The Experts below are selected from a list of 2007 Experts worldwide ranked by ideXlab platform
Juliane Leger - One of the best experts on this subject based on the ideXlab platform.
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high resolution heavily t2 weighted magnetic resonance imaging for evaluation of the Pituitary Stalk in children with ectopic neurohypophysis
Pediatric Radiology, 2017Co-Authors: Imane El Sanharawi, Juliane Leger, Loukia C Tzarouchi, Liesbeth Cardoen, Laetitia Martinerie, Jeanclaude Carel, Monique Elmalehberges, M AlisonAbstract:Background In anterior Pituitary deficiency, patients with non visible Pituitary Stalk have more often multiple deficiencies and persistent deficiency than patients with visible Pituitary Stalk.
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high resolution heavily t2 weighted magnetic resonance imaging for evaluation of the Pituitary Stalk in children with ectopic neurohypophysis
Pediatric Radiology, 2017Co-Authors: Imane El Sanharawi, Juliane Leger, Loukia C Tzarouchi, Liesbeth Cardoen, Laetitia Martinerie, Jeanclaude Carel, Monique ElmalehbergesAbstract:In anterior Pituitary deficiency, patients with non visible Pituitary Stalk have more often multiple deficiencies and persistent deficiency than patients with visible Pituitary Stalk. To compare the diagnostic value of a high-resolution heavily T2-weighted sequence to 1.5-mm-thick unenhanced and contrast-enhanced sagittal T1-weighted sequences to assess the presence of the Pituitary Stalk in children with ectopic posterior Pituitary gland. We retrospectively evaluated the MRI data of 14 children diagnosed with ectopic posterior Pituitary gland between 2010 and 2014. We evaluated the presence of a Pituitary Stalk using a sagittal high-resolution heavily T2-weighted sequence and a 1.5-mm sagittal T1-weighted turbo spin-echo sequence before and after contrast medium administration. A Pituitary Stalk was present on at least one of the sequences in 10 of the 14 children (71%). T2-weighted sequence depicted the Pituitary Stalk in all 10 children, whereas the 1.5-mm-thick T1-weighted sequence depicted 2/10 (20%) before contrast injection and 8/10 (80%) after contrast injection (P=0.007). Compared with 1.5-mm-thick contrast-enhanced T1-weighted sequences, high-resolution heavily T2-weighted sequence demonstrates better sensitivity in detecting the Pituitary Stalk in children with ectopic posterior Pituitary gland, suggesting that contrast injection is unnecessary to assess the presence of a Pituitary Stalk in this setting.
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thickened Pituitary Stalk on magnetic resonance imaging in children with central diabetes insipidus
Hormone Research in Paediatrics, 2000Co-Authors: Paul Czernichow, Catherine Garel, Juliane LegerAbstract:Magnetic resonance imaging (MRI) has revealed isolated Pituitary Stalk thickening (PST) in certain cases of idiopathic or secondary central diabetes insipidus (DI) due to infiltrative processes. Twent
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growth hormone deficiency with ectopic neurohypophysis anatomical variations and relationship between the visibility of the Pituitary Stalk asserted by magnetic resonance imaging and anterior Pituitary function
The Journal of Clinical Endocrinology and Metabolism, 1999Co-Authors: Stephanie Chen, Juliane Leger, Catherine Garel, Max Hassan, Paul CzernichowAbstract:In GH-deficient children showing ectopic posterior Pituitary hyperintense signal (EPP), the anatomical details of the Pituitary-hypothalamic region and the relationship between the visibility of the Pituitary Stalk and anterior Pituitary function were studied by magnetic resonance imaging (MRI). The absence or presence of the Pituitary Stalk was recorded by MRI before and after the injection of gadolinium in 25 children with GH deficiency and EPP at the age of 8.7 ± 5.0 yr (16 males and 9 females). Patients were classified into 2 groups according to the presence (group 1; n = 14), or the absence (group 2; n = 11) of Pituitary Stalk visibility after gadolinium injection. Most patients in group 1 (12 of 14) demonstrated isolated GH deficiency, whereas all but 1 patient in group 2 showed multiple anterior Pituitary hormone deficiency. The prevalence of a normally sized adenohypophysis was higher in group 1 than in group 2 (50% vs. 9%; P < 0.05). Although the EPP was found at the median eminence in all group ...
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growth hormone deficiency with ectopic neurohypophysis anatomical variations and relationship between the visibility of the Pituitary Stalk asserted by magnetic resonance imaging and anterior Pituitary function
The Journal of Clinical Endocrinology and Metabolism, 1999Co-Authors: Stephanie Chen, Juliane Leger, Catherine Garel, Max Hassan, Paul CzernichowAbstract:In GH-deficient children showing ectopic posterior Pituitary hyperintense signal (EPP), the anatomical details of the Pituitary-hypothalamic region and the relationship between the visibility of the Pituitary Stalk and anterior Pituitary function were studied by magnetic resonance imaging (MRI). The absence or presence of the Pituitary Stalk was recorded by MRI before and after the injection of gadolinium in 25 children with GH deficiency and EPP at the age of 8.7+/-5.0 yr (16 males and 9 females). Patients were classified into 2 groups according to the presence (group 1; n = 14), or the absence (group 2; n = 11) of Pituitary Stalk visibility after gadolinium injection. Most patients in group 1 (12 of 14) demonstrated isolated GH deficiency, whereas all but 1 patient in group 2 showed multiple anterior Pituitary hormone deficiency. The prevalence of a normally sized adenohypophysis was higher in group 1 than in group 2 (50% vs. 9%; P<0.05). Although the EPP was found at the median eminence in all group 2 patients, it was visualized in group 1 at different levels of the Pituitary Stalk in 60% of cases (8 of 14; at the proximal end of the Pituitary Stalk, n = 4; in the middle of the Pituitary Stalk, n = 2; at the distal end of the Pituitary Stalk, n = 2). This demonstrates that the ectopic posterior Pituitary migration abnormality may be complete or partial. In conclusion, although the pathogenesis of GH deficiency with EPP remains unclear, these results suggest that in cases of GH deficiency associated with ectopic posterior Pituitary hyperintense signal, patients with no visible Pituitary Stalk on MRI after gadolinium injection present a more severe form of the disease in childhood associated with multiple anterior Pituitary hormone deficiency, whereas visibility of the Pituitary Stalk is related to isolated GH deficiency. Nevertheless, careful follow-up of these latter patients is necessary, as the natural history of the disease is not established until adulthood.
R Brauner - One of the best experts on this subject based on the ideXlab platform.
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mutations in the human robo1 gene in Pituitary Stalk interruption syndrome
The Journal of Clinical Endocrinology and Metabolism, 2017Co-Authors: Anu Bashamboo, Ken Mcelreavey, Joelle Bignontopalovic, Nasser Moussi, R BraunerAbstract:Context Pituitary Stalk interruption syndrome (PSIS) is characterized by a thin or absent Pituitary Stalk usually in association with an ectopic posterior Pituitary and hypoplasia/aplasia of the anterior Pituitary. Associated phenotypes include varied ocular anomalies, hypoglycemia, micropenis/cryptorchidism, growth failure, or combined Pituitary hormone deficiencies. Although genetic causes have been identified, they explain only around 5% of PSIS cases. Objective To identify genetic causes of PSIS by exome sequencing. Design Exon enrichment was performed using the Agilent SureSelect Human All Exon V4. Paired-end sequencing was performed on the Illumina HiSeq2000 platform with an average sequencing coverage of ×50. Patients Patients with unexplained PSIS were included in the study. Results In five cases of unexplained PSIS including two familial cases, we identified a novel heterozygous frameshift and nonsense and missense mutations in the ROBO1 gene (p.Ala977Glnfs*40, two affected sibs; p.Tyr1114Ter, sporadic case, and p.Cys240Ser, affected child and paternal aunt) that controls embryonic axon guidance, and branching in the nervous system. Interestingly, four of the five cases of PSIS also presented with ocular anomalies, including hypermetropia with strabismus as well as ptosis. Conclusions These data suggest that mutations in ROBO1 contribute to PSIS and associated ocular anomalies.
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cholestasis reveals severe cortisol deficiency in neonatal Pituitary Stalk interruption syndrome
PLOS ONE, 2016Co-Authors: Francoisxavier Mauvais, Emmanuel Gonzales, Anne Davitspraul, Emmanuel Jacquemin, R BraunerAbstract:Objectives Cholestasis has been reported during the course of congenital hypothalamic-Pituitary deficiency, but crucial information is lacking regarding both its origin and prognosis. We aimed to characterize the course of cholestasis and factors contributing to it in patients with deficiency due to Pituitary Stalk interruption syndrome (PSIS).
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Pituitary Stalk interruption syndrome in 53 postpubertal patients factors influencing the heterogeneity of its presentation
PLOS ONE, 2013Co-Authors: Luuly Pham, Jeanclaude Souberbielle, Pierre Lemaire, Annie Harroche, R BraunerAbstract:Background Pituitary Stalk interruption syndrome (PSIS) may induce an isolated growth hormone (GH) deficiency or multiple hypothalamic-Pituitary (HP) deficiencies. Patients with multiple HP deficiencies, primarily those with adrenocorticotropin (ACTH) deficiency, are at increased risk of morbidity and mortality. Our objective was to identify the factors influencing each symptom and the MRI features of the syndrome to enhance its diagnosis and genetic analysis.
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Pituitary Stalk interruption syndrome diagnostic delay and sensitivity of the auxological criteria of the growth hormone research society
PLOS ONE, 2011Co-Authors: Geraldine Gascoinlachambre, R Brauner, Laetitia Duche, Martin ChalumeauAbstract:Objectives To study the diagnostic delay for Pituitary Stalk interruption syndrome (PSIS) with growth hormone deficiency (GHD) and the sensitivity of the auxological criteria of the Growth Hormone Research Society (GHRS) consensus guidelines.
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diagnosis of growth hormone gh deficiency comparison of Pituitary Stalk interruption syndrome and transient gh deficiency
BMC Pediatrics, 2009Co-Authors: Murielle Louvel, Jeanclaude Souberbielle, Mariana Marcu, Christine Trivin, R BraunerAbstract:Background Most patients with childhood non-organic growth hormone (GH) deficiency (GHD) produce a normal GH peak as young adults. Our objectives were to better define this transient GHD and evaluate the factors influencing the growth response of patients with Pituitary Stalk interruption syndrome (PSIS).
Paul Czernichow - One of the best experts on this subject based on the ideXlab platform.
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thickened Pituitary Stalk on magnetic resonance imaging in children with central diabetes insipidus
Hormone Research in Paediatrics, 2000Co-Authors: Paul Czernichow, Catherine Garel, Juliane LegerAbstract:Magnetic resonance imaging (MRI) has revealed isolated Pituitary Stalk thickening (PST) in certain cases of idiopathic or secondary central diabetes insipidus (DI) due to infiltrative processes. Twent
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growth hormone deficiency with ectopic neurohypophysis anatomical variations and relationship between the visibility of the Pituitary Stalk asserted by magnetic resonance imaging and anterior Pituitary function
The Journal of Clinical Endocrinology and Metabolism, 1999Co-Authors: Stephanie Chen, Juliane Leger, Catherine Garel, Max Hassan, Paul CzernichowAbstract:In GH-deficient children showing ectopic posterior Pituitary hyperintense signal (EPP), the anatomical details of the Pituitary-hypothalamic region and the relationship between the visibility of the Pituitary Stalk and anterior Pituitary function were studied by magnetic resonance imaging (MRI). The absence or presence of the Pituitary Stalk was recorded by MRI before and after the injection of gadolinium in 25 children with GH deficiency and EPP at the age of 8.7 ± 5.0 yr (16 males and 9 females). Patients were classified into 2 groups according to the presence (group 1; n = 14), or the absence (group 2; n = 11) of Pituitary Stalk visibility after gadolinium injection. Most patients in group 1 (12 of 14) demonstrated isolated GH deficiency, whereas all but 1 patient in group 2 showed multiple anterior Pituitary hormone deficiency. The prevalence of a normally sized adenohypophysis was higher in group 1 than in group 2 (50% vs. 9%; P < 0.05). Although the EPP was found at the median eminence in all group ...
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growth hormone deficiency with ectopic neurohypophysis anatomical variations and relationship between the visibility of the Pituitary Stalk asserted by magnetic resonance imaging and anterior Pituitary function
The Journal of Clinical Endocrinology and Metabolism, 1999Co-Authors: Stephanie Chen, Juliane Leger, Catherine Garel, Max Hassan, Paul CzernichowAbstract:In GH-deficient children showing ectopic posterior Pituitary hyperintense signal (EPP), the anatomical details of the Pituitary-hypothalamic region and the relationship between the visibility of the Pituitary Stalk and anterior Pituitary function were studied by magnetic resonance imaging (MRI). The absence or presence of the Pituitary Stalk was recorded by MRI before and after the injection of gadolinium in 25 children with GH deficiency and EPP at the age of 8.7+/-5.0 yr (16 males and 9 females). Patients were classified into 2 groups according to the presence (group 1; n = 14), or the absence (group 2; n = 11) of Pituitary Stalk visibility after gadolinium injection. Most patients in group 1 (12 of 14) demonstrated isolated GH deficiency, whereas all but 1 patient in group 2 showed multiple anterior Pituitary hormone deficiency. The prevalence of a normally sized adenohypophysis was higher in group 1 than in group 2 (50% vs. 9%; P<0.05). Although the EPP was found at the median eminence in all group 2 patients, it was visualized in group 1 at different levels of the Pituitary Stalk in 60% of cases (8 of 14; at the proximal end of the Pituitary Stalk, n = 4; in the middle of the Pituitary Stalk, n = 2; at the distal end of the Pituitary Stalk, n = 2). This demonstrates that the ectopic posterior Pituitary migration abnormality may be complete or partial. In conclusion, although the pathogenesis of GH deficiency with EPP remains unclear, these results suggest that in cases of GH deficiency associated with ectopic posterior Pituitary hyperintense signal, patients with no visible Pituitary Stalk on MRI after gadolinium injection present a more severe form of the disease in childhood associated with multiple anterior Pituitary hormone deficiency, whereas visibility of the Pituitary Stalk is related to isolated GH deficiency. Nevertheless, careful follow-up of these latter patients is necessary, as the natural history of the disease is not established until adulthood.
F. Severi - One of the best experts on this subject based on the ideXlab platform.
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dynamic mri in the congenital agenesis of the neural Pituitary Stalk syndrome the role of the vascular Pituitary Stalk in predicting residual anterior Pituitary function
Clinical Endocrinology, 1996Co-Authors: Mohamad Maghnie, A. Villa, L. Spagnolo, R. Campan, Eugenio Annibale Genovese, F. SeveriAbstract:OBJECTIVE Magnetic resonance imaging (MRI) without contrast medium is unable to give detailed information on the hypothalamic-Pituitary structures. MRI using gadopentetate dimeglumine (Gd-DTPA), and dynamic MRI, were performed in patients with hypopituitarism previously diagnosed as having anterior Pituitary hypoplasia, ectopic posterior Pituitary and unidentified Pituitary Stalk (1) to determine whether Gd-DTPA improves the delineation of hypothalamic-Pituitary structures; (2) to verify whether, if so, such improvement can be correlated with residual Pituitary function in patients subjected to long-term follow-up; and (3) to identify the hypothalamic-Pituitary vascular network in such cases. PATIENTS Eighteen patients (13 males, 5 females) aged 10–26.4 years with unidentified Pituitary Stalk at first MRI study were evaluated. Eight had isolated GH deficiency (IGHD), and 10 had multiple Pituitary hormone defect (MPHD) with the progression to complete anterior Pituitary deficits seen by the age of 15 years in 8 patients (1 had GH and FSH–LH deficiency and 1 had GH, TSH and FSH–LH deficiency). RESULTS The MRI revealed a very thin Pituitary Stalk in 7 patients (38.8%), 6 with IGHD (75%) and 1 (10%) with MPHD (GH and FSH-LH deficiency), after Gd-DTPA administration. Reassessment of anterior Pituitary function showed that the thyroid, adrenal and gonadal functions were intact in the 6 patients with IGHD and Pituitary Stalk identified by Gd-DTPA as well as in one IGHD patient with no evidence of Pituitary Stalk. In one 10-year-old with IGHD at the time of presentation (6 years) and no Pituitary Stalk seen after Gd-DTPA, subclinical hypothalamic hypothyroidism and suspected hypogonadotropic hypogonadism were documented. Partial ACTH deficiency was recorded In the patient with TSH and FSH–LH deficiency with no Pituitary Stalk. After Gd-DTPA, patients with absent Pituitary Stalk had a risk of developing MPHD 27 times greater than had those with an identified Pituitary Stalk (relative risk r=27, 95% confidence interval 1.9–368.4, Fisher’s exact test P=0.009). Dynamic MR images obtained every 4.6 s revealed rapid enhancement of hypothalamic-Pituitary structures and allowed the determination of the times to initial enhancement of ectopic posterior Pituitary and hypoplastic anterior Pituitary which ranged between 9.2 and 18.4 s, and that of complete anterior Pituitary (32.2–41.4 s). The time to maximum enhancement of anterior Pituitary was significantly longer than in controls (35.5±3.8 s vs 25.2±1.6 s, P<0.0001). CONCLUSIONS MRI with Gd-DTPA proved more sensitive in identifying the vascular component of Pituitary Stalk and added new information about the partial preservation of hypothalamo-hypophyseal portal vessels. The vascular Pituitary Stalk is easily recognized after Gd-DTPA in most IGHD patients, but exceptionally in MPHD; this sheds light on the possible normal course of affected patients. The neural component of the Pituitary Stalk is lacking regardless of whether patients have IGHD or MPHD, indicating that the term congenital agenesis of the neural Pituitary Stalk is more appropriate than Pituitary Stalk interruption. The times to enhancement of ectopic posterior Pituitary and residual anterior Pituitary obtained by the fast-framing MRI technique disclose dynamic changes in regional blood supply which appear direct, arterial and mainly independent of the portal system
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Dynamic MRI in the congenital agenesis of the neural Pituitary Stalk syndrome: the role of the vascular Pituitary Stalk in predicting residual anterior Pituitary function.
1996Co-Authors: Mohamad Maghnie, E. Genovese, A. Villa, L. Spagnolo, R. Campan, F. SeveriAbstract:Magnetic resonance imaging (MRI) without contrast medium is unable to give detailed information on the hypothalamic-Pituitary structures. MRI using gadopentetate dimeglumine (Gd-DTPA), and dynamic MRI, were performed in patients with hypopituitarism previously diagnosed as having anterior Pituitary hypoplasia, ectopic posterior Pituitary and unidentified Pituitary Stalk (1) to determine whether Gd-DTPA improves the delineation of hypothalamic-Pituitary structures; (2) to verify whether, if so, such improvement can be correlated with residual Pituitary function in patients subjected to long-term follow-up; and (3) to identify the hypothalamic-Pituitary vascular network in such cases.Eighteen patients (13 males, 5 females) aged 10-26.4 years with unidentified Pituitary Stalk at first MRI study were evaluated. Eight had isolated GH deficiency (IGHD), and 10 had multiple Pituitary hormone defect (MPHD) with the progression to complete anterior Pituitary deficits seen by the age of 15 years in 8 patients (1 had GH and FSH-LH deficiency and 1 had GH, TSH and FSH-LH deficiency).The MRI revealed a very thin Pituitary Stalk in 7 patients (38.8\%), 6 with IGHD (75\%) and 1 (10\%) with MPHD (GH and FSH-LH deficiency), after Gd-DTPA administration. Reassessment of anterior Pituitary function showed that the thyroid, adrenal and gonadal functions were intact in the 6 patients with IGHD and Pituitary Stalk identified by Gd-DTPA as well as in one IGHD patient with no evidence of Pituitary Stalk. In one 10-year-old with IGHD at the time of presentation (6 years) and no Pituitary Stalk seen after Gd-DTPA, subclinical hypothalamic hypothyroidism and suspected hypogonadotropic hypogonadism were documented. Partial ACTH deficiency was recorded in the patient with TSH and FSH-LH deficiency with no Pituitary Stalk. After Gd-DTPA, patients with absent Pituitary Stalk had a risk of developing MPHD 27 times greater than had those with an identified Pituitary Stalk (relative risk = 27, 95\% confidence interval 1.9-368.4, Fisher's exact test P = 0.009). Dynamic MR images obtained every 4.6 s revealed rapid enhancement of hypothalamic-Pituitary structures and allowed the determination of the times to initial enhancement of ectopic posterior Pituitary and hypoplastic anterior Pituitary which ranged between 9.2 and 18.4 s, and that of complete anterior Pituitary (32.2-41.4 s). The time to maximum enhancement of anterior Pituitary was significantly longer than in controls (35.5 +/- 3.8 s vs 25.2 +/- 1.6 s, P < 0.0001).MRI with Gd-DTPA proved more sensitive in identifying the vascular component of Pituitary Stalk and added new information about the partial preservation of hypothalamo-hypophyseal portal vessels. The vascular Pituitary Stalk is easily recognized after Gd-DTPA in most IGHD patients, but exceptionally in MPHD; this sheds light on the possible normal course of affected patients. The neural component of the Pituitary Stalk is lacking regardless of whether patients have IGHD or MPHD, indicating that the term congenital agenesis of the neural Pituitary Stalk is more appropriate than Pituitary Stalk interruption. The times to enhancement of ectopic posterior Pituitary and residual anterior Pituitary obtained by the fast-framing MRI technique disclose dynamic changes in regional blood supply which appear direct, arterial and mainly independent of the portal system
Stephanie Chen - One of the best experts on this subject based on the ideXlab platform.
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growth hormone deficiency with ectopic neurohypophysis anatomical variations and relationship between the visibility of the Pituitary Stalk asserted by magnetic resonance imaging and anterior Pituitary function
The Journal of Clinical Endocrinology and Metabolism, 1999Co-Authors: Stephanie Chen, Juliane Leger, Catherine Garel, Max Hassan, Paul CzernichowAbstract:In GH-deficient children showing ectopic posterior Pituitary hyperintense signal (EPP), the anatomical details of the Pituitary-hypothalamic region and the relationship between the visibility of the Pituitary Stalk and anterior Pituitary function were studied by magnetic resonance imaging (MRI). The absence or presence of the Pituitary Stalk was recorded by MRI before and after the injection of gadolinium in 25 children with GH deficiency and EPP at the age of 8.7 ± 5.0 yr (16 males and 9 females). Patients were classified into 2 groups according to the presence (group 1; n = 14), or the absence (group 2; n = 11) of Pituitary Stalk visibility after gadolinium injection. Most patients in group 1 (12 of 14) demonstrated isolated GH deficiency, whereas all but 1 patient in group 2 showed multiple anterior Pituitary hormone deficiency. The prevalence of a normally sized adenohypophysis was higher in group 1 than in group 2 (50% vs. 9%; P < 0.05). Although the EPP was found at the median eminence in all group ...
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growth hormone deficiency with ectopic neurohypophysis anatomical variations and relationship between the visibility of the Pituitary Stalk asserted by magnetic resonance imaging and anterior Pituitary function
The Journal of Clinical Endocrinology and Metabolism, 1999Co-Authors: Stephanie Chen, Juliane Leger, Catherine Garel, Max Hassan, Paul CzernichowAbstract:In GH-deficient children showing ectopic posterior Pituitary hyperintense signal (EPP), the anatomical details of the Pituitary-hypothalamic region and the relationship between the visibility of the Pituitary Stalk and anterior Pituitary function were studied by magnetic resonance imaging (MRI). The absence or presence of the Pituitary Stalk was recorded by MRI before and after the injection of gadolinium in 25 children with GH deficiency and EPP at the age of 8.7+/-5.0 yr (16 males and 9 females). Patients were classified into 2 groups according to the presence (group 1; n = 14), or the absence (group 2; n = 11) of Pituitary Stalk visibility after gadolinium injection. Most patients in group 1 (12 of 14) demonstrated isolated GH deficiency, whereas all but 1 patient in group 2 showed multiple anterior Pituitary hormone deficiency. The prevalence of a normally sized adenohypophysis was higher in group 1 than in group 2 (50% vs. 9%; P<0.05). Although the EPP was found at the median eminence in all group 2 patients, it was visualized in group 1 at different levels of the Pituitary Stalk in 60% of cases (8 of 14; at the proximal end of the Pituitary Stalk, n = 4; in the middle of the Pituitary Stalk, n = 2; at the distal end of the Pituitary Stalk, n = 2). This demonstrates that the ectopic posterior Pituitary migration abnormality may be complete or partial. In conclusion, although the pathogenesis of GH deficiency with EPP remains unclear, these results suggest that in cases of GH deficiency associated with ectopic posterior Pituitary hyperintense signal, patients with no visible Pituitary Stalk on MRI after gadolinium injection present a more severe form of the disease in childhood associated with multiple anterior Pituitary hormone deficiency, whereas visibility of the Pituitary Stalk is related to isolated GH deficiency. Nevertheless, careful follow-up of these latter patients is necessary, as the natural history of the disease is not established until adulthood.