Characteristics of Familial Isolated Pituitary Adenomas

Adrian F Daly; Jean-François Vanbellinghen; Albert Beckers


Expert Rev Endocrinol Metab. 2007;2(6):725-733. 

In This Article

Overview of Familial Pituitary Tumors: MEN-1, CNC & IFS

MEN-1, an autosomal dominant disease syndrome, is characterized by endocrine tumors of the parathyroid, enteropancreatic tissues and the anterior pituitary, while endocrine-inactive tumors (e.g., lipomas and angiofibromas) are also seen.[10] MEN-1 is caused by mutations in the MEN1 gene on chromosome 11q13, which encodes the protein menin.[11] In up to 20% of sporadic and familial patients with the clinical MEN-1 phenotype, no MEN1 mutation is identified.[12,13] From a functional standpoint, the biological role of MEN1 appears to be to act as a tumor-suppressor gene, albeit one with an immensely elaborate series of interactions. Recent studies from the NIH group indicate that menin, the protein product of MEN1, interacts with the promoter regions of thousands of genes in pancreatic cells, indicating that it has a very generalized regulatory role.[14] Loss of menin, however, appears not to have a major impact on gene transcription, although in pancreatic islet cells, a transcription factor, HLXB9, was overexpressed in the absence of menin.[14] In a subsequent large study of menin-occupied chromatin regions, the NIH group has noted that menin-binding regions are found, not only within promoter regions but also at 3´ sites, at sites within genes and a full third of binding sites occurred outside of genes.[15] Menin binding to such 'intragenic' sites is a novel finding, which suggests a potential structural regulatory role.

Murine Men1-knockout models have shown that homozygous deletion of Men1 is associated with a severe phenotype that is fatal in embryonic life.[16,17] In mice with a knockout of Men1 limited to the pituitary, prolactinomas developed,[18] while in heterozygotic mice followed over a prolonged period of time, pituitary tumors were seen in over 36% of animals after 2 years.[17] In the tumors of Men1-knockout mice and in humans with MEN-1, the loss of the wild-type allele has been noted, in keeping with the two-hit hypothesis of tumorigenesis.[19]

Approximately 40% of patients with MEN-1 have pituitary adenomas and 17% present with a pituitary tumor.[20] Among patients with familial MEN-1, pituitary disease is more commonly seen than in sporadic MEN-1 (59 vs 34%, respectively). In addition, in MEN-1, pituitary tumors are larger, are associated with more local tumor effects and are more difficult to control with therapy.[21] In general, pituitary tumors in MEN-1 are most commonly prolactinomas (often macroadenomas). Acromegaly is seen in 9% of cases and has a greater female preponderance in MEN-1 than in sporadic acromegaly.[20] Nonsecreting adenomas, thyroid-stimulating hormone (TSH)-secreting and adrenocorticotropic hormone (ACTH)-secreting adenomas occur in the setting of MEN-1, the latter two tumor types occurring rarely.[20]

In 1985 Carney described a syndrome of lentigines, cardiac myxomas, hormonal hypersecretion and schwannomas, which has become known as CNC.[22] CNC is caused in most cases by mutations in the protein kinase A regulatory subunit Iα gene (PRKAR1A) on chromosome 17q22.[23] Another disease locus on chromosome 2p16 remains under investigation. CNC is a rare disease with approximately 500 patients affected worldwide. Most cases of CNC (> 70%) are familial.[24] As in MEN-1, homozygous Prkar1a-knockout mice are associated with early embryonic death, whereas a transgenic mouse with an antisense Prkar1a exon 2 construct develops a CNC phenotype.[25,26] Thus, PRKAR1A appears to function as a tumor-suppressor gene. In terms of pituitary disease, 75% of patients with CNC have excessive growth hormone (GH), IGF-I or prolactin secretion, whereas only approximately 10% have clinical acromegaly.[27] Pituitary tumors from patients with CNC have a typical pattern of multifocal somatomammotropic cell hyperplasia interspersed among islands of normal pituitary tissue.[28] Acromegaly in CNC appears to develop gradually due to somatomammotrope hyperplasia that progresses to adenoma formation.

As noted previously, the occurrence of acromegaly or gigantism in a hereditary or familial setting has been recognized for many years (Figure 1). This condition was later formalized by Frohman and others as IFS, which occurs in the absence of CNC or MEN-1.[29] A series of genetic studies by Yamada et al.[30] and others, localized a region in chromosome 11q13 close to the MEN1 locus that was linked to IFS in some families.[31] Patients with IFS have been reported as being younger at diagnosis than patients with nonfamilial acromegaly.[29]

Photograph of brothers Battista Ugo (right) and Paolo Antonio Ugo (left), two men with familial acrogigantism, photographed with their family in early years of the 20th Century. Post-mortem examination of Paolo Antonio Ugo revealed a giant pituitary adenoma (50 x 25 x 23 mm) with suprasellar, retrosellar and left parasellar expansion.


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