Multiple Pituitary Deficiency

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MULTIPLE PITUITARY HORMONE DEFICIENCY |

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Genetic Forms of Multiple Pituitary Hormone Deficiency. |

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Quite a few genes involved in embryonic development are candidates to explain multiple pituitary hormone deficiency (MPHD) (Chapter 550). There are several distinctive heritable forms of MPHD. Mutations of transcription factor genes that are only expressed in the anterior pituitary lead to simple phenotypes with varying combinations of anterior pituitary hormone deficiencies. Mutations of transcription factor genes that are also expressed in other embryonic tissues give rise to more complex phenotypes that include multiple congenital anomalies. |

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POU1F1 (PIT1) was originally identified as a nuclear protein that bound to the GH and PRL promoters. Mutations in POU1F1 are responsible for combined hormone deficiencies in humans. Many different types of recessive loss of function mutations have been identified in humans. Most of the dominant cases have involved a mutation causing substitution of tryptophan for arginine at position 271. The mutant protein has normal to increased promoter-binding activity but is incapable of activating transcription. Persons with POU1F1 mutations exhibit nearly normal fetal growth but experience severe growth failure in the 1st yr of life. There are complete deficiencies of GH and PRL. The severity of TSH deficiency and resultant central hypothyroidism is variable. There is no impairment of ACTH, luteinizing hormone (LH), or follicle-stimulating hormone (FSH) production. Puberty develops spontaneously, though, at a later than normal age. |

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PROP1 (Prophet of PIT-1) mutations are a very common explanation for the distinctly uncommon phenotype of MPHD. Studies from Switzerland, Poland, and Russia indicate that loss of function mutations are responsible in the majority of cases with a recessive inheritance and about half of the cases with sporadic MPHD. The proportion of sporadic cases that can be explained by PROP1 mutations is even higher when a selection is made for those who have subnormal TSH responses to thyrotropin-releasing hormone (TRH) stimulation. The most common types of mutation involve one or two base pair deletions in the second of three exons. These deletions cause frame shifts and early transcriptional termination, rendering the mutant proteins incapable of binding to promoter sites or activating transcription of target genes. Missense, nonsense, and splice site mutations have also been described. The hormonal phenotypes associated with PROP1 mutations differ in several respects from those associated with POU1F1 mutations. Although the gene defects are present from conception, the hormone deficiencies show the characteristics of an acquired disease. Growth in the 1st yr of life is considerably better than with POU1F1 defects and the median age at diagnosis of GH deficiency is around 6 yr. Recognition of TSH deficiency is delayed relative to recognition of GH deficiency. Basal and TRH-stimulated PRL levels tend to be higher than in POU1F1 mutations. PROP1 mutations cause gonadotropin deficiency and POU1F1 mutations do not. Some patients with PROP1 mutations enter puberty spontaneously and then retreat from it. Girls experience secondary amenorrhea and boys show regression of testicular size and secondary sexual characteristics. There is a loss of LH and FSH responses to luteinizing hormone-releasing hormone (LHRH) stimulation. Partial deficiency of ACTH develops over time in about one third of patients with PROP1 defects. Anterior pituitary size is small in most patients, but in others there is progressive enlargement of the pituitary. A central mass clearly originates within the sella turcica but may extend above it. The cellular content of the mass during the active phase of enlargement is not known. With time, the contents of the mass appear to degenerate, with multiple cystic areas. The mass may persist as a nonenhancing structure or...
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