Adrenocorticotropin Deficiency in Combined Pituitary Hormone Deficiency Patients Homozygous for a Novel PROP1 Deletion

Agarwal, Gaurav; Bhatia, Vijayalakshmi; Cook, Sheridan; Thomas, Paul Q.

doi:10.1210/jcem.85.12.7013

Cited by 87 publications

(27 citation statements)

References 22 publications

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“…Individuals with PROP1 mutations exhibit normal ACTH/cortisol levels in early life but often demonstrate an evolving cortisol deficiency that is strongly and significantly correlated with increasing age (89)(90)(91)(92)(93). However, patients as young as 6-7 years have also been described with cortisol deficiency (93,94).…”

Section: Prop1mentioning

confidence: 99%

Hypothalamic and pituitary development: novel insights into the aetiology

Kelberman¹,

Dattani²

2007

eur j endocrinol

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The anterior pituitary gland is a central regulator of growth, reproduction and homeostasis, and is the end-product of a carefully orchestrated pattern of expression of signalling molecules and transcription factors leading to the development of this complex organ secreting six hormones from five different cell types. Naturally occurring and transgenic murine models have demonstrated a role for many of these molecules in the aetiology of combined pituitary hormone deficiency (CPHD). These include the transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, TBX19, SOX2 and SOX3. The expression pattern of these transcription factors dictates the phenotype that results when the gene encoding the relevant transcription factor is mutated. The highly variable phenotype may consist of isolated hypopituitarism, or more complex disorders such as septo-optic dysplasia and holoprosencephaly. Since mutations in any one transcription factor are uncommon, and since the overall incidence of mutations in known transcription factors is low in patients with CPHD, it is clear that many genes remain to be identified, and the characterization of these will further elucidate the pathogenesis of these complex conditions and also shed light on normal pituitary development.European Journal of Endocrinology 157 S3-S14

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Section: Prop1mentioning

confidence: 99%

Hypothalamic and pituitary development: novel insights into the aetiology

Kelberman¹,

Dattani²

2007

eur j endocrinol

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“…In our cohort of patients, the older brother from family II presented a slightly compromised cortisol response to hypoglycemia (15.4 µg/dl) at the age of 11 years, and the patients from families I and III presented ACTH deficiency at the ages of 16 and 17 years (table 3). Hypocortisolaemia occurring during the second decade of life is an uncommon finding but has been described before (37,40).…”

Section: Prop1 Mutations In Familial Cphdmentioning

confidence: 99%

Molecular analysis of PROP1, PIT1, HESX1, LHX3, and LHX4 shows high frequency of PROP1 mutations in patients with familial forms of combined pituitary hormone deficiency

Vieira

Boldarine

Abucham

2007

Arq Bras Endocrinol Metab

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Combined Pituitary Hormone Deficiency (CPHD) is a prevalent disease in Neuroendocrinology services. The genetic form of CPHD may originate from mutations in pituitary transcription factor (PTF) genes and the pituitary image in these cases may give a clue of what PTF is most probably mutated: defects in LHX4 are usually associated with ectopic posterior pituitary (EPP); defects in LHX3, PIT1, and PROP1, with normally placed posterior pituitary (NPPP); HESX1 mutations are associated with both. Objective: To identify mutations in PTF genes in patients with idiopathic hypopituitarism followed in our service, based on the presence or absence of EPP on sellar MRI. Methods: Forty patients with idiopathic hypopituitarism (36 families, 9 consanguineous), followed in the Neuroendocrinology Outpatient Clinic of UNIFESP, Brazil, were submitted to sequencing analyses of PTF genes as follows: LHX3, HESX1, PIT1, and PROP1 were sequenced in patients with NPPP (26/40) and HESX1 and LHX4 in patients with EPP (14/40). Results: We identified only PROP1 mutations in 9 out of 26 patients with CPHD and NPPP (35%). Since eight of them came from 4 consanguineous families, the prevalence of PROP1 mutations was higher when only consanguineous families were considered (44%, 4/9). At the end of the study, we decided to sequence PROP1 in patients with EPP, just to confirm that they were not candidates for PROP1 mutations. Deficiência Combinada de Hormônios Hipofisários (DCHH) é uma doença prevalente em todos os serviços de Neuroendocrinologia. A DCHH de origem genética pode resultar de mutações nos genes de fatores de transcrição hipofisários (FTH), e a ressonância magnética (RM) de sela desses pacientes pode indicar qual FTH tem maior probabilidade de estar mutado: mutações no LHX4 estão geralmente associadas a neuro-hipófise ectópica (NHE); mutações no LHX3, PIT1 e PROP1, a neuro-hipófise tópica (NHT); mutações no HESX1 podem estar associadas a NHE e NHT. Objetivo: Identificar mutações nos FTH em pacientes acompanhados em nosso serviço, portadores de hipopituitarismo idiopático, selecionando os genes a serem estudados de acordo com a presença ou ausência de NHE à RM sela. Métodos: Os genes dos FTH foram seqüenciados em 40 pacientes com hipopituitarismo idiopático (36 famílias, 9 consangüíneas), acompanhados na unidade de Neuroendocrinologia da UNIFESP, SP, Brasil: LHX3, HESX1, PIT1 e PROP1 foram seqüenciados nos pacientes com NHT (26/40) e HESX1 e LHX4, nos pacientes com NHE (14/40). Resultados: Somente mutações PROP1 foram identificadas em 9 de 26 pacientes (35%) com NHT, 8 deles provenientes de 4 famílias consangüíneas (4/9, 44%). Uma vez que mutações no PROP1 foram tão freqüentes, decidimos, ao final do estudo, seqüenciá-lo também nos pacientes com NHE. Nenhum paciente com NHE apresentou mutações no PROP1 ou em outro FTH. Conclusão: Mutações no gene PROP1 foram encontradas em 22,5% (9/40) de todos os pacientes, em 35% (9/26) dos pacientes com NHT e em 44% (4/9) se considerarmos somente as famílias consangüíneas. Portanto, pacien...

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“…Pathogenic Prop1 gene alterations lead to combined pituitary hormone deficiency (CPHD): growth hormone (GH), prolactin (PRL), thyrotropin (TSH) and gonadotropins of variable severity and timing of onset. Adrenocorticotropin insufficiency occasionally develops as a rather late manifestation of unknown pathogenesis (11,12,18,19). Insufficient adrenarche in the presence of a normal pituitary -adrenal axis has also been reported (20).…”

Section: Introductionmentioning

confidence: 99%

Prolonged jaundice and hypothyroidism as the presenting symptoms in a neonate with a novel Prop1 gene mutation (Q83X)

et al. 2004

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Objective: To identify the genetic defect in a neonate presented with prolonged jaundice and central hypothyroidism. Design: Central hypothyroidism was detected in a neonate initially examined for prolonged jaundice, and levothyroxine therapy was initiated. Direct sequencing of the Prop1 gene was carried out and pituitary function and morphology were evaluated using hormonal testing and magnetic resonance imaging (MRI) respectively. Methods: Dynamic hormonal testing was carried out using established methodologies. Hormones were determined by RIA or chemiluminescence immunoassays. Genomic analysis of the Prop1 gene was performed by direct sequencing. MRI protocol: sagittal spin echo T2-weighted scans 2500/90 (TR/TE), plain and contrast-enhanced sagittal and coronal spin echo T1-weighted scans 500/20 (TR/TE). Results: Low thyroid hormones (coupled with lack of TSH rise), low GH, normal cortisol and normal prolactin values were detected. Direct sequencing revealed the presence of two mutations in the Prop1 gene: GA296del and Q83X. The Q83X was further confirmed by PvuII restriction digestion and represented a novel Prop1 gene mutation, which was not detected in 100 controls tested. Pituitary enlargement was detected, with respect to normal-for-age controls. Conclusions: (i) The Q83X mutation extends the spectrum of Prop1 gene mutations; (ii) central hypothyroidism in a neonate might constitute the initial sign of Prop1 gene defect; (iii) the patient is the youngest individual with Prop1 gene defect and pituitary enlargement presented to date; and (iv) early detection of Prop1 gene mutations facilitates genetic counseling and ensures prompt management of the anticipated hormonal insufficiencies.European Journal of Endocrinology 150 257-264

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Adrenocorticotropin Deficiency in Combined Pituitary Hormone Deficiency Patients Homozygous for a Novel PROP1 Deletion

Cited by 87 publications

References 22 publications

Hypothalamic and pituitary development: novel insights into the aetiology

Hypothalamic and pituitary development: novel insights into the aetiology

Molecular analysis of PROP1, PIT1, HESX1, LHX3, and LHX4 shows high frequency of PROP1 mutations in patients with familial forms of combined pituitary hormone deficiency

Prolonged jaundice and hypothyroidism as the presenting symptoms in a neonate with a novel Prop1 gene mutation (Q83X)

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