Familial Pituitary Tumors Research Articles

Phenotypic differences between patients with familial pituitary neuroendocrine tumours due to MEN1 or AIP mutations

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

MON-335 Phenocopy of Multiple Endocrine Neoplasia Type 1 (MEN1) Due to a Germline Cell Division Cycle 73 (CDC73) Variant

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the combined occurrence of parathyroid tumors, and neuroendocrine tumors (NETs) of the pituitary and pancreas. MEN1 is caused by germline mutations of the tumor suppressor gene MEN1, which are found in >75% of MEN1 patients. The remaining patients may have mutations involving: as yet unidentified genes; or other genes with known involvement in endocrine tumors, e.g. cyclin dependent kinase inhibitor 1B (CDKN1B) which is associated with MEN4. Here, we report a patient who had primary hyperparathyroidism, acromegaly, and a pancreatic NET that showed immuno-staining for glucagon and chromogranin A, which are consistent with MEN1. However, mutational analysis did not identify a MEN1 mutation, and analysis of other genes was undertaken, after informed consent was obtained from the patient. These genes include: CDKN1B; CDKN1A; CDKN2B; CDKN2C;cell cycle division 73 (CDC73), causative for hyperparathyroidism-jaw tumour (HPT-JT) syndrome, an autosomal dominant disorder characterised by occurrence of parathyroid tumors, ossifying fibromas of the jaw, renal tumours and uterine tumors; calcium sensing receptor (CASR), causative for familial hypocalciuric hypercalcemia type 1 (FHH1); and aryl-hydrocarbon receptor-interacting protein (AIP), causative for familial pituitary tumors. This revealed a heterozygous c.1138C>T (p.Leu380Phe) missense mutation of CDC73. This is likely a disease-causing mutation as: 1) the p.Leu380Phe substitution is not present in >120,000 alleles of The Exome Aggregation Consortium (ExAc) database; 2) involves an evolutionary conserved Leu380 residue; and 3) is situated within the parafibromin domain predicted to interact with the polymerase associated factor 1 (PAF1) and RNA polymerase II, (POLR2A) complex. In addition, RNA-Scope analysis, to detect specific CDC73 mRNA transcripts in paraffin embedded sections, of the patient’s pancreatic NET revealed that CDC73 mRNA expression was significantly decreased by >13% (p<0.005) in the tumor cells, compared to normal adjacent islets. Thus, our results suggest the spectrum of tumours associated with CDC73 mutations also includes pancreatic NETs, and demonstrate that CDC73 mutations may result in a phenocopy of MEN1.

AIP mutation causing familial pituitary tumours

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

The role of the microenvironment in the invasive phenotype of familial pituitary tumours

The role of the microenvironment in the invasive phenotype of familial pituitary tumours

Pathology of GH-producing pituitary adenomas and GH cell hyperplasia of the pituitary.

Histologic, immunohistochemical and electron microscopic studies have provided conclusive evidence that a marked diversity exists between tumors which secrete growth hormone (GH) in excess. GH cell hyperplasia can also be associated with acromegaly in patients with extrapituitary GH-releasing hormone secreting tumors or in familial pituitary tumor syndromes. A literature search was performed for information regarding pathology, GH-producing tumors and acromegaly. This review summarizes the current knowledge on the morphology of GH-producing and silent GH adenomas, as well as GH hyperplasia of the pituitary. The importance of morphologic classification and identification of different subgroups of patients with GH-producing adenomas and their impact on clinical management is discussed.

Chapter 23 - Familial pituitary tumors

Pituitary adenomas are benign intracranial neoplasms that present a major clinical concern due to hormone overproduction and/or tumor mass effects. The majority of pituitary adenomas occur sporadically; however, familial cases are increasingly being recognized, such as multiple endocrine neoplasia type 1 (MEN1), Carney complex (CNC), and familial isolated pituitary adenoma (FIPA). Familial pituitary tumors appear to differ from their sporadic counterparts both in their genetic basis and in clinical characteristics. Evidence suggests that, especially in MEN1 and FIPA, tumors are more aggressive and affect patients at a younger age, therefore justifying the importance of early diagnosis, while in Carney complex pituitary hyperplasia is common. The genetic alterations responsible for the formation of familial pituitary syndromes include the MEN1 gene, responsible for about 80% of MEN1 cases, the regulatory subunit of the protein kinase A, PRKAR1A, responsible for about 70% of Carney complex cases, and AIP, the gene coding the aryl hydrocarbon receptor interacting protein, responsible for about 20% of FIPA cases. Rarely other genes have also been found responsible for familial pituitary adenoma cases. McCune-Albright syndrome (MAS) also has a genetic origin due to mosaic mutations in the G protein-coupled α subunit coded by the GNAS1 gene. In this chapter, we summarize the genetic and clinical characteristics of these familial pituitary syndromes and MAS.

Familial isolated pituitary adenomas: An emerging clinical entity

Familial pituitary tumors are increasingly recognized. While some of these cases are related to wellknown syndromic conditions such as multiple endocrine neoplasia type 1 (MEN1) or Carney complex, others belong to the familial isolated pituitary adenoma (FIPA) patient group. The discovery of heterozygous, loss-of-function germline mutations in the gene encoding the aryl hydrocarbon receptor interacting protein (AIP) in 2006 has subsequently enabled the identification of a mutation in this gene in 20% of FIPA families and 20% of childhood-onset simplex soma- totroph adenomas. The exact mechanism by which the lack of AIP leads to pituitary adenomas is not clear. AIP mutations cause a low penetrance autosomal dominant disease with often a distinct phenotype characterized by young-onset, aggressive, large GH, mixed GH and PRL or PRL-secreting adenomas. This review aims to summarize currently available clinical data on AIP mutation-positive and negative FIPA patients.

The epidemiology and genetics of pituitary adenomas

According to data derived from autopsy and radiological imaging series, pituitary tumours occur very commonly in the general population; however, most of these tumours are incidental findings with no obvious clinical impact. The historical data on the prevalence of pituitary adenomas in the clinical setting are scant and point to such tumours being relatively rare. Recent studies have shown that the prevalence of clinically relevant pituitary adenomas is 3-5 times higher than previously reported, which adds impetus to research into the aetiology of these tumours. Although the majority of pituitary adenomas are sporadic, approximately 5% of all cases occur in a familial setting and over half of these are due to Multiple Endocrine Neoplasia Type 1 (MEN-1) and Carney's Complex (CNC) disorders. Since the late 1990 s, we have described non-MEN1/CNC familial pituitary tumours that include all tumour phenotypes as a condition termed Familial Isolated Pituitary Adenomas (FIPAs). The clinical characteristics of the FIPAs vary from those sporadic pituitary adenomas, as patients with FIPAs have a younger age at diagnosis and larger tumours. About 15% of the FIPA patients have mutations in the aryl hydrocarbon receptor-interacting protein gene (AIP), which indicates that the FIPA may have a diverse genetic pathophysiology.

Familial pituitary tumor syndromes

The vast majority of pituitary tumors are benign and occur sporadically; however, they can still result in significant morbidity and even premature mortality through mass effects and hormone dysfunction. The etiology of sporadic tumors is still poorly understood; by contrast, advances have been made in our understanding of familial pituitary adenoma syndromes in the past decade. Currently, four genes are known to be associated with familial pituitary tumor syndromes: MEN1, CDKN1B, PRKAR1A and AIP. The first three genes are associated with a variety of extrapituitary pathologies, for example, primary hyperparathyroidism with multiple endocrine neoplasia type 1, which might aid identification of these syndromes. By contrast, AIP mutations seem to occur in the setting of isolated familial pituitary adenomas, particularly of the growth-hormone-secreting subtype. Awareness and identification of familial pituitary tumor syndromes is important because of potential associated pathologies and important implications for family members. Here, we review the current knowledge of familial pituitary tumor syndromes.

Familial pituitary adenomas

The majority of pituitary adenomas occur sporadically, however, about 5% of all cases occur in a familial setting, of which over half are due to multiple endocrine neoplasia type 1 (MEN-1) and Carney's complex (CNC). Since the late 1990s we have described non-MEN1/CNC familial pituitary tumours that include all tumour phenotypes, a condition named familial isolated pituitary adenomas (FIPA). The clinical characteristics of FIPA vary from those of sporadic pituitary adenomas, as patients with FIPA have a younger age at diagnosis and larger tumours. About 15% of FIPA patients have mutations in the aryl hydrocarbon receptor interacting protein gene (AIP), which indicates that FIPA may have a diverse genetic pathophysiology. This review describes the clinical features of familial pituitary adenomas like MEN1, the MEN 1-like syndrome MEN-4, CNC, FIPA, the tumour pathologies found in this setting and the genetic/molecular data that have been recently reported.

Aryl hydrocarbon receptor-interacting protein and pituitary adenomas: a population-based study on subjects exposed to dioxin after the Seveso, Italy, accident

The pathogenesis of sporadic pituitary tumors is unknown. Loss-of-function mutations of aryl hydrocarbon receptor-interacting protein (AIP) have been identified in patients with familial pituitary tumors. AIP is a chaperone protein with multifunction properties, including modulation of the transcriptional activity of the aryl hydrocarbon receptor, which mediates toxicological and carcinogenic dioxin effects. We investigated the incidence of pituitary tumors in the Seveso population exposed to 2,3,7,8-tetrachlorodibenzo-para-dioxin following an industrial accident in 1976. Through the hospital discharge registration system of Lombardy Region, we identified incident cases of pituitary adenomas between 1976 and 1996 in the Seveso population, subdivided in zone A (n=804), B (n=5.941), and R (n=38.624) according to high, intermediate, and low exposure to dioxin respectively, and in the surrounding non-contaminated area, as reference (n=232 745). We identified 42 pituitary adenomas in the reference area, 1 prolactinoma in zone A (rate ratio (RR) 6.2; 95% CI 0.9-45.5, P=0.07), 2 nonfuctioning pituitary tumors (NFPAs) in zone B (RR 1.9; 95% CI 0.5-7.7, P=0.39), and 3 prolactinomas and 2 NFPAs in zone R (RR 0.7; 95% CI 0.3-1.8, P=0.48). The study is unique with regard to the availability of epidemiological and clinical data in an area of relatively pure dioxin exposure. The study indicates no statistically significant increase of incident pituitary tumors in this area, although the tendency toward a higher risk (three cases in zones A and B) of pituitary tumors in subjects exposed to high-intermediate dioxin concentrations in comparison with nonexposed population suggests the need for extended follow-up.

Characteristics of familial isolated pituitary adenomas

The familial occurrence of pituitary adenomas has been recognized for many years and currently accounts for approximately 5% of all cases. Molecular, genetic and clinical features of familial pituitary adenomas have been well characterized in multiple endocrine neoplasia type 1 (MEN-1) and Carney’s complex (CNC), which account for the majority of familial pituitary tumor cases. These conditions are caused by MEN1 and PRKAR1A gene mutations, respectively, and the clinical and pathological features of pituitary pathology in these diseases differ from those of sporadic pituitary tumors. Familial acromegaly has been recognized for many years and, more recently, the clinical features of this clinical phenotype, referred to as isolated familial somatotropinoma, have been clarified. Over the past decade, the concept of non-MEN-1/CNC familial pituitary tumors has been expanded significantly to include all phenotypes, a condition known as familial isolated pituitary adenomas (FIPA). In FIPA, tumors can present homogeneously (same phenotype) or heterogeneously (different tumor phenotypes) within the same family. Compared with sporadic pituitary adenomas, patients with FIPA have a younger age at diagnosis and have larger tumors. The clinical features of FIPA differ from those of MEN-1 in terms of a higher frequency of somatotropinomas and a lower frequency of prolactinomas. The recent discovery of the involvement of mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene in association with pituitary tumors has provided new information regarding potential mechanisms of tumorigenesis in FIPA patients. While very infrequent in sporadic pituitary tumors, approximately 15% of FIPA patients have AIP mutations, rising to half of patients with familial acromegaly. In this review, we detail the clinical features of FIPA and discuss tumor pathology and genetic findings in this increasingly recognized clinical condition.

Germline Mutation in the Aryl Hydrocarbon Receptor Interacting Protein Gene in Familial Somatotropinoma

Acromegaly is usually sporadic, but familial cases occur in association with several familial pituitary tumor syndromes. Recently mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were associated with familial pituitary adenoma predisposition. The objective of the study was to investigate the status of AIP in a pituitary tumor predisposition family. The study was conducted at a nonprofit academic center and medical centers. Eighteen members of a Brazilian family with acromegaly were studied. A novel germline mutation in the AIP gene, Y268X, predicted to generate a protein lacking two conserved domains, was identified in four members of this family: two siblings with early-onset acromegaly; a third, 41-yr-old sibling with a microadenoma but no clinical features of disease, and his 3-yr-old son. No changes were found in 14 unaffected at-risk relatives or 92 healthy controls. We confirm the role of the AIP gene in familial acromegaly. This finding increases the spectrum of molecular defects that can give rise to pituitary adenoma susceptibility. Establishment of genotype-phenotype correlations in AIP mutant tumors will determine whether AIP screening can be used as a tool for clinical surveillance and genetic counseling of families with pituitary tumor predisposition. The underlying basis for the phenotypic variation within AIP-mutant families and the mechanism of AIP-mediated tumorigenesis remain to be defined.

Pituitary pathology in patients with Carney Complex: growth-hormone producing hyperplasia or tumors and their association with other abnormalities

First described in the mid 80's, Carney Complex (CNC) is a rare, dominantly heritable disorder with features overlapping those of McCune-Albright syndrome (MAS) and other multiple endocrine neoplasia (MEN) syndromes like MEN type 1 (MEN 1). Pituitary tumors have been described in a number of patients with CNC; they present with elevated growth hormone (GH) levels and mild hyperprolactinemia. However, most patients with CNC have mild hypersomatomammotropinemia starting in adolescence; this is similar to the situation in MAS patients: in both disorders, pituitary hyperplasia appears to precede tumor development. Familial pituitary tumor syndromes such as CNC provide an important insight into the genetics and molecular pathology of pituitary and other endocrine tumors. Our understanding of these conditions is expanding rapidly due to the identification of the causative genes and the availability of murine disease models. The present report reviews the clinical findings related to pituitary tumor development among patients with CNC and provides an update on murine models of the complex.

Clinical and Genetic Features of Familial Pituitary Adenomas

Inherited or familial pituitary tumor syndromes such as multiple endocrine neoplasia type 1 and Carney complex provide an important insight into the genetics and molecular pathology of endocrine cancers. Our understanding of these conditions is expanding rapidly due to the identification of the genes and proteins affected and the availability of murine knockout models. The successes achieved to date in understanding multiple endocrine neoplasia type 1 and Carney complex have helped in the identification and study of new inherited pituitary tumor syndromes such as isolated familial somatotropinomas. This review assesses the current status of research into the clinical features, genetics and molecular pathologies of multiple endocrine neoplasia type 1, Carney complex, and isolated familial somatotropinomas, and details ongoing work to delineate familial isolated pituitary adenomas, a potentially new clinical entity.

Molecular pathogenesis of pituitary disorders

The molecular pathogenesis of pituitary disorders is complex and has been explored in animal models and human subject studies. Hormone deficiencies are largely caused by mutations in transcription factors required for pituitary differentiation. Early developmental genes (Rpx, Lhx3, Lhx4, Pitx2) pleiotropically affect multiple pituitary hormones and adjacent physical structures, whereas genes determining specific pituitary lineages (including Prop1, Pit1, SF1, DAX1, Tpit) are involved in single or combined hormone deficiencies. Excess hormone secretion is mostly associated with monoclonal pituitary adenomas. Genes identified for familial pituitary tumor syndromes affect transcription (MEN1) and hypothalamic hormone signaling (CNC1, gsp). Murine gene-disruption studies (Rb, p27, p18) implicate cell-cycle regulatory genes, some of which have altered expression in most human pituitary tumors (p16, p27). Aberrant expression of PTTG, a mammalian securin homolog, can lead to chromosome missegregation, an early step in multistep pituitary tumor progression. Excess hypothalamic trophic hormones lead to pituitary hyperplasia and hormone excess, whereas alterations in hypothalamic hormone receptor genes are uncommon.