A New C-Terminal Located Mutation (V272ter) in the  PIT-1 Gene Manifesting with Severe Congenital Hypothyroidism

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Abstract

Objective: We describe a newborn with clinical signs of severe hypothyroidism and combined pituitary hormone deficiency due to a new mutation in the PIT-1 gene. Patient and Methods: Endocrine stimulation test revealed a deficiency for PRL, TSH and GH, suggesting a defect in the pituitary transcription factor PIT-1. Genetic analysis of the PIT-1 gene was performed by exon-specific PCR, followed by SSCP mutation screening and DNA sequencing of the abnormal migrating fragments. Results: DNA sequencing revealed a new mutation (V272ter) in direct neighborhood to a known mutational hot spot (R271W) in the C-terminal part of the PIT-1 molecule. Conclusions: Whereas the R271W mutation has a dominant negative effect on the mutant protein, the newly described mutation is inherited in an autosomal-recessive way. The biological consequences of these two different mutations are discussed.

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Most cited references 5

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PCR-SSCP: A method for detection of mutations

Kenshi Hayashi (1992)

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Characteristics of follicular cell-derived thyroid carcinomas occurring after external radiation exposure: results of a case control study nested in a cohort.

A Shamsaldin, Bernard Caillou, Ibrahima Diallo … (2002)

Radiation exposure is the only well-established risk factor for follicular cell-derived thyroid carcinoma. To compare the clinical characteristics and outcome of thyroid carcinoma in patients with and without a history of radiation exposure, we performed a case control study nested in a cohort of 2,196 patients treated for a papillary or a follicular thyroid cancer at the Institut Gustave Roussy. The study was performed on 91 cases (71% females) and their 273 controls matched for gender, age at thyroid cancer diagnosis (+/-3 years), and period of initial thyroid cancer treatment (+/-6 years). More than 85% of the cases have been first exposed to external radiation before the age of 30 years. Thyroid cancers were more frequently multifocal in cases than in controls (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.3-4.8), and local residual tumor was more frequently observed in cases, but the other clinical features did not differ overall. Female cases with a history of radiation exposure more frequently had a tumor of follicular histology than female controls (OR = 2.7, 95% CI: 1.1-6.5), and conversely the frequency of follicular histology was similar in male cases and in male controls (OR = 0.3, 95% CI: 0.1-1.4). The risks of recurrence and of thyroid cancer related death were similar in cases and in controls.

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Central Hypothyroidism Reveals Compound Heterozygous Mutations in the Pit-1 Gene

Milton R Brown, John S Parks, Matthew Adess … (1998)

Mutations in the gene encoding the Pit-1 transcriptional activator interfere with the embryologic determination and ultimate functions of anterior pituitary cells that produce growth hormone (GH), prolactin (Prl) and thyroid-stimulating hormone (TSH). Central hypothyroidism is often the presenting feature of combined pituitary hormone deficiency (CPHD), but it is not detected in screening programs that rely upon elevation of TSH. We report a child whose hypothyroidism was recognized clinically at age 6 weeks, and subsequently found to have GH and Prl as well as TSH deficiency. With thyroxine and GH replacement he has reached the 70th percentile for height and has normal intelligence. Molecular analysis of genomic DNA for Pit-1 revealed the presence of compound heterozygous recessive mutations: a nonsense mutation in codon 172 and a novel missense mutation substituting glycine for glutamate at codon 174. This case is the first demonstration of CPHD due to compound heterozygous Pit-1 point mutations, as most reported cases of the CPHD phenotype involve either the dominant negative R271W allele or homozygosity for recessive Pit-1 mutations. Therefore, in cases of CPHD, the possibilities of compound heterozygosity for two different Pit-1 mutations, or homozygosity for mutations in the epigenetic gene, Prop-1, should be considered.

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Author and article information

Journal

Journal ID (publisher-id): HRE

Journal ID (nlm-ta): Horm Res Paediatr

Journal ID (doi): 10.1159/issn.1663-2818

Title: Hormone Research in Paediatrics

Publisher: S. Karger AG

ISSN (Print): 1663-2818

ISSN (Electronic): 1663-2826

Publication date Subscription-year: 2001

Publication date (Print): 2001

Publication date (Electronic): 15 February 2002

Volume: 56

Issue: 3-4

Pages: 81-86

Affiliations

^aKinderklinik, Universitätsklinikum der RWTH Aachen; ^bKinderklinik, Klinikum Krefeld, und ^cAbteilung der Transfusionsmedizin, Universität Köln, Deutschland

Article

Publisher ID: 48096 Other ID: Horm Res 2001;56:81–86

DOI: 10.1159/000048096

PubMed ID: 11847467

SO-VID: 5025f9f9-5f8e-4b3a-bfbf-96f4ae3d35fd

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A New C-Terminal Located Mutation (V272ter) in the PIT-1 Gene Manifesting with Severe Congenital Hypothyroidism

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Karger: Endocrinology

Most cited references 5

PCR-SSCP: A method for detection of mutations

Characteristics of follicular cell-derived thyroid carcinomas occurring after external radiation exposure: results of a case control study nested in a cohort.

Central Hypothyroidism Reveals Compound Heterozygous Mutations in the Pit-1 Gene

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