Isolated adrenocorticotropic hormone deficiency presenting as an acute neurologic emergency in a peripubertal girl.

Isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) is extraordinarily rare, and the clinical manifestations of its accompanying adrenal insufficiency are diverse. Early-onset forms of IAD have been linked to mutations in the Tpit transcription factor gene TPIT; however, the genetic basis of juvenile- or late-onset IAD is unknown. Herein, we describe a case of a peripubertal girl with IAD and a normal TPIT gene who presented with an acute neurologic emergency, demonstrating both the variable clinical presentation of IAD and the need for continued investigation into the molecular mechanisms underlying juvenile- and late-onset IAD.

The TPIT gene mutation M86R associated with isolated adrenocorticotropin deficiency interferes with protein: protein interactions.

Context: Tpit is a T-box transcription factor important for terminal differentiation of pituitary proopiomelanocortin-expressing cells. We previously showed that human and murine mutations in the gene encoding this highly cortico/melanotrope-specific transcription factor cause a neonatal onset form of congenital isolated ACTH deficiency (IAD). We characterized the largest series of neonatal IAD patients caused by TPIT mutations, and this revealed a highly homogeneous clinical presentation.

Identification and functional analysis of the novel S179R POU1F1 mutation associated with combined pituitary hormone deficiency.

Context: The pituitary-specific transcription factor 1 plays a key role in the development and differentiation of three pituitary cell types: somatotrophs, lactotrophs, and thyrotrophs. Several mutations of the human gene (called POU1F1) have been shown to be responsible for a phenotype of combined pituitary hormone deficiency involving GH, prolactin (PRL), and TSH.

Objective: We have identified a novel homozygous C to G mutation in exon 4 of the POU1F1 gene (S179R) in a patient with this rare phenotype.

Genetic screening of combined pituitary hormone deficiency: experience in 195 patients.

Context: Mutations in transcription factors result in combined pituitary hormone deficiency (CPHD).

Objective: A genetic screening strategy, based on endocrine and neuroradiological phenotype according to published knowledge, was applied to establish the prevalence of gene defects in each category of patients and provide a useful framework for clinicians to determine the genetic etiology and recurrence risks for individuals and families.

Design: One hundred ninety-five CPHD patients from the international GENHYPOPIT network were studied, according to their phenotype, for POU1F1, PROP1, LHX3, LHX4, and HESX1.

Low estriol levels in the maternal triple-marker screen as a predictor of isolated adrenocorticotropic hormone deficiency caused by a new mutation in the TPIT gene.

Isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) is a rare cause of adrenocortical insufficiency, especially in children, and may be an underestimated cause of neonatal death. Early postnatal diagnosis may prevent hypoglycemic seizures, Addisonian crises, and death. There are also occasional reports of prenatal diagnosis of IAD by findings on the maternal triple-marker screen (TMST), a combined serum analyte test that measures levels of alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol for the detection of Down syndrome and open neural-tube defects.

An uncommon phenotype with familial central hypogonadism caused by a novel PROP1 gene mutant truncated in the transactivation domain.

Context: PROP1 gene mutations are usually associated with childhood onset GH and TSH deficiencies, whereas gonadotroph deficiency is diagnosed at pubertal age.

Objectives: We report a novel PROP1 mutation revealed by familial normosmic hypogonadotropic hypogonadism. We performed in vitro transactivation and DNA binding experiments to study functional consequences of this mutation.

Congenital isolated adrenocorticotropin deficiency: an underestimated cause of neonatal death, explained by TPIT gene mutations.

Tpit is a T box transcription factor important for terminal differentiation of pituitary proopiomelanocortin-expressing cells. We demonstrated that human and mouse mutations of the TPIT gene cause a neonatal-onset form of congenital isolated ACTH deficiency (IAD). In the absence of glucocorticoid replacement, IAD can lead to neonatal death by acute adrenal insufficiency.

The desmopressin test as a predictive factor of outcome after pituitary surgery for Cushing's disease.

Objective: Taking advantage of the over-expression of V3 receptors in adenomatous corticotroph cells, we evaluated the response to the vasopressin agonist desmopressin in 22 patients operated on for Cushing's disease, with a mean follow-up of 4.5 years.

Subjects And Methods: Twenty-two patients (17 women) operated on for Cushing's disease with a follow-up >2 years (median, 48; range, 24-141 months) underwent one desmopressin test (10 microg i.

A familial form of congenital hypopituitarism due to a PROP1 mutation in a large kindred: phenotypic and in vitro functional studies.

We report the natural history of a hypopituitarism in a large Tunisian kindred including 29 subjects from the same consanguineous family. The index case was a 9-yr-old girl with severe growth retardation due to complete GH deficiency and partial corticotroph, lactotroph, and thyrotroph deficiencies. Magnetic resonance imaging showed a hyperplastic anterior pituitary.

[Tpit mutations reveal a new model of pituitary differentiation and account for isolated ACTH deficiency].

Pituitary hormone-producing cells differentiate sequentially from a common epithelial primordium, Rathke's pouch, under the combinatorial action of a subset of tissue- and cell-restricted transcription factors. Some factors have been implicated in early events of pituitary induction and morphogenesis while other factors like Pit-1 and SF-1 have been associated with differentiation of particular lineages. In POMC-expressing cells, Pitx1, NeuroD1 and Tpit were shown to be important for cell specific transcription of the POMC gene.

Differential regulation of proopiomelanocortin and pituitary-restricted transcription factor (TPIT), a new marker of normal and adenomatous human corticotrophs.

Since the identification of the pituitary-restricted transcription factor Tpit, a novel T-box factor that is only present in mouse in the two pituitary proopiomelanocortin (POMC)-expressing lineages, no information was available on its pattern of expression in human pituitary. We investigated by immunohistochemistry and in situ hybridization the expression of TPIT in normal human anterior pituitary tissue and in several types of human pituitary adenomas (n = 52). TPIT expression was restricted to the nucleus of normal or adenomatous human corticotroph cells.

Tpit determines alternate fates during pituitary cell differentiation.

The T-box transcription factor Tpit was identified as a cell-specific factor for expression of the pituitary proopiomelanocortin (POMC) gene. Expression of this factor is exclusively restricted to the pituitary POMC-expressing lineages, the corticotrophs and melanotrophs. We have now determined the role of this factor in pituitary cell differentiation.

Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency.

Tpit is a highly cell-restricted transcription factor that is required for expression of the pro-opiomelanocortin (POMC) gene and for terminal differentiation of the pituitary corticotroph lineage. Its exclusive expression in pituitary POMC-expressing cells has suggested that its mutation may cause isolated deficiency of pituitary adrenocorticotropin (ACTH). We now show that Tpit-deficient mice constitute a model of isolated ACTH deficiency (IAD) that is very similar to human IAD patients carrying TPIT gene mutations.

Macroprolactinemia revisited: a study on 106 patients.

The predominance of high molecular weight PRL, or macroprolactinemia, has long been known in hyperprolactinemic patients with maintained fertility. Among 1,106 consecutive patients investigated for hyperprolactinemia in our center over a 10-yr period, serum PRL chromatography was performed in 368 cases because of discordant clinical, biological, or neuroradiological findings. We prospectively studied the 106 patients with macroprolactinemia (96 women, 6 men, 4 children) and compared them with the 262 hyperprolactinemic patients with a normal PRL elution pattern.

PROP1 gene screening in patients with multiple pituitary hormone deficiency reveals two sites of hypermutability and a high incidence of corticotroph deficiency.

Alterations of the gene encoding the pituitary transcription factor PROP1 were associated with congenital forms of multiple pituitary hormone deficiencies in several families. Among 23 patients with multiple pituitary hormone deficiencies screened for a PROP1 gene abnormality, nine belonging to eight unrelated families had homozygous PROP1 gene defects. All mutations were located in exon 2 and affected only two different sites: a homozygous AG deletion at codons 99/100/101 (n = 5); homozygous point mutations affecting codon 73: R73C (n = 2) or R73H (n = 1), and a R73C/R99X double-heterozygous mutation (n = 1).

Combined pituitary hormone deficiency due to the F135C human Pit-1 (pituitary-specific factor 1) gene mutation: functional and structural correlates.

The pituitary-specific transcription factor Pit-1 (pituitary-specific factor 1) is known to play a key role in the differentiation of PRL-, GH-, and TSH-secreting cells, and in the regulation of expression of the corresponding genes. In recent years, 12 distinct mutations of the Pit-1 gene have been shown to be responsible for a phenotype of multiple congenital pituitary hormone deficiency involving PRL, GH, and TSH. We had previously identified, in four siblings with GH, PRL, and TSH deficiencies, a mutation (F135C) resulting in a single amino acid change within the POU-specific binding domain of the Pit-1 molecule.

Markers of tumor invasion are major predictive factors for the long-term outcome of corticotroph microadenomas treated by transsphenoidal adenomectomy.

Objective: To assess the postsurgical outcome of patients with corticotroph microadenomas and to define predictors of the long-term outcome, with special emphasis on markers of tumor extension.

Design: Prospective study of 53 corticotroph microadenomas treated by enlarged adenomectomy. Patients followed for at least 2 years were classified into two groups: those in long-term remission and uncured patients (immediate failures and recurrences).

[Pituitary development and pathology of transcription factors].

Over the last 10 years, important data on pituitary development have been reported using spontaneous or experimental models of gene inactivation. The development pathways of the anterior pituitary lobe include organogenesis resulting in Rathke pouch formation and cell differentiation. Pituitary development is controlled by sequential series of specific signaling molecules and specific transcription factors.