Total Deficiency of Growth Hormone and Prolactin, and Partial Deficiency of Thyroid Stimulating Hormone in Two Dutch Families: a New Variant of Hereditary Pituitary Deficiency

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In vivo studies in experimental animals and in vitro studies using human lymphocytes have indicated that growth hormone (GH) is important for the development and function of the immune system. This is most clearly illustrated by the underdevelopment of the thymus in dwarf Snell mice, which is prevented by GH treatment. In contrast, in vivo studies in humans have generally shown only minor alterations of immune function in GH deficiency. GH administration to children with various growth disorders may lead to variable and subtle changes in some laboratory parameters of immune function, but no clinical symptoms associated with immune dysfunction have been reported.

mentioning

confidence: 99%

Immunological Findings in Growth Hormone-Treated Patients

Wit

Kooijman²,

Rijkers³

et al. 1993

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“…Sec ond, a patient heterozygous for a G -» T substitution in codon 271 was reported. The mechanism of the dominant effect of this GGG (arginine) TGG (tryptophan) muta tion is not completely understood [44], The third and fourth Pit-1 mutations were found in two Dutch families in which affected individuals had postnatal growth failure with complete deficiencies of GH and PrL, while their T4 levels were low prior to or following GH replacement [45,46], The family having normal T4 levels prior to GH replacement were homozygous for a G -» C substitution in codon 158 changing GCA (alanine) -» CCA (proline). This mutations interferes with the formation of Pit-1 homodimers and dramatically reduces the altered Pit-l's ability to activate transcription.…”

Section: Panhypopituitary Dwarfismmentioning

confidence: 99%

DNA Mapping in Growth and Developmental Disorders

Phillips

1994

DNA mapping techniques are being increasingly applied to familial and acquired disorders affecting growth and development. To understand the potential applications of these techniques, one must first have a good understanding of the components and basic structure of DNA, the genetic code, the basic structure of genes and the roles that various components of gene structure play in regulating gene expression. Following review of this basic information, a variety of DNA mapping techniques including in situ hybridization, Southern blotting, polymerase chain reaction amplification, DNA sequencing and linkage analysis will be covered. Applications of these techniques can enable mapping of unknown genes by detection of loss of allelic heterozygosity or use of linkage analysis and genetic maps. With increasing ease, mutations such as deletions, expansions, rearrangements and point mutations can be detected in diseases such as congenital adrenal hyperplasia, cystic fibrosis, diabetes insipidus, growth hormone deficiency, fragile X syndrome, Laron dwarfism and Turner syndrome. From this discussion, a better understanding of methods of gene localization, uses of genetic maps and rapid, convenient methods to detect a variety of molecular derangements causing familial disorders affecting growth and development will be gained.

“…In August 1992, Pfaffle et al [12] described the molecular defect responsible for GH, Prl and TSH deficiency in the two Dutch families originally described by Wit et al [13], Two children in the first family had mild central hypothyroidism and were homozygous for a mutation that changed codon 158 from an alanine to a proline. In the second family, the children had more severe central hypothyroidism.…”

Section: ]mentioning

confidence: 99%

Genetics of Growth Hormone Gene Expression

Parks

Abdullatif²,

Kinoshita³

et al. 1993

The regulation of pituitary GH gene expression depends on binding of transcriptional activation proteins to cis-active DNA sequences preceding the GH-1 gene. The POU homeodomain protein Pit-1 is found in the nuclei of somatotrophs, lactotrophs and thyrotrophs. It fosters differentiation of these pituitary cell types and is required for hormone production by mature cells. In theory, defects in GH secretion can be caused by mutations in the GH-1 promoter sequence or in the gene encoding Pit-1. In the former case, deficiency would be limited to GH, and in the latter deficiencies extend to prolactin (Prl) and thyrotropin (TSH) as well as to GH. Both the Pit-1 gene and the GH-1 gene have been examined in children with extreme growth failure. Studies of kindreds with GH, Prl and TSH deficiency have disclosed a variety of mutations in the Pit-1 gene. These include nonsense mutations, missense mutations that diminish binding and transcriptional activation, and also mutations that appear to increase promoter binding while eliminating transcriptional activation. This latter class of mutation exerts a dominant negative effect in vivo as well as in vitro. There are many examples of deletions in the GH-1 coding sequence. Some are very large and cause the loss of GH-1, chorionic somatomammotropin and placental GH genes. Others are very small, involving only 1 or 2 bases. They produce frameshifts and premature stop signals. All types produce complete deficiency of GH, but antibody development during treatment has proven to be quite variable. The cDNA for the GH-releasing hormone receptor has recently been cloned and sequenced. It is a leading candidate gene for mutations that cause isolated GH deficiency. Additional advances at the basic science level will bring forward other candidate genes whose disruption may account for more common forms of multiple pituitary hormone deficiency involving GH, TSH, adrenocorticotropin and gonadotropins, but not Prl.