scholarly journals Contribution of LHX4 Mutations to Pituitary Deficits in a Cohort of 417 Unrelated Patients

2016 ◽  
Vol 102 (1) ◽  
pp. 290-301 ◽  
Author(s):  
Enzo Cohen ◽  
Mohamad Maghnie ◽  
Nathalie Collot ◽  
Juliane Leger ◽  
Florence Dastot ◽  
...  
Keyword(s):  
Sella Turcica ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Incomplete Penetrance ◽  
Posterior Pituitary ◽  
Variable Expressivity ◽  
Functional Studies ◽  
Ectopic Posterior Pituitary ◽  
Congenital Hypopituitarism

Abstract Context: LHX4 encodes a LIM-homeodomain transcription factor that is implicated in early pituitary development. In humans, only 13 heterozygous LHX4 mutations have been associated with congenital hypopituitarism. Objective: The aims of this study were to evaluate the prevalence of LHX4 mutations in patients with hypopituitarism, to define the associated phenotypes, and to characterize the functional impact of the identified variants and the respective role of the 2 LIM domains of LHX4. Design and Patients: We screened 417 unrelated patients with isolated growth hormone deficiency or combined pituitary hormone deficiency associated with ectopic posterior pituitary and/or sella turcica anomalies for LHX4 mutations (Sanger sequencing). In vitro studies were performed to assess the functional consequences of the identified variants. Results: We identified 7 heterozygous variations, including p.(Tyr131*), p.(Arg48Thrfs*104), c.606+1G>T, p.Arg65Val, p.Thr163Pro, p.Arg221Gln, and p.Arg235Gln), that were associated with variable expressivity; 5 of the 7 were also associated with incomplete penetrance. The p.(Tyr131*), p.(Arg48Thrfs*104), p.Ala65Val, p.Thr163Pro, and p.Arg221Gln LHX4 variants are unable to transactivate the POU1F1 and GH promoters. As suggested by transactivation, subcellular localization, and protein-protein interaction studies, p.Arg235Gln is probably a rare polymorphism. Coimmunoprecipitation studies identified LHX3 as a potential protein partner of LHX4. As revealed by functional studies of LIM-defective recombinant LHX4 proteins, the LIM1 and LIM2 domains are not redundant. Conclusion: This study, performed in the largest cohort of patients screened so far for LHX4 mutations, describes 6 disease-causing mutations that are responsible for congenital hypopituitarism. LHX4 mutations were found to be associated with variable expressivity, and most of them with incomplete penetrance; their contribution to pituitary deficits that are associated with an ectopic posterior pituitary and/or a sella turcica defect is ∼1.4% in the 417 probands tested.

scholarly journals Role of GLI2 in hypopituitarism phenotype

2015 ◽  
Vol 54 (3) ◽  
pp. R141-R150 ◽  
Author(s):  
Ivo J P Arnhold ◽  
Marcela M França ◽  
Luciani R Carvalho ◽  
Berenice B Mendonca ◽  
Alexander A L Jorge
Keyword(s):  
Gh Deficiency ◽  
Ethanol Exposure ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Incomplete Penetrance ◽  
Relative Role ◽  
Posterior Pituitary ◽  
Prenatal Ethanol Exposure ◽  
Pituitary Glands ◽  
Posterior Pituitary Lobe

GLI2 is a zinc-finger transcription factor involved in the Sonic Hedgehog pathway. Gli2 mutant mice have hypoplastic anterior and absent posterior pituitary glands. We reviewed the literature for patients with hypopituitarism and alterations in GLI2. Twenty-five patients (16 families) had heterozygous truncating mutations, and the phenotype frequently included GH deficiency, a small anterior pituitary lobe and an ectopic/undescended posterior pituitary lobe on magnetic resonance imaging and postaxial polydactyly. The inheritance pattern was autosomal dominant with incomplete penetrance and variable expressivity. The mutation was frequently inherited from an asymptomatic parent. Eleven patients had heterozygous non-synonymous GLI2 variants that were classified as variants of unknown significance, because they were either absent from or had a frequency lower than 0.001 in the databases. In these patients, the posterior pituitary was also ectopic, but none had polydactyly. A third group of variants found in patients with hypopituitarism were considered benign because their frequency was ≥0.001 in the databases. GLI2 is a large and polymorphic gene, and sequencing may identify variants whose interpretation may be difficult. Incomplete penetrance implies in the participation of other genetic and/or environmental factors. An interaction between Gli2 mutations and prenatal ethanol exposure has been demonstrated in mice dysmorphology. In conclusion, a relatively high frequency of GLI2 mutations and variants were identified in patients with congenital GH deficiency without other brain defects, and most of these patients presented with combined pituitary hormone deficiency and an ectopic posterior pituitary lobe. Future studies may clarify the relative role and frequency of GLI2 alterations in the aetiology of hypopituitarism.

scholarly journals SUN-067 Pituitary Dysfunction in Children with Ectopic Posterior Pituitary

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Ghada Naji ◽  
Erica Poletto ◽  
Rita Ann Kubicky
Keyword(s):  
Diabetes Insipidus ◽  
Median Eminence ◽  
Third Ventricle ◽  
Retrospective Chart Review ◽  
Pituitary Stalk ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Posterior Pituitary ◽  
Pituitary Dysfunction ◽  
Ectopic Posterior Pituitary

Abstract Background: Imaging studies aid in the detection of structural abnormalities that may be associated with pituitary dysfunction, such as ectopic posterior pituitary (EPP). The location of the ectopic lobe can vary, but it is most commonly located along the median eminence in the floor of the third ventricle. An EPP could result from complete or partial defective neural migration during embryogenesis, which could explain the different loci of EPP. Affected individuals have either severe isolated growth hormone deficiency (IGHD) or combined pituitary hormone deficiencies (CPHD); diabetes insipidus is not a feature, indicating that the EPP is functioning normally. Aim: To detect the prevalence of IGHD or CPHD in children with EPP. In addition, to evaluate the association between the location of EPP and pituitary dysfunction. Methods: A retrospective chart review of MRI reports at St. Christopher’s Hospital for Children (SCHC) from 2006-2018 that were found to have EPP. Pituitary hormone function was evaluated in the majority of the patient population. Results: Of the 26 patients with EPP, [16 males (M) and 10 females (F)], mean chronologic age was 5.98+5.18 yrs, only 20 patients had an endocrine evaluation at SCHC. Of the 20 children, 14 had CPHD and 4 had IGHD. Patients were classified into 3 groups (upper, middle & lower) according to EPP location along the pituitary stalk. Of the 21 patients with upper EPP, 17 had pituitary dysfunction (14 with CPHD, 3 with IGHD). Of the 4 children with middle EPP, only 1 had pituitary dysfunction which was IGHD. One patient had lower EPP with hyperprolactinemia. Diabetes insipidus was not identified in any of the children. Conclusion: Our study supports previous reports that CPHD and IGHD are frequent in patients with EPP. Similarly, our data further demonstrate that no cases of diabetes insipidus have been reported in children with EPP. In our study, EPP is most commonly located along the upper third of pituitary stalk at the median eminence level, with a higher prevalence of CPHD and IGHD, a finding similar to prior studies. No CPHD was reported in middle/lower but IGHD was found in the middle EPP group.

scholarly journals Pituitary Hypoplasia Is the Best MRI Predictor of the Severity and Type of Growth Hormone Deficiency in Children With Congenital Growth Hormone Deficiency

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A683-A683
Author(s):  
Himanshu Sharma ◽  
Anshul Kumar ◽  
Naincy Purwar ◽  
Nitish Mathur ◽  
Balram Sharma ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Deficiency ◽  
Pituitary Stalk ◽  
Hormone Deficiency ◽  
Common Finding ◽  
Pituitary Hormone ◽  
Posterior Pituitary ◽  
Mri Findings ◽  
Pituitary Hypoplasia ◽  
Ectopic Posterior Pituitary

Abstract Background and Objectives: Congenital idiopathic growth hormone deficiency(GHD) is associated with various MRI abnormalities, including both sellar anomalies such as pituitary hypoplasia, ectopic pituitary, empty sella and abnormalities of the pituitary stalk and extrasellar abnormalities such as Arnold Chiari malformation, corpus callosum agenesis, arachnoid cyst, septum pellucidum agenesis, enlarged ventricles, vermis dysplasia, and sphenoid cyst. However, it remains contentious whether MRI brain findings could provide an additional avenue for precisely predicting the differentiation of GHD based on severity(severe or partial) and type(isolated GHD or multiple pituitary hormone deficiency MPHD). This study aimed to ascertain the abnormality that is the best predictor of severe GHD and type of GHD amongst the different MRI findings. Methods: This was an analytical cross-sectional study conducted from 2018-2020. During the study period, we included a total of 100 subjects diagnosed to have idiopathic GHD after the exclusion of syndromic causes, system illness, presence of pituitary mass, and those with h/o cranial irradiation. Patients were divided into severe GHD and partial GHD based on peak stimulated GH of <5 ng/dl and ≥ 5 ng/dl respectively and into groups based on isolated GHD and MPHD. Patients were further divided into groups based on the presence of pituitary hypoplasia,extrasellar brain abnormalities (EBA), and presence of ectopic posterior pituitary and/or pituitary stalk abnormalities(EPP/PSA), respectively. Analyses were performed using SPSS version 24.0 software. Results: Amongst 100 subjects with idiopathic congenital GHD, 66 (66%) subjects had Isolated GHD while the remaining 34 (34%) had MPHD. 71 had severe GHD, and 29 had partial GHD. Amongst the MRI findings, pituitary hypoplasia was the most common finding observed in 53% of patients, while 23(23%) had EBA, and 25(25%) had EPP/PSA. Pituitary hypoplasia was observed to be the best predictor of severity of GHD with an odds ratio(OR) of 10.8 (95% CI 3.38-29.6) followed by ectopic posterior pituitary /pituitary stalk abnormalities (OR =2.8, 95% CI 1.5-9.5) while the presence of extrasellar abnormalities was the weakest predictor (OR =1.8, 95% CI 1.05-3.2). Pituitary hypoplasia was the only finding to significantly predict MPHD (OR=9.2). On ROC analysis, a Pituitary height SDS of -2.03 had a 73.2 % sensitivity and specificity of 79.3%(AUC =0.787,95% CI 0.7-0.873) for severe GHD and a sensitivity of 88.2 % and specificity of 66.7% (AUC =0.745, 95% CI 0.68-0.877) for MPHD. Conclusion: We observed Pituitary hypoplasia to be not only the most frequent MRI abnormality but also the best predictor of severe GHD and MPHD amongst various sellar and extrasellar abnormalities.

scholarly journals OR16-04 OTX2 Mutations in Congenital Hypopituitarism Patients

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Louise Cheryl Gregory ◽  
Peter Gergics ◽  
Giuseppa Patti ◽  
Mark J McCabe ◽  
Mohamad Maghnie ◽  
...  
Keyword(s):  
Retinal Dystrophy ◽  
Hormone Deficiency ◽  
Luciferase Reporter ◽  
Pituitary Hormone ◽  
The Novel ◽  
Posterior Pituitary ◽  
Functional Consequences ◽  
Multiple Levels ◽  
Congenital Hypopituitarism

Abstract The transcription factor OTX2 is implicated in pituitary, ocular and craniofacial development. Mutations have been described in patients with variable congenital hypopituitarism (CH) ranging from isolated growth hormone deficiency (IGHD) to combined pituitary hormone deficiency (CPHD) with/without an ectopic posterior pituitary (EPP).We aimed (i) to establish the contribution of OTX2 mutations in the etiology of CH in a sub-cohort of patients and to study their functional consequences and (ii) establish a detailed human OTX2 expression profile in a hypothalamo-pituitary (HP) context. We screened 127 patients from national (n=103) and international centers (n=24) on the septo-optic dysplasia (SOD) spectrum with variable eye abnormalities. Eye abnormalities included micro/anophthalmia, retinal dystrophy and/or coloboma in 29 of these patients, with the rest having optic nerve hypoplasia (ONH). An EPP was reported on MRI in 35 patients. The cohort previously tested negative for mutations in HESX1, SOX2, SOX3, PROKR2 and GH1. Transactivation assays involved a dual-luciferase reporter in murine hypothalamic GT1-7 neurons transiently transfected with OTX2 constructs. In situ hybridization was performed to analyze human brain OTX2 expression during embryogenesis. Seven heterozygous OTX2 changes were identified: two chromosomal deletions spanning OTX2 in patients with micro/anophthalmia, GHD and an EPP, with one patient having cerebellar hypoplasia. Three missense substitutions resulting in truncated proteins: (i) the previously reported p.S138* and (ii) p.C170*, in two patients with retinal dystrophy, EPP and IGHD respectively, and (iii) the novel p.E79* in a patient with micro/anophthalmia, EPP and CPHD. A novel insertion-deletion resulting in a truncated protein p.S167* in a patient with microphthalmia, GHD, ONH, EPP and an enlarged abnormal pituitary, and a novel deletion resulting in a frameshift p.Val139Aspfs*39 in a patient with microcephaly, microphthalmia, ONH and an EPP were also identified. The human OTX2 variants caused a significant reduction in transactivation compared to wild type. Our gene expression data identified human OTX2 transcripts in the posterior pituitary, retina, ear, thalamus, choroid plexus, and in the hypothalamus during embryogenesis, but not in RP. To conclude, we identified OTX2 variants in 7 unrelated CH patients with eye abnormalities including 3 with retinal dystrophy and one with a cerebellar abnormality. As OTX2 is involved at multiple levels during HP development, these patients should be monitored for evolving endocrinopathies. Human OTX2 is expressed in the posterior pituitary, the retina and the ear at CS19 and 20 (between 6-7 weeks gestation), and in areas of the hindbrain at CS23, but not in RP at any stage analyzed in this study. The endocrine phenotypes in patients with OTX2 mutations are most likely of hypothalamic origin.

scholarly journals Allelic Variants in Established Hypopituitarism Genes Expand Our Knowledge of the Phenotypic Spectrum

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1128
Author(s):  
Marilena Nakaguma ◽  
Nathalia Garcia Bianchi Pereira Ferreira ◽  
Anna Flavia Figueredo Benedetti ◽  
Mariana Cotarelli Madi ◽  
Juliana Moreira Silva ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Male Patient ◽  
Missense Variant ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Incomplete Penetrance ◽  
Growth Hormone Gene ◽  
Posterior Lobe ◽  
Allelic Variants ◽  
Phenotypic Spectrum

We report four allelic variants (three novel) in three genes previously established as causal for hypopituitarism or related disorders. A novel homozygous variant in the growth hormone gene, GH1 c.171delT (p.Phe 57Leufs*43), was found in a male patient with severe isolated growth hormone deficiency (IGHD) born to consanguineous parents. A hemizygous SOX3 allelic variant (p.Met304Ile) was found in a male patient with IGHD and hypoplastic anterior pituitary. YASARA, a tool to evaluate protein stability, suggests that p.Met304Ile destabilizes the SOX3 protein (ΔΔG = 2.49 kcal/mol). A rare, heterozygous missense variant in the TALE homeobox protein gene, TGIF1 (c.268C>T:p.Arg90Cys) was found in a patient with combined pituitary hormone deficiency (CPHD), diabetes insipidus, and syndromic features of holoprosencephaly (HPE). This variant was previously reported in a patient with severe holoprosencephaly and shown to affect TGIF1 function. A novel heterozygous TGIF1 variant (c.82T>C:p.Ser28Pro) was identified in a patient with CPHD, pituitary aplasia and ectopic posterior lobe. Both TGIF1 variants have an autosomal dominant pattern of inheritance with incomplete penetrance. In conclusion, we have found allelic variants in three genes in hypopituitarism patients. We discuss these variants and associated patient phenotypes in relation to previously reported variants in these genes, expanding our knowledge of the phenotypic spectrum in patient populations.

Extra pituitary midline structural abnormalities associated with ectopic posterior pituitary detected on a new rapid MR protocol (FAST1.2)

2021 ◽  
Author(s):  
Arthur Lyra ◽  
Daniel de Faria Guimarães ◽  
Altino Sá Meira ◽  
Arthur Castello Berchielli Nunes ◽  
Guilherme Vieira Peixoto ◽  
...  
Keyword(s):  
Sella Turcica ◽  
Pituitary Stalk ◽  
Control Group ◽  
Hypothalamic Hamartoma ◽  
Pars Intermedia ◽  
Posterior Pituitary ◽  
Pineal Cyst ◽  
Imaging Results ◽  
Structural Abnormalities ◽  
Ectopic Posterior Pituitary

Abstract Background Ectopic posterior pituitary (EPP) is a malformation of the hypothalamic-pituitary region. Our goal was to describe midline structural brain abnormalities in patients with EPP using a dedicated protocol (FAST1.2 protocol) of magnetic resonance imaging (MRI) to evaluate the hypothalamus and pituitary gland, highlighting their clinical-laboratory correlations. Methods A cross-sectional study of patients diagnosed with EPP, and a control group. All individuals were submitted to a dedicated MRI protocol called FAST1.2, which combines the FAST1 protocol developed by our group with 3D T2DRIVE imaging. Results We evaluated 36 individuals with EPP and 78 individuals as a control group. One patient had two posterior pituitary lobes, one inside the sella turcica and the other along the pituitary stalk; in five patients, the EPP was along the pituitary stalk; in 28 the EPP was at the infundibular recess of the third ventricle, and in two the EPP was hypothalamic. In the EPP group, eleven individuals had interhypothalamic adhesion (IHA), three septo-optic dysplasia, one a cerebellar malformation, and one a pineal cyst. We did not observe a higher frequency of severe hormonal deficiency or developmental delay in patients with IHA. In the control group, eleven patients had a pineal cyst, three pars intermedia cysts, one hydrocephalus, and one hypothalamic hamartoma. Conclusion FAST1.2 acquisition allows confident recognition of regional anatomy and recognition of midline structural abnormalities on T2DRIVE, particularly including the pituitary stalk and IHA, thereby making MRI acquisition faster with no need for intravenous contrast administration. We suggest that IHA could be associated with defects in neuronal migration, as might occur in patients with EPP.

scholarly journals Novel Mutations within the POU1F1 Gene Associated with Variable Combined Pituitary Hormone Deficiency

2005 ◽  
Vol 90 (8) ◽  
pp. 4762-4770 ◽  
Author(s):  
James P. G. Turton ◽  
Rachel Reynaud ◽  
Ameeta Mehta ◽  
John Torpiano ◽  
Alexandru Saveanu ◽  
...  
Keyword(s):  
Dna Binding ◽  
Mutational Analysis ◽  
Hot Spot ◽  
Dominant Negative ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Novel Mutations ◽  
Pituitary Hormone Deficiency ◽  
Combined Pituitary Hormone Deficiency ◽  
Functional Studies

Context: Mutations within the gene encoding the pituitary-specific transcription factor POU1F1 are associated with combined pituitary hormone deficiency (CPHD). Most of the affected individuals manifest GH, prolactin, and TSH deficiency. Objective: We have now screened 129 individuals with CPHD and isolated GH deficiency for mutations within POU1F1. Results: Causative mutations were identified in 10 of 129 individuals (7.8%). Of these, five patients harbored the dominant negative R271W mutation, which is a well-recognized mutational hot spot. We have also identified a second frequently occurring mutation, E230K, which appears to be common in Maltese patients. Additionally, we describe two novel mutations within POU1F1, an insertion of a single base pair (ins778A) and a missense mutation (R172Q). Functional studies have revealed that POU1F1 (E230K) is associated with a reduction in transactivation, although DNA-binding affinity is similar to the wild-type protein. On the other hand, POU1F1 (R172Q) is associated with a reduction in DNA binding and transactivation, whereas POU1F1 (ins778A) is associated with loss of DNA binding and a reduction in transactivation. Conclusions: Our data suggest that the phenotype associated with POU1F1 mutations may be more variable, with the occasional preservation of TSH secretion. Additionally, our data revealed POU1F1 mutations in three patients who were diagnosed as having ACTH deficiency but who, on further evaluation, were found to have normal cortisol secretion. Hence, elucidation of the genotype led to further evaluation of the phenotype, with the cessation of cortisol replacement that had been commenced unnecessarily. These data reflect the importance of mutational analysis in patients with CPHD.

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