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Pituitary Disorders
Figure 1: Familial Acromegaly in Two French Brothers Due to limited genealogical data, the exact penetrance (proportion of
individuals with the mutation who develop the disease) of pituitary
tumours is difficult to calculate accurately. However, a best estimate
emerges from the largest well-studied family with an AIP mutation:
one-third of individuals (three of nine subjects with AIP mutations)
developed pituitary tumours at the time of the study.
14
We find similar
penetrance in our largest family with AIP mutations.
AIP Mutations Described
The AIP protein was thought to be associated with the receptor of an
environmental toxin and with a protein important in cAMP
degradation (a second messenger signalling molecule in the cell).
Currently, it is unclear which mechanism leads to 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 key role in the functioning of the
molecule. Most studies have used sequencing methods with AIP
primers covering just the exons and the area around them. However,
a new technique called multiplex ligation-dependent probe
amplification (MLPA) reveals large genomic rearrangements in
families who previously may have tested negative for germline AIP
mutations by conventional sequencing.
15
Prevalence of AIP Mutations in Familial
Isolated Pituitary Adenoma Families
Two brothers, 226cm (1887–1914) and 231cm (1876–1916) tall, are shown with their siblings Out of more than 170 FIPA families described in the literature, 30
and their family tree. Source: Dr WW de Herder.
families have been reported as having 24 different types of AIP
mutations. However, the prevalence of AIP mutations is difficult to
Figure 2: AIP Gene and AIP Protein
assess because not all of the reported FIPA families have been
sequenced for AIP mutations, and the vast majority were not tested
Chr 11q13.1
using MLPA. A best estimate is provided by the three largest FIPA
family cohorts.
7,9–12
Out of all 136 FIPA families sequenced for AIP, there
are 27 (20%) families with AIP mutations. Looking only at families with
acromegaly, 21 of 53 (40%) families have an AIP mutation.
1 2 3 4 5 6
Prevalence of AIP Mutations in
‘Apparently’ Sporadic Patients
Several studies have searched for AIP mutations in sporadic
pituitary adenoma patients, i.e. in patients with no family history of
AIP
pituitary disease.
7,9,11,13,16–24
About 2% of these patients have an AIP
1
12 90
mutation in their DNA (27 of 1,100 sporadic pituitary adenoma
182 215 234 267 301 330
The AIP gene is located on the long arm of the 11th chromosome at the band named
11q13.1. The gene consists of so-called exons, which will be translated to a protein of
Forty-one AIP mutations have been330 amino acids.
Tumours with
identified to date, including deletions,
AIP mutations are diagnosed in subjects at
significantly younger ages, and are larger than those found in FIPA
insertions, segmental duplications,
patients without AIP mutations, as well as those found in patients
with sporadic tumours.
9,10,12
Patients with an
non-sense and missense mutations
AIP mutation have a
mean age of diagnosis of 25 years compared with 40 years for those
and large deletions.
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 patients). When the tumour tissue itself is studied in pituitary
age or under.
9,10,12
AIP mutation patients have larger pituitary adenoma samples, no somatic AIP mutations are found, i.e. no
tumours, suggesting more aggressive disease.
10
In our cohort, a poor changes in the tumour itself.
9,13
Most patients with AIP mutations in
biochemical response to somatostatin analogues (<50% reduction in the ‘apparently’ sporadic cohort have a diagnosis of acromegaly,
growth hormone [GH]/insulin-like growth factor 1 [IGF-I]) occurred but there are two reported cases of mutations in patients with
in eight of the 15 patients with familial acromegaly. Cushing’s disease.
11,19
56 EUROPEAN ENDOCRINOLOGY
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