A new imaging entity consistent with partial ectopic posterior pituitary gland: report of six cases.

BACKGROUND: Abnormal posterior pituitary development including ectopic location has been associated with endocrine manifestations of anterior pituitary dysfunction. OBJECTIVE: We describe an unreported clinical and radiologic entity we call partial ectopic posterior pituitary for which associated endocrine consequences are not known. MATERIALS AND METHODS: We selected pediatric head MRI examinations from 2005 to 2017 based on the finding of a double midline sellar and suprasellar bright spot on T1-weighted sequence. Medical history, physical examination, pituitary hormonal profile and bone age evaluation were extracted from the medical record of the selected patients. An experienced pediatric neuroradiologist reviewed head MRIs, which were performed on 3-tesla (T) magnet and included at least sagittal T1-weighted imaging centered on the sella turcica obtained with and without fat suppression. RESULTS: In six cases, two midline bright spots were identified on T1-weighted sequences obtained both with and without fat suppression. While one spot was located at the expected site of the neurohypophysis in the posterior sella, the second one was in the region of the median eminence, suggesting partial ectopic posterior pituitary gland. Growth hormone deficiency, either isolated (n=1) or combined with thyroid stimulating hormone deficiency (n=1) was found. None of the children had clinical signs of posterior pituitary dysfunction. CONCLUSION: We describe an unreported imaging entity suggesting partial ectopic posterior pituitary gland in six children. Anterior pituitary hormone deficiencies might be detected in those children and long-term follow-up could provide additional information on the development of other pituitary hormone deficiencies.

Bilateral Optic Disc Pits With Posterior Pituitary Ectopia.

Posterior pituitary ectopia has been reported previously in association with optic nerve hypoplasia, as a variant of septo-optic dysplasia. We describe a 14-year-old boy with posterior pituitary ectopia and bilateral optic disc pits. He had hypopituitarism and a reduction in visual acuity to 20/40 in each eye, owing to loss of foveal ganglion cells. Optic pits and posterior pituitary ectopia may have occurred together in the same subject by chance, but the rarity of both conditions suggests a possible association.

High-resolution heavily T2-weighted magnetic resonance imaging for evaluation of the pituitary stalk in children with ectopic neurohypophysis.

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. OBJECTIVE: 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. MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Two novel heterozygous missense variations within the GLI2 gene in two unrelated Argentine patients.

Several heterozygous GLI2 gene mutations have been reported in patients with isolated GH deficiency (IGHD) or multiple pituitary hormone deficiency (MPHD) with or without other malformations. The primary aim of this study was to analyze the presence of GLI2 gene alterations in a cohort of patients with IGHD or MPHD and ectopic/absent posterior pituitary. The coding sequence and flanking intronic regions of GLI2 gene were amplified and directly sequenced from gDNA of 18 affected subjects and relatives. In silico tools were applied to identify the functional impact of newly found variants (Polyphen2, SIFT, Mutation Taster). We identified two novel heterozygous missense variations in two unrelated patients, p.Arg231Gln and p.Arg226Leu, located in the repressor domain of the protein. Both variations affect highly conserved amino acids of the Gli2 protein and were not found in the available databases. In silico tools suggest that these variations might be disease causing. Our study suggests that the GLI2 gene may be one of the candidate genes to analyze when an association of pituitary hormone deficiency and developmental defects in posterior pituitary gland. The highly variable phenotype found suggests the presence of additional unknown factors that could contribute to the phenotype observed in these patients.

Neuronal defects and posterior pituitary hypoplasia in mice lacking the receptor tyrosine phosphatase PTPsigma.

The LAR-family protein tyrosine phosphatase sigma (PTPsigma, encoded by the gene Ptprs) consists of a cell adhesion-like extracellular domain composed of immunoglobulin and fibronectin type-III repeats, a single transmembrane domain and two intracellular catalytic domains. It was previously shown to be expressed in neuronal and lung epithelial tissues in a developmentally regulated manner. To study the role of PTPsigma in mouse development, we inactivated Ptprs by gene targeting. All Ptprs+/- mice developed normally, whereas 60% of Ptprs-/- mice died within 48 hours after birth. The surviving Ptprs-/- mice demonstrated stunted growth, developmental delays and severe neurological defects including spastic movements, tremor, ataxic gait, abnormal limb flexion and defective proprioception. Histopathology of brain sections revealed reduction and hypocellularity of the posterior pituitary of Ptprs-/- mice, as well as a reduction of approximately 50-75% in the number of choline acetyl transferase-positive cells in the forebrain. Moreover, peripheral nerve electrophysiological analysis revealed slower conduction velocity in Ptprs-/- mice relative to wild-type or heterozygous animals, associated with an increased proportion of slowly conducting, small-diameter myelinated fibres and relative hypomyelination. By approximately three weeks of age, most remaining Ptprs-/- mice died from a wasting syndrome with atrophic intestinal villi. These results suggest that PTPsigma has a role in neuronal and epithelial development in mice.

The pituitary stalk transection syndrome: multifaceted presentation in adulthood.

The pituitary stalk transection syndrome was characterized after introducing the MRI scan in the evaluation of children with hypopituitarism. Its prevalence and natural history into adulthood have not been clearly established. We present 4 cases of stalk transection syndrome diagnosed by the adult endocrinologist that reflect its pleiotropic manifestations. In all cases, MRI showed pathognomonic findings with small anterior pituitary, diminutive or absent infundibulum and ectopic posterior pituitary at the median eminence. Clinical presentation occurred in childhood or the second decade of life. The hormonal deficits were variable in severity and onset, with adrenal insufficiency diagnosed in the second and forth decade in three patients, and absent in another. Growth hormone deficiency was diagnosed before age 10 in three cases and at age 20 in one case with normal spontaneous linear growth. Hypothyroidism had onset in the first or second decade of life and hypogonadism was diagnosed during work-up for lack of pubertal development in all cases. The pituitary stalk transection syndrome should be considered in patients who were previously thought to have idiopathic GH deficiency or multiple pituitary hormone deficiencies. Presence of MRI characteristics compatible with the pituitary stalk transection syndrome should prompt a full pituitary hormonal evaluation. Long-term follow-up by the adult endocrinologist is warranted as new hormone deficiencies might appear later in life.

[Hypoplasia adrenal congenita of anencephalic type: two cases with pituitary abnormalities and review of literature]. / L'hypoplasie surrénale congénitale de type anencéphalique: deux cas avec anomalies hypophysaires, sans mutation de DAX-1 et SF-1 et revue de la littérature.

Hypoplasia adrenal congenita is an extremely uncommon disease of early onset. This condition can be lethal in the absence of treatment. Some forms are due to the congenital adrenal hypoplasia of anencephalic type whose origin is even unknown. Here, we present two cases of congenital adrenal hypoplasia of anencephalic type with pituitary abnormalities. The two male newborns died because adrenal insufficiency in the neonatal period. The adrenal glands were hypoplastic with a histological structure of anencephalic type Immunocytochemical study of the pituitary revealed an absence of the gonadotrophs. No mutation of DAX 1 and SF-1 was found.

Pituitary stalk interruption syndrome: A rare case report and literature review.

RATIONALE: Pituitary stalk interruption syndrome (PSIS) is a congenital pituitary anatomical defect. It is characterized by the triad of thin or interrupted pituitary stalk, absent or ectopic posterior lobe, and hypoplastic or aplastic anterior lobe. Moreover, this condition is considered rare. PATIENT CONCERNS: A 23-year-old male patient presented with a history of short stature and hypogonadism. Laboratory assessment revealed low thyroxine, cortisol, and adrenocorticotropic hormone levels, which are consistent with adrenal insufficiency without hypoglycemia. The insulin-induced hypoglycemia tolerance test finding indicated growth hormone (GH) deficiency. Moreover, magnetic resonance imaging revealed an interrupted pituitary stalk, ectopic posterior pituitary, and hypoplastic anterior pituitary. This triad of symptoms was indicative of PSIS. DIAGNOSIS: INTERVENTIONS:: The patient was deficient in adrenaline, thyroxine, gonadal steroid, and GH. Thus, glucocorticoid replacement therapy was initiated, followed by euthyrox, androgen, and human chorionic gonadotropin treatment. Calcium tablets, calcitriol, and alendronate sodium were used for the management of osteoporosis. The patient was 164 cm tall, and his bone age was approximately 15 years old. However, owing to a poor economic condition, the family did not proceed with GH therapy. OUTCOMES: The patient did not present with adrenal or hypothyroidism crisis after receiving poly-hormonal replacement therapy. His secondary sexual characteristics began to develop. However, owing to a short treatment window period, the patient could not receive the required treatment. Hence, whether the patient would have a normal fertility function needs to be confirmed. LESSONS: PSIS is a rare disease with various clinical characteristics. During the neonatal period and infancy, the signs and symptoms of PSIS are often not evident. Therefore, diagnosis is delayed. The early detection of hormone deficiency and treatment initiation can affect both the quality of life and the prognosis of patients with PSIS. Thus, the diagnosis and treatment of this disease must be improved to help patients achieve a better quality of life and to prevent reproductive health problems.

Ectopic Posterior Pituitary, Polydactyly, Midfacial Hypoplasia and Multiple Pituitary Hormone Deficiency due to a Novel Heterozygous IVS11-2A>C(c.1957-2A>C) Mutation in the GLI2 Gene

A novel heterozygous IVS11-2A>C(c.1957-2A>C) mutation in the GLI2 gene is reported. There was an extremely distinct phenotypical expression in two siblings and their father. The index case was a boy who developed cholestasis and hypoglycaemia in the neonatal period. He had bilateral postaxial polydactyly, mid-facial hypoplasia, high palatal arch, micropenis, and bilateral cryptorchidism. Laboratory examination revealed a diagnosis of multiple pituitary hormone deficiency. There was severe anterior pituitary hypoplasia, absent pituitary stalk and ectopic posterior pituitary on magnetic resonance imaging which suggested pituitary stalk interruption syndrome with no other midline structural abnormality. Molecular genetic analysis revealed a novel heterozygous splicing IVS11-2A>C(c.1957-2A>C) mutation detected in the GLI2 gene. His father and a six-year-old brother with the identical mutation also had unilateral postaxial polydactyly and mid-facial hypoplasia although there was no pituitary hormone deficiency. This novel heterozygous GLI2 mutation detected appears to present with an extremely variable clinical phenotype, even in related individuals with an identical mutation, suggesting incomplete penetrance of this GLI2 mutation.

OTX2 loss of function mutation causes anophthalmia and combined pituitary hormone deficiency with a small anterior and ectopic posterior pituitary.

CONTEXT: Orthodenticle homeobox 2 (OTX2) is a transcription factor necessary for ocular and forebrain development. In humans, heterozygous mutations of OTX2 cause severe ocular malformations. However, whether mutations of OTX2 cause pituitary structural abnormalities or combined pituitary hormone deficiency (CPHD) has not been clarified. OBJECTIVES: We surveyed the functional consequences of a novel OTX2 mutation that was detected in a patient with anophthalmia and CPHD. PATIENT: We examined a Japanese patient with growth disturbance, anophthalamia, and severe developmental delay. He showed deficiencies in GH, TSH, LH, FSH, and ACTH. Brain magnetic resonance imaging revealed a small anterior pituitary gland, invisible stalk, ectopic posterior lobe, and Chiari malformation. RESULTS: Sequence analysis of OTX2 demonstrated a heterozygous two bases insertion [S136fsX178 (c.576-577insCT)] in exon 3. The mutant Otx2 protein localized to the nucleus, but did not activate the promoter of the HESX1 and POU1F1 gene, indicating a loss of function mutation. No dominant negative effect in the presence of wild-type Otx2 was observed. CONCLUSION: This case indicates that the OTX2 mutation is a cause of CPHD. Further study of more patients with OTX2 defects is necessary to clarify the clinical phenotypes and endocrine defects caused by OTX2 mutations.

Likelihood of persistent GH deficiency into late adolescence: relationship to the presence of an ectopic or normally sited posterior pituitary gland.

OBJECTIVES: The presence of an ectopic posterior pituitary gland (EPP) in childhood is associated with isolated GH deficiency (IGHD) and multiple pituitary hormone deficiency. GHD in late adolescence has been defined as a peak GH level <5 microg/l. The aim of this study was to identify the likelihood of persistent GHD in late adolescence in patients with an EPP compared with those with a normally sited posterior pituitary (NPP). METHODS: In 18 patients with an EPP and 15 patients with an NPP, clinical, biochemical and radiographic data were collected. RESULTS: In the EPP vs. the NPP group, the change in peak GH levels at the end of growth was less (+0.4[95% confidence interval (CI) - 0.8 to 2.7] vs. +4.1[95%CI + 0.4 to +10.5] microg/l, P-value for ancova = 0.03, after adjustment for age and sex). Using a peak GH level of <5 microg/l as a cut-off for GHD, 66% of EPP subjects compared with 40% of NPP subjects had GHD (P = 0.3). Hundred per cent of EPP subjects had a peak GH level on retesting <10 microg/l, compared with 40% of NPP subjects (P < 0.001). CONCLUSION: It is important to document GH status at the end of growth, even if there is a structural abnormality of the hypothalamic-pituitary axis. The presence of an EPP compared to an NPP increases the likelihood of persistent GHD by 26%. As all EPP patients had a peak GH level of <10 microg/l, the cut-off for persistent GHD in late adolescence may need to be revised.

Developmental abnormalities of the posterior pituitary gland.

While the molecular mechanisms of anterior pituitary development are now better understood than in the past, both in animals and in humans, little is known about the mechanisms regulating posterior pituitary development. The posterior pituitary gland is formed by the evagination of neural tissue from the floor of the third ventricle. It consists of the distal axons of the hypothalamic magnocellular neurones that shape the neurohypophysis. After its downward migration, it is encapsulated together with the ascending ectodermal cells of Rathke's pouch which form the anterior pituitary. By the end of the first trimester, this development is completed and vasopressin and oxytocin can be detected in neurohypophyseal tissue. Abnormal posterior pituitary migration such as the ectopic posterior pituitary lobe appearing at the level of median eminence or along the pituitary stalk have been reported in idiopathic GH deficiency or in subjects with HESX1, LHX4 and SOX3 gene mutations. Another intriguing feature of abnormal posterior pituitary development involves genetic forms of posterior pituitary neurodegeneration that have been reported in autosomal-dominant central diabetes insipidus and Wolfram disease. Defining the phenotype of the posterior pituitary gland can have significant clinical implications for management and counseling, as well as providing considerable insight into normal and abnormal mechanisms of posterior pituitary development in humans.

Diabetes insipidus.

Diabetes insipidus (DI) is a disorder characterized by excretion of large amounts of hypotonic urine. Central DI results from a deficiency of the hormone arginine vasopressin (AVP) in the pituitary gland or the hypothalamus, whereas nephrogenic DI results from resistance to AVP in the kidneys. Central and nephrogenic DI are usually acquired, but genetic causes must be evaluated, especially if symptoms occur in early childhood. Central or nephrogenic DI must be differentiated from primary polydipsia, which involves excessive intake of large amounts of water despite normal AVP secretion and action. Primary polydipsia is most common in psychiatric patients and health enthusiasts but the polydipsia in a small subgroup of patients seems to be due to an abnormally low thirst threshold, a condition termed dipsogenic DI. Distinguishing between the different types of DI can be challenging and is done either by a water deprivation test or by hypertonic saline stimulation together with copeptin (or AVP) measurement. Furthermore, a detailed medical history, physical examination and imaging studies are needed to ensure an accurate DI diagnosis. Treatment of DI or primary polydipsia depends on the underlying aetiology and differs in central DI, nephrogenic DI and primary polydipsia.

Utility of AVP gene testing in familial neurohypophyseal diabetes insipidus.

CONTEXT: Familial neurohypophyseal diabetes insipidus (FNDI) is a rare disorder resulting from arginine vasopressin (AVP) gene mutations. A partial defect in AVP secretion occurs early in the course of FNDI and may not be detected by a water deprivation test (WDT). Testing for AVP gene mutations may confirm a diagnosis of FNDI when a WDT is inconclusive and may also predict individuals who will later develop FNDI. OBJECTIVE: To test the utility of AVP gene analysis in confirming the diagnosis of FNDI. PATIENTS: Five families (20 subjects, 14 symptomatic and six asymptomatic) with FNDI and nine children with idiopathic neurohypophyseal diabetes insipidus (INDI). MEASUREMENTS: Genomic DNA was analysed for AVP gene mutations using polymerase chain reaction (PCR) amplification and sequencing. RESULTS: Heterozygous AVP gene mutations were found in all subjects with FNDI but none of the ICDI patients. Each family had their own distinct mutation. We identified two novel mutations (C44W and C105S). One asymptomatic subject developed diabetes insipidus (DI) 4 months after detection of an AVP gene mutation. The WDT suggested partial DI in 4/6 but was normal in 2/6 children with FNDI. CONCLUSION: AVP gene testing allowed diagnostic confirmation of FNDI when the WDT was inconclusive in symptomatic children, therefore obviating the need for a repeat WDT and enabling earlier initiation of appropriate treatment. AVP gene testing also has the potential to identify which asymptomatic children will later develop FNDI.

Hes1 and Hes5 control the progenitor pool, intermediate lobe specification, and posterior lobe formation in the pituitary development.

The pituitary gland is composed of two distinct entities: the adenohypophysis, including the anterior and intermediate lobes, and the neurohypophysis, known as the posterior lobe. This critical endocrine organ is essential for homeostasis, metabolism, reproduction, and growth. The pituitary development requires the control of proliferation and differentiation of progenitor cells. Although multiple signaling molecules and transcription factors are required for the proper pituitary development, the mechanisms that regulate the fate of progenitor cells remain to be elucidated. Hes genes, known as Notch effectors, play a crucial role in specifying cellular fates during the development of various tissues and organs. Here, we report that mice deficient for Hes1 and Hes5 display severe pituitary hypoplasia caused by accelerated differentiation of progenitor cells. In addition, this hypoplastic pituitary gland (adenohypophysis) lacks the intermediate lobe and exhibits the features of the anterior lobe only. Hes1 and Hes5 double-mutant mice also lack the neurohypophysis (the posterior lobe), probably due to incomplete evagination of the diencephalon. Thus, Hes genes control not only maintenance of progenitor cells but also intermediate vs. anterior lobe specification during the adenohypophysis development. Hes genes are also essential for the formation of the neurohypophysis.

Remission of congenital diabetes insipidus after eight years.

Septo-optic dysplasia (SOD) (De Morsier's syndrome) is a complex developmental disorder marked by variable and often incomplete formation of cranial midline structures, resulting in absence of the septum pellucidum, optic nerve hypoplasia, and hypothalamic-pituitary dysfunction. We describe a patient with SOD who manifested symptoms in the early neonatal period with severe deficiencies of multiple pituitary hormones including anti-diuretic hormone (ADH). Her congenital diabetic insipidus (DI), consequence of an anatomic defect, can be argued to be of the most severe type. Our patient resolved her severe DI 8 years after her initial presentation, suddenly requiring no further medical treatment for DI following longstanding pharmacological replacement of ADH. This is the first report of a patient with SOD with spontaneous resolution of congenital DI.

Circadian pattern of prolactin secretion in children with growth hormone deficiency and congenital organic lesions in the hypothalamic-pituitary region.

OBJECTIVES: Prolactin (Prl) secretion in children manifests circadian rhythm. The aim of the study was to assess circadian Prl pattern in children with growth hormone deficiency (GHD) and congenital organic disorders in the hypothalamic-pituitary region (HPR). MATERIAL AND METHODS: The analysis comprised 47 children (aged: 11.05+/-3.5 years) with GHD, divided (based on MRI) into subgroups: NORM (no disturbances in HPR); HP (pituitary hypoplasia) and PSIS (pituitary stalk interruption syndrome). The profile of circadian Prl secretion was determined, based on Prl measurements in serum every 3 hours during 24 hours. The macroscopic analysis of circadian Prl rhythm in particular groups was performed. The comparison group consists of 41 children (aged: 11.45+/-3.20 years) with idiopathic short stature (ISS). RESULTS: In GHD-HP, diurnal and nocturnal Prl concentrations were low but with the dispersion between them and with normal rhythm in most of cases. In GHD-PSIS, diurnal and nocturnal Prl concentrations were on the same level and the rhythm was not observed in most of cases. No significant differences were found in Prl secretions and Prl rhythm between GHD-NORM and ISS. The rhythm of Prl secretion was disturbed in: 72.7% of children with GHD-PSIS, 23.5% - with GHD-HP, 10.5% with GHD-NORM and 7.3% with ISS, only. CONCLUSIONS: Congenital organic lesions of HPR are associated with quantitative disorders and changes of the circadian pattern of Prl secretion. In children with GHD without organic lesions of HPR, the circadian rhythm of Prl secretion was not different from that with ISS.

The Missing Link: A Case of Absent Pituitary Infundibulum and Ectopic Neurohypophysis in a Pediatric Patient with Heterotaxy Syndrome.

We report a case of absent pituitary infundibulum and ectopic neurohypophysis in a 4-year-old patient presenting clinically with hypopituitarism as well as heterotaxy syndrome complicated by global developmental delay and growth retardation. The clinical and laboratory workup of our patient suggested underlying hypopituitarism related to either congenital or acquired pathology, necessitating MRI to distinguish between them. We explain the various structural causes of hypopituitarism and detail how to predict the MRI findings and treatment, based on a fundamental understanding of the anatomy and pathophysiology of the hypothalamic pituitary axis and distinguishing anterior versus posterior pituitary hormone derangements. We also discuss two important theories widely acknowledged in the literature to explain congenital hypopituitarism: 1. Head trauma typically during birth resulting in a stretch injury to the infundibulum. 2. Congenital fetal maldevelopment of midline structures.