R93

REVIEW

Novel mutations associated with combined pituitary

hormone deficiency
Christopher J Romero, Elyse Pine-Twaddell and Sally Radovick
Division of Pediatric Endocrinology, Department of Pediatrics, The Johns Hopkins University School of Medicine, 600 North Wolfe Street,
CMSC 406, Baltimore, Maryland 21208, USA

(Correspondence should be addressed to S Radovick; Email: [email protected])

Abstract
The pituitary gland produces hormones that play important roles in both the development and the homeostasis of the
body. A deficiency of two or several of these pituitary hormones, known as combined pituitary hormone deficiency, may
present in infants or children due to an unknown etiology and is considered congenital or idiopathic. Advancements in our
understanding of pituitary development have provided a genetic basis to explain the pathophysiological basis of pituitary
hormone disease. Nevertheless, there are several challenges to the precise characterization of abnormal genotypes;
these exist secondary to the complexities of several of the hypothalamic/pituitary developmental factors and signals,
which ultimately integrate in a temporal and spatial dependent manner to produce a mature gland. Furthermore, the
clinical presentation of pituitary hormone disease may be dynamic as subsequent hormone deficiencies may develop
over time. The characterization of patients with mutations in genes responsible for pituitary development provides an
opportunity to discover potential novel mechanisms responsible for pituitary pathophysiology. The focus of this review is
to report the most recent mutations in genes responsible for pituitary development in patients with hypopituitarism and
emphasize the importance to physicians and researchers for characterizing these patients. Continuing efforts toward
understanding the molecular basis of pituitary development as well as genetic screening of patients with pituitary disease
will offer new insights into both diagnostic and potential therapeutic options that will decrease the morbidity and mortality
in patients with hypopituitarism.
Journal of Molecular Endocrinology (2011) 46, R93–R102

Introduction In humans, combined pituitary hormone deficiency

(CPHD) is diagnosed when the production of two or
The development of the human pituitary has been more of these hormones is insufficient or absent. The
mapped to the expression of transcription factors in a etiology of CPHD is typically multifactorial and may be
coordinated temporal and spatial sequence that ulti- secondary to a neurological insult. However, a subset of
mately produces five distinct pituitary cell types. These patients, who present during infancy or childhood with
cell types (along with the hormone product) include the CPHD, is classified as having idiopathic disease. These
somatotroph (GH), thyrotroph (TSH), lactotroph patients may be considered to have a genetic etiology for
(prolactin (PRL)), gonadotroph (FSH and LH), and their deficiencies, associated with mutations in several
corticotroph (ACTH). Our knowledge regarding pitu- of these transcription factors responsible for pituitary
itary embryogenesis has been gained from experimental development. Although the incidence of reported
animal models, which have helped to categorize mutations in CPHD patients remains low, current
developmental genes necessary for pituitary develop- research continues to delineate the complexities of
ment and function (Dasen & Rosenfeld 2001, Scully & pituitary development and more clearly define the
Rosenfeld 2002, Kelberman & Dattani 2006). These molecular basis of hormone deficiency in these patients.
transcription factors, in addition to signaling molecules,
initiate the formation of Rathke’s pouch and direct the
proliferation of cells into distinct cell lineages. Any Pituitary developmental factors
disruption of this cascade adversely affects the develop-
ment or survival of single or multiple cell types, thus The identification and characterization of pituitary
ultimately leading to deficiencies in hormone products. developmental factors in vivo and in vitro has helped to
Journal of Molecular Endocrinology (2011) 46, R93–R102 DOI: 10.1530/JME-10-0133
0952–5041/11/046–R93 q 2011 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org
R94 C J ROMERO and others . Mutations in pituitary hormone deficiency

establish a genetic basis for CPHD in humans who appropriate differentiation and proliferation of the
harbor similar mutations. These factors include HESX1, mature pituitary cell types (Fig. 1).
LHX3, LHX4, POU1F1, PROP1, SIX6, OTX2, PTX2, GLI2, The focus of this review is to inform the reader of
and SOX3, all of which have been shown to play a role in recently reported mutations in the most commonly
the development and maturation of the pituitary gland. studied transcription factors since w2001. Although
For example, the Hesx1 mutant mouse model demon- some of the factors have been implicated in hypopitu-
strates forebrain and pituitary malformation along with itarism for more than a decade, this review is not
abnormalities in the septum pellucidum and eye. This intended to present the reader with a comprehensive
phenotype is similar to the human phenotype of septo- list of DNA abnormalities in these patients. We hope to
optic dysplasia (SOD; Dattani et al. 1998). Despite the highlight the current advancements in molecular
identification of several HESX1 mutations in patients genetics that have allowed researchers to not simply
with SOD, reports state that !1% of patients with SOD identify mutations or deletion of genes but more
demonstrate coding region mutations (Cohen et al. importantly provide potential mechanisms of pathology
1999a, Thomas et al. 2001, Tajima et al. 2003, Sobrier through the use of functional studies.
et al. 2006, Coya et al. 2007, McNay et al. 2007). CPHD has a wide spectrum of presentations and
Consequently, the incidence of identifying a mutation quite often hypopituitarism is a developing entity as
patients may acquire hormone deficiencies overtime.
in humans remains low, but this may simply reflect that
The range of clinical presentations emphasizes the
other factors or signaling molecules remain to be
complexity of pituitary development and suggests that
identified (Reynaud et al. 2006). Figure 1 illustrates a
both compensatory mechanisms, as well as interplay
modified overview of pituitary development that has
between transcription factors, ultimately determine the
been adapted from previous embryological studies of
fate of pituitary function.
mice. This cascade of events emphasizes the import-
ance of both the temporal and the spatial expression of
both developmental factors and signals required for the HESX1
The human HESX1 gene, located on chromosome
Signals Signals
3p14.3, contains a 185 amino acid open reading frame
FGF8/10
BMP4
Nkx2.1 Wnt5a with four exons and acts as a promoter-specific
e9·5 e11 e12 e17·5 transcriptional repressor (Dattani et al. 1998, Brickman
Otx2
Anterior pituitary et al. 2001). In early development, Hesx1 transcripts are
cell type
Shh, Gli1,2
Somatotroph
expressed in the anterior visceral endoderm and neural
Lhx3, Lhx4
POU1F1 Lactotroph
ectoderm but are eventually restricted to the Rathke’s
Pitx 1,2
Hesx1 Prop1 Caudal
pouch (Hermesz et al. 1996, Thomas & Beddington
thyrotroph
Isl1
GATA2
rostral 1996, Andoniadou et al. 2007). Its role as a repressor has
Pax6
Six 3,6 Gonadotroph been demonstrated by its downregulation, which
Tbx19 Corticotroph precedes a rise in PROP1 at mouse embryonic day 12
Early development factors Late development factors (e12). Pituitary development continues as the DNA
Figure 1 Expression of developmental factors and signals binding motif of HESX1 in the presence of PROP1
required for anterior pituitary development. A modified overview changes to preferentially bind with PROP1 as a
of murine pituitary development adapted from previous embry- heterodimer (Kato et al. 2010). More recently, the
ological studies illustrates the sequence of events that determine
the proliferation and differentiation of mature pituitary cell types. complexities of HESX1’s role in pituitary development
Initially, contact of the oral ectoderm with the neural ectoderm have been demonstrated through its association with
followed by a cascade of events consisting of both signaling other pituitary factors during development. Table 1
molecules and transcription factors expressed in a specific lists several reported interactions between HESX1
temporal and spatial fashion leads to the development of Rathke’s
pouch (RP). At embryological day 9.5 (e9.5), expression of
and other factors that when perturbed can affect
BMP4 and Nkx2.1 along with sonic hedgehog (Shh) initiates the pituitary development. The discovery and character-
development of the primordial RP. The expression of the factors ization of these interactions for HESX1 and other
Gli1, Gli2, Lhx3, Pitx1, and Pitx2 result in the development of developmental factors are important steps in not only
progenitor pituitary cell types. These events are followed by the delineating pituitary development but also understand-
expression of HESX1, ISL1, PAX6, SIX3, and SIX6, which are
important for cellular development, proliferation, and migration. ing clear mechanisms of pathology in hypopituitarism
The attenuation of Hesx1 (dotted arrows at we12.5) is required (Gaston-Massuet et al. 2008, Sajedi et al. 2008a, Carvalho
for the expression of Prop1. By e12.5, RP has formed and by et al. 2010).
e17.5, differentiation of specific pituitary cell types has been In humans, clinical manifestations of mutations in
completed. The mature pituitary gland contains the differentiated
cell types: somatotrophs, lactotrophs, thyrotrophs, gonadotrophs, the HESX1 gene are variable and contribute to CPHD
and corticotrophs (Dasen & Rosenfeld 2001, Scully & Rosenfeld or as part of SOD with an inheritance pattern classified
2002, Kelberman & Dattani 2006, Zhu et al. 2007). as either autosomal recessive or autosomal dominant
Journal of Molecular Endocrinology (2011) 46, R93–R102 www.endocrinology-journals.org
 Mutations in pituitary hormone deficiency . C J ROMERO and others R95

Table 1 Factors reported to interact with HESX1

Transcription factor Role Mechanism of interaction Functional studies References

SIX3 Homeobox transcription Regulates through the Six3C/K Hesx1Cre/C Gaston-Massuet

factor important for eye and WNT/b-catenin signaling compound heterozygote et al. (2008)
pituitary development pathway to allow normal mice demonstrate
forebrain development postnatal dwarfism, low
thyroid function, and poor
testicular development;
abnormal pituitary
phenotype secondary to
disrupted signaling
DNA methyltransferase 1 Nuclear protein for CpG May induce permanent Transfected 293T cells Sajedi et al.
(DNMT1) DNA-methylation and gene silencing by the demonstrate that HESX1 (2008a,b)
gene regulation specific methylation of and DNMT1 form
coexpressed with CpG residues of HESX1 complexes; in situ hybrid-
HESX1 and acts as target genes ization with wild-type
binding protein mouse embryos suggest
that HESX1 may repress
transcription through
methylation of targets
TLE1/TLE3 Groucho-related Augment repressor Transfected 293T cells Carvalho
co-repressors that bind role of HESX1 demonstrate TLE1 and et al. (2010)
to transcription factors TLE3 augment HESX1
repression of PROP1;
transgenic mice with
ectopic TLE3 and HESX1
expression disrupt
differentiation of thyro-
trophs and gonadotrophs
PROP1 Pituitary-specific homeo- The presence of PROP1 Used random oligonucleo- Kato
box transcription factor leads to HESX1 motif tides and an electro- et al. (2010)
change: TAATT to TAAT phoretic mobility shift assay
forming heterodimer with to examine binding prefer-
HESX1; such interaction ence of HESX1
allows PROP1 to advance
pituitary development

with incomplete penetrance. This correlates with affected than I26T/(null). The authors suggested
murine models bearing Hesx1 mutations, which bear that the pituitary may be more sensitive to dosage
midline cranial defects along with pituitary and eye reductions of HESX1 than the eye and forebrain
abnormalities similar to SOD (Dattani et al. 1998). (Sajedi et al. 2008b).
A diagram summarizing the most recent HESX1 More recently, a report of a homozygous frameshift
mutations and their position in reference to their mutation, c.449_450delAC (E150delX167), and a splice
exon are shown in Fig. 2. A novel p.I26T mutation in defect, c.357C2TbOC, was demonstrated to interfere
exon 1 was reported in a patient with early GH with the translation of the homeodomain (Sobrier et al.
deficiency (GHD), FSH/LH deficiency, and evolving 2006). Functional studies of the mutated HESX1
TSH and cortisol deficiency, along with pituitary demonstrated failure to repress PROP1 activity versus
structural abnormalities (Carvalho et al. 2003). wild-type HESX1, which repressed gene activation.
Although mutations in HESX1 associated with pituitary Each patient exhibited severe CPHD and magnetic
disease appear to modulate the DNA-binding affinity resonance imaging (MRI) abnormalities, but normal
of HESX1, this mutation appeared to impair tran- optic nerves, and anterior pituitary (AP) aplasia with a
scriptional repression (Brickman et al. 2001, Carvalho flat sella turcica.
et al. 2003).
A group of investigators further studied this mutation
through the generation of a mouse model with Hesx1 LHX3
mutations p.I26T and p.R160C in order to demonstrate
the effects of HESX1 on embryonic development. Both The LHX3 transcription factor maps to the subtelo-
mutations had complete penetrance of pituitary meric region of chromosome 9 at band 9q34.3 and
defects; however, the effect on ocular and forebrain contains seven exons and six introns (Sloop et al. 2001).
development varied with the I26T/I26T less severely The protein possesses two LIM domains involved in
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R96 C J ROMERO and others . Mutations in pituitary hormone deficiency

c.357+2T>C mutations, p.E173ter and p.W224ter in exons 3 and 5

Exons 1 2 3 4 respectively, that lead to truncated proteins, a mutation
in the homeodomain (p.A210V), and a homozygous
gene deletion. All patients had CPHD; however, a
hypoplastic pituitary or limited neck rotation was not
HESX1 HD universal (Pfaeffle et al. 2007). In an earlier study, a
108 168 patient was identified to have a p.159delT (exon 2
delT) LHX3 mutation causing a frameshift and
T181A premature termination codon. The patient was diag-
Q6H l26T R160C
nosed with deficiencies of GH, PRL, LH, FSH, and TSH,
LfsX110 K176T
Q117P
E149K
S170L
a rigid cervical spine with limited head rotation, mental
E150delX167
retardation, and MRI findings of a hypodense lesion
in the pituitary consistent with a microadenoma.
Figure 2 Reported HESX1 gene mutations associated with
human CPHD since 2001. The coding exons are illustrated in The authors suggest that mutations in LHX3 may also
the top line, whereas the HESX1 mRNA structure is shown below lead to abnormal pituitary cell proliferation (Bhangoo
with the homeodomain (HD) region in yellow color. The location of et al. 2006).
reported mutations is indicated by the arrows.

protein–protein interactions, a DNA binding homeo- LHX4

domain and a carboxyl terminus that contains the
major transactivation domain. In humans, the identifi- The human LHX4 gene, located on chromosomal
cation and study of two isoforms, LHX3a and LHX3b, position 1q25 with six exons encoding 390 amino
demonstrates that these factors differentially activate acids, is another member of the LIM homeodomain of
genes, although LHX3a appears to be the most active transcription factors required for the development of
isoform (Sloop et al. 1999, West et al. 2004, McGillivray Rathke’s pouch (Machinis et al. 2001, Liu et al. 2002,
et al. 2005). In humans, homozygous loss-of-function Reynaud et al. 2004, Pfaeffle et al. 2008). The Lhx4
mutations in LHX3 have been identified in patients (K/K) mutant mouse demonstrated all five AP cell
with hypopituitarism including GH, TSH, PRL, LH, and lineages; however, there are reduced numbers leading
to a hypoplastic lobe (Sheng et al. 1997). Further studies
FSH deficiencies and AP defects and cervical abnor-
of LHX4 in conjunction with LHX3 demonstrate that
malities with or without restricted neck rotation. ACTH
LHX4 is required for the proliferation of lineage
deficiency has also been diagnosed in a subset of
precursors, whereas LHX3 is necessary to establish the
patients. Figure 3 illustrates the coding exons of LHX3a
fate of pituitary precursor cells (Sheng et al. 1997).
along with the location of reported human mutations in
The clinical manifestations of LHX4 mutations
this gene. encompass a varied presentation including GHD and
A recent published report of six patients diagnosed variable TSH, gonadotropin, and ACTH deficiencies.
with CPHD, restricted neck rotation, scoliosis, and Figure 4 illustrates the position, in reference to the
congenital hearing impairment was found to have a exon, of recently reported mutations diagnosed in
novel splice acceptor site mutation in intron 3 with patients with CPHD. A p.A210P mutation within the
recessive inheritance (Kristrom et al. 2009). In another homeodomain was found in a father and two daughters,
group of patients with CPHD, severe AP hypoplasia,
skeletal abnormalities, and bilateral sensorineural c.150A>G splice site:ter

hearing loss and also in one family hyperextensible Exons 1 1 2 3 4 5 6

a b
joints and loose skin and two homozygous recessive
mutations were reported: an intragenic deletion of
3008 bp resulting in complete loss of exons 2–5 and in
an unrelated family a homozygous transversion
LHX3a LIM 1 LIM 2 HD
31 81 90 144 157 216
c.267AOT that led to a nonsense mutation in exon 2
(Rajab et al. 2008). The authors of this study also g.159delT Y116C 23 bp del A210V

demonstrated an association of LHX3 and the tran- K50X

E173X
W224X

scription factor SOX2, in which SOX2 may play a role in

the regulation of LHX3 expression and therefore
3088 bp intragenic del
function in pituitary development (Rajab et al. 2008).
A group of investigators reported four novel recessive Figure 3 Reported LHX3 gene mutations associated with human
combined pituitary hormone deficiency. The figure illustrates the
mutations in four consanguineous pedigrees after coding exons (boxes) and the LHX3a mRNA structure with the
screening 366 patients diagnosed with isolated GHD coding regions for the LIM domains and the homeodomain (HD).
(IGHD) or CPHD. These included two homozygous The location of reported mutations is indicated by the arrows.

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 Mutations in pituitary hormone deficiency . C J ROMERO and others R97

c.607-1G>C HESX1 and as an activator of POU1F1 (Dasen &

1 2 3 4 5 6 Rosenfeld 2001). A proposed mechanism is through
the Wnt/b-catenin signaling pathway, in which the
binding of PROP1 with b-catenin represses Hesx1
expression and promotes POU1F1-dependent cellular
LHX4 LIM 1 LIM 2 HD development (Olson et al. 2006). The expression of
28 88 150 157 216
PROP1 maintains the POU1F1 lineage and allows for
differentiation of lactotrophs, somatotrophs, and thyro-
R84C V101A L190R A210P
trophs. It has been shown to be dependent on Notch
P366T
T99fsX53
signaling, which is thought to be important for late
lineage differentiation (Zhu et al. 2006). The Ames
Figure 4 Reported LHX4 gene mutations associated with human
CPHD since 2001. The coding exons are seen in the first line with
mouse, which harbors a mutated Prop1, demonstrates
the translated regions in black color. The LHX4 mRNA structure is severe dwarfism, hypothyroidism, and infertility
depicted below with the coding regions for the LIM domains and the (Sornson et al. 1996). Recently, Ward et al. (2007)
homeodomain (HD) shown in blue and yellow color respectively. created a Prop1 bacterial artificial chromosome trans-
The location of reported mutations is indicated by the arrows.
gene, which rescued the mutant mice with the Prop1
with one sister diagnosed with CPHD whereas the other dwarf phenotype when crossed with wild-type mice.
sister and father had GHD only (Pfaeffle et al. 2008). The frequency of human PROP1 mutations remains
Another patient with a p.L190R mutation also in the low among sporadic cases but accounts for 29.5–50% of
homeodomain was deficient in GH, ACTH, and TSH familial cases of CPHD (Turton et al. 2005a, Kelberman
(Pfaeffle et al. 2008). A third patient with GHD, TSH & Dattani 2006). There are at least 24 reported
deficiency, and gonadotropin deficiency was found to mutations, which have either homozygous recessive or
have a p.R84C mutation located between the LIM compound heterozygous inheritance (Kelberman &
domains of the protein. Functional studies of these Dattani 2007). Figure 5 illustrates recently reported
mutations demonstrated either a reduced or abolished human mutations associated with CPHD and the
capacity to activate an aGSU reporter. Despite the mutation location in reference to the exon affected.
previous association of LHX4 mutations with cerebellar The clinical phenotypes of human PROP1 mutations
abnormalities, the imaging of these three cases may be variable and dynamic. Typically, patients present
demonstrated only a hypoplastic AP with or without with GH, PRL, and TSH deficiencies, although
an ectopic posterior pituitary (PP). More recently, a there may be increased risk for cortisol and gonado-
novel mutation, p.V101A in the LIM2 domain in exon 3, tropin deficiency with age. Structurally, there is a
was found in a patient with CPHD, a small AP, and normal PP and stalk, but the AP may be hypoplastic,
ectopic PP. This mutation demonstrated an inability to normal, or enlarged, which may wax and wane before
activate the POU1F1 and FSHb subunit gene promoter,
indicating a loss of function mutation (Tajima et al.
c.109+1G>T c.343_11C>G
2009a). This finding highlights previous findings
suggesting that POU1F1 is an LHX4 target leading to Exons 1 2 3
the expression of GH (Machinis & Amselem 2005).
Another familial mutation resulting in CPHD and
pituitary abnormalities was identified as a C insertion
into the third exon of LHX4, resulting in a frameshift PROP1 HD TD
69 128
mutation with an early stop codon (p.Thr99fs;
Castinetti et al. 2008). Functional and structural studies c.2T>C
of the mutant LHX4 demonstrated a complete loss of F99X
F99Q
W194X
R125W
transcriptional activity on the POU1F1 promoter and a c.112_124del R71C
Q83X
fs ter37 R71H c.467insT
lack of DNA binding (Castinetti et al. 2008).
c.310delC c.629delC
F88S
R73H
c.150delA, fs ter164

Prophet of Pit1 c.157delA, fsX164

The human Prophet of Pit1 (PROP1) gene, located at Figure 5 Reported PROP1 gene mutations associated with
chromosomal position 5q35, with three exons encoding human CPHD since 2001. The coding exons are illustrated in the
226 amino acids, contains both a paired-like homeo- first line with the translated regions depicted in black color. The
PROP1 mRNA structure is shown below with homeodomain (HD)
domain for DNA binding and a C-terminal tran- and the transactivation domain (TD) in yellow and orange colors
scriptional activator domain (Duquesnoy et al. 1998). respectively. The relative positions of reported mutations are
PROP1 acts as both a repressor in downregulating indicated by the arrows.

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R98 C J ROMERO and others . Mutations in pituitary hormone deficiency

eventual involution (Turton et al. 2005a, Kelberman & IVS2-3insA ter 82) c.682+1G>A

Dattani 2007). Exons 1 2 3 4 5 6

The majority of reported mutations involves the
DNA-binding homeodomain and in part the transcrip-
tion domain (as depicted in Fig. 5). There was a recent
description of a mutation, however, in the initiation POU1F1 SD HD
codon in c.2T/C in two sisters who were diagnosed 124 198 214 273
ins778A
fs284X
with pituitary hypoplasia and CPHD in addition to late Q4X
R143L W193R
E230K F262L
V272X
onset of adrenal insufficiency. This first described exon R172Q
W193X
F233L
747delA,
fs250X
1 mutation resulted in loss of translation of the PROP1 K145X

S179R L194Q

protein (Lemos et al. 2006). Another novel homozygous Q242R

mutation upstream of the homeodomain, microdele- Figure 6 Reported POU1F1 gene mutations associated with
tion c.112_124, was described in three family members human CPHD since 2001. The coding exons are illustrated in the
with CPHD from a large consanguineous family first line with the translated regions depicted in black color. The
(Agarwal et al. 2000). This mutation leads to a POU1F1 mRNA structure is shown below with POU-specific
domain (SD) and the POU-homeodomain (HD) in orange and
premature termination codon that resulted in a protein
yellow colors respectively. The relative positions of reported
lacking the homeodomain and transactivation domain. mutations are indicated by the arrows.
Deletions of the entire PROP1 gene have also been
reported in patients with CPHD, which is similar to
a mutational ‘hotspot’ (Turton et al. 2005b). Despite a
those harboring a small deletion, thus suggesting that
majority of mutations reported as missense/nonsense, a
even a small deletion could result in the loss of activity
homozygous c.682C1GOA intronic splice site mutation
in vivo (Abrao et al. 2006, Kelberman et al. 2008a,b).
affecting the exon 4 splice donor site was described in a
patient with GH, TSH, and PRL deficiency and a
POU1F1 (PIT1) hypoplastic AP (Snabboon et al. 2008). A more recent
novel mutation, an IVS2-3insA mutation adjacent to the
The human POU1F1 gene, located on chromosome splicing site, was reported to generate a premature stop
3p11, is composed of six exons and has two protein codon that resulted in loss of the homeodomain and
domains: a POU-specific domain and a POU homeo- transactivation domain (Carlomagno et al. 2009). The
domain (Rosenfeld 1991, Tatsumi et al. 1992). Both domains function of POU1F1, furthermore, also shares an
are important in high-affinity DNA binding of genes important relationship with cyclic AMP response
encoding GH and PRL as well as in the regulation of element binding protein (CBP). A 20-year-old man
TSHb, cAMP, and PRL production (Xu et al. 1998, with congenital CPHD and a hypoplastic AP gland was
Cohen et al. 1999a). Furthermore, there is evidence to
reported to have a mutation in exon 4, p.S179R,
suggest that additional regulation of POU1F1
identified in the POU-specific domain. Functional
expression includes retinoic acid induction of the
studies revealed decreased transactivation of GH1,
POU1F1 gene distal enhancer during pituitary develop-
PRL, POU1F1, and TSHb promoters (Miyata et al.
ment (Cohen et al. 1999b). A more recent advancement
2006). The authors demonstrated that both DNA
in our understanding of POU1F1 expression and
binding and interaction with co-activators such as CBP
regulation includes a novel pituitary regulator known
are critical to POU1F1’s function (Miyata et al. 2006).
as Atbf1, which is a transcription factor belonging to the
‘giant, multiple-homeodomain, and zinc finger family’
(Qi et al. 2008). Atbf1 mutant mice demonstrated a OTX2
decrease of POU1F1 mRNA expression along with
diminished expression of GH and TSHb, although OTX2, a member of the orthodenticle family located on
products of non-Pit1-dependent cell types such as chromosome 14q23.1, is expressed early in anterior
corticotrophs and melanotrophs were unaffected. neuroectoderm development and is known for its
The clinical manifestations of POU1F1 mutations have critical role in retinal photoreceptor, rostral brain,
been well described in patients and include GH, TSH, and midbrain development (Acampora et al. 2000,
and PRL deficiency with inconsistent MRI findings of AP Kurokawa et al. 2004, Henderson et al. 2009). Although
hypoplasia. At least 27 different mutations have been mutations in OTX2 are commonly associated with eye
described, with both autosomal recessive and dominant abnormalities, several reports demonstrate its import-
negative inheritance (Kelberman et al. 2009). Recently ance in pituitary function. A recent short report that
reported POU1F1 mutations in patients diagnosed with reviewed reported OTX2 mutations states that abnor-
CPHD are illustrated in Fig. 6. A study of 129 patients mal pituitary structure and/or function occurred in
with CPHD found POU1F1 mutations in ten patients, w30% of patients with mutations (Schilter et al. 2010).
of whom five had the R271W mutation, a site considered Figure 7 illustrates several of the most recently reported
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 Mutations in pituitary hormone deficiency . C J ROMERO and others R99

Exons 1 2 3 4 5 associated with eye abnormalities, these studies high-

light the role of OTX2 in pituitary pathology as well as
the broad spectrum of phenotypes associated with
mutations in this gene.
OTX2 HD PolyQ Otx1 TF region
1 47 102 109 178 243 297

Concluding remarks
A72fsX86 L135fsX136 N233S

S186lfsX187
K74fsX103 S136fs
Over the past two decades, the pursuit of establishing a
X178
G188X genetic basis for the development of idiopathic
S138X W152X
hypopituitarism has yielded great insight into the
Figure 7 Reported OTX2 gene mutations associated with human mechanisms involved in pituitary development. As
CPHD. OTX2 is organized into five exons of which only three are more physicians become aware of centers that offer
translated (black boxes) as shown in the first line. The OTX2 DNA screening in patients with CPHD, we observe
mRNA structure is below with the coding regions for the increasing number of reports of novel mutations in
homeodomain (HD) and the Otx1 transcription factor (TF) regions
colored in yellow and green respectively. The location of reported
pituitary developmental factors, which may provide an
mutations in patients diagnosed with hormone deficiencies C/K etiology for a patient’s pituitary pathology. The reader
eye abnormalities is indicated by the arrows. should recognize that this review is not comprehensive
and, additional reports in patients with CPHD who were
OTX2 mutations in patients whose clinical presentation found to have mutations in factors such as GLI2, SOX2,
included abnormal pituitary function. In four patients, SOX3, and others have been reported (Roessler et al.
three novel heterozygous mutations were reported, 2003, Woods et al. 2005, Kelberman et al. 2006, 2008a,b,
which include frameshift and nonsense mutations Solomon et al. 2007). Furthermore, the characterization
along with a microdeletion of approximately a 2.9 Mb of several developmental factors using functional
deletion that includes OTX2 (Dateki et al. 2009). studies has demonstrated that they are interactive and
Interestingly, two patients were diagnosed with IGHD, interdependent to ultimately determine cellular func-
one patient with CPHD and two cases with normal tion as well as cell survival. This is most likely why
pituitary function, yet all patients had ocular abnor- hypopituitarism has a heterogeneous clinical pheno-
malities. The authors demonstrated either reduced or type and often a continuum of evolving pathology.
lost transactivation of four promoters including Nonetheless, the discovery of single-gene mutations
GNRH1, HESX1, POU1F1, and IRBP promoters by since the 1990s has helped further the advances in
these mutations compared with the wild-type gene. This mutation detection and offered insights into genotype/
same group also reported a de novo heterozygous phenotype correlation. Understanding the genetics of
frameshift mutation in a patient with IGHD and pituitary pathology offers a chance to improve both the
bilateral anophthalmia that led to a loss of the OTX2 morbidity and the mortality often associated with
transactivation region (Dateki et al. 2008). Brain CPHD. More importantly, the advancing science of
structural abnormalities along with CPHD and gene therapy will someday relieve many patients from
anophthalmia were reported in a boy who was found the burden of hormone replacement and provide the
to have a heterozygous 2 base insertion in the third opportunity for a potential cure.
translated exon of OTX2 [p.S136fsX178 (c.576-
577insCT)] (Tajima et al. 2009b). The mutant OTX2
demonstrated an inability to activate the promoters in Declaration of interest
the HESX1 and POU1F1 genes.
Furthermore, two unrelated patients diagnosed with The authors declare that there is no conflict of interest that could be
perceived as prejudicing the impartiality of the research reported.
CPHD and pituitary gland structural abnormalities, but
without ocular pathology, were described to harbor a
heterozygous OTX2 mutation in the third translated
Funding
exon (p.N233S) (Diaczok et al. 2008). Despite pre-
served binding to target genes, the mutant was shown to This research did not receive any specific grant from any funding
act as a dominant negative inhibitor of HESX1 gene agency in the public, commercial, or not-for-profit sector.
expression. Finally, Henderson et al. (2009) performed
a screening for OTX2 mutations in 142 patients with
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