Combined Pituitary Hormone Deficiency in an Inbred Brazilian Kindred Associated with a Mutation in the PROP-1 Gene

Nogueira, Célia Regina; Sabacan, Leah; Jameson, J. Larry; Medeiros‐Neto, Geraldo; Kopp, Peter

doi:10.1006/mgme.1999.2841

Cited by 28 publications

(8 citation statements)

References 9 publications

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“…CPHD has been documented in patients with mutations in several transcription factors involved in pituitary development and hormone expression, specifically POU1F1 (PIT1), PROP1, LHX3, LHX4, and HESX1 (for review: (27)). Among these defects, PROP1 mutations are by far the most common and they have been reported in several Brazilian families (28)(29)(30)(31)(32).…”

Section: Combined Pituitary Hormone Deficiencymentioning

confidence: 99%

Thyroglobulin gene mutations and other genetic defects associated with congenital hypothyroidism

Vono-Toniolo

Kopp

2004

Arq Bras Endocrinol Metab

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Congenital hypothyroidism affects about 1:3000-1:4000 infants. Screening programs now permit early recognition and treatment, thus avoiding the disastrous consequences of thyroid hormone deficiency on brain development. In about 85%, congenital hypothyroidism is associated with developmental defects referred to as thyroid dysgenesis. They include thyroid (hemi)agenesis, ectopic tissue and thyroid hypoplasia. Thyroid dysgenesis is usually sporadic; in only 2% it occurs in a familial fashion. It can be caused by mutations in transcription factors that are essential for the development and function of thyroid follicular cells. Thyroid hypoplasia can also result from resistance to TSH at the level of the thyrocytes. Defects in the steps required for thyroid hormone synthesis within thyroid follicular cells are referred to as dyshormonogenesis and account for about 10-15% of congenital hypothyroidism. In contrast to thyroid dysgenesis, affected patients typically present with goitrous enlargement of the thyroid. The defects leading to dyshormonogenesis typically display a recessive mode of inheritance. Careful clinical, biochemical and molecular analyses of patients with syndromic and nonsyndromic forms of thyroid dysgenesis and dyshormonogenesis have significantly enhanced our understanding of the wide spectrum of pathogenetic mechanisms underlying congenital hypothyroidism and provide unique insights into the (patho)physiology of thyroid development and hormone synthesis. RESUMO Mutações no Gene da Tireoglobulina e Outros Defeitos Genéticos Associados Com Hipotireoidismo Congênito.Hipotireoidismo congênito afeta cerca de 1:3.000-1:4.000 recém-nascidos. Atualmente, programas de triagem neonatal permitem o reconhecimento e tratamento precoces, evitando suas conseqüências desastrosas no desenvolvimento cerebral. Em cerca de 85% dos pacientes, o hipotireoidismo congênito está associado à defeitos no desenvolvimento da tireóide referidos como disgenesia tireoideana. A disgenesia tireoideana ocorre geralmente de forma esporádica; somente 2% dos casos apresentam caráter familial. Podem ser causados por mutações nos fatores de transcrição que são essenciais para o desenvolvimento e função das células foliculares tireoideanas. Hipoplasia da tireóide pode também resultar de resistência tireoideana ao TSH. Defeitos na síntese dos hormônios tireoideanos são referidos como disormonogênese tireoideana e concorrem para 10-15% dos casos de hipotireoidismo congênito. Os pacientes usualmente apresentam bócio, ao contrário da disgenesia tireoideana. Tipicamente, os defeitos que causam disormonogênese apresentam herança recessiva. Uma série de estudos recentes aumentou significativamente nosso entendimento dos mecanismos patogênicos do hipotireoidismo congênito, oferecendo

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Section: Combined Pituitary Hormone Deficiencymentioning

confidence: 99%

Thyroglobulin gene mutations and other genetic defects associated with congenital hypothyroidism

Vono-Toniolo

Kopp

2004

Arq Bras Endocrinol Metab

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“…To date, eight distinct mutations have been identified in the human PROP1 gene: (i) 301‐302delAG (Cogan et al ., 1998; Fofanova et al ., 1998b; Wu et al ., 1998; Deladoëy et al ., 1999; Mendonca et al ., 1999; Nogueira et al ., 1999; Rosenbloom et al ., 1999; Pernasetti et al ., 2000); (ii) R120C (Flück et al ., 1998; Wu et al ., 1998); (iii) F117I (Wu et al ., 1998; Deladoëy et al ., 1999); (iv) 149delAG (Fofanova et al ., 1998a; Deladoëy et al ., 1999); (v) codon50delA (Krzisnik et al ., 1999); (vi) R73C (Duquesnoy et al ., 1998; Deladoëy et al ., 1999); (vii) 343‐2A > T (Deladoëy et al ., 1999); and (viii) F88S (Osorio et al ., 2000) (Table 1). These mutations result in deficiencies in GH, PRL and TSH, as well as LH and FSH.…”

Section: Cphd Caused By Prop1 Gene Mutationsmentioning

confidence: 99%

A unique case of combined pituitary hormone deficiency caused by a PROP1 gene mutation (R120C) associated with normal height and absent puberty

Arroyo¹,

Pernasetti²,

Vasilyev

et al. 2002

Clinical Endocrinology

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We report a 28-year-old-female who presented with primary amenorrhoea, absence of puberty, obesity and normal stature. The subject was clearly short as a child, with a height more than 2 SD below normal until the age of 15 years. The pubertal growth spurt failed to develop. She continued growing at a prepubertal rate until growth ceased at the age of 20 years, reaching her final adult height of 157 cm (SDS -0.86) without hormonal treatment. A combined pituitary hormone stimulation test of anterior pituitary function showed deficiencies of GH, LH and FSH, and low normal serum levels of TSH and PRL. Magnetic resonance imaging revealed a hypoplastic pituitary with markedly reduced pituitary height. In addition, a whole body dual energy X-ray absorptiometry scan showed high levels of body fat (54%). Combined pituitary hormone deficiencies with a hypoplastic pituitary suggested the diagnosis of a Prophet of Pit-1 (PROP1) gene mutation. Normal stature in this case, however, confounded this diagnosis. Sequencing of PROP1 revealed homozygosity for a single base-pair substitution (C to T), resulting in the replacement of an Arg by a Cys at codon 120 (R120C) in the third helix of the homeodomain of the Prop-1 protein. To our knowledge, this is the first report of a patient with a mutation in the PROP1 gene that attained normal height without hormonal treatment, indicating a new variability in the PROP1 phenotype, with important implications for the diagnosis of these patients. We suggest that this can be explained by (i) the presence of low levels of GH in the circulation during childhood and adolescence; (ii) the lack of circulating oestrogen delaying epiphyseal fusion, resulting in growth beyond the period of normal growth; and (iii) fusion of the epiphyseal plates, possibly as a result of circulating oestrogens originating from peripheral conversion of androgens by adipose tissue.

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“…PIT-1 (POU1F1 gene) mutations lead to combined pituitary hormone deficiency (CPHD) featuring GH, TSH, and PRL deficiencies (7)(8)(9)(10). PROP-1 gene defects lead to CPHD associated with deficiencies in these hormones and often decreased levels of gonadotropins (11)(12)(13)(14)(15)(16). Normal expression of these two factors is restricted to the pituitary, and development of other organ systems is not affected.…”

mentioning

confidence: 99%

Molecular Analysis ofLHX3andPROP-1in Pituitary Hormone Deficiency Patients with Posterior Pituitary Ectopia¹

Sloop

Walvoord

Showalter

et al. 2000

The Journal of Clinical Endocrinology & Metabolism

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The cause of posterior pituitary ectopia associated with anterior pituitary hormone deficiencies is unknown. We describe children with combined pituitary hormone deficiency (CPHD) or isolated GH deficiency. In all cases, magnetic resonance imaging examination revealed abnormal pituitary gland development featuring ectopic posterior lobe location and frequently hypoplastic anterior lobes. Embryonic development of the pituitary requires the coordinated expression of specific transcription factors. Mutations of the PIT-1 and PROP-1 transcription factors are responsible for CPHD in some patients with normally positioned posterior pituitaries. In mice, the Lhx3 LIM homeodomain transcription factor is required for both structural development and cellular differentiation of the pituitary gland. Thus, we hypothesized that mutations in one or both of the two human LHX3 isoforms are responsible for posterior pituitary ectopia associated with anterior pituitary hypopituitarism. Comprehensive molecular analysis of the LHX3 isoforms was performed to test this hypothesis. No loss of function mutations in the LHX3 gene were detected. In addition, analysis of PROP-1 did not reveal mutations that might cause this phenotype. These studies suggest that the abnormal processes leading to the development of CPHD or GH deficiency associated with posterior pituitary ectopia are not a result of aberrant LHX3 or PROP-1 function, but may be caused by defects at other gene loci. (J Clin Endocrinol

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Combined Pituitary Hormone Deficiency in an Inbred Brazilian Kindred Associated with a Mutation in the PROP-1 Gene

Cited by 28 publications

References 9 publications

Thyroglobulin gene mutations and other genetic defects associated with congenital hypothyroidism

Thyroglobulin gene mutations and other genetic defects associated with congenital hypothyroidism

A unique case of combined pituitary hormone deficiency caused by a PROP1 gene mutation (R120C) associated with normal height and absent puberty

Molecular Analysis ofLHX3andPROP-1in Pituitary Hormone Deficiency Patients with Posterior Pituitary Ectopia¹

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Combined Pituitary Hormone Deficiency in an Inbred Brazilian Kindred Associated with a Mutation in the PROP-1 Gene

Cited by 28 publications

References 9 publications

Thyroglobulin gene mutations and other genetic defects associated with congenital hypothyroidism

Thyroglobulin gene mutations and other genetic defects associated with congenital hypothyroidism

A unique case of combined pituitary hormone deficiency caused by a PROP1 gene mutation (R120C) associated with normal height and absent puberty

Molecular Analysis ofLHX3andPROP-1in Pituitary Hormone Deficiency Patients with Posterior Pituitary Ectopia1

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Molecular Analysis ofLHX3andPROP-1in Pituitary Hormone Deficiency Patients with Posterior Pituitary Ectopia¹