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 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 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.

Growth hormone replacement for patients with adult onset growth hormone deficiency—what have we learned?

2004 ◽  
Vol 16 (4) ◽  
pp. 1-6
Author(s):  
Monique Piersanti
Keyword(s):  
Growth Hormone ◽  
Gh Deficiency ◽  
Hormone Replacement ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Adult Onset ◽  
Gh Replacement ◽  
Term Benefit

Growth hormone (GH) deficiency is a condition recognized to occur in individuals who have had multiple pituitary hormone deficiencies as a result of pathological processes or neurosurgical interventions. The indications, benefits, and risks of GH replacement therapy will be reviewed with an emphasis on those patients who were adults with the deficiency first emerged. The results of this analysis indicate that, although a measurable improvement can be detected in the patient's quality of life, body composition, and some cardiovascular parameters, the larger questions of long-term benefit and patient selection currently remain unanswered.

scholarly journals Four Novel Mutations of the LHX3 Gene Cause Combined Pituitary Hormone Deficiencies with or without Limited Neck Rotation

2007 ◽  
Vol 92 (5) ◽  
pp. 1909-1919 ◽  
Author(s):  
Roland W. Pfaeffle ◽  
Jesse J. Savage ◽  
Chad S. Hunter ◽  
Christina Palme ◽  
Martina Ahlmann ◽  
...  
Keyword(s):  
Dna Binding ◽  
Gh Deficiency ◽  
Gene Activation ◽  
Gene Mutations ◽  
Biochemical Properties ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Molecular Defects ◽  
Recessive Mutations ◽  
Neck Rotation

Abstract Context: The Lhx3 LIM-homeodomain transcription factor gene is required for development of the pituitary and motoneurons in mice. Human LHX3 gene mutations have been reported in five subjects with a phenotype consisting of GH, prolactin, TSH, LH, and FSH deficiency; abnormal pituitary morphology; and limited neck rotation. Objective: The objective of the study was to determine the frequency and nature of LHX3 mutations in patients with isolated GH deficiency or combined pituitary hormone deficiency (CPHD) and characterize the molecular consequences of mutations. Design: The LHX3 sequence was determined. The biochemical properties of aberrant LHX3 proteins resulting from observed mutations were characterized using reporter gene and DNA binding experiments. Patients: The study included 366 patients with isolated GH deficiency or CPHD. Results: In seven patients with CPHD from four consanguineous pedigrees, four novel, recessive mutations were identified: a deletion of the entire gene (del/del), mutations causing truncated proteins (E173ter, W224ter), and a mutation causing a substitution in the homeodomain (A210V). The mutations were associated with diminished DNA binding and pituitary gene activation, consistent with observed hormone deficiencies. Whereas subjects with del/del, E173ter, and A210V mutations had limited neck rotation, patients with the W224ter mutation did not. Conclusions: LHX3 mutations are a rare cause of CPHD involving deficiencies for GH, prolactin, TSH, and LH/FSH in all patients. Whereas most patients have a severe hormone deficiency manifesting after birth, milder forms can be observed, and limited neck rotation is not a universal feature of patients with LHX3 mutations. This study extends the known molecular defects and range of phenotypes found in LHX3-associated diseases.

scholarly journals From isolated GH deficiency to multiple pituitary hormone deficiency: an evolving continuum – a KIMS analysis

2009 ◽  
Vol 161 (suppl_1) ◽  
pp. S75-S83 ◽  
Author(s):  
M Klose ◽  
B Jonsson ◽  
R Abs ◽  
V Popovic ◽  
M Koltowska-Häggström ◽  
...  
Keyword(s):  
Clinical Presentation ◽  
Gh Deficiency ◽  
Dynamic Condition ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Multiple Pituitary Hormone Deficiency ◽  
Pituitary Hormone Deficiency ◽  
Gh Replacement ◽  
Baseline Characteristics

ObjectiveTo describe baseline clinical presentation, treatment effects and evolution of isolated GH deficiency (IGHD) to multiple pituitary hormone deficiency (MPHD) in adult-onset (AO) GHD.DesignObservational prospective study.MethodsBaseline characteristics were recorded in 4110 patients with organic AO-GHD, who were GH naïve prior to entry into the Pfizer International Metabolic Database (KIMS; 283 (7%) IGHD, 3827 MPHD). The effect of GH replacement after 2 years was assessed in those with available follow-up data (133 IGHD, 2207 MPHD), and development of new deficiencies in those with available data on concomitant medication (165 IGHD, 3006 MPHD).ResultsIGHD and MPHD patients had similar baseline clinical presentation, and both groups responded similarly to 2 years of GH therapy, with favourable changes in lipid profile and improved quality of life. New deficiencies were observed in 35% of IGHD patients, which was similar to MPHD patients with one additional deficit other than GH. New deficiencies most often presented within the first year but were observed up to 6 years after GH commencement. Conversion of IGHD into MPHD was not predicted by aetiology, baseline characteristics, surgery or radiotherapy, whereas in MPHD additional deficits were predicted by age (P<0.001) and pituitary disease duration (P<0.01).ConclusionBoth AO-IGHD and -MPHD patients have similar baseline clinical presentation and respond equally well to 2 years of GH replacement. Hypopituitarism in adults seems to be a dynamic condition where new deficiencies can appear years after the initial diagnosis, and careful endocrine follow-up of all hypopituitary patients, including those with IGHD, is warranted.

Growth hormone-releasing activity of growth hormone-releasing peptide-1 (a synthetic heptapeptide) in children and adolescents

1993 ◽  
Vol 129 (5) ◽  
pp. 424-426 ◽  
Author(s):  
Zvi Laron ◽  
Cyril Y Bowers ◽  
Daniel Hirsch ◽  
Antonio Selman Almonte ◽  
Moshe Pelz ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Children And Adolescents ◽  
Normal Values ◽  
Gh Deficiency ◽  
Clinical Applications ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Pituitary Insufficiency ◽  
Healthy Children ◽  
Plasma Prolactin

The heptapeptide growth hormone-releasing peptide-1 (GHRP-1 ), one of a series of recently synthesized small growth hormone (GH)-releasing peptides, was administered as an iv bolus (1 μg/kg) to 15 (six prepubertal, nine pubertal) short but healthy children and adolescents and to eight juvenile patients with pituitary insufficiency (four with isolated growth hormone deficiency, two with multiple pituitary hormone deficiencies, one with partial GH deficiency and one with GH-releasing hormone (GHRH) deficiency). Eleven out of 23 subjects also underwent an iv GHRH (1–29) test (1 μg/kg). All the healthy children responded with a progressive rise in plasma human GH (hGH) peaking at 15–30 min, with a significantly higher rise (p<0.05) in the pubertal than prepubertal group. The hGH response to GHRH (1–29) in these children was similar or slightly higher. Six hypopituitary patients had no response to either GHRP-1 or GHRH; the patient with partial GH deficiency had a hGH peak of 6.5 μg/l (at 5 min) to GHRP-1 and 9.2 μg/l (at 1 5 min) to GHRH. One patient had no response of hGH to hypoglycemia, clonidine and GHRP-1, but the plasma hGH rose to 10 μg/l after GHRH. Following the GHRP-1 bolus there was a significant (p <0.01) rise in plasma free thyroxine and a decrease of thyrotropin (p <0.01), both in the limits of normal values. There was also a transitory rise of plasma cortisol (p <0.05). Plasma prolactin, luteinizing hormone and follicle-stimulating hormone did not change. It is concluded that GHRP-1 is a potent GH-releasing drug because it acts also when administered orally and has great pharmaceutical and clinical applications.

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

2021 ◽  
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 (3 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 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 (&Delta;&Delta;G = 2.49 kcal/mol). A rare, heterozygous missense variant in the TALE homeobox protein gene, TGIF1 (c.268C&gt;T:p.Arg90Cys) was found in a patient with combined pituitary hormone deficiency (CPHD), diabetes insipidus, and syndromic features of holoprosencephaly (HPE). A novel heterozygous TGIF1 variant (c.82T&gt;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 3 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.

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