ABSTRACT

Congenital hypopituitarism refers to a deficiency of one or more pituitary hormones resulting from issues in fetal development. Embryological pituitary development involves a complex interplay of transcription factors, extrinsic and intrinsic to the oral ectoderm and neuroectoderm which develop to form the mature pituitary during early embryogenesis. Disruption of this process can result in isolated pituitary dysfunction, or effect nearby structures, such as the eye, olfactory bulbs, midline structures, and forebrain. Genetic causes make up an important portion of cases and have varying phenotypes even within identical mutations. This chapter provides an overview of pituitary development, and various causes of hypopituitarism including septo-optic dysplasia, syndromic and non-syndromic causes, isolated pituitary deficiencies, and syndromes associated with hypopituitarism. It also provides guidance on the investigation of genetic causes of hypopituitarism in the current genetic landscape. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

The pituitary gland can be thought of as the “hormonal control center” from which most endocrine organs are regulated. It is located in the sella turcica, posterior to the sphenoid sinus, inferior to the optic chiasm and the hypothalamus. The pituitary comprises 3 lobes, the anterior, intermediate and posterior.

The posterior lobe or neurohypophysis contains antidiuretic hormone (ADH or AVP) and oxytocin, contained in vesicles, as part of axonal projections from hypothalamic cells, known as the hypothalamic-hypophyseal tract. The intermediate lobe contains melanotrophs which produce alpha-melanocyte stimulating hormone (αMSH), although in humans is typically an embryological remnant and may not be present.

The anterior lobe or adenohypophysis contains 5 cell lines, producing 6 different hormones regulated by hypothalamic hormones via the hypophyseal portal system. Somatotrophs produce growth hormone (GH) while lactotrophs produce prolactin making up the somatomammotroph class of hormones. The glycoprotein hormone class consists of hormones with identical alpha subunits and different beta subunits, with thyroid stimulating hormone (TSH) produced by thyrotroph cells, and gonadotroph cells producing follicle stimulating hormone (FSH) and luteinizing hormone (LH). Corticotroph cells produce adrenocorticotrophic hormone (ACTH).

Growth hormone mediates its effect through induction of insulin like growth factor 1 (IGF-1) from the liver and is critical for linear growth in the child. Prolactin stimulates development of the mammary gland and lactation and is typically quiescent outside of pregnancy or childrearing. TSH stimulates production of thyroid hormone from the thyroid gland, which regulates metabolic rate and is critical for growth and cognitive development in early childhood. FSH and LH support gonadal development, production of testosterone or estrogen, and maturation of gamete cells. ACTH stimulates production of cortisol which is an essential stress hormone and ADH regulates plasma osmolality by inducing resorption of water in the collecting duct of the kidney.

Congenital hypopituitarism refers to a deficiency of one or more pituitary hormones resulting from events during fetal development. This may be the result of genetic mutation, antenatal insult, or as is commonly the case, be idiopathic. Pituitary deficiencies may be detected during the neonatal period; however, in some individuals’ pituitary deficiencies may not manifest until later in childhood. Furthermore, the severity can be variable.

Hypopituitarism may be isolated, affecting one cell line (isolated hormone deficiency), or multiple, termed combined or multiple pituitary hormone deficiency (CPHD, MPHD). Pan-hypopituitarism is typically used to describe deficiency of all anterior pituitary hormones; however, in some cases this term may also include the presence of AVP deficiency. AVP (or ADH) deficiency is termed as central diabetes insipidus (DI) but is undergoing a formal process to change the name to AVP deficiency. The new name is preferred as it highlights both etiology and treatment, while avoiding confusion with diabetes mellitus. AVP deficiency may coexist with other deficiency’s or be isolated.

The incidence of isolated growth hormone deficiency (IGHD) is reportedly 1 in 4000 live births (3), with CPHD also seen in 1 in 4000 live births (4), thus presenting an uncommon but important chronic condition.

Embryological pituitary development involves a complex interplay of transcription factors, extrinsic and intrinsic to the oral ectoderm and neuroectoderm which develop to form the mature pituitary. Disorders occurring during early development may affect nearby structures commonly the eye, olfactory bulbs, midline structures, and forebrain, whereas later events are typically isolated to pituitary abnormalities. Transcription factor gene defects have been demonstrated to cause different biochemical and structural forms of congenital hypopituitarism, although the majority of cases remain idiopathic. There is considerable phenotypic variability within known genetic causes of hypopituitarism, with some forms having incomplete penetrance, and presentation ranging from asymptomatic, to severe neonatal onset forms. This review discusses the clinical phenotypes of various genetic anomalies associated with hypopituitarism. Clinical manifestations and investigation of hypopituitarism are discussed in the “Hypopituitarism” chapter of Endotext.

This chapter will present an overview of the embryology of pituitary development before discussing the genetic causes of hypopituitarism. It will firstly discuss genes that cause septo-optic dysplasia, before discussing genes that cause other clinical phenotypes and hypopituitarism. After describing the genes associated with non-syndromic hypopituitarism, and isolated hormone deficiencies we will discuss other syndromes where hypopituitarism may be part of the phenotype. Each gene is described within the subheading that they most typically present; however, due to phenotypic variability some genes can present in multiple categories. For example, PROKR2 mutation classically causes isolated hypogonadotrophic hypogonadism, but can result in non-syndromic CPHD or septo-optic dysplasia in some cases (5-8). The information within this review is up to date as of May 2022; however, understanding of these genes continues to progress.

Figure 1.

Stages of rodent pituitary development. (a) Oral ectoderm. (b) Rudimentary pouch. (c) Definitive pouch. (d) Adult pituitary gland. I infundibulum; NP neural plate; N notochord; PP pituitary placode; OM oral membrane; H heart; F forebrain; MB midbrain; HB hindbrain; RP Rathke's pouch; AN anterior neural pore; O oral cavity; PL posterior lobe; OC optic chiasm; P pontine flexure; PO pons; IL intermediate lobe; AL anterior lobe; DI diencephalon; SC sphenoid cartilage. Adapted from Sheng and Westphal, Trends in Genetics 1999;15:236-240, with permission (licence number: 5420490065848” (2).

EMBRYOLOGY

Pituitary gland development is classically expressed based on timing with murine development. The pituitary gland forms from the hypophyseal placode on the anterior neural ridge of the neural plate (evident embryonic (E) day 7.5 in the mouse model). Ventral displacement leads to the formation of the oral ectoderm and the roof of the mouth. A portion of this ectoderm thickens (E8.5) before invaginating rostrally at E9. At E9.5, corresponding with 4 weeks gestation, this migrates dorsally resulting in a cone shape, known as the rudimentary Rathke’s pouch. This continues to thicken with increased rostral mitosis spreading into the mesenchyme. Following ongoing proliferation, it separates from the oral ectoderm at E12.5 (approximately 6 weeks gestation). Hormonal cell progenitors arise from ventral proliferation forming the anterior pituitary. (Figure 1) The somatotrophs arise caudomedially, gonadotrophs rostroventrally and corticotrophs ventrally. The dorsal aspect later adjoins the descending infundibulum and remains thin (Intermediate lobe) (9).

Throughout this process the tissue is in contact with the neural plate neuroectoderm, at the base of the developing diencephalon. This neuroectoderm evaginates and progress dorsally to form the posterior pituitary. The tissue immediately ventral to this evagination forms the optic chiasm. The diencephalon develops throughout this process to form the hypothalamus (9).

The olfactory placode forms immediately lateral to the hypophyseal placode on the neural plate. These cells form the olfactory bulb but also the GnRH secreting cells which migrate to the forebrain from 6 weeks gestation, progressing to the hypothalamus by week 15. Axons from these cells extend into the hypothalamic portal system allowing regulation of gonadotroph cells (10-12). The optic nerve origin and optic chiasm develop from the neuroectoderm immediately anterior to the posterior pituitary, which has a complex interplay with some causes of hypopituitarism (13).

Correlation of pituitary development in mice to humans is difficult. Whilst pluripotent stem cells have been induced to form hypothalamic and anterior pituitary cells, the complex interplay of transcription factors, as well as interaction from other anatomical structures, mean these methods cannot give us a clear timeline in humans (14). Historical embryo samples demonstrate the formation of Rathke’s pouch by week 4, with interruption of connection to the oral cavity by week 6 with the anterior pituitary fully differentiated by 16 weeks (15).

Using hormone expression to correlate these two embryonic timelines, humans start producing GH, FSH, LH and ACTH at 8 weeks gestation, with TSH and prolactin at 13 weeks (9). Somatotrophs make up 50% of the cellular composition of the anterior pituitary, with 15-20% of cells being lactotrophs, 5% thyrotropes, 10-15% gonadotrophs and 15-20% corticotrophs (16) (Figure 2).

Figure 2.

Structural development of pituitary. Lateral representation of process of oral and neuroectoderm folding. Cross-sectional representation of hormone producing pituitary cell groups. Adapted from Larkin S. et al, Endotext (1).

Various transcription factors are involved in coordinating these processes and gene mutation can result in underdevelopment or arrest of pituitary development. Figure 3 summarizes the temporal expression of various transcription factors within the pituitary. Abnormalities in genes expressed early in development such as SOX2, HESX1 and GLI2 more frequently effect other nearby structures, whereas those expressed later such as PROP1 and POU1F1 typically have localized effects. Transcription factors may be induced, upregulated or downregulated by multiple other transcription factors and the degree and site of expression can vary across the embryological development. For a diagrammatic overview of the role each transcription factor plays in pituitary development please see Figure 1 of the 2020 JCEM review by Gregory L and Dattani M (4).

Figure 3.

Timing of gene expression of transcription factors implicated in combined hypopituitarism.

Disruptions to this cascade of transcription factors causes a range of structural phenotypes, varying from a normal pituitary appearance, to anterior pituitary hypoplasia or agenesis. The infundibulum/pituitary stalk may be thin or absent and the posterior pituitary may be hypoplastic, absent, or ectopic. The combination of anterior pituitary hypoplasia (APH), infundibular thinning/absence, and ectopic posterior pituitary (EPP), is known as pituitary stalk interruption syndrome (PSIS) (Figure 4).

Figure 4.

Lateral appearance of structural pituitary phenotypes. Adapted from Larkin et al, Endotext (1).

SEPTO-OPTIC DYSPLASIA

Septo-optic dysplasia (SOD) is defined by the presence of two or more of: optic nerve hypoplasia, hypopituitarism, and midline defects (agenesis of the corpus callosum or septum pellucidum) forming a clinical triad. SOD is a rare condition with incidence estimates between 1 in 9,000 to 1 in 40,000 (17,18). The association between hypopituitarism and optic nerve hypoplasia relates to the embryological origin of the optic chiasm being immediately anterior to the infundibular tissue, thus an insult at this location can interrupt both pathways. The phenotype is highly variable even in familial SOD (13). Although several genetic causes have been identified, these make up less than 10% of cases of SOD, and are summarized in Table 1 (19). Septo-optic dysplasia is commonly seen in young primiparous mothers (20) and while antenatal exposure to alcohol and drug use have been suggested, there is a lack of evidence to support causality (21).

Optic nerve hypoplasia (ONH) is typically bilateral (80-90%) with midline defects typically being septum pellucidum (85%) or corpus callosum (30%) hypoplasia or aplasia (21). 55-80% of cases have pituitary hormone deficiency, with growth hormone (GHD) and TSH deficiency (TSHD) being the most common deficiencies, followed by ACTH. Diabetes insipidus and hypogonadotrophic hypogonadism (HH) are found in less than 30% of hormone deficient cases (22-25). Approximately half of these hormone deficiencies are detected in the first 2 years of life and can present with severe neonatal hypoglycemia and cardiovascular instability, with the remainder of cases presenting across childhood to adolescence. The degree of deficiency is also noted to progress over time (22). Children with SOD typically have at least some degree of visual impairment, with 44- 80% being legally blind (22,26), while epilepsy and behavioral issues can be seen in approximately a quarter of patients, and cognitive impairment in 42.5% (22). Recently, 31% of cases were found to be obese despite therapy, suggesting the contribution of hypothalamic obesity (22).

SYNDROMIC CAUSES OF HYPOPITUITARISM

Septo-optic dysplasia is the most common syndromic presentation of hypopituitarism. Other genes causing hypopituitarism, which do not typically cause optic nerve hypoplasia are discussed below, although GLI2 and BMP4 may present with SOD. Syndromic causes of hypopituitarism are summarized in Table 3.

Hypopituitarism Associated With Holoprosencephaly

The prosencephalon cleaves into right and left hemispheres between day 18 and 28 gestation in humans. Failure of this process results in holoprosencephaly (HPE) of varying degrees with lobar holoprosencephaly having separated 3^rd ventricles with a connection within the frontal cortex, semilobarholoprosencephaly being partially separated and alobarholoprosencephaly having a continuous single anterior ventricle. (Figure 5) Facial development is affected by the same process and can cause hypotelorism or cleft palate, but also severe cases may have anophthalmia or cyclopia with a superiorly displaced proboscis. Holoprosencephaly is present in 1 in 250 embryos’ but there is a high rate of fetal demise. It is estimated to occur in 1 in 8,000-16,000 live births (73).

Figure 5.

Types of holoprosencephaly.

Other associated midline defects include underdevelopment of olfactory bulbs and corpus callosum, single midline maxillary incisor and hypoplastic pituitary or ectopic posterior pituitary. Holoprosencephaly is associated with anterior hypopituitarism in 5-10% of cases, with 70% having diabetes insipidus (DI) (74).

Many cases are caused by trisomy 13 making up 40-60% of all causes with a genetic anomaly, trisomy 18 and triploidy are also associated. Sonic hedgehog and ZIC2 mutations make up 5% of non-syndromic cases each. Importantly, structural chromosomal anomalies in almost all chromosomes have been shown to cause holoprosencephaly (75,76).

The SHH gene on chromosome 7q36 is critical for early development of the CNS, particularly the forebrain and is present in the notochord, neural tube and posterior limb buds of the gut. It is a major gene implicated in holoprosencephaly and its effect is mediated through other transcription factors, many of which have been demonstrated to cause HPE shown in Table 2 (73).

There is limited data regarding the rates of anterior pituitary dysfunction with each gene type although cases in SHH and ZIC2 have been reported (67,77).

Table 2.

Genes Associated with Holoprosencephaly and Hypopituitarism

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Gene	Chromosome	% of HPE	Other Features
SHH	7q36	5.4-5.9%	Renal-urinary anomalies
ZIC2	13q32	4.8-5.2%	Renal-urinary anomalies
SIX3	2p21	3%	Typically, severe HPE phenotype
TGIF	18p11.3	<1%	Wide spectrum of severity
CDON	11q24.2	rare	CHD, renal dysplasia, radial defects, gallbladder agenesis

CHD – Congenital Heart Disease, HPE – Holoprosencephaly. Adapted from Tekendo-Ngongang C, et al. Holoprosencephaly Overview. GeneReviews. 2020 (76).

Pituitary Stalk Interruption Syndrome

Pituitary stalk interruption syndrome (PSIS) is a triad of a thin/absent pituitary stalk, ectopic posterior pituitary and aplasia/hypoplasia of the anterior pituitary (Figure 6). SHH and other downstream genes of the SHH signaling pathway, including SIX3, TGIF, CDON and GPR161 have all been reported in 1-2 cases with PSIS and CPHD, without holoprosencephaly (76,78-82). Other causes of hypopituitarism that have been associated include POU1F1, PROP1, LHX3, LHX4, HESX1, SOX3, OTX2, PROKR2 and FOXA2. 100% of patients have been GHD in large case series with gonadotrophin, ACTH and TSH deficiencies in the majority and hyperprolactinemia in a minority (83).

Figure 6.

Lateral appearance of pituitary stalk interruption syndrome (PSIS). Adapted from Larkin S. et al, Endotext (1).

ROBO1

Heterozygous ROBO1 gene mutations (found on chromosome 3p12.3) has been described in 5 patients with PSIS, with a 6^th case of homozygous mutation (84,85). Ocular anomalies, including hypermetropia and ptosis were also seen, but penetrance was incomplete with unaffected parents in some cases. Combined GHD and TSHD, and a case of panhypopituitarism have been described (84).

NON-SYNDROMIC CAUSES OF HYPOPITUITARISM

POU1F1

Figure 7.

Cross-sectional representation of pituitary cell groups in POU1F1. Adapted from Larkin S. et al, Endotext (1).

POU1F1 was the first genetic cause of CPHD detected, initially described in mice (known as PIT-1) and 2 years later in humans. It is a member of the POU family of transcription factors, and the gene is located at 3p11.2. Approximately 65% of cases are autosomal recessive (homozygous/compound heterozygous) with 35% having an autosomal dominant form, the most common being the R271W mutation. In a review of 15 cases, the majority had affected parents, with only 3 cases of hormonally intact parents (100). POU1F1 is present in 2.8% of CPHD, with up to 21% of familial CPHD (50). There is considerable variability between countries, with one cohort of 23 CPHD patients in India detected 6 POU1F1 mutations and many other studies having low numbers of detected mutations (50,100,101).

Expression of POU1F1 is triggered by PROP1 and is seen within the pituitary from E13.5, persisting through to adulthood. It is critical for supporting the differentiation and proliferation of thyrotroph, lactotroph and somatotroph cells, and stimulates the GH1, prolactin and TSHB genes, required for hormone synthesis (102). LHX3, LHX4 and OTX2 upregulate POU1F1 but PROP1 is essential for its function (52,57,59).

Tatsumi et al. detected the mutation in a case of “cretinism” with cognitive impairment and short stature, with GH, TSH and prolactin deficiency, reported in 1992 (103). 100% of cases in the literature have GH deficiency with 87.5% having TSH deficiency and 95.6% having prolactin deficiency (demonstrated in Figure 7). TSH deficiency is typically detected in infancy, either prior to, or simultaneously with GH and prolactin deficiency, with ~13.5% detected after GHD. 70% have anterior pituitary hypoplasia, but other midline and peripheral defects are rarely seen. Autosomal dominant forms are less likely to have an absent pituitary (63.6%) and typically have less severe GHD with 20% having an undetectable GH peak on stimulation testing, compared to 48%. Apart from hypopituitarism, there are no other phenotypic features known to be associated with POU1F1 (100).

Patients with severe short stature, GHD, prolactin deficiency and TSH deficiency only and isolated anterior pituitary findings on MRI should raise suspicion of POU1F1 mutation, especially if there is a known family history.

ISOLATED HORMONE DEFICIENCIES

The presence of any pituitary hormone deficiency raises the question of other hormone deficiencies. While isolated forms of pituitary deficiency occur, there is the potential for other deficiencies to develop over time as is seen in POU1F1 or LHX, and routine monitoring is required (53,100). It is also true that genes classically causing isolated hormone deficiencies, like GH1, can cause CPHD, and thus screening may be required (106,107).

Isolated Growth Hormone Deficiency

Figure 8.

Cross-sectional representation of pituitary cell groups in isolated growth hormone deficiency. Adapted from Larkin S. et al, Endotext (1).

Isolated growth hormone deficiency (IGHD) is reported to have a prevalence between 1 in 4,000-10,000. Whilst most cases are sporadic, suggesting an in-utero insult to development of a specific cell-line, 3-30% have a first degree relative, supporting the possibility of genetic causes (108). Approximately 6.5% of patients have a genetic cause currently detectable (39) with rates as high as 38% in those with a family history (109). Growth Hormone 1 (GH1) and Growth Hormone Releasing Hormone Receptor (GHRHR) genes are the most commonly implicated, although genes implicated in CPHD, such as HESX1, SOX3, OTX2, LHX4 and GLI2 can also present as isolated GHD, (appearance shown in Figure 8). Genetic causes are classified into 4 categories, listed in table 4. Type 1A which has undetectable GH levels caused by autosomal recessive GH1 gene deletions, Type 1B caused by GH1 gene splice site mutation or other genes (such as listed above), Type 2 caused by exon skipping mutations in GH1 cause an autosomal dominant phenotype, and Type 3 is X-linked recessive, and is associated with agammaglobulinemia (108).

The GH1 gene located on 17q22-24consists of 5 exons and 4 introns and encodes for a 191 amino acid peptide with a molecular weight of 22kDa. Transcription of GH1 is triggered by cAMP release in response to GHRH binding to the GHRHR, and is down-regulated by somatostatin via inhibiting cAMP release, in response to receptor binding (108). This pathway is demonstrated in Figure 9. GH1 mutations cause 22.7% of familial isolated GHD, the majority being type 2 autosomal dominant mutations (109).

Figure 9.

Cellular function of somatotroph cell. cAMP- Cyclic Adenosine Monophosphate, GH – Growth Hormone, GHRH – Growth Hormone Releasing Hormone, GHRHR – Growth Hormone Releasing Hormone Receptor.

TYPE 1A

In 1981 Phillips et al. described GH1 mutation in Swiss children with a homozygous deletion causing Type 1A GHD (110). Type 1A GHD is caused by a GH1 gene deletion or less commonly, by a frameshift or nonsense mutation and makes up <15% of GH1 mutation related disease (109). The resulting phenotype is of severe GHD, with undetectable levels and can present with hypoglycemia neonatally as well as growth failure in the first 6 months. Complicating therapy is the frequent occurrence of anti-GH antibodies requiring therapy with recombinant insulin-like growth factor 1 (IGF1) (108).

TYPE 1B

Type 1B GHD caused by GH1 mutations are typically the result of gene splice site mutations and are again autosomal recessive. They have a variable phenotype ranging from an IGHD Type 1A phenotype to mid-childhood growth failure (108).

GHRHR anomalies also cause a Type 1B phenotype. GHRHR is found on chromosome 7p14.3 and was reported in 1996 by Wajnrajch et al. (111). Patients have normal GHRH levels but undetectable GH and low IGF1 levels. The phenotype is of proportional short stature, with anterior pituitary hypoplasia (108). GHRHR mutations are responsible for 16-19% of familial IGHD but are rarely the cause of sporadic IGHD (109). No GHRH mutations causing short stature have been reported to date (108).

TYPE 2

Type 2 GHD originates from mutations that result in loss of exon 3 from the final protein. This causes a dominant negative effect on secretion of normal GH from the other allele, through retention in the endoplasmic reticulum, impairing Golgi apparatus activity (108). Type 2 GHD has varying degrees of severity as well as of pituitary hypoplasia and represents approximately 70% of GH1 mutation related disease (109).

TYPE 3

IGHD has been reported in 10 cases of X-linked agammaglobulinemia, known as IGHD type 3; however, an individual gene causing both associations has not been well characterized (112).

Sporadic IGHD does not typically have a genetic basis; however, familial forms have a high likelihood of detecting a mutation (38%) (107). It is important in patients with IGHD to always consider the possibility of a developing CPHD, with this occurring in 5.5% without structural anomalies, and 20.7% with structural anomalies(106,107(113)). This should be considered even in patients with GH1 mutation’s, in particular Type 2 mutations have been found to develop other deficiencies, in particular TSH and ACTH deficiency (106,107).

Table 4.

Summary of Types of Isolated Growth Hormone Deficiency.

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IGHD type	Genetic abnormalities	Inheritance	Pituitary imaging	Percentage of familial cases	Comments
1A	GH1 gene deletions and nonsense mutations	AR	Normal/ hypoplastic	2-4%	GH levels undetectable, anti-GH antibodies, transient response to GH therapy,
1B	GH1 gene splice site mutations	AR	Normal/ hypoplastic	2-4%
	GHRHR gene mutations	AR	Normal/ hypoplastic	16-19%
2	GH1 gene splice site and missense mutations and intronic deletions	AD	Normal/ hypoplastic	15-22%	Variable height, CPHD may occur
3	Unknown	XR	EPP	Unknown	Agammaglobulinemia

AD – Autosomal Dominant, AR – Autosomal Recessive, CPHD – Combined Pituitary Hormone Deficiency, EPP – Ectopic Posterior Pituitary, GHRHR – Growth Hormone Releasing Hormone Receptor, IGHD – Isolated Growth Hormone Deficiency, XR – X-li linked Recessive. Adapted from Alatzoglou K. et al, JCEM;94:3191-3199 and Casteras A. et al, Endocrinology, Diabetes and Metabolic Case Reports (109,114).

Central Hypothyroidism

Neonatal screening studies using T4 testing determined neonatal central hypothyroidism to occur in 1 in 16000-30000 infants (115,116). Up to 40% of these cases have isolated central hypothyroidism, with neonatal rates between 1 in 40,000 to 75,000, while some cases of isolated central hypothyroidism develop after the neonatal period (117). Thyroid hormone receptors (THR) are present on both the hypothalamus and pituitary and downregulate hormone secretion. Thyrotropin releasing hormone (TRH) is released from the hypothalamus and binds the TRH receptor (TRHR) upregulating TSH production (pathway demonstrated in Figure 10). 5 different genes have been implicated but there is limited data on the frequency of genetic mutations in patient with isolated central hypothyroidism (118).

Figure 10.

Cellular function of thyrotroph cell. cAMP- Cyclic Adenosine Monophosphate, TRH – Thyrotropin Releasing Hormone, TRHR – Thyrotropin Releasing Hormone Receptor, TSH – Thyroid Stimulating Hormone.

TSHB

Thyroid stimulating hormone beta subunit (TSHB) gene is found on chromosome 1p13.1 and is associated with autosomal recessive inheritance (118). Hayashizaki et al. described the mutation in 1989 in a patient with severe neonatal onset hypothyroidism associated with prolonged jaundice, failure to thrive and developmental delay (119). Subsequent cases have also had severe deficiencies presenting neonatally (118).

TRHR

The thyrotropin releasing hormone receptor (TRHR) gene is found on chromosome 8q23.1 and again has autosomal recessive inheritance. The phenotype is milder than for TSHB with detection ranging from neonatal period to late childhood, and other patients being asymptomatic in adulthood. This is likely due to the presence of thyroid hormone receptors on the thyrotroph cells, upregulating TSH release independently of TRH (118).

IGSF1

Immunoglobulin superfamily 1 (IGSF1) gene is found on chromosome Xq26.1 and is associated with X-linked recessive central hypothyroidism. Hypothyroidism is seen in all cases, but the degree of deficiency can be variable, with many presenting in the neonatal period with jaundice and failure to thrive, others are detected asymptomatically on family screening (118).

IGSF1 is expressed in Rathke’s pouch and the adult pituitary gland and mutation results in low TSHB and TRHR mRNA, thus it is proposed IGSF1 has a role in regulating expression of these genes. 60% of patients have prolactin deficiency, supporting the involvement of decreased TRHR activity. GHD has been reported in a few cases, and 1 patient has been reported to have a hypoplastic anterior pituitary and ectopic posterior pituitary (118).

Other known associations include macroorchidism in 80% with low adulthood testosterone levels but preserved fertility. Follow up shows that despite thyroxine replacement, 25% of children and 75% of adults are overweight and 65% of cases have ADHD (attention deficit hyperactivity disorder) (118).

OTHER X-LINKED CAUSES

Transducing b-like protein X-linked (TBL1X) gene is found at chromosome Xp22.2 and mutations are thought to prevent upregulation of TSHB and TRHR transcription, causing central hypothyroidism. It has a mild hypothyroid phenotype and is associated with hearing loss, and ADHD (118).

Insulin receptor substrate 4 (IRS4) is found on chromosome Xq22.3 is often described as a cause of TSHD; however, mutations to date have resulted in low T4 but normal T3 and TSH, which does not suggest true central hypothyroidism (118).

Central hypothyroidism is rare and while genetic testing may be appropriate, the prevalence of individual causative genes is unknown. If genetics are not performed, siblings of patients should have formal thyroid function tests including a T4 arranged in the newborn period.

Table 5.

Genetic Causes of Isolated Central Hypothyroidism

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Gene	Inheritance	Degree of hypothyroidism	Other pituitary deficiency	Other features
TSHB 1p13.1	AR	Severe	Nil	Jaundice, FTT, developmental delay
TRHR 8q23.1	AR	Mild	Prolactin
IGSF1 Xq26.1	XR	Variable (mild to severe)	Prolactin, (rarely GH)	Macroorchidism, low testosterone, obesity, ADHD
TBL1X Xp22.2	XR	Mild	Nil	Hearing loss, ADHD

AD – Autosomal Dominant, ADHD – Attention Deficit Hyperactivity Disorder, AR – Autosomal Recessive, XR – X-linked Recessive. Adapted from Tajima T. et al, Clin Pediatr Endocrinol;28(3):69-79 (118).

Isolated ACTH Deficiency

Isolated ACTH deficiency (IAD) is an extremely rare but serious condition with mortality rates of up to 25% in severe neonatal-onset forms (120).

Corticotrophin releasing hormone (CRH) is produced by the hypothalamus in response to low cortisol levels and binds to corticotroph cells. CRH stimulates cAMP release triggering protein kinase A (PKA) which binds CRH response element-binding protein (CREB) which in turn stimulates TBX19 which stimulates production of pro-opiomelanocortin (POMC). This is converted by prohormone convertase 1/3 (PCSK1 gene) to ACTH, which stimulates glucocorticoid production in the adrenal gland (Figure 11) (121). Abnormalities in TBX19, POMC and PCSK1 genes have all been shown to cause IAD, and NFKB2 mutation causes IAD and immunodeficiency. Genetic causes are summarized in Table 6.

Figure 11.

Cellular function of the corticotroph cell. ACTH – Adrenocorticotrophic Hormone, cAMP- Cyclic Adenosine Monophosphate, CRH – Corticotropin Releasing Hormone, CRHR – Corticotropin Releasing Hormone Receptor, PC 1/3 – Prohormone Convertase 1/3, POMC – Pro-opiomelanocortin, TBX19 – T-Box Transcription Factor 19.

TBX19

T-box transcription factor 19 (TBX19) previously known as TPIT is located on chromosome 1q24.2 and causes severe neonatal onset IAD. It has an autosomal recessive inheritance and has been detected in 65% of cases of severe IAD, with 100% penetrance reported to date (120). As reported above, TBX19 is an important part of the pathway from CRH stimulation to ACTH release but is also critical for terminal differentiation of corticotrophs and can result in absence or severely hypoplastic cells (120).

All patients present with severe neonatal hypoglycemia and >50% have hypoglycemic seizures, with a mortality rate of 25%. >60% have prolonged cholestatic/ conjugated jaundice and if diagnosis is delayed, intellectual impairment and developmental delay have been reported (120). Other abnormalities have occasionally been reported including Chiari type 1 malformation, and subtle dysmorphic features (120,122).

Cortisol assessment should be performed in any neonate with recurrent hypoglycemia and cholestatic jaundice, and consideration of TBX19 gene assessment on confirmation of the diagnosis. Low levels of maternal estriol on antenatal testing has been shown to herald adrenal steroidogenesis issues and seen in a case of IAD caused by TBX19, but estriol is no longer routinely used in antenatal screening (123).

PCSK1

Proprotein convertase of Subtisilin/Kexin 1 gene (PCSK1) found on chromosome 5q15-21, codes for prohormone convertase 1/3 (PC 1/3) and has an autosomal recessive pattern of inheritance. It is found throughout the body including the pituitary, hypothalamus and endocrine pancreas. It plays a critical role in processing POMC, proinsulin and proglucagon but multiple other hormones as well (124).

PC 1/3 is required for conversion of POMC to ACTH in corticotroph cells. Deficiency thus results in low levels or absence of ACTH production. Despite this, there is typically a mild clinical phenotype, only 75% of patients have ACTH deficiency and not all are associated with hypocortisolemia. It is unclear whether this is due to partial ACTH binding capacity of POMC or other ACTH precursors, or whether an alternative enzyme compensates (124).

PC1/3 deficiency can also cause CPHD. HH, TSHD, and GHD are seen in approximately 50%, 70% and 35% of cases respectively and have been demonstrated or proposed to be secondary to failure of hypothalamic conversion of pro-releasing hormones (proGnRH to GnRH (suspected), proTRH to TRH, proGHRH to GHRH). Like with the corresponding adrenal insufficiency, thyroid and GH deficiency are often phenotypically mild. DI, presumed due to ineffective provasopressin conversion to vasopressin is also reported in a subset of patients (124).

Other associated features include obesity, occurring in nearly all patients, associated with hyperphagia and develops from approximately 2 years of age, the cause of which is multifactorial. Like in Prader-Willi syndrome, initially children present with failure to thrive; however, this is likely due to the presence of malabsorptive diarrhea. All cases to date have had severe neonatal diarrhea with demonstrated fat, amino acid and monosaccharide malabsorption, with the majority requiring hospitalization and parenteral nutrition. The underlying mechanism is not understood, and the intestinal architecture is typically normal on biopsy. The malabsorptive state typically displays partial improvement after the first year of life (124).

PC1/3 is also critical for cleavage of proinsulin to insulin, resulting in undetectable insulin levels. To compensate, much higher quantities of proinsulin are produced which typically prevents diabetes mellitus as it is maintains a 2-5% activity at the insulin receptor. The most common symptom is in fact postprandial hypoglycemia, resulting from proinsulins four to six times longer half-life, causing a relative hyperinsulinism after meals. Later in life some patients proceed to diabetes mellitus likely due to b-cell exhaustion (124).

PCSK1 mutation should be considered in patients with early onset malabsorptive diarrhea and later onset obesity. Other features may include post-prandial hypoglycemia, gonadal abnormalities and reduced linear growth. CPHD and DI should be screened for but are typically mild (124).

POMC

Pro-opiomelanocortin gene (POMC) is found on chromosome 2p23.3 and deficiency manifests in an autosomal recessive inheritance pattern (125). It causes a classic triad of adrenal insufficiency, hypopigmented skin with red hair, and obesity associated with hyperphagia, that can commence within infancy (125,126).

Children typically present with neonatal hypoglycemia (~70%) and adrenal insufficiency is detected at this point. Convulsions, hyperbilirubinemia and hyponatremia were present in over 30% of presenting cases. All known cases to date have been reported to have adrenal insufficiency and obesity, with 75% having red or Reddish-brown hair (125).

Other endocrinopathies have been reported, TSHD being the most common. Melanocyte stimulating hormones (MSH) bind the melanocortin 4 receptor which has been shown to regulate TRH release and it is hypothesized that the limited production of MSH’s drives the hypothyroidism. TSHD is reported in 35% of cases to date and is often subclinical. GHD and HH have been reported in 10-20% of patients with mechanisms not well understood. Type 1 diabetes has also been seen in 10-20% of cases (double antibody positive) it is thought this may be secondary to the increased inflammatory state in the absence of melanocortin which have been demonstrated to have an anti-inflammatory effect (125).

DAVID SYNDROME

DAVID syndrome (Deficient Anterior pituitary with Variable Immune Deficiency) was first described in 2011 and results from a mutation of NFKB2 gene on chromosome 10q24.32. Classically it presents with common variable immunodeficiency (CVID) due to hypogammaglobulinemia, typically resulting in recurrent sinopulmonary infections. IAD typically develops years or decades later; however, initial presentation with IAD has been reported in 1 case (127). GHD has been reported in 2 cases and TSHD in a single case, and imaging may demonstrate a normal or hypoplastic anterior pituitary (127,128).

Neonatal onset isolated adrenal deficiency should be screened for TBX19 mutations, and if absent, especially in a child with red hair, POMC gene testing should be considered, similarly the possibility of PCSK1 mutation in children with malabsorptive diarrhea and adrenal insufficiency.

Table 6.

Summary of Genetic Causes of Isolated ACTH Deficiency (IAD).

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Gene	Inheritance	Onset of IAD	Presentation	Other pituitary deficiencies	Other phenotypes
TBX19 Chr 1q24.2	AR, 100% penetrance	65% of severe neonatal onset IAD	Neonatal hypoglycemia, cholestatic jaundice	Nil	Intellectual impairment if delayed diagnosis, Chiari type 1 malformation
PCSK1 Chr 5q15-21	AR	Variable	Infantile malabsorptive diarrhea,	FSH, LH, GH, TSH, Rarely ADH	Obesity in early childhood
POMC Chr 2p23.3	AR	Neonatal	Neonatal hypoglycemia, jaundice	TSH (35%), GH, LH/FSH (10%)	Obesity, reddish brown hair. Type 1 diabetes
NFKB2 Chr 10q24.32	AD	Variable	Recurrent sinopulmonary infections	GH, TSH (rare)	Combined variable immunodeficiency

AD -- Autosomal Dominant, AR – Autosomal Recessive.

SYNDROMES ASSOCIATED WITH HYPOPITUITARISM

Hypopituitarism has been reported in a wide variety of syndromes as an associated feature. These syndromes are reported separately as hypopituitarism is a less common association.

INDICATIONS FOR GENETIC TESTING

Known genetic causes make up only a small proportion of the current hypopituitarism population, thus routine broad screening will not be appropriate at most centers and currently remains in the realms of research. Testing should be targeted to patients with consistent features, such as anophthalmia and SOX2 or a short stiff neck in LHX4. Individual genes can have a wide range of presentations and thus presence of a family history of hypopituitarism, whether similar in presentation or varied, should raise a high index of suspicion and screening should be strongly considered. Autosomal recessive causes are frequently seen, and dominant causes often have incomplete penetrance thus even relatively distant family associations should cause consideration for testing. Finally, presence of hypopituitarism in the context of a consanguineous parents should again raise suspicion of a likely genetic cause. Genetic testing typically is through next generation sequencing (NGS), although some mutations may be detectable on chromosomal microarray. Deletions on chromosomal microarray may include associated genes causing hypopituitarism. All the genes described above are summarized in table 9, in order of gene location, to assist in determining which mutations may be associated in such cases.

ABBREVIATION LIST

ACTH – Adrenocorticotrophic Hormone

AD – Autosomal Dominant

ADH – Antidiuretic Hormone (also known as AVP)

ADHD – Attention Deficit Hyperactivity Disorder

APH – Anterior Pituitary Hypoplasia

αMSH – Alpha-Melanocyte Stimulating Hormone

AR – Autosomal Recessive

AVP – Arginine Vasopressin (also known as ADH)

CC – Corpus Callosum

CHD – Congenital Heart Disease

CPHD – Combined Pituitary Hormone Deficiency

CRH – Corticotrophin Releasing Hormone

CVID – Common Variable Immunodeficiency

DI – Diabetes Insipidus

EPP – Ectopic Posterior Pituitary

FSH – Follicle Stimulating Hormone

GH – Growth Hormone

GHD – Growth Hormone Deficiency

HH – Hypogonadotrophic Hypogonadism

HPE – Holoprosencephaly

IAD – Isolated ACTH Deficiency

ID – Intellectual Disability

IGF1 – Insulin-like Growth Factor 1

IGHD – Isolated Growth Hormone Deficiency

LH – Luteinizing Hormone

MPHD – Multiple Pituitary Hormone Deficiency

NGS – Next Generation Sequencing

ONH – Optic Nerve Hypoplasia

PSIS – Pituitary Stalk Interruption Syndrome

SOD – Septo-Optic Dysplasia

SP – Septum Pellucidum

THR – Thyroid Hormone Receptor

TRH – Thyrotropin Releasing Hormone

TRHR – Thyrotropin Releasing Hormone Receptor

TSH – Thyroid Stimulating Hormone

TSHD – Thyroid Stimulating Hormone Deficiency

XR – X-linked Recessive

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