Pituitary Stalk Interruption Syndrome and Isolated Pituitary Hypoplasia May Be Caused by Mutations in Holoprosencephaly-Related Genes

Context: Holoprosencephaly (HPE) is a developmental defect characterized by wide phenotypic variability, ranging from minor midline malformations (eg, single central incisor) to severe deformities. In 10–15% of HPE patients, mutations in specific genes have been identified (eg, SHH, TGIF, SIX3). Pituitary stalk interruption syndrome (PSIS) constitutes a distinct abnormality of unknown pathogenesis, whereas isolated pituitary hypoplasia (IPH) has been linked to various developmental genes. Objective: Three of our patients with PSIS had a single central incisor, a malformation encountered in some HPE cases. Based on this observation, we initiated a search for mutations in HPE-associated genes in 30 patients with PSIS or IPH. Design and Participants: The entire coding region of the TGIF, SHH, and SIX3 genes was sequenced in patients with combined pituitary hormone deficiency associated with either PSIS or IPH and in healthy controls. Results: Two novel mutations in the HPE-related genes were detected (ie, c.799 C>T, p.Q267X in the TGIF gene, and c.1279G>A, p.G427R in the SHH gene) in 2 of our patients. The overall incidence of HPE-related gene mutations in our nonsyndromic and nonchromosomal patients was 6.6%. No molecular defect in the SIX3 gene was detected in our cohort. Conclusions: The data suggest that HPE-related gene mutations are implicated in the etiology of isolated pituitary defects (PSIS or IPH). Alternatively, PSIS or IPH may constitute mild forms of an expanded HPE spectrum.

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DIAGNOSIS OF ENDOCRINE DISEASE: Pituitary stalk interruption syndrome: etiology and clinical manifestations

Acta Endocrinologica ◽

10.1530/eje-19-0168 ◽

2019 ◽

Vol 181 (5) ◽

pp. R199-R209 ◽

Cited By ~ 4

Author(s):

Julia Vergier ◽

Frederic Castinetti ◽

Alexandru Saveanu ◽

Nadine Girard ◽

Thierry Brue ◽

...

Keyword(s):

Current Knowledge ◽

Environmental Influence ◽

Age At Onset ◽

Clinical Manifestations ◽

Gene Mutations ◽

Current Data ◽

Pituitary Stalk ◽

Pituitary Hormone ◽

Developmental Defect ◽

Posterior Lobe

Pituitary stalk interruption syndrome (PSIS) is a congenital pituitary anatomical defect. This syndrome is an antenatal developmental defect belonging to the holoprosencephaly phenotype spectrum. It is heterogeneous regarding clinical, biological and radiological presentation and is characterized by the following triad: thin (<1 mm) or interrupted pituitary stalk connecting the hypothalamus to the pituitary gland, no eutopic posterior lobe, and hypoplasia or aplasia of the anterior lobe. This review reports current knowledge about the composite pathogenesis, for which underlying mechanisms remain unclear. Current data suggest genetic origins involving early developmental gene mutations with complex inheritance patterns and environmental influence, placing PSIS at the crossroads between Mendelian and multifactorial diseases. The phenotype associated with PSIS is highly heterogeneous with a high incidence of various combinations of hormonal deficiencies, sometimes associated with extra-pituitary birth defects. The age at onset is variable, but typical presentation is evolutive combined anterior pituitary hormone deficiencies at pediatric age, which progress even during adulthood to panhypopituitarism. Therefore, patients’ follow-up throughout life is essential for adequate management.

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

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1392 ◽

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.

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Pituitary Morphology and Function in 43 Children with Central Diabetes Insipidus

International Journal of Endocrinology ◽

10.1155/2016/6365830 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 8

Author(s):

Wendong Liu ◽

Limin Wang ◽

Minghua Liu ◽

Guimei Li

Keyword(s):

Diabetes Insipidus ◽

Central Diabetes Insipidus ◽

Pituitary Function ◽

Pituitary Stalk ◽

Hormone Deficiency ◽

Pituitary Hormone ◽

Initial Manifestation ◽

Stalk Diameter ◽

And Function

Objective. In pediatric central diabetes insipidus (CDI), etiology diagnosis and pituitary function monitoring are usually delayed. This study aimed to illustrate the importance of regular follow-up and pituitary function monitoring in pediatric CDI.Methods. The clinical, hormonal, and neuroradiological characteristics of children with CDI at diagnosis and during 1.5–2-year follow-up were collected and analyzed.Results. The study included 43 CDI patients. The mean interval between initial manifestation and diagnosis was 22.29 ± 3.67 months (range: 2–108 months). The most common complaint was polyuria/polydipsia. Causes included Langerhans cell histiocytosis, germinoma, and craniopharyngioma in 2, 5, and 4 patients; the remaining were idiopathic. No significant changes were found during the 1.5–2 years after CDI diagnosis. Twenty-three of the 43 cases (53.5%) had ≥1 anterior pituitary hormone deficiency. Isolated growth hormone deficiency was the most frequent abnormality (37.5%) and was not associated with pituitary stalk diameter. Multiple pituitary hormone deficiencies were found in 8 cases with pituitary stalk diameter > 4.5 mm.Conclusion. Diagnosis of CDI is usually delayed. CDI with a pituitary stalk diameter > 4.5 mm carries a higher risk of multiple pituitary hormone deficiencies. Long-term MRI and pituitary function follow-ups are necessary for children with idiopathic CDI.

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Evaluation of pituitary imaging in patients with PROP-1 gene mutation

Medicina ◽

10.3390/medicina45090090 ◽

2009 ◽

Vol 45 (9) ◽

pp. 693 ◽

Cited By ~ 1

Author(s):

Natalija Tkačenko ◽

Danutė Lašienė ◽

Silvija Jakštienė ◽

Algidas Basevičius ◽

Rasa Verkauskienė

Keyword(s):

Transcription Factor ◽

Pituitary Gland ◽

Gene Mutation ◽

Anterior Pituitary ◽

Hormone Deficiency ◽

Pituitary Hormone ◽

Imaging Studies ◽

Pituitary Hyperplasia ◽

Pituitary Hypoplasia ◽

Genetically Determined

The most common genetically determined cause of multiple pituitary hormone deficiency is PROP-1 gene mutation. PROP-1 is a transcription factor involved in the development of pituitary gland and affects hormonal synthesis of anterior pituitary. The aim of our study was to evaluate radiological aspects of the pituitary region in patients with PROP-1 gene mutation. Pituitary imaging studies were performed in 12 patients with a confirmed PROP-1 gene mutation. Pituitary hyperplasia was found in 5 (42%) and pituitary hypoplasia in 4 (33%) patients. Changes in pituitary size were not associated with the type of PROP-1 gene mutation.

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Central diabetes insipidus as a very late relapse limited to the pituitary stalk in Langerhans cell histiocytosis

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2015-0391 ◽

2016 ◽

Vol 29 (7) ◽

Cited By ~ 2

Author(s):

Shunsuke Nakagawa ◽

Yuichi Shinkoda ◽

Daisuke Hazeki ◽

Mari Imamura ◽

Yasuhiro Okamoto ◽

...

Keyword(s):

Diabetes Insipidus ◽

Langerhans Cell Histiocytosis ◽

Langerhans Cell ◽

Central Diabetes Insipidus ◽

Pituitary Stalk ◽

Hormone Deficiency ◽

Late Relapse ◽

Pituitary Hormone ◽

Anterior Pituitary Hormone ◽

The Central Nervous System

AbstractCentral diabetes insipidus (CDI) and relapse are frequently seen in multifocal Langerhans cell histiocytosis (LCH). We present two females with multifocal LCH who developed CDI 9 and 5 years after the initial diagnosis, respectively, as a relapse limited to the pituitary stalk. Combination chemotherapy with cytarabine reduced the mass in the pituitary stalk. Although CDI did not improve, there has been no anterior pituitary hormone deficiency (APHD), neurodegenerative disease in the central nervous system (ND-CNS) or additional relapse for 2 years after therapy. It was difficult to predict the development of CDI in these cases. CDI might develop very late in patients with multifocal LCH, and therefore strict follow-up is necessary, especially with regard to symptoms of CDI such as polydipsia and polyuria. For new-onset CDI with LCH, chemotherapy with cytarabine might be useful for preventing APHD and ND-CNS.

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

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2006-2177 ◽

2007 ◽

Vol 92 (5) ◽

pp. 1909-1919 ◽

Cited By ~ 80

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.

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Pituitary stalk interruption syndrome is characterized by genetic heterogeneity

PLoS ONE ◽

10.1371/journal.pone.0242358 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0242358

Author(s):

Raja Brauner ◽

Joelle Bignon-Topalovic ◽

Anu Bashamboo ◽

Ken McElreavey

Keyword(s):

Genetic Heterogeneity ◽

Hypogonadotropic Hypogonadism ◽

Gene Mutations ◽

Pituitary Stalk ◽

Specific Gene ◽

Genetic Syndromes ◽

Pituitary Development ◽

Pediatric Endocrinologist ◽

Novel Variants ◽

Pituitary Hypoplasia

Pituitary stalk interruption syndrome is a rare disorder characterized by an absent or ectopic posterior pituitary, interrupted pituitary stalk and anterior pituitary hypoplasia, as well as in some cases, a range of heterogeneous somatic anomalies. A genetic cause is identified in only around 5% of all cases. Here, we define the genetic variants associated with PSIS followed by the same pediatric endocrinologist. Exome sequencing was performed in 52 (33 boys and 19 girls), including 2 familial cases single center pediatric cases, among them associated 36 (69.2%) had associated symptoms or syndromes. We identified rare and novel variants in genes (37 families with 39 individuals) known to be involved in one or more of the following—midline development and/or pituitary development or function (BMP4, CDON, GLI2, GLI3, HESX1, KIAA0556, LHX9, NKX2-1, PROP1, PTCH1, SHH, TBX19, TGIF1), syndromic and non-syndromic forms of hypogonadotropic hypogonadism (CCDC141, CHD7, FANCA, FANCC, FANCD2, FANCE, FANCG, IL17RD, KISS1R, NSMF, PMM2, SEMA3E, WDR11), syndromic forms of short stature (FGFR3, NBAS, PRMT7, RAF1, SLX4, SMARCA2, SOX11), cerebellum atrophy with optic anomalies (DNMT1, NBAS), axonal migration (ROBO1, SLIT2), and agenesis of the corpus callosum (ARID1B, CC2D2A, CEP120, CSPP1, DHCR7, INPP5E, VPS13B, ZNF423). Pituitary stalk interruption syndrome is characterized by a complex genetic heterogeneity, that reflects a complex phenotypic heterogeneity. Seizures, intellectual disability, micropenis or cryptorchidism, seen at presentation are usually considered as secondary to the pituitary deficiencies. However, this study shows that they are due to specific gene mutations. PSIS should therefore be considered as part of the phenotypic spectrum of other known genetic syndromes rather than as specific clinical entity.

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Molecular analysis of the PROP1 and HESX1 genes in patients with septo-optic dysplasia and/or pituitary hormone deficiency

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302010000500009 ◽

2010 ◽

Vol 54 (5) ◽

pp. 482-487 ◽

Cited By ~ 3

Author(s):

Juliana B. Cruz ◽

Vania S. Nunes ◽

Sueli A. Clara ◽

Denise Perone ◽

Peter Kopp ◽

...

Keyword(s):

Gene Mutations ◽

Genetic Alterations ◽

Hormone Deficiency ◽

Pituitary Hormone ◽

Pituitary Hormone Deficiency ◽

Exon 1 ◽

Genetic Mechanisms ◽

Direct Sequence Analysis ◽

Prop1 Gene ◽

Pathogenic Process

OBJECTIVE: The present study aimed at evaluating the PROP1 and HESX1 genes in a group of patients with septo-optic dysplasia (SOD) and pituitary hormone deficiency (combined - CPHD; isolated GH deficiency - GHD). Eleven patients with a clinical and biochemical presentation consistent with CPHD, GHD or SOD were evaluated. SUBJECTS AND METHODS: In all patients, the HESX1 gene was analyzed by direct sequence analysis and in cases of CPHD the PROP1 gene was also sequenced. RESULTS: A polymorphism (1772 A > G; N125S) was identified in a patient with SOD. We found three patients carrying the allelic variants 27 T > C; A9A and 59 A > G; N20S in exon 1 of the PROP1 gene. Mutations in the PROP1 and HESX1 genes were not identified in these patients with sporadic GHD, CPHD and SOD. CONCLUSION: Genetic alterations in one or several other genes, or non-genetic mechanisms, must be implicated in the pathogenic process.

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Pituitary Stalk Interruption Syndrome: Presentation of a Rare Case

Journal of Pediatric Neurology ◽

10.1055/s-0038-1661412 ◽

2018 ◽

Vol 17 (05) ◽

pp. 176-179

Author(s):

Burcin Agridag Ucpinar ◽

Ahmet Ucar ◽

Evrim Ozmen

Keyword(s):

Mental Retardation ◽

Incidence Rate ◽

Anterior Pituitary ◽

Hormone Replacement ◽

Pituitary Stalk ◽

Hormone Deficiency ◽

Magnetic Resonance Imaging Scan ◽

Pituitary Hormone ◽

Posterior Pituitary ◽

Mild Mental Retardation

AbstractPituitary stalk interruption syndrome is a congenital anomaly characterized by interrupted or thin pituitary stalk, hypoplastic or absent anterior pituitary, and an absent or ectopic posterior pituitary gland. The exact incidence rate of this syndrome is not known. However, the estimated incidence rate is 0.5/1,000,000 births. In this case report, we wanted to present a case of interrupted pituitary stalk syndrome, which presented with seizures and thyroid hormone deficiency. A 5-year-old female patient was admitted to our emergency department with vomiting, fever, and seizures with new onset. She had a twin who was ex-utero intrapartum in taken history. She was diagnosed with hypothyroidism and started on levothyroxine. Her height was in 25 to 50th percentile and her weight was in 10 to 25th percentile. She had mild mental retardation. On contrast-enhanced cranial magnetic resonance imaging scan, the pituitary stalk was absent, posterior pituitary was ectopic, and anterior pituitary was hypoplastic. The patient was diagnosed with interrupted pituitary stalk syndrome. After the symptoms were relieved, patient started on carbamazepine for epileptic seizures and hormone replacement therapy with levothyroxine and hydrocortisone. She was routinely followed up after the proper diagnosis. Leuprolide (gonadotropin-releasing hormone) and Norditropin (biosynthetic growth hormone) were added to medical therapy. Her height and weight were in 25th percentile after the long-term follow-up of approximately 10 years. On neurological examination, situation of mild mental retardation persisted. Pituitary stalk interruption syndrome is a very rare entity. However, radiologists should keep this syndrome in mind for patients who present with hypoglycemia, seizures, jaundice, cryptorchidism, and hypothyroidism in neonatal period and growth retardation with pituitary hormone deficiencies in childhood.

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Lhx4 Deficiency: Increased Cyclin-Dependent Kinase Inhibitor Expression and Pituitary Hypoplasia

Molecular Endocrinology ◽

10.1210/me.2014-1380 ◽

2015 ◽

Vol 29 (4) ◽

pp. 597-612 ◽

Cited By ~ 6

Author(s):

Peter Gergics ◽

Michelle L. Brinkmeier ◽

Sally A. Camper

Keyword(s):

Kinase Inhibitor ◽

Developmental Regulation ◽

Hormone Deficiency ◽

Pituitary Hormone ◽

Pituitary Cells ◽

Cyclin Dependent Kinase ◽

Cyclin Dependent Kinase Inhibitor ◽

Show Evidence ◽

Progenitor Cell Proliferation ◽

Pituitary Hypoplasia

Abstract Defects in the Lhx4, Lhx3, and Pitx2 genes can cause combined pituitary hormone deficiency and pituitary hypoplasia in both humans and mice. Not much is known about the mechanism underlying hypoplasia in these mutants beyond generally increased cell death and poorly maintained proliferation. We identified both common and unique abnormalities in developmental regulation of key cell cycle regulator gene expression in each of these three mutants. All three mutants exhibit reduced expression of the proliferative marker Ki67 and the transitional marker p57. We discovered that expression of the cyclin-dependent kinase inhibitor 1a (Cdkn1a or p21) is expanded dorsally in the pituitary primordium of both Lhx3 and Lhx4 mutants. Uniquely, Lhx4 mutants exhibit reduced cyclin D1 expression and have auxiliary pouch-like structures. We show evidence for indirect and direct effects of LHX4 on p21 expression in αT3-1 pituitary cells. In summary, Lhx4 is necessary for efficient pituitary progenitor cell proliferation and restriction of p21 expression.

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