Introduction

Several transcription factors involved in the embryological development of the murine pituitary appear to also be involved in human pituitary organogenesis [1-4]. Spontaneous or artificially induced mutations and gene knockouts in the mouse have led to significant insights into human pituitary disease, with the identification of human mutations in a number of genes which give rise to hypopituitary phenotypes in their respective murine orthologues. Many have been implicated in the aetiology of both murine and human hypopituitarism including Hesx1, Lhx3, Lhx4, Prophet of Pit1 (Prop1), Pou1f1 (previously called Pit-1), Sox2 and Sox3. More recently, the use of Next Generation Sequencing has led to the identification of a number of novel genes implicated in the aetiology of Congenital Hypopituitarism [5,6]. These include ARNT2, IGSF1, EIF2S3, MAGEL2, RNPC3 and TBC1D32.

Transcription factors implicated in early hypothalamo-pituitary development

HESX1

Given the closely linked development of the pituitary gland and forebrain during normal embryogenesis, abnormalities of the two structures can be linked in human disease. One example of this is septo-optic dysplasia (SOD), often referred to as de Morsier syndrome [7], a rare, highly heterogeneous condition initially described by Reeves [8] in a seven-month old baby with absence of the septum pellucidum and optic nerve abnormalities. The condition is defined loosely by any combination of the triad of optic nerve hypoplasia, midline neuroradiological abnormalities (such as agenesis of the corpus callosum and absence of the septum pellucidum) and pituitary hypoplasia with consequent panhypopituitarism [7-11].

Homeobox gene expressed in embryonic stem cells (Hesx1) is one of the earliest markers of the pituitary primordium, suggesting that it has a critical role in early determination and differentiation of the pituitary gland. It is a member of the paired-like class of homeobox genes. The gene is first expressed during mouse embryogenesis in a small patch of cells in the anterior midline visceral endoderm as gastrulation commences. Hesx1 continues to be expressed in the developing anterior pituitary until E12, when it disappears in a spatiotemporal sequence that corresponds to progressive pituitary cell differentiation. Extinction of Hesx1 is important for activation of other downstream genes such as Prop1. Targeted disruption of Hesx1 in the mouse revealed a reduction in the prospective forebrain tissue, absence of developing optic vesicles, markedly decreased head size and severe microphthalmia reminiscent of the syndrome of septo-optic dysplasia (SOD) in humans. Other abnormalities included absence of the optic cups, the olfactory placodes and Rathke’s pouch, reduced telencephalic vesicles, hypothalamic abnormalities and aberrant morphogenesis of Rathke’s pouch. In 5% of null mutants, the phenotype was characterized by complete lack of the pituitary gland. In the majority of mutant mice, they were characterized by formation of multiple oral ectodermal invaginations and hence multiple pituitary glands.

HESX1 therefore appeared to be a candidate for SOD in humans. Screening of human hypopituitary patients for mutations in HESX1 led to the identification of mutations in two siblings with SOD and subsequently other mutations have been shown to present with varying phenotypes characterized by IGHD, CPHD and SOD [12-14]. MRI revealed anterior pituitary hypoplasia, an infundibulum that is either normal or absent, and a posterior pituitary that is either eutopic or ectopic. Mutations can be variably penetrant dominant or recessive in humans.

Mutations have been identified in less than 1% of individuals with congenital hypopituitarism/SOD, confirming the rarity of HESX1 mutations [15]. These data suggest that mutations in other known or unknown genes contribute to this complex disorder, together with a likely contribution from environmental factors [16,17].

OTX2

OTX2 regulates the expression of HESX1 and POU1F1 during AP development and is required for the formation of anterior structures and maintenance of the forebrain, with mutations being described in ~3% of CH patients with anophthalmia/microphthalmia [18, 19]. Mice heterozygous for OTX2 loss of function may have pituitary hypoplasia, missing or misplaced pituitary glands, and/or pituitary dysmorphology [20]. Patients with OTX2 mutations manifest highly variable phenotypes including IGHD, CPHD or HH, with severe ocular malformations including ONH, retinal dystrophy or coloboma with or without anophthalmia/microphthalmia [21-23].  

RAX

The transcription factor RAX is implicated in eye and forebrain development, with murine null mutants manifesting anophthalmia, cleft palate, and an abnormal hypothalamus resulting in perinatal lethality [24]. Recessive RAX mutations are associated with bilateral microphthalmia or anophthalmia in some patients, with variable associated clinical features [25-28]. Recently, a homozygous truncating RAX mutation, p.Pro89Argfs*114, has been reported in a patient with anophthalmia, CH (including GH, TSH and ACTH deficiencies with probable gonadotrophin deficiency), diabetes insipidus, bilateral cleft lip and palate, micropenis (likely hypogonadotropic hypogonadism) and an absent anterior and PP gland on MRI [29]. This is the most severe phenotype to date, and appears to correspond to the severity of the mutation itself, as opposed to the previously published missense mutations associated with less severe protein dysfunction and milder phenotypes.

SOX3

The identification of a chromosomal abnormality (46, X, inv[X][p21q27]) in a patient with mental retardation led to the identification of SOX3 as a candidate gene for X-linked mental retardation (XLMR). SOX3 (OMIM 313430) is a member of the SOX (SRY-related HMG box) family of transcription factors, which were initially identified based on homology to the conserved binding motif of the high mobility group (HMG) class, present in the mammalian sex-determining gene, SRY [30]. Approximately 20 different SOX genes have been identified in mammals and variation in homology exhibited within the HMG box between different members allows them to be grouped into different subfamilies [31]. SOX3 was among the first of the SOX genes to be cloned, and together with SOX1 and SOX2, belongs to the SOXB1 subfamily exhibiting the highest degree of similarity to SRY [30]. SOX3 is encoded by a single exon producing a transcript with a coding region of approximately 1.3Kb, mapping to chromosome Xq27. The SOX3 protein consists of a short 66 amino acid N-terminal domain of unknown function, the 79 amino acid DNA binding HMG domain and a longer C-terminal domain, containing four polyalanine stretches, shown to be involved in transcriptional activation [30,32].

Members of the SOXB1 subfamily of genes are expressed throughout the developing central nervous system (CNS) and are some of the earliest neural markers that are believed to play a role in neuronal determination [33]. High levels of expression have also been noted in the ventral diencephalon, including the infundibulum and presumptive hypothalamus [34]. Targeted disruption of Sox3 in mice results in mutants that have a variable and complex phenotype including craniofacial abnormalities, midline CNS defects, and a reduction in size and fertility indicative of hypopituitarism which is probably secondary to hypothalamic dysfunction [34,35]. Pituitary levels of GH, luteinizing hormone (LH), follicle stimulating hormone (FSH) and TSH were all lower in mutant compared to wild-type mice at 2 months of age.

In humans, both tandem duplications involving chromosome Xq26-27 and loss of function mutations, often expansions within the polyalanine tract, have been identified in several pedigrees with mental retardation and hypopituitarism [36-40]. All affected males manifest GH deficiency and varying degrees of developmental delay or mental retardation. Some individuals have been reported to have varying combinations of deficiencies of other hormones including ACTH, TSH or gonadotrophins, and complete panhypopituitarism has been documented in some cases [41]. Other findings include a persistent craniopharyngeal canal.

In summary, both duplications of Xq27 encompassing SOX3 and loss-of-function polyalanine expansion mutations are essentially associated with similar phenotypes, predominantly infundibular hypoplasia, suggesting that gene dosage of SOX3 is critical for normal development of the diencephalon and infundibulum and, consequently the anterior pituitary [42].

SOX2

SOX2 (OMIM 184429) is also a member of the same SOXB1 subfamily as SOX3 and SOX1 (OMIM 602148). In the mouse, initial expression of Sox2 is detected at 2.5 dpc at the morula stage, and then in the inner cell mass of the blastocyst at 3.5 dpc. Later expression of Sox2, following gastrulation, is restricted to the presumptive neuroectoderm and by 9.5 dpc it is expressed throughout the brain, CNS, sensory placodes, branchial arches, gut endoderm and the esophagus and trachea [43,44]. Homozygous loss of Sox2 results in peri-implantation lethality, whereas Sox2 heterozygous mice appear relatively normal but show a reduction in size and male fertility [45]. Further studies that have resulted in the reduction of Sox2 expression levels below 40% compared to normal levels result in anophthalmia in the affected mutants [46]. Studies have also suggested that Sox2 plays a critical role in maintenance of pituitary progenitor/stem cells, and that embryonic and adult Sox2+ pituitary progenitor/stem cells can differentiate into all hormone-producing lineages, highlighting the physiological maintenance of the adult mouse pituitary by Sox2 [47].

Given the observation of growth retardation and reduced fertility, we investigated the role of Sox2 in murine pituitary development, showing that a proportion of heterozygous animals manifested a variable hypopituitary phenotype, with hypoplasia and abnormal morphology of the anterior pituitary gland with concomitant reduction in levels of GH, LH, ACTH and TSH [48]. Like its murine counterpart, the human SOX2 gene is composed of a single exon encoding a 317 amino acid protein containing an N-terminal domain of unknown function, a DNA binding HMG domain and a C-terminal transcriptional activation domain. Several de novo intragenic heterozygous mutations have been reported (45,48-55), in addition to eight de novo heterozygous deletions of the entire gene and one case of a partial deletion [48,49,55,56], as well as three heterozygous non-synonymous sequence changes identified in individuals who inherited the variant from a clinically unaffected parent [48,57]. The phenotypes include bilateral anophthalmia or severe microphthalmia with additional abnormalities including developmental delay, learning difficulties, oesophageal atresia and genital abnormalities [45,49-52]. SOX2 mutations were also associated with anterior pituitary hypoplasia on MRI and hypogonadotrophic hypogonadism, which resulted in the absence of puberty in 9/10 patients studied by our group, and genital abnormalities in males [48,58]. All affected individuals exhibited learning difficulties with other variable manifestations including hippocampal abnormalities and defects of the corpus callosum on MRI, esophageal atresia, hypothalamic hamartoma and sensorineural hearing loss (58). Rarely, hypothalamo-pituitary masses have been associated with SOX2 mutations.

LHX3/LHX4

Lhx3 is a member of the LIM family of homeobox genes which are characterized by the presence of a unique cysteine/histidine-rich zinc binding LIM domain. The protein contains two such tandemly repeated LIM motifs between the N-terminus and the homeodomain, which are likely to be involved in protein-protein interactions [59,60]. Lhx3 is one of the earliest transcription factors expressed within the developing pituitary, initially detectable with strong uniform expression in Rathke’s pouch. Expression is maintained in the pouch and is subsequently restricted to fields fated to form the anterior and intermediate lobes. Lhx3 is essential for the establishment of hormone producing cell types. Expression persists throughout development and is also detected in the adult pituitary suggesting a role in maintenance of one or more of the mature anterior pituitary cell types [59,60]. In addition to the pituitary, Lhx3 is also detected transiently in regions of the developing spinal cord, prior to neural tube closure, and later within restricted regions of the hindbrain, in addition to cells in immediate proximity to the otic vesicles. Mice with a targeted homozygous disruption of Lhx3 die shortly after birth, although the cause of death is unknown, and exhibit pituitary aplasia, suggesting an essential role of Lhx3 in differentiation and proliferation of anterior pituitary cell lineages. Although Rathke’s pouch is initially formed in Lhx3 null mice, a failure of proliferation and growth results in a lack of the anterior and intermediate lobes of the pituitary with depletion of all hormone-producing cell types except corticotropes, which differentiate and express pro-opiomelanocortin (POMC), but fail to proliferate [61,62].        

Homozygous mutations in LHX3 (OMIM 600577) have been identified in several unrelated consanguineous families, all of which result in loss of LHX3 function [63-67]. The patients presented with an endocrine phenotype similar to that observed in individuals with PROP1 mutations with a deficit in all anterior pituitary hormones except ACTH. This was additionally associated in 9/12 patients with a short rigid, cervical spine with limited head rotation and trunk movement. As with PROP1-deficient patients, pituitary morphology is variable between patients with LHX3 mutations, with both anterior pituitary hypoplasia as well as a markedly enlarged anterior pituitary being described [68].

Lhx4 is closely related to Lhx3 and is expressed in specific fields of the developing brain and spinal cord. Similar to Lhx3, Lhx4 is initially expressed throughout the invaginating Rathke’s pouch, however subsequent expression is transient and restricted to the future anterior lobe, whereas Lhx3 expression is maintained throughout the whole pouch. Null murine mutations of Lhx4 lead to a pouch that is defective with reduced numbers of the various anterior pituitary cell types. It is likely that the two genes may act in a redundant manner during early pituitary development [69].

Mutational analysis of the first reported patient, with CPHD (GH, TSH and ACTH deficiency), revealed a heterozygous intronic mutation in LHX4 [70]. MR imaging revealed anterior pituitary hypoplasia, an undescended posterior pituitary, an absent pituitary stalk, a poorly formed sella and pointed cerebellar tonsils. Several variably penetrant heterozygous LHX4 variants have been identified subsequently and associated with highly variable phenotypes. Furthermore, a recessive homozygous variant has recently been associated with a neonatal lethal hypopituitarism phenotype with severe lung abnormalities [71]. Mutations in LHX4 are rare and the resultant phenotype in patients with mutations suggests that LHX4 tightly coordinates brain development and skull shape in addition to pituitary development.

PROP1 

Prop1 is a paired-like homeodomain transcription factor, expressed exclusively within the embryonic pituitary. Expression is first detected in the dorsal portion of the murine Rathke’s pouch in a region overlapping the expression domain of Hesx1. Maximal expression of Prop1 is achieved at 12 dpc in the full caudomedial area of the developing anterior pituitary followed by a marked decrease, becoming undetectable by 15.5 dpc [72]. The Ames dwarf (df) mouse harbours a naturally occurring serine to proline (S83P) substitution within the homeodomain of Prop1, resulting in a mutant protein with an 8-fold lower DNA binding affinity than wild-type Prop1 [73]. Homozygous Ames dwarf mice exhibit severe proportional dwarfism, hypothyroidism and infertility and although early pituitary development is similar to wild-type mice, the emerging anterior pituitary gland is reduced by about 50%, displaying an abnormal looping appearance [58]. The adult Ames dwarf mouse exhibits GH, TSH and prolactin deficiency resulting from a severe reduction of somatotroph, lactotroph and caudomedial thyrotroph lineages with approximately 1% of the normal complement of each cell type. Additionally, these mice have reduced gonadotrophin expression correlating with low LH and FSH plasma levels [74].

Following the identification of Prop1 as the gene underlying the Ames dwarf phenotype in mice, Wu et al. [75] reported the first mutations in PROP1 (OMIM 601538) in human patients with GH, TSH and PRL deficiency in addition to reduced gonadotrophins and a failure to enter puberty spontaneously. To date, many distinct mutations have been identified in several patients, suggesting that PROP1 mutations are the most common cause of CPHD reported, accounting for approximately 50% of familial cases [76,77], although the incidence in sporadic cases is much lower [78]. All affected individuals exhibit recessive inheritance, and the majority of mutations identified to date involve the DNA binding homeodomain, which is highly conserved between mouse and human sharing 91% identity at the nucleotide level [79]. By far the most common mutation (50%-72% of all familial PROP1 mutations) [80-82], detected in multiple unrelated families from several different countries, is a 2 bp deletion among three tandem GA repeats (²⁹⁶-GAGAGAG-³⁰²) within exon 2 resulting in a frameshift at codon 101 and the introduction of a termination codon at position 109 (often referred to as S109X), and probably represents a mutational hot spot within the gene, rather than a single common founder mutation [83].

Recessive PROP1 mutations are typically associated with GH, TSH, PRL and gonadotrophin deficiencies, although the time of initiation and severity of pituitary hormone deficiencies is highly variable. Most patients present with early onset GH deficiency and growth retardation; however normal growth in early childhood has been reported in a patient who attained a normal final height without GH replacement therapy [84]. TSH deficiency is also highly variable and has been reported as the first presenting symptom in some cases, while others show delayed TSH deficiency which may not be present at birth [76,85-87]. Individuals with PROP1 mutations exhibit normal ACTH/cortisol levels in early life but often demonstrate an evolving cortisol deficiency that is strongly and significantly correlated with increasing age [87-91]. However, patients as young as 6 – 7 years have also been described with cortisol deficiency [91,92].

Although Prop1 is essential for the differentiation of gonadotrophs in fetal life, the spectrum of gonadotrophin deficiency is again extremely variable in patients with PROP1 mutations. Clinical variability can range from hypogonadism with complete lack of pubertal development to reports of spontaneous, albeit often delayed, onset of puberty with subsequent development of gonadotrophin deficiency requiring hormone replacement [76,85,86,89].

The pituitary morphology in patients with PROP1 mutations is also highly variable; most individual reports have documented a normal pituitary stalk and posterior lobe, with a small or normal size anterior pituitary gland on MRI. However, in some cases, an enlarged anterior pituitary gland has been reported [75,87,93]. Longitudinal analyses of anterior pituitary size over time have revealed that a significant number of patients demonstrated pituitary enlargement in early childhood with subsequent regression and involution; thus, ensuing MRI in older patients usually demonstrates anterior pituitary hypoplasia [90,94]. The pituitary enlargement consists of a mass lesion interposed between the anterior and posterior lobes, possibly originating from the intermediate lobe [94]. Turton et al. (2005) recently demonstrated that the mass can wax and wane in size prior to eventual involution [78].  To date, the underlying mechanism for the mass remains unknown. There has been only one report of a biopsy of the “tumour”, and the histology was non-specific with the presence of amorphous material with no signs of apoptosis, and no recognisable cell types [95]. Consequent to the highly variable phenotype associated with PROP1 mutations, no genotype-phenotype correlation has been identified; furthermore, phenotypic differences have been reported in siblings with identical mutations [85]. The evolving nature of hormone insufficiencies in patients with PROP1 mutations suggests a progressive decline in the anterior pituitary axis, indicating a need for continual monitoring of patients for the development of hormone insufficiencies that may not be apparent at initial presentation.

POU1F1

POU1F1 (OMIM 173110; previously known as PIT1) is a pituitary-specific transcription factor belonging to the POU homeodomain family of transcription factors (named after the genes PIT1, OCT1 and unc-86) characterized by a highly conserved DNA binding domain consisting of a POU-specific domain and a POU homeodomain. In the mouse, Pou1f1 is expressed relatively late during pituitary development (14.5 dpc), and expression persists throughout post-natal life and adulthood, restricted to the anterior pituitary lobe [96]. Pou1f1 is essential for the development of somatotroph, lactotroph and thyrotroph cell lineages in the anterior pituitary [97], and for the subsequent expression of the GH-1 (OMIM 139250), prolactin (PRL; OMIM 176760) and TSH- (OMIM 188540) genes between 15.5-17 dpc [98]. Two naturally-occurring murine models have shed light on the role of Pou1f1 in normal pituitary development. In the Snell dwarf (dw) mouse, a recessive point mutation (W261C) results in the absence of somatotrophs, lactotrophs and thyrotrophs [99]. A similar phenotype results in the Jackson dwarf mouse (dwJ) that harbours a recessive null mutation due to rearrangement of Pou1f1. Pou1f1 binding sites have also been found in the GHRHR (OMIM 139191) and the Pou1f1 gene itself [97,100], and autoregulation is required to sustain gene expression once the Pou1f1 protein has reached a critical threshold [101].

The first mutation within POUIFI was identified by Tatsumi et al (1992) in a child with GH, prolactin and profound TSH deficiency caused by homozygosity for a nonsense mutation within the gene [102].  The majority of mutations identified in POU1F1 to date are recessive, however in addition a number of heterozygous point mutations have been reported [103]. Of these the amino acid substitution R271W appears to be a “hotspot” for POU1F1 mutations [104], and has been identified in several unrelated patients of different ethnic backgrounds. When co-transfected with wild-type POU1F1, this mutant protein prevented transcriptional activation by the wild-type protein acting as a dominant negative [104], although this has been recently disputed [105].

The spectrum of hormone deficiency can vary in patients with POU1F1 mutations; GH and prolactin deficiencies generally present early in life, however TSH deficiency can be highly variable with presentation later in childhood [106-108]. Magnetic resonance imaging demonstrates a small or normal anterior pituitary with a normal posterior pituitary and infundibulum, and no midline abnormalities. Since the first report, several POU1F1 mutations have been described including both recessive and dominant mutations in over 60 patients originating from 19 different countries, all of which have been associated with a broadly similar phenotype of GH, TSH and prolactin deficiency [109].

Genes implicated in hypothalamic development

ARNT2 (aryl-hydrocarbon receptor nuclear translocator 2) is a member of the basic-helix-loop-helix-Per-Arnt-Sim (bHLH-PAS) superfamily of transcription factors. This protein forms heterodimers with sensor proteins from the same family that then bind regulatory DNA sequences. Arnt2(-/-) null murine embryos die perinatally and exhibit impaired hypothalamic development [110]. Recent studies showed expression of ARNT2 within the CNS, including the hypothalamus, as well as the renal tract during human embryonic development. A homozygous frameshift ARNT2 mutation was previously described in six patients from a highly consanguineous pedigree with CPHD (GH, TSH and ACTH deficiencies associated with diabetes insipidus), post-natal microcephaly, fronto-temporal lobe hypoplasia and visual and renal abnormalities, proving lethal in several of the infants. This pedigree highlights the importance of ARNT2, in HP development and post-natal brain growth [111].

Signaling molecules

The Sonic hedgehog (SHH) signaling pathway

GLI2 encodes a transcription factor component of the SHH signaling pathway, and is implicated in the etiology of HPE and other midline neurodevelopmental anomalies [112,113]. Unlike mutated SHH, described to specifically cause HPE, mutated GLI2 is also associated with CH in the absence of midline brain defects, giving rise to the Culler-Jones syndrome [114]. These patients may have loss of function missense or truncation mutations that delete the entire C-terminus, with variable phenotypes ranging from IGHD to complex CPHD, in combination with variable polydactyly, cleft lip/palate, diabetes insipidus, dysmorphic features and an EPP on MRI [115-118]. Phenotypic variability may be marked within pedigrees [119] and incomplete penetrance may also be observed with GLI2 mutations, whereby a heterozygous mutation with functional consequences in the child is also present in an unaffected parent or a parent with a mild form of the disease respectively. Although several variants have been identified in cohort studies, functional studies have been performed in only a minority. Gene-environment interactions may underlie the variable penetrance associated with GLI2 mutations [120].

Pituitary stalk interruption syndrome (PSIS) encompasses the presence of a thin or discontinuous pituitary stalk, a hypoplastic AP gland and an EPP on MRI. In rare cases, mutations in HESX1, OTX2, SOX3, LHX4 and PROKR2 have been described in patients with PSIS [5,6]. More recently, a mutation in CDON, a Shh co-receptor and a component of the SHH signaling pathway previously implicated in the etiology of HPE, has been identified in a patient with PSIS with GH, TSH, and ACTH deficiencies, and neonatal hypoglycemia and cholestasis [121]. A recessive variant in a further SHH component, GPR161, encoding the orphan G protein-coupled receptor 161, has also been reported in a consanguineous family with PSIS [122]. These data suggest that the Shh signaling pathway is critical for normal HP development. 

Wnt signaling pathway

The WNT/β-catenin signaling pathway regulator, TCF7L1, has been implicated in the etiology of SOD. Conditional deletion of Tcf7L1 in mice results in forebrain and eye defects with partially penetrant dwarfism [123]. Heterozygous missense TCF7L1 variants were subsequently identified in two unrelated SOD patients, one of whom had hypopituitarism [123], implicating Wnt signalling in human HP development.

Slit/Robo signaling

Variably penetrant mutations in the receptor ROBO1, regulating embryonic axon guidance and branching in the nervous system via Slit/Robo signaling during development [124], have been implicated in PSIS patients. Four out of these five patients had ocular anomalies including hypermetropia with strabismus, and ptosis [125]. Additionally, a recent homozygous mutation was reported in a child with syndromic CPHD [126].

Other genes implicated in Congenital Hypopituitarism

Whole exome (WES) or whole genome sequencing (WGS)

Recent studies using WES or WGS have led to the identification of a number of novel genes implicated in the aetiology of Congenital Hypopituitarism. These include the following:

IGSF1

Mutations in Immunoglobulin Superfamily Member 1 (IGSF1) have been associated with an X-linked form of central hypothyroidism, often associated with macroorchidism, GH deficiency, and variable prolactin deficiency [127-129]. Igsf1-deficient male mice have lower pituitary and serum TSH concentrations, pituitary TRH receptor expression and triiodothyronine concentrations, with an increase in body mass [127]. Interestingly, female carriers of IGSF1 mutations occasionally manifest mild hypothyroidism [130]. 

EIF2S3

The Eukaryotic Translation Initiation Factor 2 Subunit 3 (EIF2S3) gene encodes eIF2γ which is the largest subunit (52kDa) of this heterotrimeric GTP-binding protein and contains all 3 consensus GTP-binding domains. The gene is located on the X chromosome. Mutations in this gene have been previously associated with MEHMO syndrome, including mental retardation, epilepsy, hypogonadotrophic hypogonadism, microcephaly and obesity. We recently described a milder phenotype including mild learning difficulties, GH and TSH deficiencies, and glucose dysregulation [131].

MAGEL 2

MAGEL2 is a maternally imprinted gene in the Prader-Willi locus, mutations in which are associated with arthrogryposis and autistic spectrum disorder. We and others have recently described variable hypopituitarism including GHD, other anterior pituitary hormone deficiencies, and Diabetes Insipidus [132] in association with mutations in this gene.  MAGEL2 is a member of the type II MAGE gene family involved in neurogenesis and brain function.

TBC1D32

Recessive mutations in TBC1D32 are associated with polydactyly, Joubert-like findings on MRI, and variable hypopituitarism with an EPP on MRI. The syndrome that results is a ciliopathy, and includes features of Oro-Facio-Digital syndrome Type IX [133]. It is likely that this phenotype is the result of mislocalisation of GLI2 in cilia. 

KCNQ1

KCNQ1, encoding a voltage-gated ion channel Kv7.1 subunit, is known to be associated with cardiac arrhythmia syndromes [134]. However, patients with variably penetrant phenotypes including GH and gonadotrophin deficiencies, maternally inherited gingival fibromatosis, and accompanying mild craniofacial dysmorphic features have recently been reported to harbor missense mutations in this paternally imprinted gene [135]. Studies have revealed transcripts in somatotrophs and gonadotrophs in mice and humans, in embryonic murine hypothalamic GHRH neurons and in the human hypothalamus [135].

FOXA2

De novo heterozygous mutations in FOXA2 have recently been implicated in the etiology of CPHD and congenital hyperinsulinism (CHI) with other features including craniofacial dysmorphic features, choroidal coloboma and endo­derm‐derived organ malformations in the liver, lung and gastrointestinal tract [136]. A further case had CH with childhood-onset diabetes, cardiac malformation and anal atresia [137]. These findings confirm those of a previous report describing a 277 kb heterozygous deletion on chromosome 20, incorporating FOXA2, in a family with CH, situs inversus, polysplenia, dysmorphic features, cardiovascular defects and biliary atresia [138].

Conclusions

Several transcription factors and signalling molecules are critical for cell differentiation and proliferation in the pituitary gland at a very early stage of gestation. The mouse has served as an excellent model for understanding the genetic basis of congenital hypopituitarism in humans, although the correlation between mouse and human disease phenotypes is variable.  This candidate gene approach, based on mouse studies, had led to the identification of several human mutations that disrupt hypothalamo-pituitary development resulting in specific patterns of hormone dysfunction.

Establishing the genotype can aid in the management of individual patients with hypopituitarism. For example, a patient with an identified PROP1 mutation exhibiting an enlarged anterior pituitary may be at risk of visual impairment due to anterior pituitary hyperplasia; however, a number of reports in individuals with PROP1 mutations have shown the enlarged anterior pituitary to undergo spontaneous involution. Careful monitoring of the anterior pituitary in such cases may prevent the patient undergoing further invasive procedures. Additionally, identification of a mutation within POU1F1 predicts that cortisol and gonadotrophin secretion will remain normal in the patient. Identification of the genotype can also aid in genetic counselling and early diagnosis, particularly in autosomal dominant POU1F1 mutations.

However, no genetic aetiology has been established to date in most patients with hypopituitarism. Given that a number of these patients may represent familial cases, it is clear that many genes implicated in hypopituitarism remain to be identified. It is highly likely that next generation sequencing will reveal a number of novel genes and pathways implicated in pituitary development.

Conflicts of interests

The author declares no conflict of interests in relation to this article.

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