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Clinicopathologic features of familial pituitary adenomas
MINI-SYMPOSIUM: PATHOLOGY OF INHERITED ENDOCRINE TUMORS
include X-linked acrogigantism (X-LAG) syndrome,5,6 Carney complex (CNC),7 multiple endocrine neoplasia type 4 (MEN4),8 somatotropinoma/paraganglioma,9 pituitary blastoma10 and McCuneeAlbright syndrome (MAS)11 (Figure 1). Here, we present the clinicopathological features and morphological characteristics of pituitary adenomas associated with these familial syndromes.
Clinicopathologic features of familial pituitary adenomas Luis V Syro Fabio Rotondo
Familial isolated pituitary adenoma (FIPA)
Kalman Kovacs
FIPA (Online Mendelian Inheritance in Man, http://www.ncbi. nlm.nih.gov/omim, OMIM #102200) represents families with two or more members with pituitary adenomas without other syndromic features or simplex (i.e. sporadic) patients with germline mutation in genes associated with FIPA3,12: arylhydrocarbon receptor interacting protein (AIP) and G proteincoupled receptor 101 (GPR101) (Table 1). Within FIPA, currently three subgroups can be identified: AIP-mutation positive, GPR101-mutation positive X-linked acrogigantism (X-LAG) and the AIP & GPR101-negative group. There are significant phenotypic differences between the three types of FIPA kindreds.
rta Korbonits Ma
Abstract Pituitary adenomas are common neoplasms. Initially considered as sporadic tumours, some of them are associated with familial syndromes such as familial isolated pituitary adenoma, multiple endocrine neoplasia type 1 and type 4, X-linked acrogigantism syndrome, Carney complex, pheochromocytoma/paragangliomaepituitary adenoma, pituitary blastoma and McCuneeAlbright syndrome. They represent a group of diseases with different genetic background and variable phenotype. Here, we summarize the clinicopathological features of pituitary adenomas associated with these familial syndromes.
AIP-mutation positive patients 17e20% of FIPA families and 11e17% of <30 years simplex pituitary adenoma patients possess a mutation in the AIP gene.3,13 There is incomplete penetrance in AIP-mutation positive kindreds. The mean age of onset is around 20e24 years. A slight male predominance has been previously described (63.5%),3 but ascertainment bias cannot be ruled out as a more recent comprehensive study did not find male predominance being statistically significant.13 AIP-mutation positive patients present with growth hormone (GH) or GH and prolactin (PRL) producing tumours in 85% of the cases (Figure 2). AIP-mutation positive patients with acromegaly have larger and more invasive tumours.3
Keywords AIP; Carney complex; classification; diagnosis; DICER1; familial isolated; familial syndromes; genetics; McCuneeAlbright syndrome; multiple endocrine neoplasia type 1; pathology; pituitary adenoma; pituitary blastoma; X-linked acrogigantism syndrome
Introduction Pituitary adenomas are benign tumours representing approximately 15e20% of intracranial neoplasms.1 While the majority are sporadic tumours, a significant minority are associated with familial syndromes with different genetic background and variable phenotype.2 The two most frequently seen forms are familial isolated pituitary adenoma (FIPA)3 and multiple endocrine neoplasia type 1 (MEN1),4 while the more uncommon forms
X-linked acrogigantism syndrome (X-LAG) X-LAG (OMIM #300942) is a syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the GPR101 gene6 (Table 1) which encodes an orphan G protein-coupled receptor of unknown function. A significant percentage of patients (w10%) with pituitary gigantism harbour this microduplication14 which shows full penetrance. This is a distinctive clinical entity characterized by excessive growth caused by GH hypersecretion beginning during the first years of life in previously normal infants. GH excess originates from a pituitary adenoma or pituitary hyperplasia.5 X-LAG occur as a simplex condition due to a de novo mutation in the majority of cases or it could be associated with FIPA; until now, two mother to child transmission has been described. The patients usually present with increased growth velocity before the end of the first year of their life. Acral enlargement and coarsened facial features can be noticed. GH and insulin-like growth factor 1 (IGF-1) blood levels are elevated and the oral glucose tolerance test (OGTT) is abnormal. Magnetic resonance imaging (MRI) usually discloses a pituitary macroadenoma or in some cases, pituitary enlargement suggestive of hyperplasia. Morphological findings are mixed GH-PRL producing adenomas or, less common, diffuse pituitary hyperplasia. Treatment includes surgery, medical therapy and in some cases, radiotherapy5 as
Luis V Syro MD Professor of Neurosurgery, Department of Neurosurgery, Hospital Pablo Tobon Uribe and Clinica Medellin, Medellin, Colombia. Conflicts of interest: none declared. Fabio Rotondo BSc Research Associate, Laboratory Manager, Department of Laboratory Medicine, Division of Pathology and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada. Conflicts of interest: none declared. Kalman Kovacs MD PhD Professor Emeritus, Department of Laboratory Medicine, Division of Pathology and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada. Conflicts of interest: none declared. rta Korbonits MD Professor of Endocrinology and Metabolism, Ma Consultant in Endocrinology, Co-Centre Head of Endocrinology, Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK. Conflicts of interest: none declared.
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Figure 1 Pituitary adenomas due to germline mutations.
to medical therapy and have higher recurrence rates.15 PRLproducing adenomas are the most frequent (62e60%), followed by clinically non-functioning adenomas (15%), GHsecreting and ACTH-secreting adenomas.16 The proportion of plurihormonal adenomas and multiple adenomas is significantly higher in MEN1 patients.17 In MEN1 patients with acromegaly and normal or enlarged pituitary gland on MRI, pituitary hyperplasia should be suspected and tumours (usually pancreas) producing a releasing hormone such as GHRH (GH-releasing hormone) must be searched for.17
response to somatostatin analogues are poor. GH receptor antagonist treatment has been described successfully.5 AIP & GPR101-mutation negative patients This is the largest group of FIPA cases. The age of onset of disease is similar to that of the sporadic cases, but larger and more invasive tumours have been identified. The tumour types are more varied than in the other types of FIPA: excess GHproducing adenomas still predominates, but the other tumour types represent over one third of the tumour types.13 The affected families can be classified as i) homogenous, if the same type of pituitary adenoma is present, or ii) heterogeneous, if different types of tumours occur within the same family. Penetrance is low, probably lower that of AIP-mutation positive kindreds.12
Carney complex (CNC) CNC (OMIM #160980), is an autosomal dominant syndrome produced by an inactivating mutation of the regulatory subunit 1-a of the protein kinase A (PRKAR1A) (Table 1). Recent studies have associated elements of the CNC phenotype with cAMP-dependent protein kinase catalytic subunit alpha (PRKACA)18 and cAMP-dependent protein kinase catalytic subunit beta (PRKACB)19 gene defects but their precise roles remain to be elucidated.7 CNC is characterized by multiple skin lesions (blue nevus, spotty skin pigmentation and mucosal lentigines), cardiac, breast, cutaneous or mucosal myxomas, acromegaly or mild GH/PRL excess, breast ductal adenoma, psammomatous melanocytic schwannoma, thyroid carcinoma or multiple hypoechoic thyroid nodules, large-cell calcifying Sertoli cell tumours (LCCSCT), osteochondromyxoma and primary pigmented nodular adrenocortical disease (PPNAD).7 The diagnosis can be established when two of the above mentioned features occur, or in the presence of one major feature and PRKR1A mutation or a first-degree relative with CNC. Clinical manifestations are variable even within members of the same family and one third of the patients present as simplex (sporadic) cases. Lentiginosis is the most common feature of CNC (70%) consisting of small, 2e10 mm brown to black maculae on the lips, eyelids, ears and genitals and can be
Multiple endocrine neoplasia type 1 (MEN1) MEN1 (OMIM #131100) is an autosomal-dominant disorder characterized by tumours of the pituitary, parathyroid, endocrine cells of the gastrointestinal tract, endocrine pancreas and adrenal cortex.4 MEN1, a tumour suppressor gene localized on chromosome 11q13, encodes menin, a nuclear protein involved in transcriptional regulation, genome stability, cell division and proliferation (Table 1). Patients with MEN1 syndrome usually have a positive family history and MEN1 gene mutations can be identified in 70%e95% of patients.4 Clinical diagnosis is established when at least two of these features are present or when one feature is present together with a first-degree relative with established MEN1. Pituitary tumours in MEN1 syndrome patients can be documented in 10%e60% of cases and can be the first clinical manifestation in up to 25% of the cases. Pituitary adenomas associated with MEN1 differ from sporadic tumours.15 MEN1-related pituitary adenomas are usually diagnosed at an earlier age, they are frequently macroadenomas, often resistant
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Bioinformatic resources for common familial pituitary adenomas OMIM
Gene
Localization UNIPROT
Familial isolated pituitary adenomas (FIPA) FIPA#102200 AIP 11q13.2 AIP https://omim.org/ entry/102200
FIPA-X- #300942 LAG https://omim.org/ entry/300942
Multiple endocrine neoplasia MEN1 #131100 https://omim.org/ entry/131100 MEN4
GPR101 Xq26.3
MEN1
11q13.1
#610755 CDKN1B 12p13.1 http://www.omim.org/ entry/610755
Carney complex CNC #160980 https://omim.org/ entry/160980
PRKAR1A 17q24.2
*601639 PRKACA 19p13.12 http://www.omim.org/ entry/601639
PRKACB 1p36.1 *176892 http://www.omim.org/ entry/176892
DICER1 syndrome DICER1 #601200 DICER1 http://www.omim.org/ entry/601200
STRING
GeneReviews
O00170 AH receptor-interacting protein http://www.uniprot.org/ uniprot/O00170 Q96P66 Probable G-protein coupled receptor 101 http://www.uniprot.org/ uniprot/Q96P66
http://string-db.org/ http://www.ncbi.nlm.nih.gov/ newstring_cgi/show_network_ books/NBK97965/ section.pl?identifier¼9606. ENSP00000279146
O00255 Menin http://www.uniprot.org/ uniprot/O00255 P46527 (protein also called p27) Cyclin-dependent kinase inhibitor 1B http://www.uniprot.org/ uniprot/P46527
http://string-db.org/ newstring_cgi/show_network_ section.pl?identifier¼9606. ENSP00000337088 http://string-db.org/ newstring_cgi/show_network_ section.pl?identifier¼9606. ENSP00000228872
P10644 cAMP-dependent protein kinase type I-alpha regulatory subunit http://www.uniprot.org/ uniprot/P10644 P17612 cAMP-dependent protein kinase catalytic subunit alpha http://www.uniprot.org/ uniprot/P17612 P22694 cAMP-dependent protein kinase catalytic subunit beta http://www.uniprot.org/ uniprot/P22694
http://string-db.org/ http://www.ncbi.nlm.nih.gov/ newstring_cgi/show_network_ books/NBK1286/ section.pl?identifier¼9606. ENSP00000351410
14q32.13
Q9UPY3 Endoribonuclease Dicer http://www.uniprot.org/ uniprot/Q9UPY3 Succinate dehydrogenase complex genes syndrome (SDHx) SDHB #115310 SDHB 1p36.13 P21912 http://www.omim.org/ Succinate dehydrogenase entry/115310 [ubiquinone] iron-sulfur subunit, mitochondrial http://www.uniprot.org/ uniprot/P21912 SDHC SDHC 1q23.3 Q99643 Succinate dehydrogenase
http://string-db.org/ newstring_cgi/show_network_ section.pl?identifier¼9606. ENSP00000298110
http://www.ncbi.nlm.nih.gov/ books/NBK1538/
http://www.ncbi.nlm.nih.gov/ books/NBK1538/
http://string-db.org/ http://www.ncbi.nlm.nih.gov/ newstring_cgi/show_network_ books/NBK1286/ section.pl?identifier¼9606. ENSP00000309591 http://www.ncbi.nlm.nih.gov/ http://string-db.org/ newstring_cgi/show_network_ books/NBK1286/ section.pl?identifier¼9606. ENSP00000359719
http://www.ncbi.nlm.nih.gov/ http://string-db.org/ newstring_cgi/show_network_ books/NBK196157/ section.pl?identifier¼9606. ENSP00000343745 http://string-db.org/ http://www.ncbi.nlm.nih.gov/ newstring_cgi/show_network_ books/NBK1548/ section.pl?identifier¼9606. ENSP00000364649
http://string-db.org/ http://www.ncbi.nlm.nih.gov/ newstring_cgi/show_network_ books/NBK1548/ (continued on next page)
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Table 1 (continued ) OMIM
Gene
Localization UNIPROT
#605373 http://www.omim.org/ entry/605373 SDHD
#168000 SDHD http://www.omim.org/ entry/168000
11q23.1
SDHA
#614165 SDHA http://www.omim.org/ entry/614165
5p15.33
SDHAF2 *613019 SDHAF2 11q12.2 http://www.omim.org/ entry/613019
McCuneeAlbright syndrome MAS #174800 GNAS http://www.omim.org/ entry/174800
20q13.32
STRING
GeneReviews
cytochrome b560 subunit, mitochondrial http://www.uniprot.org/ uniprot/Q99643 O14521 Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial http://www.uniprot.org/ uniprot/O14521 P31040 Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial http://www.uniprot.org/ uniprot/P31040 Q9NX18 Succinate dehydrogenase assembly factor 2, mitochondrial http://www.uniprot.org/ uniprot/Q9NX18
section.pl?identifier¼9606. ENSP00000356953
P63092 Guanine nucleotide-binding protein G(s) subunit alpha isoforms short http://www.uniprot.org/ uniprot/P63092
http://string-db.org/ http://www.ncbi.nlm.nih.gov/ newstring_cgi/show_network_ books/NBK274564/ section.pl?identifier¼9606. ENSP00000360141
http://string-db.org/ http://www.ncbi.nlm.nih.gov/ newstring_cgi/show_network_ books/NBK1548/ section.pl?identifier¼9606. ENSP00000364699
http://string-db.org/ http://www.ncbi.nlm.nih.gov/ newstring_cgi/show_network_ books/NBK1548/ section.pl?identifier¼9606. ENSP00000264932
http://string-db.org/ http://www.ncbi.nlm.nih.gov/ newstring_cgi/show_network_ books/NBK1548/ section.pl?identifier¼9606. ENSP00000301761
OMIM: Online Mendelian Inheritance in Man; UNIPROT: Universal Protein Resource; STRING: Search Tool for the Retrieval of Interacting Genes/Proteins.
Table 1
present at birth and acquire their clinical characteristics at puberty.7 ACTH independent Cushing’s syndrome due to primary pigmented nodular adrenocortical disease (PPNAD) is the main endocrine manifestation (60%) followed by acromegaly due to pituitary adenoma or adenohypophysial hyperplasia.
Multiple endocrine neoplasia type 4 (MEN4) An MEN1-like syndrome has been identified in a small group of human patients caused by mutations in the cell cycle inhibitor CDKN1B coding for p27 protein. This condition was named MEN48 (OMIM #610755) (Table 1). The most common tumour
Figure 2 Growth hormone (GH)-producing pituitary adenoma. There is no difference between the familial and non-familial pituitary adenomas. Morphology is not a useful tool to differentiate between familial and non-familial cases. (a). H&E. Magnification: 100. (b) GH stain. Magnification: 250.
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Figure 3 Pituitary Blastoma. (a) H&E. A combination of Rathke-type epithelial rosettes, small primitive appearing cells and secretory cells. Magnification: 250. (b) GH stain. Magnification: 400. (c) ACTH stain. Magnification: 400. (d) A corticotroph containing cytokeratin filaments as well as glycogen is actually part of a well-defined follicle. Magnification: 15,000. (e) An example of follicle comprising differentiating and undifferentiated cells. Magnification: 10,000.
type is somatotropinoma and a childhood-onset case has also been described. Mutation types include frameshift, nonsense and missense mutations and interestingly, two patients have been described with mutation affecting the 50 open reading frame.8,20 Other tumours described in patients with MEN4 includes parathyroid adenomas as well as renal angiomyolipoma, an adrenal non-functional tumour, uterine fibroids, gastrinoma, neuroendocrine cervical carcinoma, bronchial carcinoid, papillary thyroid carcinoma and gastric carcinoma. Other cell cycle inhibitors, such as p15 (CDKN2B), p18 (CDKN2C ) and p21 (CDKN1A) have also been found mutated in a few MEN1 syndrome cases.21
Pituitary blastoma DICER1 syndrome (OMIM #601200), or pleuropulmonary blastoma (PPB) familial tumour and dysplasia syndrome, is caused by heterozygous germline mutations in the DICER1 gene, located in chromosome 14q31 (Table 1). It encodes DICER1, a small RNA processing endoribonuclease that cleaves precursor microRNAs (miRNA) into mature miRNAs. DICER1 mutations are associated with a variety of tumour types (pleuropulmonary blastoma, ovarian sex-cord stromal tumours, cystic nephroma, thyroid nodular hyperplasia, multinodular goiter, thyroid adenomas or differentiated thyroid cancer, ciliary body medulloepithelioma, botryoid-type embryonal rhabdomyosarcoma, nasal chondromesenchymal hamartoma, pituitary blastoma and pineoblastoma) and can be considered a tumour predisposition syndrome with typical agespecific presentation.22 It has been proposed, that if a second somatic mutation e a second “hit” e occurs in the RNase IIIb domain of DICER1 in a pituitary cell, then a pituitary blastoma develops.10 Pituitary blastoma has been identified as a distinct entity. It is an early childhood invasive neoplasm arising within the foetal adenohypophysis consisting of a combination of Rathke-type epithelial rosettes, small primitive appearing cells and secretory cells (Figure 3). The latter are immunopositive for synaptophysin and chromogranin and express adrenocorticotrophc hormone (ACTH), or less commonly GH.10 Patients with pituitary blastoma usually present in neonatal or early childhood age as Cushing’s disease and a sellar tumour usually extending to the suprasellar and parasellar regions. Ophthalmoplegia and strabismus are present in almost 50% of the cases. Mortality rate is approximately 40%. Pituitary blastoma can be considered a pathognomonic manifestation
Figure 4 SDH-x related adenoma. H&E stain. A SDH-x related pituitary adenoma showing prominent vacuolar changes in most cells, an interesting feature seen in some of these cases. Magnification: 400.
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of a germline DICER1 mutation and even in the absence of genetic diagnosis, other DICER1-related tumours should be in the patient and family.10
2 Lecoq AL, Kamenicky P, Guiochon-Mantel A, Chanson P. Genetic mutations in sporadic pituitary adenomas-what to screen for? Nat Rev Endocrinol 2015; 11: 43e54. 3 Daly AF, Tichomirowa MA, Petrossians P, et al. Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study. J Clin Endocrinol Metabol 2010; 95: E373e83. 4 Thakker RV. Multiple endocrine neoplasia type 1 (MEN1). Best Pract Res Clin Endocrinol Metab 2010; 24: 355e70. 5 Beckers A, Lodish MB, Trivellin G, et al. X-linked acrogigantism syndrome: clinical profile and therapeutic responses. Endocr Relat Cancer 2015; 22: 353e67. 6 Trivellin G, Daly AF, Faucz FR, et al. Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. N Engl J Med 2014; 371: 2363e74. 7 Correa R, Salpea P, Stratakis CA. Carney complex: an update. Eur J Endocrinol 2015; 173: M85e97. 8 Occhi G, Regazzo D, Trivellin G, et al. A novel mutation in the upstream open reading frame of the CDKN1B gene causes a MEN4 phenotype. PLoS Genet 2013; 9: e1003350. 9 Xekouki P, Szarek E, Bullova P, et al. Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice. J Clin Endocrinol Metabol 2015; 100: E710e9. 10 de Kock L, Sabbaghian N, Plourde F, et al. Pituitary blastoma: a pathognomonic feature of germ-line DICER1 mutations. Acta Neuropathol 2014; 128: 111e22. 11 Salpea P, Stratakis CA. Carney complex and McCune Albright syndrome: an overview of clinical manifestations and human molecular genetics. Mol Cell Endocrinol 2014; 386: 85e91. 12 Leontiou CA, Gueorguiev M, van der Spuy J, et al. The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas. J Clin Endocrinol Metabol 2008; 93: 2390e401. 13 Hernandez-Ramirez LC, Gabrovska P, Denes J, et al. Landscape of familial isolated and young-onset pituitary adenomas: prospective diagnosis in AIP mutation carriers. J Clin Endocrinol Metabol 2015; jc20151869. 14 Rostomyan L, Daly AF, Petrossians P, et al. Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients. Endocr Relat Cancer 2015; 22: 745e57. 15 Toledo SP, Lourenco Jr DM, Toledo RA. A differential diagnosis of inherited endocrine tumors and their tumor counterparts. Clinics (Sao Paulo, Brazil) 2013; 68: 1039e56. 16 de Laat JM, Dekkers OM, Pieterman CR, et al. Long-term natural course of pituitary tumors in patients with MEN1: results from the DutchMEN1 study group (DMSG). J Clin Endocrinol Metabol 2015; 100: 3288e96. 17 Trouillas J, Labat-Moleur F, Sturm N, et al. Pituitary tumors and hyperplasia in multiple endocrine neoplasia type 1 syndrome (MEN1): a case-control study in a series of 77 patients versus 2509 non-MEN1 patients. Am J Surg Pathol 2008; 32: 534e43. 18 Lodish MB, Yuan B, Levy I, et al. Germline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: molecular mechanisms and clinical presentations. Eur J Endocrinol 2015; 172: 803e11. 19 Forlino A, Vetro A, Garavelli L, et al. PRKACB and carney complex. N Engl J Med 2014; 370: 1065e7.
Pheochromocytoma/paraganglioma e pituitary adenoma syndrome Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase or mitochondrial complex II, is a multimeric enzyme bound to the inner mitochondrial membrane. It transfers electrons directly to the ubiquinone pool in Krebs cycle and the respiratory chain (Table 1). SDH consists of hydrophilic subunits, a flavoprotein (SDHA), and an iron-sulfur protein (SDHB), which form the catalytic core of the enzyme. The two hydrophobic subunits, SDHC and SDHD, anchor the homotetramer to the membrane. Mutations in genes coding for SDHA, SDHB, SDHC, SDHD and SDHAF2 (known collectively as SDHx) have been identified in familial paragangliomas (PGLs) and pheochromocytomas (PHEOs) and recently pituitary adenomas9,23 were added to the increasing list of SDH-associated tumour types24 (Figure 4). Based on the SDHx mutation-associated w15 cases reported, PRL-producing pituitary adenomas are the most common followed by GH and clinically non-functional pituitary adenomas. They usually present as macroadenomas with aggressive behaviour and resistant to medical therapy.24
McCuneeAlbright syndrome (MAS) McCuneeAlbright syndrome (OMIM #174800) is a postzygotic mutation in GNAS which encodes the guanine nucleotide-binding protein subunit a isoform short (Gas), leading to somatic mosaicism and activation of the cAMP pathway11 (Table 1). They present with the triad of polyostotic fibrous dysplasia of bone, cafe au-lait skin pigmentation, and precocious puberty. The pituitary gland is also affected in McCuneeAlbright syndrome cases and acromegaly is present in 20e30% of the cases.25
Conclusion Although individual families were known since the 18th century, attention was only recently turned to familial pituitary adenomas. There are several distinct, well-defined syndromes differing in genetic alterations, penetrance, clinical presentation, endocrine changes and morphology. Our review focuses on germline genetic alterations which are of crucial importance causing the disease and making a conclusive diagnosis. Familial pituitary adenomas should be recognized not only to select the most effective therapy but also because it provides the opportunity to diagnose family members in the early phase of the disease when clinical symptoms are not yet evident. Genetic testing and careful morphologic investigation are necessary to make the proper diagnosis. Although progress was remarkable, many details including frequency, genetic changes and tumour progression are still obscure and more work is needed to better understand familial pituitary adenomas. A
REFERENCES 1 Melmed S. Pathogenesis of pituitary tumors. Nat Rev Endocrinol 2011; 7: 257e66.
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20 Sambugaro S, Di Ruvo M, Ambrosio MR, et al. Early onset acromegaly associated with a novel deletion in CDKN1B 5’UTR region. Endocrine 2015; 49: 58e64. 21 Agarwal SK, Mateo CM, Marx SJ. Rare germline mutations in cyclin-dependent kinase inhibitor genes in multiple endocrine neoplasia type 1 and related states. J Clin Endocrinol Metabol 2009; 94: 1826e34. 22 Slade I, Bacchelli C, Davies H, et al. DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome. J Med Genet 2011; 48: 273e8. 23 Denes J, Swords F, Rattenberry E, et al. Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort. J Clin Endocrinol Metabol 2015; 100: E531e41. 24 O’Toole SM, Denes J, Robledo M, Stratakis CA, Korbonits M. 15 YEARS OF PARAGANGLIOMA: the association of pituitary adenomas and phaeochromocytomas or paragangliomas. Endocr Relat Cancer 2015; 22: T105e22. 25 Salenave S, Boyce AM, Collins MT, Chanson P. Acromegaly and McCuneeAlbright syndrome. J Clin Endocrinol Metabol 2014; 99: 1955e69.
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Authors are grateful to the Jarislowsky and Lloyd Carr-Harris Foundations for their support.
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While the majority of pituitary adenomas are sporadic tumours, some of them are associated with familial syndromes with different genetic background and variable phenotype. The two most frequently seen forms are familial isolated pituitary adenoma (FIPA) and multiple endocrine neoplasia type 1 (MEN1). Uncommon forms include X-linked acrogigantism (X-LAG) syndrome, Carney complex (CNC), multiple endocrine neoplasia type 4 (MEN4), somatotropinoma/paraganglioma and pituitary blastoma. Young pituitary adenoma patients should be assessed for a genetic predisposition for pituitary adenomas. FIPA represents families with two or more members with pituitary adenomas. Three subgroups can be identified: AIP-mutation positive, GPR101-mutation positive X-linked acrogigantism (XLAG) and the AIP&GPR101-negative cases. Comparing with sporadic cases, MEN1-related pituitary adenomas are usually diagnosed at earlier ages, they are frequently macroadenomas, often resistant to medical therapy and have high recurrence rates. Pituitary blastoma is an early childhood invasive neoplasm arising within the foetal adenohypophysis. It occurs when a second somatic mutation e a second “hit” e occurs in patients with DICER1 syndrome. Mutations in genes coding for SDHA, SDHB, SDHC, SDHD and SDHAF2 (known collectively as SDHx) have been identified in familial paragangliomas (PGLs) and pheochromocytomas (PHEOs) and recently pituitary adenomas.
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include X-linked acrogigantism (X-LAG) syndrome,5,6 Carney complex (CNC),7 multiple endocrine neoplasia type 4 (MEN4),8 somatotropinoma/paraganglioma,9 pituitary blastoma10 and McCuneeAlbright syndrome (MAS)11 (Figure 1). Here, we present the clinicopathological features and morphological characteristics of pituitary adenomas associated with these familial syndromes.
Clinicopathologic features of familial pituitary adenomas Luis V Syro Fabio Rotondo
Familial isolated pituitary adenoma (FIPA)
Kalman Kovacs
FIPA (Online Mendelian Inheritance in Man, http://www.ncbi. nlm.nih.gov/omim, OMIM #102200) represents families with two or more members with pituitary adenomas without other syndromic features or simplex (i.e. sporadic) patients with germline mutation in genes associated with FIPA3,12: arylhydrocarbon receptor interacting protein (AIP) and G proteincoupled receptor 101 (GPR101) (Table 1). Within FIPA, currently three subgroups can be identified: AIP-mutation positive, GPR101-mutation positive X-linked acrogigantism (X-LAG) and the AIP & GPR101-negative group. There are significant phenotypic differences between the three types of FIPA kindreds.
rta Korbonits Ma
Abstract Pituitary adenomas are common neoplasms. Initially considered as sporadic tumours, some of them are associated with familial syndromes such as familial isolated pituitary adenoma, multiple endocrine neoplasia type 1 and type 4, X-linked acrogigantism syndrome, Carney complex, pheochromocytoma/paragangliomaepituitary adenoma, pituitary blastoma and McCuneeAlbright syndrome. They represent a group of diseases with different genetic background and variable phenotype. Here, we summarize the clinicopathological features of pituitary adenomas associated with these familial syndromes.
AIP-mutation positive patients 17e20% of FIPA families and 11e17% of <30 years simplex pituitary adenoma patients possess a mutation in the AIP gene.3,13 There is incomplete penetrance in AIP-mutation positive kindreds. The mean age of onset is around 20e24 years. A slight male predominance has been previously described (63.5%),3 but ascertainment bias cannot be ruled out as a more recent comprehensive study did not find male predominance being statistically significant.13 AIP-mutation positive patients present with growth hormone (GH) or GH and prolactin (PRL) producing tumours in 85% of the cases (Figure 2). AIP-mutation positive patients with acromegaly have larger and more invasive tumours.3
Keywords AIP; Carney complex; classification; diagnosis; DICER1; familial isolated; familial syndromes; genetics; McCuneeAlbright syndrome; multiple endocrine neoplasia type 1; pathology; pituitary adenoma; pituitary blastoma; X-linked acrogigantism syndrome
Introduction Pituitary adenomas are benign tumours representing approximately 15e20% of intracranial neoplasms.1 While the majority are sporadic tumours, a significant minority are associated with familial syndromes with different genetic background and variable phenotype.2 The two most frequently seen forms are familial isolated pituitary adenoma (FIPA)3 and multiple endocrine neoplasia type 1 (MEN1),4 while the more uncommon forms
X-linked acrogigantism syndrome (X-LAG) X-LAG (OMIM #300942) is a syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the GPR101 gene6 (Table 1) which encodes an orphan G protein-coupled receptor of unknown function. A significant percentage of patients (w10%) with pituitary gigantism harbour this microduplication14 which shows full penetrance. This is a distinctive clinical entity characterized by excessive growth caused by GH hypersecretion beginning during the first years of life in previously normal infants. GH excess originates from a pituitary adenoma or pituitary hyperplasia.5 X-LAG occur as a simplex condition due to a de novo mutation in the majority of cases or it could be associated with FIPA; until now, two mother to child transmission has been described. The patients usually present with increased growth velocity before the end of the first year of their life. Acral enlargement and coarsened facial features can be noticed. GH and insulin-like growth factor 1 (IGF-1) blood levels are elevated and the oral glucose tolerance test (OGTT) is abnormal. Magnetic resonance imaging (MRI) usually discloses a pituitary macroadenoma or in some cases, pituitary enlargement suggestive of hyperplasia. Morphological findings are mixed GH-PRL producing adenomas or, less common, diffuse pituitary hyperplasia. Treatment includes surgery, medical therapy and in some cases, radiotherapy5 as
Luis V Syro MD Professor of Neurosurgery, Department of Neurosurgery, Hospital Pablo Tobon Uribe and Clinica Medellin, Medellin, Colombia. Conflicts of interest: none declared. Fabio Rotondo BSc Research Associate, Laboratory Manager, Department of Laboratory Medicine, Division of Pathology and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada. Conflicts of interest: none declared. Kalman Kovacs MD PhD Professor Emeritus, Department of Laboratory Medicine, Division of Pathology and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada. Conflicts of interest: none declared. rta Korbonits MD Professor of Endocrinology and Metabolism, Ma Consultant in Endocrinology, Co-Centre Head of Endocrinology, Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK. Conflicts of interest: none declared.
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Figure 1 Pituitary adenomas due to germline mutations.
to medical therapy and have higher recurrence rates.15 PRLproducing adenomas are the most frequent (62e60%), followed by clinically non-functioning adenomas (15%), GHsecreting and ACTH-secreting adenomas.16 The proportion of plurihormonal adenomas and multiple adenomas is significantly higher in MEN1 patients.17 In MEN1 patients with acromegaly and normal or enlarged pituitary gland on MRI, pituitary hyperplasia should be suspected and tumours (usually pancreas) producing a releasing hormone such as GHRH (GH-releasing hormone) must be searched for.17
response to somatostatin analogues are poor. GH receptor antagonist treatment has been described successfully.5 AIP & GPR101-mutation negative patients This is the largest group of FIPA cases. The age of onset of disease is similar to that of the sporadic cases, but larger and more invasive tumours have been identified. The tumour types are more varied than in the other types of FIPA: excess GHproducing adenomas still predominates, but the other tumour types represent over one third of the tumour types.13 The affected families can be classified as i) homogenous, if the same type of pituitary adenoma is present, or ii) heterogeneous, if different types of tumours occur within the same family. Penetrance is low, probably lower that of AIP-mutation positive kindreds.12
Carney complex (CNC) CNC (OMIM #160980), is an autosomal dominant syndrome produced by an inactivating mutation of the regulatory subunit 1-a of the protein kinase A (PRKAR1A) (Table 1). Recent studies have associated elements of the CNC phenotype with cAMP-dependent protein kinase catalytic subunit alpha (PRKACA)18 and cAMP-dependent protein kinase catalytic subunit beta (PRKACB)19 gene defects but their precise roles remain to be elucidated.7 CNC is characterized by multiple skin lesions (blue nevus, spotty skin pigmentation and mucosal lentigines), cardiac, breast, cutaneous or mucosal myxomas, acromegaly or mild GH/PRL excess, breast ductal adenoma, psammomatous melanocytic schwannoma, thyroid carcinoma or multiple hypoechoic thyroid nodules, large-cell calcifying Sertoli cell tumours (LCCSCT), osteochondromyxoma and primary pigmented nodular adrenocortical disease (PPNAD).7 The diagnosis can be established when two of the above mentioned features occur, or in the presence of one major feature and PRKR1A mutation or a first-degree relative with CNC. Clinical manifestations are variable even within members of the same family and one third of the patients present as simplex (sporadic) cases. Lentiginosis is the most common feature of CNC (70%) consisting of small, 2e10 mm brown to black maculae on the lips, eyelids, ears and genitals and can be
Multiple endocrine neoplasia type 1 (MEN1) MEN1 (OMIM #131100) is an autosomal-dominant disorder characterized by tumours of the pituitary, parathyroid, endocrine cells of the gastrointestinal tract, endocrine pancreas and adrenal cortex.4 MEN1, a tumour suppressor gene localized on chromosome 11q13, encodes menin, a nuclear protein involved in transcriptional regulation, genome stability, cell division and proliferation (Table 1). Patients with MEN1 syndrome usually have a positive family history and MEN1 gene mutations can be identified in 70%e95% of patients.4 Clinical diagnosis is established when at least two of these features are present or when one feature is present together with a first-degree relative with established MEN1. Pituitary tumours in MEN1 syndrome patients can be documented in 10%e60% of cases and can be the first clinical manifestation in up to 25% of the cases. Pituitary adenomas associated with MEN1 differ from sporadic tumours.15 MEN1-related pituitary adenomas are usually diagnosed at an earlier age, they are frequently macroadenomas, often resistant
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Bioinformatic resources for common familial pituitary adenomas OMIM
Gene
Localization UNIPROT
Familial isolated pituitary adenomas (FIPA) FIPA#102200 AIP 11q13.2 AIP https://omim.org/ entry/102200
FIPA-X- #300942 LAG https://omim.org/ entry/300942
Multiple endocrine neoplasia MEN1 #131100 https://omim.org/ entry/131100 MEN4
GPR101 Xq26.3
MEN1
11q13.1
#610755 CDKN1B 12p13.1 http://www.omim.org/ entry/610755
Carney complex CNC #160980 https://omim.org/ entry/160980
PRKAR1A 17q24.2
*601639 PRKACA 19p13.12 http://www.omim.org/ entry/601639
PRKACB 1p36.1 *176892 http://www.omim.org/ entry/176892
DICER1 syndrome DICER1 #601200 DICER1 http://www.omim.org/ entry/601200
STRING
GeneReviews
O00170 AH receptor-interacting protein http://www.uniprot.org/ uniprot/O00170 Q96P66 Probable G-protein coupled receptor 101 http://www.uniprot.org/ uniprot/Q96P66
http://string-db.org/ http://www.ncbi.nlm.nih.gov/ newstring_cgi/show_network_ books/NBK97965/ section.pl?identifier¼9606. ENSP00000279146
O00255 Menin http://www.uniprot.org/ uniprot/O00255 P46527 (protein also called p27) Cyclin-dependent kinase inhibitor 1B http://www.uniprot.org/ uniprot/P46527
http://string-db.org/ newstring_cgi/show_network_ section.pl?identifier¼9606. ENSP00000337088 http://string-db.org/ newstring_cgi/show_network_ section.pl?identifier¼9606. ENSP00000228872
P10644 cAMP-dependent protein kinase type I-alpha regulatory subunit http://www.uniprot.org/ uniprot/P10644 P17612 cAMP-dependent protein kinase catalytic subunit alpha http://www.uniprot.org/ uniprot/P17612 P22694 cAMP-dependent protein kinase catalytic subunit beta http://www.uniprot.org/ uniprot/P22694
http://string-db.org/ http://www.ncbi.nlm.nih.gov/ newstring_cgi/show_network_ books/NBK1286/ section.pl?identifier¼9606. ENSP00000351410
14q32.13
Q9UPY3 Endoribonuclease Dicer http://www.uniprot.org/ uniprot/Q9UPY3 Succinate dehydrogenase complex genes syndrome (SDHx) SDHB #115310 SDHB 1p36.13 P21912 http://www.omim.org/ Succinate dehydrogenase entry/115310 [ubiquinone] iron-sulfur subunit, mitochondrial http://www.uniprot.org/ uniprot/P21912 SDHC SDHC 1q23.3 Q99643 Succinate dehydrogenase
http://string-db.org/ newstring_cgi/show_network_ section.pl?identifier¼9606. ENSP00000298110
http://www.ncbi.nlm.nih.gov/ books/NBK1538/
http://www.ncbi.nlm.nih.gov/ books/NBK1538/
http://string-db.org/ http://www.ncbi.nlm.nih.gov/ newstring_cgi/show_network_ books/NBK1286/ section.pl?identifier¼9606. ENSP00000309591 http://www.ncbi.nlm.nih.gov/ http://string-db.org/ newstring_cgi/show_network_ books/NBK1286/ section.pl?identifier¼9606. ENSP00000359719
http://www.ncbi.nlm.nih.gov/ http://string-db.org/ newstring_cgi/show_network_ books/NBK196157/ section.pl?identifier¼9606. ENSP00000343745 http://string-db.org/ http://www.ncbi.nlm.nih.gov/ newstring_cgi/show_network_ books/NBK1548/ section.pl?identifier¼9606. ENSP00000364649
http://string-db.org/ http://www.ncbi.nlm.nih.gov/ newstring_cgi/show_network_ books/NBK1548/ (continued on next page)
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Table 1 (continued ) OMIM
Gene
Localization UNIPROT
#605373 http://www.omim.org/ entry/605373 SDHD
#168000 SDHD http://www.omim.org/ entry/168000
11q23.1
SDHA
#614165 SDHA http://www.omim.org/ entry/614165
5p15.33
SDHAF2 *613019 SDHAF2 11q12.2 http://www.omim.org/ entry/613019
McCuneeAlbright syndrome MAS #174800 GNAS http://www.omim.org/ entry/174800
20q13.32
STRING
GeneReviews
cytochrome b560 subunit, mitochondrial http://www.uniprot.org/ uniprot/Q99643 O14521 Succinate dehydrogenase [ubiquinone] cytochrome b small subunit, mitochondrial http://www.uniprot.org/ uniprot/O14521 P31040 Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial http://www.uniprot.org/ uniprot/P31040 Q9NX18 Succinate dehydrogenase assembly factor 2, mitochondrial http://www.uniprot.org/ uniprot/Q9NX18
section.pl?identifier¼9606. ENSP00000356953
P63092 Guanine nucleotide-binding protein G(s) subunit alpha isoforms short http://www.uniprot.org/ uniprot/P63092
http://string-db.org/ http://www.ncbi.nlm.nih.gov/ newstring_cgi/show_network_ books/NBK274564/ section.pl?identifier¼9606. ENSP00000360141
http://string-db.org/ http://www.ncbi.nlm.nih.gov/ newstring_cgi/show_network_ books/NBK1548/ section.pl?identifier¼9606. ENSP00000364699
http://string-db.org/ http://www.ncbi.nlm.nih.gov/ newstring_cgi/show_network_ books/NBK1548/ section.pl?identifier¼9606. ENSP00000264932
http://string-db.org/ http://www.ncbi.nlm.nih.gov/ newstring_cgi/show_network_ books/NBK1548/ section.pl?identifier¼9606. ENSP00000301761
OMIM: Online Mendelian Inheritance in Man; UNIPROT: Universal Protein Resource; STRING: Search Tool for the Retrieval of Interacting Genes/Proteins.
Table 1
present at birth and acquire their clinical characteristics at puberty.7 ACTH independent Cushing’s syndrome due to primary pigmented nodular adrenocortical disease (PPNAD) is the main endocrine manifestation (60%) followed by acromegaly due to pituitary adenoma or adenohypophysial hyperplasia.
Multiple endocrine neoplasia type 4 (MEN4) An MEN1-like syndrome has been identified in a small group of human patients caused by mutations in the cell cycle inhibitor CDKN1B coding for p27 protein. This condition was named MEN48 (OMIM #610755) (Table 1). The most common tumour
Figure 2 Growth hormone (GH)-producing pituitary adenoma. There is no difference between the familial and non-familial pituitary adenomas. Morphology is not a useful tool to differentiate between familial and non-familial cases. (a). H&E. Magnification: 100. (b) GH stain. Magnification: 250.
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Figure 3 Pituitary Blastoma. (a) H&E. A combination of Rathke-type epithelial rosettes, small primitive appearing cells and secretory cells. Magnification: 250. (b) GH stain. Magnification: 400. (c) ACTH stain. Magnification: 400. (d) A corticotroph containing cytokeratin filaments as well as glycogen is actually part of a well-defined follicle. Magnification: 15,000. (e) An example of follicle comprising differentiating and undifferentiated cells. Magnification: 10,000.
type is somatotropinoma and a childhood-onset case has also been described. Mutation types include frameshift, nonsense and missense mutations and interestingly, two patients have been described with mutation affecting the 50 open reading frame.8,20 Other tumours described in patients with MEN4 includes parathyroid adenomas as well as renal angiomyolipoma, an adrenal non-functional tumour, uterine fibroids, gastrinoma, neuroendocrine cervical carcinoma, bronchial carcinoid, papillary thyroid carcinoma and gastric carcinoma. Other cell cycle inhibitors, such as p15 (CDKN2B), p18 (CDKN2C ) and p21 (CDKN1A) have also been found mutated in a few MEN1 syndrome cases.21
Pituitary blastoma DICER1 syndrome (OMIM #601200), or pleuropulmonary blastoma (PPB) familial tumour and dysplasia syndrome, is caused by heterozygous germline mutations in the DICER1 gene, located in chromosome 14q31 (Table 1). It encodes DICER1, a small RNA processing endoribonuclease that cleaves precursor microRNAs (miRNA) into mature miRNAs. DICER1 mutations are associated with a variety of tumour types (pleuropulmonary blastoma, ovarian sex-cord stromal tumours, cystic nephroma, thyroid nodular hyperplasia, multinodular goiter, thyroid adenomas or differentiated thyroid cancer, ciliary body medulloepithelioma, botryoid-type embryonal rhabdomyosarcoma, nasal chondromesenchymal hamartoma, pituitary blastoma and pineoblastoma) and can be considered a tumour predisposition syndrome with typical agespecific presentation.22 It has been proposed, that if a second somatic mutation e a second “hit” e occurs in the RNase IIIb domain of DICER1 in a pituitary cell, then a pituitary blastoma develops.10 Pituitary blastoma has been identified as a distinct entity. It is an early childhood invasive neoplasm arising within the foetal adenohypophysis consisting of a combination of Rathke-type epithelial rosettes, small primitive appearing cells and secretory cells (Figure 3). The latter are immunopositive for synaptophysin and chromogranin and express adrenocorticotrophc hormone (ACTH), or less commonly GH.10 Patients with pituitary blastoma usually present in neonatal or early childhood age as Cushing’s disease and a sellar tumour usually extending to the suprasellar and parasellar regions. Ophthalmoplegia and strabismus are present in almost 50% of the cases. Mortality rate is approximately 40%. Pituitary blastoma can be considered a pathognomonic manifestation
Figure 4 SDH-x related adenoma. H&E stain. A SDH-x related pituitary adenoma showing prominent vacuolar changes in most cells, an interesting feature seen in some of these cases. Magnification: 400.
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of a germline DICER1 mutation and even in the absence of genetic diagnosis, other DICER1-related tumours should be in the patient and family.10
2 Lecoq AL, Kamenicky P, Guiochon-Mantel A, Chanson P. Genetic mutations in sporadic pituitary adenomas-what to screen for? Nat Rev Endocrinol 2015; 11: 43e54. 3 Daly AF, Tichomirowa MA, Petrossians P, et al. Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study. J Clin Endocrinol Metabol 2010; 95: E373e83. 4 Thakker RV. Multiple endocrine neoplasia type 1 (MEN1). Best Pract Res Clin Endocrinol Metab 2010; 24: 355e70. 5 Beckers A, Lodish MB, Trivellin G, et al. X-linked acrogigantism syndrome: clinical profile and therapeutic responses. Endocr Relat Cancer 2015; 22: 353e67. 6 Trivellin G, Daly AF, Faucz FR, et al. Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. N Engl J Med 2014; 371: 2363e74. 7 Correa R, Salpea P, Stratakis CA. Carney complex: an update. Eur J Endocrinol 2015; 173: M85e97. 8 Occhi G, Regazzo D, Trivellin G, et al. A novel mutation in the upstream open reading frame of the CDKN1B gene causes a MEN4 phenotype. PLoS Genet 2013; 9: e1003350. 9 Xekouki P, Szarek E, Bullova P, et al. Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice. J Clin Endocrinol Metabol 2015; 100: E710e9. 10 de Kock L, Sabbaghian N, Plourde F, et al. Pituitary blastoma: a pathognomonic feature of germ-line DICER1 mutations. Acta Neuropathol 2014; 128: 111e22. 11 Salpea P, Stratakis CA. Carney complex and McCune Albright syndrome: an overview of clinical manifestations and human molecular genetics. Mol Cell Endocrinol 2014; 386: 85e91. 12 Leontiou CA, Gueorguiev M, van der Spuy J, et al. The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas. J Clin Endocrinol Metabol 2008; 93: 2390e401. 13 Hernandez-Ramirez LC, Gabrovska P, Denes J, et al. Landscape of familial isolated and young-onset pituitary adenomas: prospective diagnosis in AIP mutation carriers. J Clin Endocrinol Metabol 2015; jc20151869. 14 Rostomyan L, Daly AF, Petrossians P, et al. Clinical and genetic characterization of pituitary gigantism: an international collaborative study in 208 patients. Endocr Relat Cancer 2015; 22: 745e57. 15 Toledo SP, Lourenco Jr DM, Toledo RA. A differential diagnosis of inherited endocrine tumors and their tumor counterparts. Clinics (Sao Paulo, Brazil) 2013; 68: 1039e56. 16 de Laat JM, Dekkers OM, Pieterman CR, et al. Long-term natural course of pituitary tumors in patients with MEN1: results from the DutchMEN1 study group (DMSG). J Clin Endocrinol Metabol 2015; 100: 3288e96. 17 Trouillas J, Labat-Moleur F, Sturm N, et al. Pituitary tumors and hyperplasia in multiple endocrine neoplasia type 1 syndrome (MEN1): a case-control study in a series of 77 patients versus 2509 non-MEN1 patients. Am J Surg Pathol 2008; 32: 534e43. 18 Lodish MB, Yuan B, Levy I, et al. Germline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: molecular mechanisms and clinical presentations. Eur J Endocrinol 2015; 172: 803e11. 19 Forlino A, Vetro A, Garavelli L, et al. PRKACB and carney complex. N Engl J Med 2014; 370: 1065e7.
Pheochromocytoma/paraganglioma e pituitary adenoma syndrome Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase or mitochondrial complex II, is a multimeric enzyme bound to the inner mitochondrial membrane. It transfers electrons directly to the ubiquinone pool in Krebs cycle and the respiratory chain (Table 1). SDH consists of hydrophilic subunits, a flavoprotein (SDHA), and an iron-sulfur protein (SDHB), which form the catalytic core of the enzyme. The two hydrophobic subunits, SDHC and SDHD, anchor the homotetramer to the membrane. Mutations in genes coding for SDHA, SDHB, SDHC, SDHD and SDHAF2 (known collectively as SDHx) have been identified in familial paragangliomas (PGLs) and pheochromocytomas (PHEOs) and recently pituitary adenomas9,23 were added to the increasing list of SDH-associated tumour types24 (Figure 4). Based on the SDHx mutation-associated w15 cases reported, PRL-producing pituitary adenomas are the most common followed by GH and clinically non-functional pituitary adenomas. They usually present as macroadenomas with aggressive behaviour and resistant to medical therapy.24
McCuneeAlbright syndrome (MAS) McCuneeAlbright syndrome (OMIM #174800) is a postzygotic mutation in GNAS which encodes the guanine nucleotide-binding protein subunit a isoform short (Gas), leading to somatic mosaicism and activation of the cAMP pathway11 (Table 1). They present with the triad of polyostotic fibrous dysplasia of bone, cafe au-lait skin pigmentation, and precocious puberty. The pituitary gland is also affected in McCuneeAlbright syndrome cases and acromegaly is present in 20e30% of the cases.25
Conclusion Although individual families were known since the 18th century, attention was only recently turned to familial pituitary adenomas. There are several distinct, well-defined syndromes differing in genetic alterations, penetrance, clinical presentation, endocrine changes and morphology. Our review focuses on germline genetic alterations which are of crucial importance causing the disease and making a conclusive diagnosis. Familial pituitary adenomas should be recognized not only to select the most effective therapy but also because it provides the opportunity to diagnose family members in the early phase of the disease when clinical symptoms are not yet evident. Genetic testing and careful morphologic investigation are necessary to make the proper diagnosis. Although progress was remarkable, many details including frequency, genetic changes and tumour progression are still obscure and more work is needed to better understand familial pituitary adenomas. A
REFERENCES 1 Melmed S. Pathogenesis of pituitary tumors. Nat Rev Endocrinol 2011; 7: 257e66.
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20 Sambugaro S, Di Ruvo M, Ambrosio MR, et al. Early onset acromegaly associated with a novel deletion in CDKN1B 5’UTR region. Endocrine 2015; 49: 58e64. 21 Agarwal SK, Mateo CM, Marx SJ. Rare germline mutations in cyclin-dependent kinase inhibitor genes in multiple endocrine neoplasia type 1 and related states. J Clin Endocrinol Metabol 2009; 94: 1826e34. 22 Slade I, Bacchelli C, Davies H, et al. DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome. J Med Genet 2011; 48: 273e8. 23 Denes J, Swords F, Rattenberry E, et al. Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort. J Clin Endocrinol Metabol 2015; 100: E531e41. 24 O’Toole SM, Denes J, Robledo M, Stratakis CA, Korbonits M. 15 YEARS OF PARAGANGLIOMA: the association of pituitary adenomas and phaeochromocytomas or paragangliomas. Endocr Relat Cancer 2015; 22: T105e22. 25 Salenave S, Boyce AM, Collins MT, Chanson P. Acromegaly and McCuneeAlbright syndrome. J Clin Endocrinol Metabol 2014; 99: 1955e69.
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Authors are grateful to the Jarislowsky and Lloyd Carr-Harris Foundations for their support.
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While the majority of pituitary adenomas are sporadic tumours, some of them are associated with familial syndromes with different genetic background and variable phenotype. The two most frequently seen forms are familial isolated pituitary adenoma (FIPA) and multiple endocrine neoplasia type 1 (MEN1). Uncommon forms include X-linked acrogigantism (X-LAG) syndrome, Carney complex (CNC), multiple endocrine neoplasia type 4 (MEN4), somatotropinoma/paraganglioma and pituitary blastoma. Young pituitary adenoma patients should be assessed for a genetic predisposition for pituitary adenomas. FIPA represents families with two or more members with pituitary adenomas. Three subgroups can be identified: AIP-mutation positive, GPR101-mutation positive X-linked acrogigantism (XLAG) and the AIP&GPR101-negative cases. Comparing with sporadic cases, MEN1-related pituitary adenomas are usually diagnosed at earlier ages, they are frequently macroadenomas, often resistant to medical therapy and have high recurrence rates. Pituitary blastoma is an early childhood invasive neoplasm arising within the foetal adenohypophysis. It occurs when a second somatic mutation e a second “hit” e occurs in patients with DICER1 syndrome. Mutations in genes coding for SDHA, SDHB, SDHC, SDHD and SDHAF2 (known collectively as SDHx) have been identified in familial paragangliomas (PGLs) and pheochromocytomas (PHEOs) and recently pituitary adenomas.
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