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Developmental disorders of the hypothalamus and pituitary gland associated with congenital hypopituitarism

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The pituitary gland is a complex organ secreting six hormones from five different cell types. It is the end product of a carefully orchestrated pattern of expression of signalling molecules and transcription factors. Naturally occurring and transgenic murine models have demonstrated a role for many of these molecules in the aetiology of congenital hypopituitarism. These include the transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, PITX1, PITX2, SOX2 and SOX3. The expression pattern of these transcription factors dictates the phenotype that results when the gene encoding the relevant transcription factor is mutated. The highly variable phenotype may consist of isolated hypopituitarism or more complex disorders such as septo-optic dysplasia and holoprosencephaly. However, the overall incidence of mutations in known transcription factors in patients with hypopituitarism is low, indicating that many genes remain to be identified; characterization of these will further elucidate the pathogenesis of this complex condition and also shed light on normal pituitary development and function.

Section snippets

Embryology of the pituitary gland

Pituitary development is similar in all vertebrates, and human pituitary development would appear to mirror that of the rodent. The anterior and intermediate lobes of the pituitary gland are derived from oral ectoderm, while the posterior pituitary is derived from neural ectoderm.1, 2 The development of the pituitary gland in the rodent occurs in four distinct stages (Figure 1).

  • 1.

    The pituitary placode: the anterior neural ridge, the most anterior midline portion of the embryo, is displaced

Morphogenetic signals (Bmp, Fgf, Shh, Wnt)

Extrinsic molecules within the ventral diencephalon and surrounding structures – such as bone morphogenetic proteins 2 and 4 (Bmp 2, 4), fibroblast growth factor 8 (Fgf8), sonic hedgehog (Shh), wingless (Wnt4), thyroid transcription factor (Ttf1; also called Nkx2.1) – and molecules involved in Notch signalling play critical roles in early organogenesis.3, *4 Rathke's pouch develops in a two-step process requiring sequential inductive signals present only in the diencephalon; induction and

Terminal cell differentiation genes

Terminal pituitary cell differentiation is a culmination of a complex interaction between extrinsic signalling molecules and transcription factors such as Lhx3, Lhx4, Gata2, Isl1, Prop1 and Pit1. Pit1 and Prop1 are the best characterized in terms of function in both humans and mice.

Mutations in PROP1

Human PROP1 maps to chromosome 5q. The gene spans 3 Kb and consists of three exons encoding a protein product of 226 amino acids. The DNA-binding homeodomain consists of three α-helical regions, and most mutations reported to date affect this region. Since the first report of mutations in PROP1 in four unrelated pedigrees with GH, TSH, prolactin, LH and FSH deficiencies, 22 distinct mutations have been identified in over 170 patients, suggesting that PROP1 mutations are the commonest cause of

The clinical spectrum of hypopituitarism

The signs and symptoms of CPHD are essentially a combination of individual hormone abnormalities, and may be non-specific in the early neonatal period, with poor feeding, lethargy, apnoea, jitteriness, hypoglycaemia, temperature instability, prolonged neonatal jaundice and poor weight gain. The condition may be life-threatening in patients with ACTH deficiency characterized by conjugated hyperbilirubinaemia, recurrent sepsis, apnoea and seizures. Males may present with undescended testes and a

Summary

Hypopituitarism is defined as a deficiency of one or several pituitary hormones and can vary in severity and age at presentation. Additionally, the hormone abnormalities may evolve with time, necessitating frequent evaluation. These hormonal deficits can also be present as part of a syndrome, with patients manifesting extra-pituitary abnormalities such as in the eye and forebrain. Over the past decade there has been a considerable advance in our knowledge of the genetic cascade that

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