Autosomal dominant resistance to thyrotropin as a distinct entity in five multigenerational kindreds: Clinical characterization and exclusion of candidate loci

Helmut Grasberger, Aviva Mimouni-Bloch, Marie Christine Vantyghem, Guy Van Vliet, Marc Abramowicz, Daniel L. Metzger, Hussein Abdullatif, Catherine Rydlewski, Paolo E. Macchia, Neal H. Scherberg, Jacqueline Van Sande, Marc Mimouni, Roy E Weiss, Gilbert Vassart, Samuel Refetoff

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Context: Resistance to TSH (RTSH) is an inherited disorder of variable hyposensitivity to TSH. The metabolic consequences can range from euthyroid hyperthyrotropinemia to severe congenital hypothyroidism with thyroid hypoplasia. Although subclinical and mild hypothyroidism fitting the RTSH phenotype is common in the population, the role of genetic factors is far from being understood. Only in rare cases has RTSH been attributed to TSHR or PAX8 gene mutations. Objective, Setting, and Participants: Toward the identification of novel RTSH genes, we studied five large, unrelated families comprising 102 individuals, 56 of whom were affected. Results: Inheritance of RTSH in these families followed an autosomal dominant pattern without evidence for incomplete penetrance, yet expressivity was variable. Considering only fully phenotyped generations, 64% of the progeny was affected, with a 1:1.4 male-to-female ratio. Of 18 affected individuals tested in the neonatal period, two were undetected because of borderline results. The thyroid phenotype was indistinguishable from that observed with PAX8 and TSHR defects. In four families, untreated affected subjects of all ages had elevated serum thyroglobulin levels, consistent with a defect in the thyroid follicle cells. Linkage of RTSH to TSHR and PAX8 was excluded in all five families. For the largest families, we likewise excluded a contribution of genes previously only associated with syndromic forms of RTSH, namely TITF1, GNAS, and FOXE1. Conclusions: These kindreds represent a distinct etiological entity of autosomal dominant RTSH. According to the clinical presentation of these families, genetic causes of mild hyperthyrotropinemia in the general population may be more common than currently appreciated.

Original languageEnglish (US)
Pages (from-to)4025-4034
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Volume90
Issue number7
DOIs
StatePublished - Jul 2005
Externally publishedYes

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Thyrotropin
Genes
Thyroid Gland
Thyroid Dysgenesis
Phenotype
Congenital Hypothyroidism
Defects
Penetrance
Thyroglobulin
Population Genetics
Hypothyroidism
Mutation
Serum
Population

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

Autosomal dominant resistance to thyrotropin as a distinct entity in five multigenerational kindreds : Clinical characterization and exclusion of candidate loci. / Grasberger, Helmut; Mimouni-Bloch, Aviva; Vantyghem, Marie Christine; Van Vliet, Guy; Abramowicz, Marc; Metzger, Daniel L.; Abdullatif, Hussein; Rydlewski, Catherine; Macchia, Paolo E.; Scherberg, Neal H.; Van Sande, Jacqueline; Mimouni, Marc; Weiss, Roy E; Vassart, Gilbert; Refetoff, Samuel.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 90, No. 7, 07.2005, p. 4025-4034.

Research output: Contribution to journalArticle

Grasberger, H, Mimouni-Bloch, A, Vantyghem, MC, Van Vliet, G, Abramowicz, M, Metzger, DL, Abdullatif, H, Rydlewski, C, Macchia, PE, Scherberg, NH, Van Sande, J, Mimouni, M, Weiss, RE, Vassart, G & Refetoff, S 2005, 'Autosomal dominant resistance to thyrotropin as a distinct entity in five multigenerational kindreds: Clinical characterization and exclusion of candidate loci', Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 7, pp. 4025-4034. https://doi.org/10.1210/jc.2005-0572
Grasberger, Helmut ; Mimouni-Bloch, Aviva ; Vantyghem, Marie Christine ; Van Vliet, Guy ; Abramowicz, Marc ; Metzger, Daniel L. ; Abdullatif, Hussein ; Rydlewski, Catherine ; Macchia, Paolo E. ; Scherberg, Neal H. ; Van Sande, Jacqueline ; Mimouni, Marc ; Weiss, Roy E ; Vassart, Gilbert ; Refetoff, Samuel. / Autosomal dominant resistance to thyrotropin as a distinct entity in five multigenerational kindreds : Clinical characterization and exclusion of candidate loci. In: Journal of Clinical Endocrinology and Metabolism. 2005 ; Vol. 90, No. 7. pp. 4025-4034.
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abstract = "Context: Resistance to TSH (RTSH) is an inherited disorder of variable hyposensitivity to TSH. The metabolic consequences can range from euthyroid hyperthyrotropinemia to severe congenital hypothyroidism with thyroid hypoplasia. Although subclinical and mild hypothyroidism fitting the RTSH phenotype is common in the population, the role of genetic factors is far from being understood. Only in rare cases has RTSH been attributed to TSHR or PAX8 gene mutations. Objective, Setting, and Participants: Toward the identification of novel RTSH genes, we studied five large, unrelated families comprising 102 individuals, 56 of whom were affected. Results: Inheritance of RTSH in these families followed an autosomal dominant pattern without evidence for incomplete penetrance, yet expressivity was variable. Considering only fully phenotyped generations, 64{\%} of the progeny was affected, with a 1:1.4 male-to-female ratio. Of 18 affected individuals tested in the neonatal period, two were undetected because of borderline results. The thyroid phenotype was indistinguishable from that observed with PAX8 and TSHR defects. In four families, untreated affected subjects of all ages had elevated serum thyroglobulin levels, consistent with a defect in the thyroid follicle cells. Linkage of RTSH to TSHR and PAX8 was excluded in all five families. For the largest families, we likewise excluded a contribution of genes previously only associated with syndromic forms of RTSH, namely TITF1, GNAS, and FOXE1. Conclusions: These kindreds represent a distinct etiological entity of autosomal dominant RTSH. According to the clinical presentation of these families, genetic causes of mild hyperthyrotropinemia in the general population may be more common than currently appreciated.",
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T1 - Autosomal dominant resistance to thyrotropin as a distinct entity in five multigenerational kindreds

T2 - Clinical characterization and exclusion of candidate loci

AU - Grasberger, Helmut

AU - Mimouni-Bloch, Aviva

AU - Vantyghem, Marie Christine

AU - Van Vliet, Guy

AU - Abramowicz, Marc

AU - Metzger, Daniel L.

AU - Abdullatif, Hussein

AU - Rydlewski, Catherine

AU - Macchia, Paolo E.

AU - Scherberg, Neal H.

AU - Van Sande, Jacqueline

AU - Mimouni, Marc

AU - Weiss, Roy E

AU - Vassart, Gilbert

AU - Refetoff, Samuel

PY - 2005/7

Y1 - 2005/7

N2 - Context: Resistance to TSH (RTSH) is an inherited disorder of variable hyposensitivity to TSH. The metabolic consequences can range from euthyroid hyperthyrotropinemia to severe congenital hypothyroidism with thyroid hypoplasia. Although subclinical and mild hypothyroidism fitting the RTSH phenotype is common in the population, the role of genetic factors is far from being understood. Only in rare cases has RTSH been attributed to TSHR or PAX8 gene mutations. Objective, Setting, and Participants: Toward the identification of novel RTSH genes, we studied five large, unrelated families comprising 102 individuals, 56 of whom were affected. Results: Inheritance of RTSH in these families followed an autosomal dominant pattern without evidence for incomplete penetrance, yet expressivity was variable. Considering only fully phenotyped generations, 64% of the progeny was affected, with a 1:1.4 male-to-female ratio. Of 18 affected individuals tested in the neonatal period, two were undetected because of borderline results. The thyroid phenotype was indistinguishable from that observed with PAX8 and TSHR defects. In four families, untreated affected subjects of all ages had elevated serum thyroglobulin levels, consistent with a defect in the thyroid follicle cells. Linkage of RTSH to TSHR and PAX8 was excluded in all five families. For the largest families, we likewise excluded a contribution of genes previously only associated with syndromic forms of RTSH, namely TITF1, GNAS, and FOXE1. Conclusions: These kindreds represent a distinct etiological entity of autosomal dominant RTSH. According to the clinical presentation of these families, genetic causes of mild hyperthyrotropinemia in the general population may be more common than currently appreciated.

AB - Context: Resistance to TSH (RTSH) is an inherited disorder of variable hyposensitivity to TSH. The metabolic consequences can range from euthyroid hyperthyrotropinemia to severe congenital hypothyroidism with thyroid hypoplasia. Although subclinical and mild hypothyroidism fitting the RTSH phenotype is common in the population, the role of genetic factors is far from being understood. Only in rare cases has RTSH been attributed to TSHR or PAX8 gene mutations. Objective, Setting, and Participants: Toward the identification of novel RTSH genes, we studied five large, unrelated families comprising 102 individuals, 56 of whom were affected. Results: Inheritance of RTSH in these families followed an autosomal dominant pattern without evidence for incomplete penetrance, yet expressivity was variable. Considering only fully phenotyped generations, 64% of the progeny was affected, with a 1:1.4 male-to-female ratio. Of 18 affected individuals tested in the neonatal period, two were undetected because of borderline results. The thyroid phenotype was indistinguishable from that observed with PAX8 and TSHR defects. In four families, untreated affected subjects of all ages had elevated serum thyroglobulin levels, consistent with a defect in the thyroid follicle cells. Linkage of RTSH to TSHR and PAX8 was excluded in all five families. For the largest families, we likewise excluded a contribution of genes previously only associated with syndromic forms of RTSH, namely TITF1, GNAS, and FOXE1. Conclusions: These kindreds represent a distinct etiological entity of autosomal dominant RTSH. According to the clinical presentation of these families, genetic causes of mild hyperthyrotropinemia in the general population may be more common than currently appreciated.

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