of the cohort - had germline mutations in AIP. Ten separate mutations were found, one Italian family, with three affected members, who were apparently unrelated to the family reported by Vierimaa et al. had an R304X mutation. The nine remaining mutations and the clinical findings are described in Table 1 . Those patients with AIP mutations were significantly younger at diagnosis (12 years) than those FIPA patients without AIP mutations. Tumors were also larger in the AIP mutation-positive groups compared with the remainder of the FIPA cohort. Despite the predominance of somatotropinomas and somatolactotrope tumors in the AIP mutation-positive families, only half of those with homogeneous acromegaly had mutations. Furthermore, many kindreds with strong familiality for pituitary tumors (three or four affected members) were negative for AIP mutations. These data indicate that other genes may be involved in the causation of FIPA.
Further analysis of the disease characteristics of FIPA patients with AIP mutations indicates that even among those phenotypically presenting with acromegaly, the tumor and hormonal data are, in fact, heterogeneous. Over 60% of AIP mutation positive patients with somatotropinomas had increased GH/IGF-I only and the remaining 38% also had elevated prolactin. Somatotropinoma patients with AIP mutations can have immunohistochemical evidence of GH staining alone (59%), GH and prolactin staining (33%) or GH and follicle-stimulating hormone (FSH) staining (8%). As noted earlier, an R271W mutation led to GH-secreting somatotropinomas in one family and a GH-secreting tumor paired with a prolactin-secreting tumor in another family.
Since these initial studies, a number of publications have assessed aspects of AIP in familial and sporadic pituitary tumors, and in other endocrine and nonendocrine cancers. Families with somatotropinomas and AIP mutations have been reported from Brazil and Japan.[36,37] Vierimaa et al. reported initially that patients with sporadic pituitary adenomas exhibited Q14X and an exon 4 splice acceptor site mutation. The Q14X mutation, although found with moderate frequency in Finland, was not found in populations of sporadic adenomas from the EU, the USA, Brazil and Japan, indicating that this is likely to be a founder mutation.[35,36,38,39] Overall, while sporadic pituitary tumor patients infrequently have AIP mutations, they are not extremely rare as had been initially suggested. Taking the published literature as a whole, sporadic pituitary tumor patients with AIP mutations seem to present at a young age and mainly with somatotropinomas, although other pituitary tumor types do occur.[8,39,40] In the most recent series reported by Cazabat et al. in France, of a total of 154 sporadic patients with acromegaly, five patients (3.2%) demonstrated AIP mutations.AIP mutations do not appear to play a major role in tumorigenesis in other tissues, as studies in other tumors have revealed germline R16H mutations in the setting of colorectal cancer, but none in prostate or breast tumors.
The manner in which AIP mutations cause tumorigenesis is unknown at this time. Of the over 20 AIP mutations described to date (Figure 2, Table 2 ), most would involve truncations of the AIP protein, with the loss of the a tetratricopeptide repeat domain and the carboxy terminal that are important for interactions with the other proteins, such as heat shock protein 90 (hsp90) and the aryl hydrocarbon receptor (AhR) - also known as the dioxin receptor.[43,44,45,46,47] Other missense mutations, such as R16H, appear to involve highly conserved amino acids across multiple species, which may alter AIP protein function in an as yet unknown fashion. Whether mutated AIP proteins are actually expressed or if mutated mRNA is targeted for degradation is unknown at this time. A variety of cellular effects are related to AhR, hsp90 and AIP activity, including cytochrome P450 subtype 1A1 induction, hypoxia-inducible factor 1α regulation (via aryl hydrocarbon nuclear translocator) and modulation of cAMP-specific phosphodiesterase PDE4A5 and phosphodiesterase PDE2A activities.[48,49,50,51] The pathological role of AIP mutations in the regulation of these elements remains to be determined in in vitro expression studies of mutated AIP protein and in knockout murine models that are in development.
Aryl hydrocarbon receptor-interacting protein (AIP) with important domains highlighted, denoting potential sites affected by AIP mutations in patients with pituitary tumors (FIPA and sporadic). AhR: Aryl hydrocarbon receptor; FKBP-PPI: FK506 binding protein-type peptidyl prolyl cis-trans isomerase; hsp90: Heat-shock protein 90; TPR: Tetratricopeptide repeat domain. Adapted with permission from .
Expert Rev Endocrinol Metab. 2007;2(6):725-733. © 2007 Future Drugs Ltd.
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