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Familial Isolated Pituitary Adenomas
also positive for AIP mutations. Mutations of AIP have mainly been found Figure 1: Familial Acromegaly in Two French Brothers
in families with either pure somatotroph adenomas or families with
mixed somatotroph and lactotroph adenomas. Interestingly, none of the
pure prolactinoma families have AIP mutations, and no AIP mutation has
been found in a known FIPA family with at least one member not having
either a somatotroph or lactotroph adenoma. Pituitary adenoma tissue
has also been studied for AIP mutations in cases where the DNA
extracted from blood (germline) is negative, but has never revealed any
AIP mutations.
9,13
Tumors with AIP mutations are diagnosed in subjects at significantly
younger ages, and are larger than those found in FIPA patients without
AIP mutations, as well as those found in patients with sporadic
tumors.
9,10,12
Patients with an AIP mutation have a mean age of diagnosis
of 25 years compared with 40 years for those without AIP
mutations.
9,10,12
The youngest patient described as having AIP mutations
is six years old (unpublished data), and around two-thirds of patients
with AIP mutations are diagnosed at 25 years of age or under.
9,10,12
AIP
mutation patients have larger pituitary tumors, suggesting more
aggressive disease.
10
In our cohort, a poor biochemical response to
somatostatin analogs (<50% reduction in growth hormone [GH]/
insulin-like growth factor 1 [IGF-I]) occurred in eight of the 15 patients
with familial acromegaly.
Due to limited genealogical data, the exact penetrance (proportion
of individuals with the mutation who develop the disease) of
pituitary tumors is difficult to calculate accurately. However, a best
estimate emerges from the largest well-studied family with an AIP Two brothers, 226cm (1887–1914) and 231cm (1876–1916) tall, are shown with their siblings and
mutation: one-third of individuals (three of nine subjects with
their family tree. Source: Dr WW de Herder.
AIP mutations) developed pituitary tumors at the time of the study.
14
We
find similar penetrance in our largest family with Figure 2: AIP Gene and AIP ProteinAIP mutations.
Chr 11q13.1
AIP Mutations Described
The AIP protein was thought to be associated with the receptor of an
environmental toxin and with a protein important in cyclic adenosine
monophosphate (cAMP) degradation (a second messenger signalling
molecule in the cell). Currently, it is unclear which mechanism leads to 1 2 3 4 5 6
DNA
pituitary tumorigenesis in patients with AIP mutations. Forty-one AIP
mutations have been identified to date, including deletions, insertions,
segmental duplications, non-sense and missense mutations, and large
deletions. Mutations usually disrupt the structure of the end of
the protein molecule that plays a major role in the functioning of the
AIP
protein
molecule. Most studies have used sequencing methods with
1 330
AIP
primers covering just the exons and the area around them. However, a
The aryl hydrocarbon receptor interacting protein (AIP) gene is located on the long arm of the
new technique called multiplex ligation-dependent probe amplification
11th chromosome at the band named 11q13.1. The gene consists of so-called exons, which will
(MLPA) reveals large genomic rearrangements in families who
be translated to a protein of 330 amino acids.
previously may have tested negative for germline AIP mutations by
conventional sequencing.
15
using MLPA. A best estimate is provided by the three largest FIPA family
cohorts,
7,9–12
suggesting that 20% of all FIPA families have AIP mutations.
Prevalence of AIP Mutations in Familial Isolated Looking only at families with acromegaly, 21 of 53 (40%) families have an
Pituitary Adenoma Families AIP mutation.
Out of more than 170 FIPA families described in the literature, 30
families have been reported as having 24 different types of AIP Prevalence of AIP Mutations in
mutations. However, the prevalence of AIP mutations is difficult to ‘Apparently’ Sporadic Patients
assess because not all of the reported FIPA families have been Several studies have searched for AIP mutations in sporadic pituitary
sequenced for AIP mutations, and the vast majority were not tested adenoma patients, i.e. in patients with no family history of
US ENDOCRINOLOGY 105
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