Genetic forms of hypopituitarism and their manifestation in the neonatal period
Introduction
The pituitary gland is a central regulator of growth, metabolism, reproduction and homeostasis. The mature gland consists of the adenohypophysis, which comprises the anterior and the later involuting intermediate lobe, and the neurohypophysis or posterior lobe. The anterior pituitary is populated by five different cell types producing six different hormones: somatotrophs (growth hormone, GH), thyrotrophs (thyrotrophin or thyroid stimulating hormone, TSH), lactotrophs (prolactin, PRL), gonadotrophs (follicle-stimulating hormone, FSH and luteinizing hormone, LH) and corticotrophs (corticotrophin or adrenocorticotrophic hormone, ACTH). The intermediate lobe contains melanotrophs producing pro-opiomelanocortin (POMC), which is the precursor to melanocyte-stimulating hormone (MSH) and endorphins. The posterior lobe of the pituitary consists of the axonal projections of neurons, the cell bodies of which reside in the hypothalamus and secrete arginine vasopressin (AVP) (supraoptic nuclei) and oxytocin (paraventricular nuclei).
The development of the pituitary gland depends on the sequential temporal and spatial expression of transcription factors and signalling molecules. Congenital hypopituitarism is the deficiency in one or more pituitary hormones, and may be caused by mutations in any of the genes involved in pituitary development (Table 1). It manifests either as an isolated hormone deficiency, the commonest being isolated growth hormone deficiency (IGHD), or combined pituitary hormone deficiencies (CPHD) when two or more pituitary hormones are affected. In some patients, the hormonal deficits may present as part of a syndrome with patients manifesting abnormalities in structures that share a common embryological origin with the pituitary gland, such as the eye and forebrain. As a general rule, mutations in genes implicated in the early stages of development of the pituitary tend to result in syndromic forms of hypopituitarism in association with extra-pituitary defects and midline abnormalities. On the other hand, mutations in genes required for the specification of particular cell types or encoding specific hormone subunits give rise to isolated pituitary hormone deficiencies. The clinical features of hypopituitarism are variable both in severity and time of presentation and onset may be in the neonatal period or evolve later in life [1], [2].
Section snippets
Embryology of the pituitary gland
The pituitary gland has a dual embryonic origin: the anterior and intermediate lobes are derived from the oral ectoderm whilst the posterior pituitary is derived from the neural ectoderm. The development of the gland occurs in a well defined sequence of events that has been studied extensively in the mouse and reflects that in humans [3]. These include the formation of (i) the pituitary placode, (ii) the rudimentary Rathke's pouch, (iii) the definitive Rathke's pouch and (iv) the adult
Hypopituitarism with spine abnormalities (LHX3)
Expression of the LIM homeobox 3 (Lhx3) gene is detected in the developing nervous system and Rathke's pouch and persists in the adult pituitary gland. It is one of the earliest markers for cells that are destined to form the anterior and intermediate lobes and its continued expression is essential for the formation of gonadotrophs, thyrotrophs, somatotrophs and lactotrophs [13]. Mice with a targeted homozygous disruption of Lhx3 die shortly after birth and exhibit pituitary aplasia, suggesting
Mutations in PROP1
Prop1 is a member of the paired-like family of homeodomain transcription factors. It is first expressed within Rathke's pouch at E10, in a region overlapping the expression domain of Hesx1. Expression peaks at E12 throughout the pouch and is then markedly decreased and restricted until E15.5 when it disappears [60]. Prop1 can act as both a transcriptional repressor (for Hesx1 expression) or a transcriptional activator [for expression of Pou1f1 (Pit-1)] [60], [61]. On the other hand,
Isolated hormone deficiencies
Congenital isolated GH deficiency (IGHD) has a reported incidence of 1:4000–1:10,000 live births, with most cases being sporadic. There are four described familial forms of IGHD, that account for 5–30% of cases [78], [79] (Table 2). Congenital IGHD may result from mutations in the genes encoding growth hormone (GH1) or the growth hormone releasing hormone receptor (GHRHR), from mutations within transcription factors SOX3 and HESX1, or it may be the presenting symptom in some cases of CPHD [2],
Clinical manifestations of congenital hypopituitarism in neonates
Neonates with congenital hypopituitarism may present with non-specific symptoms, with or without associated developmental defects such as ocular, midline and genital abnormalities. Alternatively, they may be initially asymptomatic but at risk of developing pituitary hormone deficiencies over time. For example neonates with optic nerve hypoplasia, midline abnormalities or syndromes known to be associated with hypopituitarism will need, in the first instance, assessment of their endocrine status,
Assessment of the HPA axis
As ACTH deficiency and the resulting hypocortisolism can be life threatening, it is important to establish if the hypothalamo-pituitary-adrenal axis is intact. However, this can be quite challenging, especially in asymptomatic neonates with midline defects who are at risk of developing ACTH deficiency. During the first six months of life the circadian rhythm of cortisol excretion has not yet been established, baseline morning versus evening samples are not conclusive and treatment with steroids
The role of magnetic resonance imaging
Magnetic resonance imaging (MRI) of the brain and pituitary is important for the work-up of neonates with suspected or diagnosed hypopituitarism, as there is a correlation between the neuro-radiological abnormalities and the severity and evolution of the endocrinopathy [84]. Signs to look for include the size of the anterior pituitary, the presence and location of the posterior pituitary (absent or ectopic/undescended), the presence and morphology of the infundibulum, the presence and
Management and follow-up of neonates with diagnosed/suspected hypopituitarism
Neonates diagnosed with congenital hypopituitarism require life long follow-up by a multidisciplinary team. The aim is to (a) optimize hormone replacement therapy, (b) monitor for evolving hormone deficiencies, (c) address the complex needs of patients with syndromic hypopituitarism and SOD, including visual assessment and neurodevelopmental support, and (d) offer genetic counseling in cases where a genetic defect has been detected. The mainstay of treatment is replacement therapy with
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