Arzt E, Bronstein M, Guitelman M (eds): Pituitary Today II: New Molecular, Physiological and Clinical Aspects.

Front Horm Res. Basel, Karger, 2010, vol 38, pp 121126

Pathogenesis of Familial Acromegaly

Mnica R. Gadelhaa,b Lawrence A. Frohmanc
a
Division of Endocrinology, Department of Internal Medicine, Hospital Universitrio Clementino Fraga Filho,
Universidade Federal do Rio de Janeiro, and bInstituto Estadual de Diabetes e Endocrinologia Luiz Capriglione,
Rio de Janeiro, Brazil; cSection of Endocrinology, Department of Medicine, University of Illinois at Chicago,
Chicago, Ill., USA

Abstract
Familial acromegaly may occur as a component of syndromes of multiple endocrine neoplasia or as
isolated familial somatotropinoma (IFS), which is included in the spectrum of familial isolated pitu-
itary adenoma (FIPA). We review the pathogenesis of IFS, from the detection of loss of heterozygos-
ity at chromosome 11q13 and establishment of linkage to this chromosome region to the
description of germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene.
Approximately 40% of IFS families harbor an AIP mutation. In addition, we summarize the clinical
features of IFS families with AIP mutations: The adenomas are diagnosed at a young age and are
larger than in IFS patients without AIP mutations or in sporadic somatotropinomas, indicating more
aggressive disease. Copyright 2010 S. Karger AG, Basel

Somatotropinomas occur with an annual incidence of three cases per million and a
prevalence of 4060 cases per million [1, 2]. Although the majority of GH-secreting
adenomas are sporadic, a small number of somatotropinomas occur with a familial
aggregation as a component of the classic syndromes of multiple endocrine neoplasia
type 1 (MEN-1) and Carney complex (CNC) [3]. The MEN-1 syndrome is inherited
in an autosomal dominant pattern with a high penetrance and is caused by a mutation
in the tumor suppressor MEN-1 gene that is located on chromosome region 11q13.
GH-secreting adenomas occur in approximately 6% of patients with MEN-1. Most
of these adenomas are associated with acromegaly, rather than gigantism, with the
diagnosis being made between 30 and 50 years of age. The clinical characteristics of
acromegaly in MEN-1 patients are similar to those described for sporadic acromegaly
[3]. The CNC exhibits an autosomal dominant inheritance pattern and can be caused
by a mutation in the tumor suppressor PRKAR1A (type 1 alpha regulatory subunit of
protein kinase A) gene located on chromosome region 17q2224 or by a mutation in
a yet unidentified gene located at chromosome region 2p16 [4, 5]. Somatotropinomas
are present in approximately 10% of patients with the CNC and can be associated
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with gigantism or acromegaly [3]. In 2006, patients with the MEN-1 phenotype but
no MEN-1 gene mutation have been described to harbor a germline mutation in the
tumor suppressor p27Kip1 gene, and this condition has been called multiple endocrine
neoplasia type 4 (MEN-4) [68].
Familial acromegaly can also occur as isolated familial GH-secreting adenomas.
This condition is designated isolated familial somatotropinoma (IFS) and is included
in the syndrome of familial isolated pituitary adenoma (FIPA) [9, 10]. Isolated famil-
ial somatotropinoma is, therefore, defined as the occurrence of at least two cases of
acromegaly or gigantism in a family that does not exhibit MEN-1, MEN-4 or CNC.
The transmission pattern of IFS is autosomal-dominant with incomplete penetrance
and, to date, approximately 90 IFS families have been reported in the literature [3,
1113]. In around 70% of patients with IFS, the diagnosis occurs before the age of
30 years [12]. This young age is similar to that described for GH-secreting pituitary
adenomas associated with CNC, but is in contrast to sporadic and MEN-1-associated
somatotropinomas, which typically occurs between 30 and 50 years of age. The vast
majority of IFS adenomas are macroadenomas that exhibit extra-sellar extension [3].

Isolated Familial Somatotropinoma: From Loss of Heterozygosity at Chromosome

Region 11q13 to AIP Gene Mutation

In 1999, we described an IFS family from Brazil that consisted of 13 siblings, 6 of

whom were affected [9]. In addition, the fathers brother died at the age of 18 years
and was suspected of having the disease. All affected members were diagnosed at a
young age, between 13 and 24 years, and 5 of the 6 had aggressive octreotide-resistant
macroadenomas. Molecular analysis revealed loss of heterozygosity on chromosome
region 11q13 (MEN-1 locus) [9], which was previously reported by Yamada et al.
[14] in a Japanese IFS family. However, neither a MEN-1 mutation nor decreased
gene expression were detected [9]. Subsequently, tumor deletion mapping and haplo-
type analyses in the Brazilian family established linkage to chromosome region 11q13
and identified the IFS tumor suppressor gene candidate interval (fig. 1). In addition,
a potential second locus at chromosome region 2p1612 was identified [15]. These
data suggested that a tumor suppressor gene located at chromosome region 11q13 but
distinct from the MEN-1 gene was involved in the pathogenesis of IFS.
Recently, Vierimaa et al. [16] studied two Finnish families with FIPA using chip-
based technologies and genealogic data. One family consisted of patients with
somatotropinomas and prolactinomas, but only the individuals with acromegaly or
gigantism were considered affected for the linkage analysis. The other family exhibited
IFS. The authors found germline mutations in a gene located at chromosome region
11q13 in the IFS candidate interval, the aryl hydrocarbon receptor (AhR)-interacting
protein (AIP) gene (fig. 1). Mutation analysis of the Brazilian family revealed a germline
AIP stop codon mutation (E24X) within exon one (fig. 2) [12]. Because this mutation
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122 Gadelha Frohman

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 Gigantism
Acromegaly
At risk D11S956 2 1 3 4
D11S1335 2 1 3 3
D11S4191 4 3 2 1
D11S1883 1 3 2 4
PYGM 3 2 1 4
D11S4941 3 1 4 2
D11S4908 2 1 2 2
D11S4095 3 1 2 2
INT-2 3 1 2 2

1 2 3 4 5 6 7 8 9 10 11 12 13

D11S956 1 4 2 3 2 4 2 4 1 3 1 3 1 4 2 4 2 4 2 3 2 4
D11S1335 1 3 2 3 2 3 2 3 1 3 1 3 1 3 2 3 2 3 2 3 2 3
D11S4191 3 1 4 2 4 1 4 1 3 2 3 2 3 1 4 1 4 1 4 2 4 1
D11S1883 3 2 1 4 3 4 1 4 3 2 3 4 3 4 1 2 1 4 1 2 1 4
PYGM 2 1 3 4 2 4 3 4 2 1 2 4 2 4 3 1 3 4 3 1 3 4
D11S4941 1 4 3 2 1 2 3 2 1 4 1 2 * 2 3 4 3 2 3 4 3 2
Location of AIP gene D11S4908 1 2 2 2 1 2 2 2 1 2 1 2 1 2 2 2 2 2 2 2 2 2
D11S4095 1 2 3 2 1 2 3 2 1 2 1 2 3 2 3 2 3 2 3 2 3 2
INT-2 1 2 3 2 1 2 3 2 1 2 1 2 3 2 3 2 1 2 3 2 3 2

Fig. 1. Haplotype analysis of the Brazilian family. Numbers indicate allele size for 9 polymorphic
microsatellite markers located at chromosome 11q12.313.3. Open rectangles represent meiotic
recombination events. The markers that are included in the candidate interval are shown in bold (the
centromeric limit of the interval was established with allelotype analysis and the telomeric limit by
the meiotic recombination event present in the haplotype of individual 11 [15]). The location of the
AIP gene is shown. The asterisk denotes an uncommon allele size.

occurs in the 5 region of the gene, the AIP protein is predicted not to be generated.
Approximately 40% of IFS families studied were shown to have an AIP mutation [12].
Therefore, another gene is involved in the pathogenesis of the AIP negative IFS fami-
lies or these families harbor large AIP genomic rearrangements, intronic mutations
leading to abnormal splicing of the exons or promoter mutations. In addition, no
somatic AIP mutation has been found in sporadic somatotropinomas [12], supporting
the involvement of other gene(s) in the pathogenesis of GH-secreting adenomas.

The Aryl Hydrocarbon Receptor Interacting Protein (AIP) Gene

The AIP gene is located in chromosome region 11q13, contains six exons, and encodes
a 330 amino acid chaperone protein. Leontiou et al. [12] demonstrated that the AIP
gene has properties consistent with a tumor suppressor gene since overexpression of the
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Familial Acromegaly 123

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 E24X

1 2 3 4 5 6

a helix
Fig. 2. The AIP gene and the
mutation found in the
AIP TPR1 TPR2 TPR3
Brazilian family. The structure

1
12

90

182

215
234

267

301
330
of the AIP protein is shown at
the bottom.

wild-type AIP decreased cell proliferation in various cell lines. In addition, the authors
showed that the protein derived from the mutant AIP genes completely or partially
loses this function. Among the several possible interacting partners of AIP are AhR and
phosphodiesterase (PDE) isoforms [17, 18]. However, to date, the exact mechanism by
which this chaperone protein causes tumor suppression remains unknown. AIP has
both stimulating and inhibiting effects on the AhR gene, but the importance of these
actions in the process of tumor formation requires further investigation. Alterations
in the cAMP pathway seem to be involved in somatotropinoma pathogenesis: Carney
complex patients have an inactivating mutation in the PRKAR1A gene and up to 40%
of sporadic GH-secreting adenomas have a gsp-activating mutation [4, 19, 20]. In addi-
tion, Leontiou et al. [12] reported that all AIP mutations that they studied led to a dis-
ruption of the interaction between AIP and PDE4A5. Therefore, the AIP interaction
with PDE may be involved in the control of cell proliferation exerted by AIP.
In the normal pituitary, AIP is present only in GH and prolactin cells in which it is
associated with secretory granules. In contrast, AIP is expressed in all types of sporadic
pituitary adenomas. However, AIP is normally colocalized only in sporadic soma-
totropinomas and not in prolactin-, ACTH- and FSH-secreting tumors [12]. Based on
these findings, we can speculate that the AIP tumor suppressor function is primarily
of importance for GH-secreting cells. In prolactinomas, Cushings disease and non-
functioning adenomas, the AIP expression may represent a secondary phenomenon,
a mechanism turned on to control tumor growth. In support of this hypothesis is the
observation that germline AIP mutations occur mainly in typical IFS families or in
FIPA families in which at least one member has a somatotroph adenoma.

Clinical Features of Families with AIP Mutations

Adenomas from IFS families containing an AIP mutation are diagnosed at a young
age; approximately 70% being diagnosed by the age of 25 years. The tumors are larger
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124 Gadelha Frohman

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than in IFS patients without AIP mutations or in sporadic somatotropinomas, indi-
cating more aggressive disease [12]. The Brazilian IFS family, in which we established
linkage to the AIP gene region, may be considered a paradigm of a family containing
an AIP mutation [15]: The index case was diagnosed at 24 years, had a huge mac-
roadenoma that was treated by surgery, radiotherapy and somatostatin analogs. The
other affected members were diagnosed at ages between 1318 years and, except for
one patient who was diagnosed during genetic screening, all had aggressive disease.
These patients were resistant to treatment with octreotide; although whether this is a
characteristic of AIP positive patients as a group requires further investigation.

Conclusion

The spectrum of familial acromegaly has increased over the past decade to include
syndromes associated with multiple endocrine tumors (MEN-1, MEN-4, and CNC)
and FIPA of which IFS constitute the largest subgroup. Although mutations in the
AIP gene have been found in 40% of families with IFS, the genetic abnormalities
in the remaining families are yet to be identified as are their relevance to sporadic
somatotropinomas.

References
1 Alexander L, Appleton D, Hall R, Ross WM,
Wilkinson R: Epidemiology of acromegaly in
Newcastle region. Clin Endocrinol (Oxf) 1980;12:
7179.
2 Etxabe J, Gaztambide P, Latorre P, Vasquez JA:
Acromegaly: an epidemiological study. J Endocrinol
Invest 1993;16:181187.
3 Gadelha MR, Kineman RD, Frohman LA: Familial
somatotropinomas: clinical and genetic aspects.
Endocrinologist 1999;9:277285.
4 Kirschner LS, Carney JA, Pack SD, Taymans SE,
Giatzakis C, Cho YS, Cho-Chung YS, Stratakis
CA: Mutations of the gene encoding the protein
kinase A type I-alpha regulatory subunit in pat-
ients with the Carney complex. Nat Genet 2000;26:
8992.
5 Stratakis CA, Carney JA, Lin JP, Papanicolaou DA,
Karl M, Kastner DL, Pras E, Chrousos GP: Carney
complex, a familial multiple neoplasia and lentigi-
nosis syndrome: analysis of 11 kindreds and linkage
to the short arm of chromosome 2. J Clin Invest
2006;97:699705.
6 Pellegata NS, Quintanilla-Martinez L, Siggelkow H,
Samson E, Bink K, Hofler H, Fend F, Graw J,
Atkinson MJ: Germ-line mutations in p27Kip1
cause a multiple endocrine neoplasia syndrome in
rats and humans. Proc Natl Acad Sci USA 2006;
103:1555815563.
7 Owens M, Stals K, Ellard S, Vaidya B: Germline
mutations in the CDKN1B gene encoding p27Kip1
are a rare cause of multiple endocrine neoplasia
type 1. Clin Endocrinol (Oxf) 2009;70:499500.
8 Igreja S, Chahal HS, Akker SA, Gueorguiev M,
Popovic V, Damjanovic S, Wass JA, Quinton R,
Grossman AB, Korbonits M: Assessment of p27
(cyclin-dependent kinase inhibitor 1B) and AIP
(aryl hydrocarbon receptor-interacting protein)
genes in MEN1 syndrome patients without any
detectable MEN1 gene mutations. Clin Endocrinol
(Oxf) 2009;70:259264.
9 Gadelha MR, Prezant TR, Une KN, Glick RP, Moskal
SF, Vaisman M, Melmed S, Kineman RD, Frohman
LA: Loss of heterozygosity on chromosome 11q13
in two families with acromegaly/gigantism is inde-
pendent of mutations of the multiple endocrine
neoplasia type I gene. J Clin Endocrinol Metab
1999;84:249256.
132.239.1.231 - 6/8/2015 11:03:47 PM
Univ. of California San Diego

Familial Acromegaly 125

Downloaded by:
10 Daly AF, Jaffrain-Rea ML, Ciccarelli A, et al: Clinical
characterization of familial isolated pituitary ade-
nomas. J Clin Endocrinol Metab 2006;91:3316
3323.
11 Daly AF, Vanbellinghen JF, Khoo SK, et al: Aryl
hydrocarbon receptor-interacting protein gene
mutations in familial isolated pituitary adenomas:
analysis in 73 families. J Clin Endocrinol Metab
2007;92:18911896.
12 Leontiou CA, Gueorguiev M, van der SJ, et al: The
role of the AIP gene in familial and sporadic pitu-
itary adenomas. J Clin Endocrinol Metab 2008;93:
23902401.
13 Georgitsi M, Heliovaara E, Paschke R, et al: Large
Genomic Deletions in AIP in Pituitary Adenoma
Predisposition. J Clin Endocrinol Metab 2008;93:
41464151.
14 Yamada S, Yoshimoto K, Sano T, Takada K, Itakura
M, Usui M, Teramoto A: Inactivation of the tumor
suppressor gene on 11q13 in brothers with familial
acrogigantism without multiple endocrine neopla-
sia type 1. J Clin Endocrinol Metab 1997;82:239
242.
15 Gadelha MR, Une KN, Rohde K, Vaisman M,
Kineman RD, Frohman LA: Isolated familial soma-
totropinomas: establishment of linkage to chromo-
some 11q13.111q13.3 and evidence for a potential
second locus at chromosome 2p1612. J Clin
Endocrinol Metab 2000;85:707714.
Mnica R. Gadelha
Hospital Universitrio Clementino Fraga Filho
Rua Professor Rodolpho Paulo Rocco, 255, 9E23 Cidade Universitria Ilha do Fundo
Rio de Janeiro CEP 21941913 (Brasil)
Tel. +55 21 2562 2323, Fax +55 21 2562 2111, E-Mail mgadelha@hucff.ufrj.br
126
16 Vierimaa O, Georgitsi M, Lehtonen R, Vahteristo P,
Kokko A, Raitila A, Tuppurainen K, Ebeling TM,
Salmela PI, Paschke R, Gundogdu S, De ME,
Makinen MJ, Launonen V, Karhu A, Aaltonen LA:
Pituitary adenoma predisposition caused by ger-
mline mutations in the AIP gene. Science 2006;312:
12281230.
17 Carver LA, Bradfield CA: Ligand-dependent inter-
action of the aryl hydrocarbon receptor with a novel
immunophilin homolog in vivo. J Biol Chem 1997;
272:1145211456.
18 Bolger GB, Peden AH, Steele MR, MacKenzie C,
McEwan DG, Wallace DA, Huston E, Baillie GS,
Houslay MD: Attenuation of the activity of the
cAMP-specific phosphodiesterase PDE4A5 by
interaction with the immunophilin XAP2. J Biol
Chem 2003;278:3335133363.
19 Donangelo I, Gadelha M: Bases moleculares dos
adenomas hipofisrios com nfase nos somatotro-
pinomas. Arq Bras Endocrinol Metab 2004;48:464
479.
20 Taboada GF, Tabet ALO, Naves LA, Carvalho DP,
Gadelha MR: Prevalence of gsp oncogene in soma-
totropinomas and clinically non-functioning pitu-
itary adenomas: our experience. Pituitary 2009;12:
165169.
132.239.1.231 - 6/8/2015 11:03:47 PM
Univ. of California San Diego
Gadelha Frohman
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