BackgroundPituitary stalk interruption syndrome (PSIS) is a particular entity in the population of patients with hypopituitarism. Only rare cases have a known genetic cause.Objectivesi) To compare ...subgroups with or without extra-pituitary malformations (EPM) in a cohort of PSIS patients to identify predictive factors of evolution, ii) to determine the incidence of mutations of the known pituitary transcription factor genes in PSIS.Study designWe analyzed features of 83 PSIS patients from 80 pedigrees and screened HESX1, LHX4, OTX2, and SOX3 genes.ResultsPSIS had a male predominance and was rarely familial (5%). Pituitary hypoplasia was observed only in the group with EPM. Multiple hormone deficits were observed significantly more often with versus without EPM (87.5 vs 69.5% respectively). Posterior pituitary location along the stalk was a significant protective factor regarding severity of hormonal phenotype. A novel HESX1 causative mutation was found in a consanguineous family, and two LHX4 mutations were present in familial PSIS.ConclusionPSIS patients with EPM had a more severe hormonal disorder and pituitary imaging status, suggesting an antenatal origin. HESX1 or LHX4 mutations accounted for <5% of cases and were found in consanguineous or familial cases.
Over the last two decades, the understanding of the mechanisms involved in pituitary ontogenesis has largely increased. Since the first description of
POU1F1
human mutations responsible for a ...well-defined phenotype without extra-pituitary malformation, several other genetic defects of transcription factors have been reported with variable degrees of phenotype–genotype correlations. However, to date, despite the identification of an increased number of genetic causes of isolated or multiple pituitary deficiencies, the etiology of most (80–90 %) congenital cases of hypopituitarism remains unsolved. Identifying new etiologies is of importance as a post-natal diagnosis to better diagnose and treat the patients (delayed pituitary deficiencies, differential diagnosis of a pituitary mass on MRI, etc.), and as a prenatal diagnosis to decrease the risk of early death (undiagnosed corticotroph deficiency for instance). The aim of this review is to summarize the main etiologies and phenotypes of combined pituitary hormone deficiencies, associated or not with extra-pituitary anomalies, and to suggest how the identification of such etiologies could be improved in the near future.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The pituitary gland has provided unique insight into molecular mechanisms and regulatory factors controling both differentiation and gene transcription. We identified Tpit, a novel T box factor only ...present in the two pituitary POMC-expressing lineages, the corticotrophs and melanotrophs, and apparently in no other tissue, including hypothalamic POMC neurons. In pituitary cells, Tpit activation of POMC gene transcription requires cooperation with Pitx1, the two factors binding to contiguous sites within the same regulatory element. In gain-of-function experiments, Tpit induces POMC expression in undifferentiated pituitary cells, indicating that it can initiate differentiation into POMC-expressing lineages.
TPIT gene mutations were found in patients with isolated deficiency of pituitary POMC-derived ACTH, in support of an essential role of Tpit for differentiation of the pituitary POMC lineage.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In acromegaly, the combination of somatostatin (SS) and dopamine (DA) agonists has been shown to enhance suppression of GH secretion. In the present study, a new chimeric molecule, BIM-23A387, which ...selectively binds to the SS subtype 2 receptor (sst2; Ki = 0.10 nm) and to the DA D2 receptor (D2DR; Ki = 22.1 nm) was tested in cultures prepared from 11 human GH-secreting tumors for its ability to suppress GH and prolactin (PRL) secretion. The chimeric compound was compared with individual sst2 and D2DR agonists of comparable activity at the individual receptors. All tumors expressed both sst2 and D2DR mRNAs (0.8 ± 0.2 and 4.7 ± 0.7 copy/copy β-glucuronidase mRNA, respectively). In cell cultures from seven octreotide-sensitive tumors, the maximal inhibition of GH release induced by the individual sst2 and D2DR analogs and by BIM-23A387 was similar. However, the mean EC50 for GH suppression by BIM-23A387 (0.2 pm) was 50 times lower than that of the individual sst2 and D2DR analogs, either used individually or combined. Similar data were obtained in four tumors that were only partially responsive to octreotide. The inhibition of GH release by BIM-23A387 was only partially reversed by the D2R2 antagonist, sulpiride, or by the sst2 antagonist, BIM-23454. Only when both antagonists were combined was the GH suppressive effect of BIM-23A387 totally reversed. Finally, BIM-23A387 produced a mean 73 ± 6% inhibition of PRL in six mixed GH plus PRL tumors. These data demonstrate an enhanced potency of the chimeric molecule, BIM-23A387, in suppressing GH and PRL secretion from acromegalic tumors, which cannot be explained merely on the basis of binding affinity for SS and/or DA receptors.
Objective: This study compared the potency of a somatostatin receptor (sstr)2–sstr5 analog, BIM-23244, of an sstr2-dopamine D2 receptor (sstr2-DAD2) molecule, BIM-23A387 and of new ...somatostatin-dopamine chimeric molecules with differing, enhanced affinities for sstr2, sstr5 and DAD2, BIM-23A758, BIM-23A760 and BIM-23A761, to suppress GH and prolactin (PRL) from 18 human GH adenomas that are partially responsive to octreotide or lanreotide. Materials and methods: The sstr2, sstr5 and DAD2 mRNA levels were determined by RT-PCR. The effect of drugs was tested in cell cultures at various concentrations. Results: In all tumors, the sstr2, sstr5 and DAD2 mRNA levels were coexpressed (mean levels±s.e.m. 0.4±0.1, 5.3±1.9 and 2.0±0.4 copy/copy β-glucuronidase). In 13 tumors, the maximal suppression of GH secretion produced by BIM-23A387 (30±3%) and BIM-23244 (28±3%) was greater than that produced by octreotide (23±3%). In six out of 13 tumors, BIM-23A758, BIM-23A760 and BIM- 23A761 produced greater maximal suppression of GH secretion than octreotide (33±5, 38±2 and 41±2 vs 24±2%). Their EC50 values were 10, 2 and 4 pmol/l. BIM-23A761 was more effective than BIM-23A387 in GH suppression (41±2 vs 32±4%). The new chimeric molecules produced maximal PRL suppression greater than octreotide (62±8 to 74±5 vs 46±11%). Conclusions: Novel dopamine-somatostatin chimeric molecules with differing, enhanced activity at sstr2, sstr5 and DAD2, consistently produced significatly greater suppression of GH and PRL than either octreotide or single-receptor-interacting ligands in tumors from patients classified as only partially responsive to octreotide therapy. The higher efficacy of the chimeric compounds was, at least partially, linked to their high affinity for sstr2 (IC50 1–10 pmol/l). The other mechanisms by which such molecules produce an enhanced inhibition of GH remain to be elucidated.
Context:
Congenital isolated ACTH deficiency (IAD) is a rare disease characterized by low plasma ACTH and cortisol levels and preservation of all other pituitary hormones. This condition was poorly ...defined before we identified TPIT, a T-box transcription factor with a specific role in differentiation of the corticotroph lineage in mice and humans, as its principal molecular cause.
Objective:
We have enlarged our series of IAD patients to better characterize the phenotype and the genotype of this rare disease.
Design:
Each exon of the TPIT gene was amplified and sequenced in IAD patients without any identified cause. A functional analysis of each new TPIT mutation was performed.
Results:
We described the largest series of 91 IAD patients and identified three distinct groups: neonatal onset complete or partial IAD or late onset IAD. We did not identify any TPIT mutation in patients with partial or late-onset IAD. However, we found a TPIT mutation in 65% of patients with neonatal-onset complete IAD. These patients are homozygous or compound heterozygous for TPIT mutations, and their parents are healthy heterozygous carriers. We identified nine new mutations: four missense, one one-nucleotide deletion, three splice-site mutations, and one large deletion. TPIT mutations lead to loss of function by different mechanisms, such as non-sense-mediated mRNA decay, abnormal mRNA splicing, loss of TPIT DNA binding or protein-protein interaction defects.
Conclusion:
TPIT mutations are responsible for two thirds of neonatal-onset complete IAD but can not be detected in partial or late-onset IAD.
Despite extensive research on sporadic pituitary adenomas, it is not yet possible to assign one protein alteration to one specific type of pituitary adenomas. Nevertheless, alterations of the cAMP ...pathway appear to be molecular hallmarks of most growth hormone (GH)‐secreting adenomas. However, these alterations do not confer specific phenotypes to patients carrying these alterations. In this review, we summarise the literature regarding signalling alterations observed in GH‐secreting adenomas. We focus on Gsα alterations and their possible cross‐talk with the extracellular signal‐related kinase (ERK)1/2 pathway. In the light of results obtained on human somatotroph adenoma cells in primary culture and on models of murine somatotroph cell lines, we postulate a crucial role for ERK1/2 in GH‐secreting adenomas downstream of cAMP pathway alterations that might impact the tumoural phenotype.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Context: LHX4 is a LIM homeodomain transcription factor involved in pituitary ontogenesis. Only a few heterozygous LHX4 mutations have been reported to be responsible for congenital pituitary hormone ...deficiency.
Subjects and Methods: A total of 136 patients with congenital hypopituitarism associated with malformations of brain structures, pituitary stalk, or posterior pituitary gland was screened for LHX4 mutations.
Results: Three novel allelic variants that cause predicted changes in the protein sequence of LHX4 (2.3%) were found (p.Thr99fs, p.Thr90Met, and p.Gly370Ser). On the basis of functional studies, p.Thr99fs mutation was responsible for the patients’ phenotype, whereas p.Thr90Met and p.Gly370Ser were likely polymorphisms. Patients bearing the heterozygous p.Thr99fs mutation had variable phenotypes: two brothers presented somato-lactotroph and thyrotroph deficiencies, with pituitary hypoplasia and poorly developed sella turcica; the youngest brother (propositus) also had corpus callosum hypoplasia and ectopic neurohypophysis; their father only had somatotroph deficiency and delayed puberty with pituitary hyperplasia. Functional studies showed that the mutation induced a complete loss of transcriptional activity on POU1F1 promoter and a lack of DNA binding. Cotransfection of p.Thr99fs mutant and wild-type LHX4 failed to evidence any dominant negative effect, suggesting a mechanism of haploinsufficiency. We also identified prolactin and GH promoters as potential target genes of LHX4 and found that the p.Thr99fs mutant was also unable to transactivate these promoters.
Conclusions: The present report describes three new exonic LHX4 allelic variants with at least one being responsible for congenital hypopituitarism. It also extends the phenotypical heterogeneity associated with LHX4 mutations, which includes variable anterior pituitary hormone deficits, as well as pituitary and extrapituitary abnormalities.
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. This clinical entity was not previously well characterized because of the small number of published cases. Since identification of the first TPIT mutations, we have enlarged our series of neonatal IAD patients to 27 patients from 21 unrelated families. We found TPIT mutations in 17 of 27 patients. We identified 10 different TPIT mutations, with one mutation found in five unrelated families. All patients appeared to be homozygous or compound heterozygous for TPIT mutations, and their unaffected parents are heterozygous carriers, confirming a recessive mode of transmission. We compared the clinical and biological phenotype of the 17 IAD patients carrying a TPIT mutation with the 10 IAD patients with normal TPIT-coding sequences. This series of neonatal IAD patients revealed a highly homogeneous clinical presentation, suggesting that this disease may be an underestimated cause of neonatal death. Identification of TPIT gene mutations as the principal molecular cause of neonatal IAD permits prenatal diagnosis for families at risk for the purpose of early glucocorticoid replacement therapy.
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