Familial pituitary adenomas.

Abstract

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.

Full text

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doi: 10.1111/j.1365-2796.2009.02109.x
Familial pituitary adenomas
M. A. Tichomirowa, A. F. Daly & A. Beckers
From the Department of Endocrinology, Centre Hospitalier Universitaire de Lie `ge, University of Lie `ge, Domaine Universitaire
du Sart-Tilman, Lie `ge, Belgium
Abstract. Tichomirowa MA, Daly AF, Beckers A
(Centre Hospitalier Universitaire de Lie `ge, University
of Lie `ge, Lie `ge, Belgium). Familial pituitary adenomas
(Review). J Intern Med 2009; 266: 5–18.
The majority of pituitary adenomas occur sporadi-
cally, 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 clini-
cal 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⁄moleculardatathat
reported.
havebeenrecently
Keywords:
tary adenomas, multiple endocrine neoplasia type 1,
pituitary adenoma.
Carney’s complex, familial isolated pitui-
Introduction
Pituitary adenomas are an important and frequently
occurring form of intracranial tumour, comprising up
to 10–15% of intracranial tumours at surgery and
6–23% of intracranial tumours at autopsy [1]. They
comprise 20% of all primary brain and central ner-
vous system tumours and are the second most
common type overall by histology in young adults
(20–34 years) according to the Central Brain Tumor
Registry of the United States (CBTRUS) [2]. In a rig-
orous cross-sectional epidemiological study of preva-
lence, we showed that clinically relevant pituitary
tumours occur in about 1 : 1000 people, supporting
the view that pituitary tumours are a major burden on
the population [3]. They are usually benign but can
give rise to severe clinical syndromes due to hor-
monal excess, or to visual⁄cranial disturbances due to
mass effect. The clinical importance of pituitary ade-
nomas together with their peculiar biological charac-
teristics and the complex regulation of the anterior
pituitary have made these tumours the subject of
intensive studyfor many
causative genes or molecular pathways are known
to be responsible for the pathogenesis of pituitary
adenomas.
years.However,few
Pituitary tumorigenesis
The monoclonality of pituitary adenomas is still a
widely accepted model, according to which genetic
events in one cell transform it and trigger adenoma
formation. At the tissue level, however, the picture
can be more complex, as a single pituitary can con-
tain multiple tumours or hyperplastic areas, each
with its own clonal origin. The development of a
pituitary adenoma has been shown in a proportion
of cases to be dependent on the activities of a vari-
ety of oncogenes and tumour suppressor genes
(Table 1).
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The most important oncogene involved in sporadic
pituitary tumourigenesis is gsp, which encodes the Gsa
subunit, a stimulatory guanine binding protein that
regulates hypothalamic growth hormone-releasing hor-
mone (GHRH) effects in somatotropes. Mutations in
gsp are most closely associated with somatotropino-
mas, and they are found to occur in up to 40% of these
tumours [4]. Activating mutations in Gsa inhibit GTP
hydrolysis and maintain Gsa in a constitutively acti-
vated state. Whilst Gsa is expressed monoallelically in
the normal pituitary, it is biallelically expressed in
tumours and in some adenomas a mutation has been
identified on the maternal allele [5]. The oncogene ras
has also been implicated in pituitary tumourigenesis,
although in a very small number of cases. Mutations in
ras appear to be associated with high levels of tumour
aggression and occur amongst rare pituitary carcino-
mas [6, 7]. Cyclin D1 plays an important role in the
regulation of cell progression through the G1 phase of
the cell [8] and is disrupted in a proportion of pituitary
tumours. Cyclin D1 is overexpressed in ?70% of the
nonfunctioning tumours and in?40% of somatotropi-
nomas [9]. Pituitary tumour transforming gene (PTTG)
or securin is usually poorly expressed in normal pitui-
tary, but is upregulated in most pituitary tumour types,
especially in aggressive hormone-secreting pituitary
tumours [10]. Possible mechanisms of securin⁄PTTG
action are via activation of bFGF, a potent mitogenic
and angiogenic factor [11], or through activation of the
c-myc oncogene [12]. In addition, securin is involved
in sister chromatid separation and possibly its onco-
genic potential resides in its ability to block chromatid
separation, resulting in increased chromosomal insta-
bility [13].
Table 1 Germline and somatic genetic abnormalities associated with pituitary adenomas. Genes associated with familial pituitary
adenomas shown in bold
GeneDefect
Germline mutations and loss of heterozygosity in 15% of FIPA cases. Seen in familial⁄sporadic AIP
somatotropinomas, somatolactotrope adenomas, prolactinomas, nonsecreting adenomas, and Cushing’s
disease
BMP-4
CDKN1B (p27Kip1)
CDKN2A (p16INK4A)
CDKN2C (p18INK4C)
Diminished expression in prolactinoma
Germline heterozygous nonsense mutation in MEN4, a novel, rare MEN1-like syndrome
Promoter methylation in pituitary adenomas
Promoter methylation in pituitary adenomas
Cyclin D1 Overexpression in nonsecreting adenomas and somatotropinomas
GADD45G Promoter methylation in nonsecreting adenomas, prolactinomas, and somatotropinomas
Gsp Somatic activating mutations in up to 40% of somatotropinomas
Mosaicism in McCune–Albright syndrome (somatotropinoma, somatomammotropinoma, and Cushing’s
syndrome in association with precocious puberty, hyperthyroidism, and dermal and bony lesions)
MEG3aPromoter methylation in nonsecreting adenomas and gonadotropinomas
MEN1Inactivating mutations in all pituitary adenoma types
p53Somatic inactivating mutations and overexpression in pituitary carcinomas
Pdt-FGFR4Alternative transcription initiation in pituitary adenomas
PKCPoint mutations in invasive pituitary adenomas
PRKAR1A Truncating mutations in Carney’s complex leading to somatolactotrope hyperplasia and adenomas
PTTG Increased expression in more aggressive pituitary tumours
RASSomatic activating mutations in pituitary carcinomas
RetinoblastomaPromoter methylation in pituitary adenomas
WIF 1Promoter methylation in pituitary adenomas
ZAC Promoter methylation in nonfunctioning adenomas
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Mutations in tumour suppressor genes have been
identified in the setting of pituitary adenomas. The
best known amongst these is the gene MEN1 that is
responsible for multiple endocrine neoplasia type 1
(MEN1) and which is discussed in detail below. Het-
erozygotic retinoblastoma gene (Rb) mutation status is
associated with the development of pituitary adeno-
mas derived from the intermediate lobe in mice [14,
15]. However, in humans the role of Rb is less cer-
tain. Somatic Rb loss may occur only in invasive pitu-
itaryadenomasand in
carcinomas [16–18], whilst Rb promoter hypermethy-
lation has also been reported [19].
rare casesofpituitary
Cell cycle regulators have also been implicated in
pituitary tumorigenesis and development. p53 encodes
a nuclear protein, which regulates the cyclin-depen-
dent kinase inhibitor (CDK) inhibitor p21. Mice defi-
cient for both Rb1 and p53 develop pituitary tumours
[20]. p53 protein overexpression was found in a small
fraction of invasive adenomas and carcinomas [21],
while abnormal p53 accumulation was described in
high percentage of Cushing’s and in invasive non-
functioning adenomas [22]. Moreover, a recent study
showed p53 mutations in a subset of pituitaries, which
was associated with a high percentage of overexpres-
sion of the p53 protein by tumour cells [23].
In pituitary adenomas, the CDK inhibitors p16 and
p18 can be heavily downregulated due to gene pro-
moter hypermethylation [24–26]. The CDK inhibitor,
p27kip1appears to play an important role in pituitary
tumourigenesis, as evidenced by data that mice with
homozygous deletion of
tumours of the intermediate lobe [27–29]. p27 protein
was reported as being lower in pituitary adenomas
than in normal pituitary [30, 31]. The reduction of
p27 protein was predominant in corticotropinomas
and in metastatic tumours [32]. The relevance of
mutations in the CDKN1B gene that encodes p27kip1
is discussed below as they may be rarely associated
with inherited endocrine tumours, including pituitary
adenomas, in the setting of MEN-4.
p27developpituitary
The protein zinc finger, apoptosis and cell cycle
(ZAC) (encoded by the gene ZAC1) is normally
expressed at high levels in healthy pituitary tissue. In
pituitary adenomas (predominantly
tumours), ZAC expression is strongly reduced. The
somatostatin analogue, octreotide, requires ZAC to
exert its effects in somatotropinomas [33, 34]. MEG3,
a maternal imprinting gene appears to play a role as a
growth suppressor in pituitary tissue; a pituitary-
derived variant is absent from both functional and
nonsecreting pituitary adenomas, potentially due to
promoter hypermethylation [35, 36]. Expression of
the growth arrest and DNA damage-inducible gene
(GADD45G) is decreased in somatotropinomas, pro-
lactinomas and nonfunctioning adenomas [37]. The
mechanism of GADD45G gene silencing is derived
from CpG island promoter methylation [38]. Wnt
inhibitory factor-1 (WIF1) is reduced in pituitary ade-
nomas, specifically in nonfunctioning adenomas, as
a result of promoter methylation. Moreover, overex-
pression of WIF1 in GH3 cells (rat mammosomato-
tropinomas) decreases cell proliferation, suggesting
that WIF1 could be a potential tumour suppressor
gene, particularly in nonfunctioning pituitary tumours
[39].
nonsecreting
Pituitary cells have been shown to produce various
growth factors and cytokines and express their
receptors. These factors may regulate pituitary cell
proliferation and hormone secretion in an auto-
crine⁄paracrine fashion. This has led to the hypothe-
sis that in pituitary adenomas, excessive hormone
production and the loss of growth control is a con-
sequence of altered expression of cytokines⁄growth
factors and⁄or their receptors resulting in distur-
bances of auto-paracrine regulation [40]. Fibroblast
growth factor receptors (FGFR) play a role in the
growth and development of many tissues. A trun-
cated pituitary tumour-derived form of FGFR4 has
been identified in humans and was reported be asso-
ciated with invasive pituitary tumourigenesis in a
transgenic mouse model [41]. Bone morphogenetic
proteins (BMPs), as well as other members of the
TGFb family, transduce signals through Smad4, a
signal cotransducer, which regulates c-myc, a pro-
tooncogene that controls cell cycle and mediates the
effects of TGFb on cell proliferation. BMP-4 is
overexpressed in prolactinomas as compared with
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other tissues [42]. Epidermal growth factor receptor
(EGFR) expression is more frequent in hormonally
active pituitary adenomas, particularly in corticotrop-
inomas,than inthe
tumours, suggesting a role for EGF signalling in the
unbalanced growth of corticotrope tumoural cells,
possibly through the downregulation of p27Kip1pro-
tein levels [43].
nonfunctioningpituitary
Familial pituitary tumour syndromes
Pituitary adenomas that occur in a familial setting
account for no more than 4–5% of all pituitary adeno-
mas. They can be part of established endocrine related
tumour syndromes such as MEN1 or Carney’s com-
plex (CNC).
Multiple endocrine neoplasia type I
Scheithauer et al. estimated that 2.7% of pituitary ade-
nomas were due to MEN1 [44]. Pituitary tumours
occurring in the setting of MEN were first described in
1903 by Erdheim in a patient with adenomas in the
parathyroid and pituitary [45]. Later in the 1950s, Wer-
mer described a family with four sisters affected with
pituitary adenomas, hypercalcaemia and adenomatosis
of the pancreas and gut [46]. Wermer suggested an
autosomal dominant mode of inheritance for this condi-
tion, which would later be termed MEN1.
Multiple endocrine neoplasia type 1 syndrome is an
autosomal dominant condition with high penetrance
that is associated with the occurrence of endocrine-
active parathyroid, enteropancreatic and anterior pitui-
tary tumours, amongst others [47]. Primary hyperpara-
thyroidism is the most common and the first clinical
manifestation of the disease 80–100% of MEN1
patients before the age of 40. Gastrinomas are the
most common of enteropancreatic neuroendocrine
tumours and encountered in 50% of MEN1 cases
before he age of 50 and being the main cause of mor-
bidity and mortality in MEN1 patients [48]. MEN1
associated insulinomas comprise 10–35% of MEN1
cases. Endocrine-inactive tumours, such as, lipomas,
angiofibromas and collagenomas are also a frequent
finding in MEN1.
In 1988, Larsson et al. first linked the MEN1 sus-
ceptibility gene to a locus on chromosome 11q13
[49]. The MEN1 gene was cloned in 1997 [50].
The MEN1 gene has 10 exons of which exons 2–
10 encode a 610 aa nuclear protein, menin [51].
The MEN1 gene has a complex upstream promoter
apparatus,elementsof
menin activity; this echoes the known interactions
of menin itself with the transcription of various
endocrine gene promoters [52–55]. Differential regu-
lation of menin expression in different tissues via
upstream genetic elements may explain in part how
mutations of MEN1 preferentially involve cells of
the endocrine system, despite the fact that menin is
also expressed in a variety of nonendocrine cells
and tissues.
whichare regulated by
Lemos and Thakker undertook a review of the status
of MEN1 in 2008 and reported that 1336 indepen-
dently reported sequence abnormalities in the MEN1
gene have been described [56]. Of these, 1133 were
germline and 203 were somatic MEN1 abnormalities.
Taking discrete individual mutations only, a total of
565 different MEN1 mutations have been described.
These consisted of 41% frameshift mutations, 23%
nonsense mutations, 20% missense mutations and 9%
splice site mutations. Over 70% of MEN1 mutations
would be predicted to cause truncated forms of
menin. Amongst the reported mutations, four each
account for 2.5–5% of cases.
About 70–80% of typical MEN1 families harbour
MEN1 mutations, however, in 20–30% of cases that
are clinically suggestive of MEN1, no MEN1 muta-
tion is found. These patients, sometimes termed as
having ‘MEN1 phenocopy’ can present sporadically
or as part of MEN1 families [57, 58]. In MEN1 muta-
tion positive patients there is no correlation between
genotype and tumoural phenotype.
The biological role of MEN1 appears to be to act as a
tumour suppressor gene, albeit one with an immensely
elaborate series of interactions. Menin potentially
interacts with the promoter regions of thousands of
genes, indicating that it has a wide transcriptional
regulatory role [59–67].
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Pituitary tumorigenesis in MEN1. Menin knockout
(KO) mice have been developed to study tumourigene-
sis [68–70]. Mice that are homozygous KOs for Men1
(Men1) ⁄ )) die as embryos due to widespread and
severe developmental defects [71]. Over a period of
26 months in Men1+ ⁄ )heterozygotic mice, enlarge-
ment of the pars distalis (which corresponds to the
human anterior pituitary) was commonly seen by
13 months. Pituitary tumours were noted in 19% of
mice at 13–18 months, rising to 36.6% at 19–
26 months, whereas wild-type controls did not develop
pituitary tumours. These tumours were more common
in female mice, and over 50% of all pituitary tumours
were carcinomas. Tumours were immunohistochemi-
cally positive for prolactin or GH. Complete or partial
loss of the wild-type Men1 allele occurred in the pitui-
taries of these heterozygotic mice, which is similar to
the situation in humans with MEN1 [70]. In a condi-
tional homozygous model with a Men1) ⁄ )genotype
restricted to the pancreas and the pituitary gland, nor-
mal development was seen but pancreatic hyperplasia
and prolactinomas occurred frequently [72].
MEN1-related pituitary tumours. About 40% of
patients with MEN1 have pituitary adenomas [73–75]
and this is the presenting tumour in about 17% of cases
[76]. Patients who present with a pituitary adenoma do
so 7 years before patients presenting with enteropan-
creatic lesions. Amongst familial MEN1 cases, pitui-
tary disease was significantly more frequent than in
nonfamilial MEN1 cases (59% vs. 34% respectively).
Females with MEN1 have a somewhat increased
chance of having a pituitary adenoma. Prolactinomas
predominate amongst both MEN1 associated and
nonMEN1 pituitary adenomas, and the proportions of
prolactinomas, GH-secreting, adrenocorticotropic hor-
mone (ACTH)-secreting, nonsecreting and co-secreting
adenomas are similar between MEN1 and nonMEN1
patients. MEN1-related prolactinomas are predomi-
nantly macroadenomas (84%) and higher rates of inva-
sion are seen than in nonMEN1 prolactinomas. The
response of MEN1-related prolactinomas to dopamine
agonists is poor, with only 44% of patients being nor-
malized. Pituitary tumours in MEN1 appear to be lar-
ger and more aggressive than in patients without
MEN1 [77], with macroadenomas being present in
85% of the former, compared with only 42% of spo-
radic cases. MEN1-associated pituitary tumours are
significantly more likely to cause signs due to tumour
size and have a significantly lower rate of hormonal
normalisation than nonMEN1 pituitary tumours.
Although MEN1 mutations are found in around 30%
of sporadic enteropancreatic tumours [78] and 20%
of sporadic parathyroid tumours [79], they appear
extremely rarely in nonMEN1 sporadic pituitary ade-
nomas [80–84]. Loss of heterozygosity (LOH) in
11q13 has been described in 5–30% of sporadic pitu-
itary tumours [85], however, the MEN1 gene is not
down regulated in the pituitary tumours [84, 86, 87].
Theodoropoulou et al. found that menin was detect-
able in 67 of 68 sporadic nonMEN1 pituitary
tumours [88]. There is no recognized relationship
between the site or type of genetic mutation in the
MEN1 gene and the expressed MEN1 disease pheno-
type [89], although disease clustering and variations
in severity have been recognized [90]. Such clusters
include the ‘prolactinoma variant’ seen in kindreds
from the Burin peninsula in Canada (MEN1BURIN)
[91, 92] and MEN1TASMANwas described in patients
with prolactinomas and nonfunctioning tumours [74].
Multiple endocrine neoplasia type 4
A MEN-like syndrome (MENX) that occurred sponta-
neously in the rat, and MEN4 that occurred in
humans were reported between 2002 and 2004 [93,
94]. The rat phenotype consisted of multiple neuroen-
docrine cancers that included pheochromocytoma,
medullary thyroid cell neoplasia, parathyroid adeno-
mas, paragangliomas, pancreatic hyperplasia and pitu-
itary adenomas.These
development of early cataracts within a few weeks of
life. MENX was initially mapped to a chromosome 4
locus and was later revealed to occur due to a muta-
tion in the cyclin-dependent kinase n1b (cdkn1b) gene
[95]. In humans the corresponding CDKN1B gene
(which codes for p27kip1) is on chromosome 12 and
Pellagata et al. identified a nonsense mutation in the
CDKN1B gene in a German family exhibiting acro-
megaly, primary hyperparathyroidism, renal angio-
myolipoma, and testicular cancer amongst various
were preceded bythe
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members. A Dutch patient with a pituitary adenoma
(Cushing’s disease), a cervical carcinoid tumour,
hyperparathyroidism and no MEN1 mutation was
found to have a CDKN1B mutation [96]. Several
studies of a population with MEN1 phenotype and no
MEN1 mutation noted no abnormalities in CDKN1B
[97–99], however, three novel mutations (P95S,
5¢UTR-7G>C, and stop>Q) were found in three sus-
pected MEN1 families with parathyroid and other
endocrine lesions without pituitary tumours [100].
Clinical investigation and management of MEN1⁄MEN4
Consensus guidelines for the investigation and man-
agement of MEN1 were developed 10 years ago [47].
Assessment of which patients to test for MEN1 germ-
line mutations depends on their meeting the criteria
for the disease (practically, 2 of the 3 constituent
major affected tissues: parathyroid, enteropancreatic
or pituitary tumours). All adults with MEN1 germline
mutations should have assessment of calcium, para-
thyroid hormone, gastrin and prolactin levels annually.
Less often (every 3–5 years), carriers will need addi-
tional imaging tests to screen for carcinoid, pancre-
atic, pituitary and other tumours. Screening for
anterior pituitary abnormalities and insulinoma has
been recommended as early as age five for children
with positive family history and at 8-years of age for
parathyroid involvement. In cases that are negative
for MEN1 mutation but display a MEN 1 phenotype,
screening for large genomic deletions in the MEN 1
gene, for CDKN1B gene mutations in an investiga-
tional laboratory could be considered. The clinical
treatment of pituitary adenomas in the setting of
MEN1 or MEN4 does not differ in a practical sense
from the management of sporadic pituitary adenomas.
Carney Complex
Carney described a complex of myxomas, spotty pig-
mentation, and endocrine over-activity that included
pituitary adenomas causing acromegaly in four of 40
cases [101]. This condition, termed Carney complex,
is rare and has been described in about 500 people
[102]. CNC is familial in 70% of cases, occurs in all
racial groups and has a slight female preponderance
[103]. Two gene loci have been identified, one on
chromosome 17q22-24 [104]; the other is on chromo-
some 2p16 [105]. The former is associated with the
gene encoding the protein kinase A regulatory subunit
Ia (PRKAR1A); mutations in PRKAR1A have been
identified in up to 60% of CNC patients [106]. Most
PRKAR1A
mutationslead
decreased or absent protein expression and PRKAR1A
haploinsufficiency in CNC tumours [107]. LOH at
17q22-24 and allelic loss have been shown in CNC
tumours, whilst the loss of PRKAR1A function
enhances intracellular response to cAMP in CNC
tumours [108]. In KO mouse models, the Prkar1a) ⁄ )
state is lethal in embryonic life [109, 110]. In heterozy-
gous Prkar1a+ ⁄ )mice, no typical CNC features are
encountered. However, a transgenic mouse with an
antisense PRKAR1A exon 2 construct develops multi-
ple endocrine abnormalities similar to CNC. In mice
carrying a tissue-specific KO of Prkar1a, pituitary ade-
nomas develop more often than in wild-type or in
Prkar1a+ ⁄ )mice. PitKO mice showed GH increases
without development of overt tumours, which mirrors
changes in CNC patients [111].
tomRNA instability,
CNC-related pituitary tumours
The main endocrine abnormalities seen in CNC are
primary pigmented nodular adrenocortical disease
(PPNAD), thyroid tumours and nodules, testicular
tumours [large cell calcifying Sertoli cell tumour
(LCCSCT), Leydig cell tumours] and acromegaly due
to a pituitary adenoma [112]. Acromegaly occurs in
only 10% of cases, but about 75% of patients have
elevations in GH, insulin-like growth factor (IGF)-1
or prolactin levels, or abnormal responses to dynamic
pituitary testing. Tumours in CNC are prolactin and
GH positive, although some also stain positively for
thyroid-stimulating hormone, luteinizing hormone or
alpha-subunit [113]. CNC-related acromegaly is dis-
tinguished by multifocal hyperplasia of somatomam-
motropic cells that includes nonadenomatous pituitary
tissue within the tumours of CNC patients. These
zones of hyperplasia are poorly demarcated and exhi-
bit altered reticulin staining. Electron microscopy
shows that tumours from acromegalic patients with
CNCdemonstrateaheterogeneousintracellular
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structure [114]. Acromegaly in CNC develops insidi-
ously and may begin in apparently normal somato-
mammotropetissuethat
hyperplasia to form GH⁄prolactin-secreting adenomas.
As in MEN1, sporadic pituitary tumours do not exhi-
bit somatic mutations the PRKAR1A gene [115, 116].
undergoes multifocal
Clinical investigation and management of CNC
The diagnosis of CNC is initially a clinical one with
patients having two or more of the following: PPNAD,
cardiac myxoma, cutaneous myxoma, lentigines, blue
naevi, LCCSCT, thyroid nodules⁄tumour, ovarian
cysts, acromegaly, melanotic Schwann cell tumour and
osteochondromyxoma. In patients that meet these crite-
ria for CNC, germline DNA sequencing for mutations
in the PRKAR1A gene should be undertaken. In nega-
tive cases the testing for large genomic deletion⁄dupli-
cation in PRKAR1A gene could be considered in an
investigatory laboratory. Carriers of a PRKAR1A muta-
tion should be screened clinically, hormonally and⁄or
with imaging studies at least yearly for manifestations
of CNC. The treatment of individual manifestations of
CNC do not differ from sporadic cases.
Familial isolated pituitary adenomas
Apart from syndromes with a known genetic patho-
physiology, familial acromegaly has been described
for over a century [117]. Immunohistochemical stud-
ies showed in 57% of cases showed positive prolactin
staining and many of patients were also hyperprolacti-
nemic [118]. The disease is present in 60% of cases
of isolated familial somatotropinoma (IFS) families in
a single generation and is rarely transmitted to the
succeeding generation by an affected person [119].
Genetic linkage studies in familial acromegaly pointed
to a region of chromosome 11q13.1-q13.3 [89, 120,
121]. In 2006 Vierimaa et al. reported that mutations
in the aryl hydrocarbon receptor interacting protein
gene (AIP) on 11q13 occurred in association with
familial acromegaly kindreds [122].
However,
appears too narrow to cover the actual clinical presen-
tation of familial pituitary tumours. In fact, pituitary
thedefinition offamilialacromegaly
tumours of all types can occur in multiple members
of single kindred in the absence of MEN1⁄CNC, a
condition we termed familial isolated pituitary adeno-
mas (FIPA) beginning in 1998–1999 [123]. Our first
single-centre study identified 27 patients in FIPA fam-
ilies, which constituted 1% of our total pituitary ade-
noma patients [124, 125]. Following investigations
amongst tertiary referral centers in France, Italy and
the USA the initial cohort was expanded to 140
patients from 64 FIPA kindreds in 2004–2005 [126].
To date we have identified >130 FIPA kindreds in our
collaborative series [127], and FIPA families have
been reported also by separate research groups [98,
128].
In FIPA, pituitary tumours of the same type can pres-
ent in all affected family members (homogeneous pre-
sentation), or affected members can have different
types of tumours (heterogeneous presentation).[129].
To date, FIPA kindreds with up to four affected mem-
bers (i.e. subjects with pituitary tumours) have been
described. The cohort is comprised equally of families
with homogeneous and heterogeneous tumour types
in affected members. The frequencies of the various
different tumour types in FIPA are: prolactinoma
(41%), somatotropinoma (30%), nonsecreting tumuor
(13%), somatolactotropinoma (7%), gonadotropinoma
(4%), Cushing’s disease (4%) and thyrotropinoma
(1%). First-degree relationship between affected mem-
bers within families occurs in approximately 75% of
FIPA families. FIPA patients present with pituitary
tumours 4 years earlier than their sporadic counter-
parts. In families with multiple affected generations,
the children⁄grandchildren presented significantly ear-
lier (20 years) than their parents⁄grandparents. Mac-
roadenomas are seen in 63% of cases in FIPA
kindreds. In terms of specific tumour types, prolacti-
nomas in FIPA are mainly microadenomas occurring
in women, while males almost invariably have mac-
roadenomas; which largely reflects the characteristics
of sporadic prolactinomas [130]. Prolactinomas in het-
erogeneous FIPA have higher rates of extension and
invasion as compared with sporadic cases. In somato-
tropinoma patients from FIPA families, half occur as
homogeneous acromegaly (familial acromegaly) fami-
lies, and 50% in combination with other tumour types
M. A. Tichomirowa et al.|
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Page 8

(heterogeneous
tumours occur in heterogeneous FIPA families and are
diagnosed 8 years earlier and have a higher rate of
extension⁄invasion than sporadic tumours. Gonado-
tropinomas and Cushing’s disease can occur rarely in
a homogeneous FIPA setting.
families).Nonsecreting pituitary
In 2006, Vierimaa et al. reported the results of a com-
prehensive genetic study that identified mutations in
the AIP gene as being associated with the familial
presentation of somatotropinomas and prolactinomas
[122]. LOH at the AIP locus in tumour samples indi-
cated that these tumours had lost the function of the
normal allele in a ‘second hit’ according the Knudson
model. In the FIPA cohort we studied 73 FIPA fami-
lies and 15% of the cohort had germline mutations in
AIP [131]. Other families tested negative for AIP
mutations. Ten separate mutations were found, one of
which (R304X) was found in a FIPA family that
is apparently unrelated to a family from the same
country (Italy) with the same mutation reported by
Vierimaa et al. Patients with AIP mutations were sig-
nificantly younger at diagnosis (12 years) than FIPA
patients without AIP mutations. Tumours were larger
in the AIP mutation-positive groups versus the
remainder of the cohort. Only 50% of those with
homogeneous acromegaly had AIP mutations. Impor-
tantly, kindreds with strong familiality for pituitary
tumours (3 or 4 affecteds) can be negative for muta-
tions in AIP (and also CDKN1B), which indicates
strongly that other genes may be involved in the cau-
sation of FIPA.
Further analysis of the disease characteristics of FIPA
patients with AIP mutations indicates that tumour and
hormonal data are heterogeneous. Over 60% of AIP
mutation positive patients with somatotropinomas had
increased GH⁄IGF-I only and remaining 38% also
had elevated prolactin. Somatotropinoma patients with
AIP mutations can be immunohistochemically positive
for GH alone (59%), GH and prolactin (33%) or GH
and follicle stimulating hormone (8%).
Since these initial studies, many AIP mutations have
been described in the FIPA setting. FIPA families
with AIP mutations have also been reported by other
groups [132, 133]. A Q14X mutation, although found
with high frequency in Finland, was not found in
populations of sporadic adenomas from across the
world, indicating that it is a founder mutation [134].
Sporadic pituitary tumour patients infrequently have
AIP mutations, but they are not entirely absent [135].
Overall, sporadic pituitary tumour patients with AIP
mutations seem to present at a young age and mainly
withsomatotropinomas,
tumour types do occur [136]. Cazabat et al. reported
that in a total of 154 sporadic patients with acro-
megaly, five patients (3.2%) demonstrated AIP muta-
tions. Studies in other tumours have revealed no firm
evidence of germline AIP mutaions as a potentially
causative factor [137].
althoughother pituitary
The manner by which AIP mutations cause pituitary
adenomas in FIPA and apparently sporadic cases is
largely unknown. Many AIP mutations described to
date would involve truncations of the AIP protein,
with the loss of the a tetratricopeptide repeat domain
and the carboxy terminal that are important for inter-
actions with the other proteins such as heat shock pro-
tein 90 (hsp90) and the aryl hydrocarbon receptor
[138–142]. Other missense mutations (e.g. R271W)
involve highly conserved amino acids, which may
alter AIP function in other ways. Whether various
mutated versions of AIP are actually expressed or
undergo mRNA degradation is unknown at this time.
A variety of cellular effects are potentially related to
AIP activity, of which modulation of phosphodiester-
ase PDE4A5 and phosphodiesterase PDE2A activities
are of interest [143, 144]. Leontiou and colleagues
found that over-expression of wild-type AIP in HEK
293, human embryonic lung fibroblast (TIG 3) and
the rat somatomammotroph (GH3) cell lines led to
marked reductions in measures of cell proliferation.
When R304X and C238Y AIP mutations (described
in the setting of FIPA) were expressed in the cell
lines, suppression of cell proliferation was negated
[98]. Also protein–protein interactions between AIP
and PDE4A5 were disrupted by C238Y, R271W,
R81X, Q217X, and R304X mutations in AIP. Immu-
nohistochemical data revealed that in normal pituitary,
AIP co-localized only with GH and prolactin secreting
cells and was found in association with secretory
M. A. Tichomirowa et al.|
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Page 9

granules. In sporadic tumours AIP is expressed in all
tumour types, however, it was only expressed in
cytoplasmin prolactinomas,
Cushing disease tumours; AIP appeared to co-localize
with secretory granules in somatotropinomas. All
germline AIP mutations reported to present are hetero-
zygous which could be due to the fact that homozy-
gous germline AIP mutations are probably not
compatible with life. Indeed, the study of Aip)⁄ )mice
showed that animals with a homozygous deletion of
this gene die at various time points throughout embry-
onic development due to cardiovascular defects [145].
Recently, mice with a hypomorphic Aip allele that
displays reduced Aip protein expression were gener-
ated. These mice were reported to have defective clo-
sure of ductus venosus [146]. The Aip knockout
model is at an early stage and no specific information
on pituitary status has been reported.
nonfunctioningand
There remains divergence about the penetrance of
pituitary adenomas amongst kindreds with AIP muta-
tions, making the true risk of disease in mutation car-
riers unclear. We suggest that the penetrance of
pituitary diseasein
AIP
kindreds may be relatively high, at least 33% in the
largest kindreds [147].
mutation-bearing FIPA
Clinical investigation and management of FIPA
Overall, management of pituitary tumours in the FIPA
setting does not differ from the management of spo-
radic cases. However, data are still required regarding
the true clinical characteristics of FIPA families with
AIP mutations as cohorts to date have only included
very limited numbers of patients. From a research and a
practical clinical perspective, it is valuable to consider
testing for AIP mutations in at least one affected mem-
ber of all families that meet the definition of FIPA. As
tumours in individuals with AIP mutations are more
aggressive and occur at an earlier age, there is potential
value in identifying carriers for the purpose of perform-
ing magnetic resonance imaging (MRI) and hormonal
testing. In the absence of a tumour on MRI, follow-up
of mutation carriers can be performed on a regular basis
(yearly), relying predominantly on clinical symp-
toms and basal hormonal tests (IGF-I and prolactin).
Evidence to date also suggests that young patients with
aggressive pituitary tumours may be more likely to
carry AIP mutations and testing for AIP mutations
amongst apparently sporadic populations should at this
time be limited to such young cases. It must also be
borne in mind that a minority (15%) of FIPA families
have an AIP mutation, so further in-depth genetic stud-
ies are clearly required to elucidate the pathophysiology
of FIPA comprehensively.
Conflict of interest statement
No conflict of interest was declared.
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Correspondence: A. Beckers, Department of Endocrinology, Centre
Hospitalier Universitaire de Lie `ge, University of Lie `ge, Domaine
Universitaire du Sart-Tilman, 4000 Lie `ge, Belgium.
(fax: +324 366 7261; e-mail: albert.beckers@chu.ulg.ac.be).
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