Magnetic resonance imaging of CNS in 15 043 children with GH deficiency in KIGS (Pfizer International Growth Database)

in European Journal of Endocrinology
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  • 1 Department of Pediatrics, Pfizer Endocrine Care, University Children's Hospital, IRCCS Giannina Gaslini, University of Genova, Largo G. Gaslini 5, 16 147 Genova, Italy

Objectives

Neuroimaging has become an essential part of the diagnostic process in children with GH deficiency (GHD). The aim of the study was to document the frequency of neuroanatomical abnormalities in a very large cohort of children with GHD and to relate these findings to patient clinical characteristics.

Design and methods

Results of magnetic resonance imaging (MRI) were reported in 15 043 of 43 725 children with non-acquired GHD (idiopathic, neurosecretory dysfunction (NSD) and known congenital cause) who were enrolled in KIGS (Pfizer International Growth Database) between 1987 and 2011. Clinical characteristics of patients before GH treatment with normal MRI (idiopathic GHD (IGHD) and NSD) were compared with those of patients with abnormal pituitaries (hypoplasia, empty sella (ES), HME (hypoplastic anterior pituitary, missing pituitary stalk and ectopic posterior pituitary)).

Results

Abnormal MRIs were found in 4032 (26.8%) children, within which ES (n=1178 (7.8%)) and HME (n=1019 (6.8%)) were the most frequent findings. In 2361 children diagnosed as IGHD or NSD before MRI examination, anatomical abnormalities ((pituitary hypoplasia: n=974); (HME: n=459)) were documented. Patients with anatomical abnormalities had more severe characteristics of GHD: normal MRI < pituitary hypoplasia < ES < HME.

Conclusions

GHD is associated with a great variety of neuroanatomical abnormalities as identified by MRI. The investigation and evaluation of MRI need to be conducted in a structured mode. There is an association between anatomical and functional abnormalities of the pituitary.

Abstract

Objectives

Neuroimaging has become an essential part of the diagnostic process in children with GH deficiency (GHD). The aim of the study was to document the frequency of neuroanatomical abnormalities in a very large cohort of children with GHD and to relate these findings to patient clinical characteristics.

Design and methods

Results of magnetic resonance imaging (MRI) were reported in 15 043 of 43 725 children with non-acquired GHD (idiopathic, neurosecretory dysfunction (NSD) and known congenital cause) who were enrolled in KIGS (Pfizer International Growth Database) between 1987 and 2011. Clinical characteristics of patients before GH treatment with normal MRI (idiopathic GHD (IGHD) and NSD) were compared with those of patients with abnormal pituitaries (hypoplasia, empty sella (ES), HME (hypoplastic anterior pituitary, missing pituitary stalk and ectopic posterior pituitary)).

Results

Abnormal MRIs were found in 4032 (26.8%) children, within which ES (n=1178 (7.8%)) and HME (n=1019 (6.8%)) were the most frequent findings. In 2361 children diagnosed as IGHD or NSD before MRI examination, anatomical abnormalities ((pituitary hypoplasia: n=974); (HME: n=459)) were documented. Patients with anatomical abnormalities had more severe characteristics of GHD: normal MRI < pituitary hypoplasia < ES < HME.

Conclusions

GHD is associated with a great variety of neuroanatomical abnormalities as identified by MRI. The investigation and evaluation of MRI need to be conducted in a structured mode. There is an association between anatomical and functional abnormalities of the pituitary.

Introduction

GH deficiency (GHD) in children is defined as a reduced secretion of GH in accordance with age- and gender-specific normative values, which is causal to an impairment of growth. GHD can be both congenital and acquired. In the case of acquired GHD, hypothalamic–pituitary structures are affected/destroyed and can be identified by neuroimaging. However, the causes of congenitally diminished GH secretion are very different and anatomical abnormalities in the pituitary region may or may not be present or identifiable.

In fact, the neuroimaging findings in GHD mainly include the following: first, normal or hypoplastic pituitary gland/empty sella (ES) without anatomical abnormalities of the hypothalamus or pituitary stalk and secondly, moderate-to-severe (pituitary height ≤3 mm) hypoplastic pituitary gland with ectopic posterior pituitary located anywhere from the median eminence to the distal stalk (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25). Isolated GHD is more commonly observed in the first category while multiple pituitary hormone deficiencies (MPHD) occur more frequently in the second. An ES occurs in 10% of idiopathic GHD (IGHD) (12). MPHD may be associated with a variety of cerebral malformations such as Arnold-Chiari I and II, agenesis of the septum pellucidum, septo-optic dysplasia, vermis dysplasia, syringomyelia, absence of the internal carotid artery, dysgenesis of the corpus callosum, arachnoid cysts and tentorium anomalies with basilar impression (11, 20, 22, 25). The frequency of these radiological findings and their endocrine spectrum is variable. In particular, MPHD is more frequently associated with ectopic posterior pituitary and anterior pituitary hypoplasia than isolated GHD (2, 3, 5, 13, 14, 15, 17, 18, 20, 21, 22, 23, 24, 25). The variability between different studies can be ascribed to the degree of restriction in the studies' diagnostic criteria, to the diagnostic limits of GHD itself (transitory deficits, recovery, false positives, etc.) and/or to the lack of a convincing standard for a normal size of the pituitary gland among the pre-pubertal paediatric population. Idiopathic MPHD, except for a few genetic conditions of hypopituitarism (25), has been reported less frequently in association with anterior pituitary hypoplasia and normal posterior pituitary and pituitary stalk.

When KIGS (Pfizer International Growth Database) was established in 1987, many of the modern developments that nowadays are essential for the aetiological definition of GHD, such as molecular genetics and neuroimaging by means of magnetic resonance imaging (MRI), were not available. Today, an MRI of the CNS is considered a well-recognized diagnostic procedure in every child with proven impaired GH secretion. MRI is not invasive, the methodology is standardized and the inconvenience caused to the patient is continuously being reduced by shortening the time of imaging with modern scanning equipment. Nevertheless, MRI is expensive and often requires sedation of the child. Furthermore, the evaluation of findings in the CNS is challenging as it requires highly specialized expertise and thus often does not provide the desired high-quality representation of all anatomical details. In addition, some existing structural findings may remain difficult to verify due to technical limitations (e.g. resolution and impaired quality of images caused by patient movement) and developmental changes (e.g. size of pituitary gland). Moreover, structural lesions identified in MRI may not be reflected by pituitary function, i.e. hormonal abnormalities. All these aspects need to be considered when evaluating the results of CNS MRIs reported within KIGS. The aim of this first analysis of MRIs in KIGS patients is to document the frequency of neuroanatomical abnormalities as reported in daily clinical practice and to relate these findings to patient clinical characteristics.

Materials and methods

Patient data were retrieved from the KIGS database (26). KIGS was established in 1987 as a worldwide observational registry to monitor outcomes and safety of Genotropin (somatropin, Pfizer, Inc., Strängnäs, Sweden) treatment in children with short stature. KIGS is conducted in accordance with the Declaration of Helsinki (27).

All patients observed in KIGS are classified according to the primary cause of short stature (primary diagnosis) as standardized in the KIGS Aetiology Classification List (28). Patients with non-acquired GHD, classified as ‘IGHD’ (KIGS codes 1.1), ‘neurosecretory dysfunction (NSD)’ (KIGS code 1.2) or ‘GHD of known and congenital origin’ (KIGS codes 2.1.ff), were included in this analysis (Fig. 1). The latter category included aetiologies such as genetic causes of GHD, central malformations, complex syndromes with congenital GHD, prenatal infections, bio-inactive GH syndrome and functional GHD.

Figure 1
Figure 1

Flow chart showing the distribution of patients analysed.

Citation: European Journal of Endocrinology 168, 2; 10.1530/EJE-12-0801

Additionally, MRI reported in patients with short stature but normal GH secretion was reviewed. Those patients were diagnosed by KIGS investigators as idiopathic short stature (ISS) (KIGS codes 3.1.ff) and small for gestational age (SGA) (KIGS code 3.4.ff, 3.5.ff). Results of MRI investigations reported until January 2011 were analysed. All diagnostic procedures were performed at KIGS centres in accordance with local clinical practice. The final diagnoses, as reported to KIGS, were established by a local KIGS investigator. The extent of pituitary deficits was established and reported by the investigators without giving details of methodology of testing.

No specific study requirements governing either MRI techniques or radiological interpretation were provided by the KIGS guidelines. In other words, MRIs reported in KIGS were performed according to the clinical standards at each KIGS centre. More than 85% of MRIs were performed before starting GH treatment.

The MRI findings, as reported in KIGS, were subsequently reviewed by one author (M B Ranke) and verified (based on) or (with reference to) reported primary diagnosis (KIGS code). In the case of discrepancy, a relevant KIGS code was applied where possible or anatomical diagnosis was assigned based on the reported MRI finding.

The MRI findings included i) normal or hypoplastic pituitary gland without anatomical abnormalities of the hypothalamus or pituitary stalk and ii) moderate-to-severe (vertical height ≤3 mm) hypoplastic pituitary gland with ectopic posterior pituitary located anywhere from the median eminence to the distal stalk (25).

In order to investigate whether groups of patients with typical MRI findings were distinguished by auxological or biochemical characteristics, an analysis of the characteristics was carried out according to the principles common for KIGS data (29). The data analysis was descriptive. Group comparisons were undertaken by Student's t-test when applicable, accepting differences at the 1% level as significant. Additionally, characteristics of patients with various diagnostic groups were tested with ANOVA and post hoc testing, as applicable.

Results

Patients with presumed congenital GHD, as classified by the KIGS Aetiology Classification System (28), are presented in Table 1. Of the 43 725 children with KIGS codes 1.1, 1.2 and 2.1.ff, 37 792 (86.4%) were diagnosed by the KIGS investigators as ‘IGHD’, 2100 (4.8%) as having GHD associated with NSD and 3833 (8.8%) as having known and congenital GHD resulting from different causes. The performance of MRI was not taken into consideration in this classification.

Table 1

Reclassification of children with presumed congenital GHD within KIGS.

Patients with or without MRIPatients after MRI reviewPatients reported as IGHD or NSD reclassified according to MRI results
DiagnosisFrequency (n; %)Frequency (n; %)Frequency (n; %)
Idiopathic GHD (classical form; IGHD)37.792 (86.4)10.378 (68.9)
Neurosecretory dysfunction (NSD)2.100 (4.8)593 (3.9)
GHD of known and congenital origin3.833 (8.8)4.032 (26.8)2.338 (99.0)
Total 43.725 (100)15.043 (100.0)a2.361 (100)a
GHD of known and congenital origin
Central malformations (not restricted to the pituitary area)
 Septo-optic dysplasia776 (1.8)363 (2.4)1
 Missing (hypoplastic) corpus callosum226
 Abnormality of septum pellucidum41
 Solitary central maxillary incisor syndrome272
 Midline palate cleft syndrome117221
 GHD with anophthalmia1
 Other (not specified)515 (1.2)123 (0.8)48
 Total 1.435 (3.3)537 (3.6)57 (2.4)
Complex syndromes with GHD
 Fanconi pancytopenia344
 Rieger syndrome11
 Ectrodactyly-ectodermal dysplasia-clefting (EEC)5
 Others (not specified)10414
 Total14419
Abnormalities within/near the pituitary area
 Empty sellab805 (1.8)449 (3.0)96
 Partial empty sella7341
 Pituitary hypoplasia1.178 (7.8)974
 HMEc268 (0.6)1.019 (6.8)459
 Pituitary – non-functioning – microadenoma7673
 Thickening of pituitary stalk97
 Duplication of pituitary11
 Abnormal pituitary infundibulum64
 Arachnoid cyst748240
 Hypothalamic hamartoma75
 Cyst in anterior pituitary99
 Cyst in pars intermedia1110
 Rathke cyst3125
 Other cyst/benign structure in/near pituitary1713
 Total1.147 (2.6)2.968 (19.7)1.757 (74.4)
CNS abnormalities outside the pituitary area
 Congenital hydrocephalus903312
 Chiari I malformation5942
 Other Chiari malformation22
 Dandy–Walker malformation32
 Leucomalacia1110
 Syringomyelia33
 Pachygyria1
 Pineal cyst3634
 Cavum septi pellucidi51
 Cyst other part brain (not arachnoidea)1512
 Cyst outside brain's structures55
 Vessel anomalies in cerebrum108
 Other brain structure anomalies (not specified)9577
 Total90 (0.2)278 (1.8)208 (8.8)
Prenatal infections, bio-inactive GH, functional GHD,  genetic causes of GHD, malformations outside  neurocranium1.017 23021
Other acquired GHD and short stature40a23a
Total1.017 (2.3)270 (1.8)44 (1.9)
Total43.725 (100)15.043 (100.0)2.361 (100)

These patients were reclassified as acquired GHD or other short stature according to the KIGS Classification List.

Empty sella (including pituitary aplasia; pituitary aplasia is well-defined life-threatening condition of neonatal onset).

Hypoplastic anterior pituitary, missing stalk and ectopic posterior pituitary.

MRI investigations were performed in 15 043 children, of which 12 434 (82.66%) were diagnosed as IGHD, 662 (4.40%) as NSD and 1947 (12.94%) as GHD due to known and congenital causes. When the reported MRI findings were considered, the number of patients with IGHD reduced to 10 378 (68.89%), the number of NSD reduced to 593 (3.94%), while the number of children with anatomical anomalies in the MRI increased to 4032 (26.80%). In many instances, the KIGS Aetiology Classification System did not include a specific code for the respective anatomical abnormality. In particular, there was no specific code for hypoplasia of the pituitary (HP) with no other structural anomaly of the brain, although this was the largest single reported anomaly within the group of known disorders (n=1.178; (7.83%)). There was, however, a great variety of findings indicating abnormalities both within and outside the hypothalamic–pituitary region. MRI abnormalities were observed in 2361 children primarily classified as IGHD or NSD. Of these children, the most frequent MRI findings were pituitary hypoplasia (n=974) and HME (n=459). The analysis of MRI findings in patients classified as ISS and SGA for a total of 1844 patients showed that 151 subjects (8.2%) displayed abnormalities that were restricted to the pituitary area, with pituitary hypoplasia (n=86) and HME (n=20) being the most common ones.

The background and clinical characteristics of patient groups, stratified by major aetiological classifications as based on the results of MRIs performed before and at the start of GH treatment, are presented in Table 2. The groups analysed were as follows: i) IGHD (code 1.1) without pathological images; ii) NSD (code 1.2) without pathological images; iii) HP (no KIGS code available); iv) ES (code 2.1.2.2); and v) HME (code 2.1.2.7). In comparison with IGHD and NSD, patients with ES and HME had more severe GHD, showed a higher frequency of MPHD, had a lesser reduction of birth weight, were more often born in breech position, had less short parents and were younger and shorter at the start of GH treatment. Patients with HP demonstrated characteristics that were in-between those of the patients with IGHD and NSD and the patients with ES and HME. The gender distribution was the same in all groups. The groups with no differences in patient characteristics are presented in Table 2. Interestingly, comparisons between patients with HP and ES showed no differences in birth weight SDS, proportion of birth by breech, height SDS at GH start and distance to midparental height SDS.

Table 2

Characteristics of patients with various diagnoses based on MRI findings before and at the start of GH.

Diagnosis

KIGS code
NSD normal MRI (A)

1.2

Median (10./90. Perc)
IGHD normal MRI (B)

1.1

Median (10./90. Perc)
Pituitary hypoplasia (C)

2.1.2.8

Median (10./90. Perc)
Empty sella (D)

2.1.2.2

Median (10./90. Perc)
HME (E)

2.1.2.7

Median (10./90. Perc)
No differences between groups (A–E)

P>0.01
Parameter (n)593 10.378 1.1784491.018
Sex male (%)66.767.967.365.569.1All
Birth weight (SDS)−0.84 (−2.22/0.52)−0.69 (−2.15/0.78)−0.54 (−2.11/0.95)−0.39 (−1.99/1.18)−0.39 (−1.82/1.08)CD, DE
Birth by breech (%)0.82.24.23.87.5CD
maxGH (μg/l)13.8 (7.9/30.2)6.6 (2.2/10.7)4.9 (0.6/10.9)3.1 (0.3/9.0)3.1 (0.5/9.3)BC, DE
MPHD (%)11.811.125.052.149.8AB, DE
At GH start
 Age (years)10.9 (5.7/14.4)11.0 (5.0/14.7)9.7 (3.5/15.1)8.2 (1.2/14.7)6.2 (1.4/14.1)AB
 Height (SDS)−2.72 (−3.80/−1.83)−2.70 (−3.97/−1.64)−3.16 (−5.04/−1.86)−3.13 (−5.40/−1.50)−3.26 (−4.98/−1.38)AB, CD, DE
 Ht – MPH (SDS)−1.72 (3.29/−0.12)−1.55 (−3.25/−0.08)−2.12 (−4.49/−0.44)−2.34 (−4.67/−0.43)−2.71 (−4.46/−0.65)AB, CD

Discussion

We aimed to define the neuroimaging phenotype in a very large database of GHD children. In addition, we sought to identify indications for pituitary imaging and the prevalence of hypothalamic–pituitary and CNS abnormalities associated with hypopituitarism.

Notably, different aetiologies are diagnosed by MRI parameters alone or by a combination of endocrine values and neuroimaging (25, 28): in particular, some specific abnormalities, such as posterior pituitary ectopia and pituitary stalk agenesis, associated with IGHD are identified by imaging of hypothalamic–pituitary anatomy. Indeed, the first report about the latter MRI findings in children with GHD was published in 1987 (1), and since then, MRI has become a standard diagnostic technique used to identify anatomical causes of GHD, which was previously diagnosed by anthropometrical and biochemical methods alone (20, 22, 25).

Ideally, the best scanning techniques to obtain an optimal amount of information are those that provide 2–3 mm thick, high-resolution T1- and T2-weighted MRI images (Fig. 2) in the coronal and sagittal planes (22, 30, 31). Coronal scans allow for the visualization of the pituitary gland, stalk, chiasm and parasellar regions while sagittal images are best suited for the evaluation of the midline plane. Recently, high-resolution, heavily T2-weighted sagittal images/T2-DRIVE (25), or fast imaging employing steady state acquisition sequence obtained at sub-millimetre thickness, provide an excellent visualization of the suprasellar region and are especially suited to the assessment of the pituitary stalk without using contrast medium. Axial T2-weighted fluid attenuation inversion recovery images covering the entire brain are recommended in order to screen for additional abnormalities (25). The main limitation of our study is related to a lack of MRI standardization as there are neither KIGS guidelines regarding the way MRIs are performed (e.g. technical requirements, timing of examination and patient selection) nor how they are evaluated and classified. However, we believe that as our study is based on a very large patient cohort, this limitation is outweighed.

Figure 2
Figure 2

Normal sellar region. (A) Sagittal T1-weighted image. The posterior pituitary lobe (PPL), physiologically bright on T1-weighted image, anterior pituitary lobe (APL), pituitary stalk (PS), median eminence (ME), optic chiasm (OC), tuber cinereum (TC), and mammillary bodies (MB) are clearly visible. (B) Anterior pituitary hypoplasia Small anterior pituitary lobe housed within a small pituitary fossa (arrow). Normal posterior lobe (arrowhead) and pituitary stalk (double arrowheads). (C) Hypoplastic anterior lobe (arrow). Small and ectopic posterior lobe, located at the level of the median eminence (arrowhead). The pituitary stalk is not visible (double arrowheads).

Citation: European Journal of Endocrinology 168, 2; 10.1530/EJE-12-0801

As shown by the KIGS database, MRI appeared to be largely used as a diagnostic tool for screening pituitary abnormalities in children with GHD by paediatric endocrinologists in daily clinical practice. From this, 73.2% of patients were identified as having a normal pituitary gland, 7.8% as having pituitary hypoplasia, 3.0% as having ES and 6.8% as having HME. It is worth noting, on the one hand, that it is not known within KIGS how ‘hypoplasia’ of the pituitary was defined in each patient and, on the other, that there are particular difficulties in measuring and establishing the size of the anterior pituitary, which varies with age, sex, pubertal status and shape (7, 8, 22, 25, 32). As ES represents an ‘epiphenomenon’ of pituitary hypoplasia (3), the latter finding appears very likely to be the most common MRI abnormality in GHD in our study.

Overall, the prevalence of pituitary abnormalities in the paediatric population undergoing neuroimaging for reasons other than pituitary disease is lacking and data are not available on pituitary incidentalomas (33). Indeed, previous studies have reported the prevalence of ES to be about 5–9% for all ages, with an increase in prevalence with age (34, 35). Most frequently, this anomaly is an incidental finding of little or no clinical importance, the only exception being pseudotumour cerebri in which clinical symptoms and additional MRI findings may confirm the diagnosis (36). Additionally, the large study published by Jordan et al. (37) identified 63 (6.6%) children with 68 incidental intracranial MRI findings in the total cohort of 953 children with sickle cell anaemia screened with MRI of the brain for the Silent Infarct Transfusion Trial. Among the children with abnormalities was one child in whom intrasellar Rathke cleft cyst was detected and no other abnormalities of hypothalamus/pituitary region.

Indeed, among our 1844 patients with ISS and SGA, 151 displayed pituitary abnormalities, and pituitary hypoplasia was the most common. Surprisingly, HME was documented in 20 of them and equally distributed between ISS and SGA patients. This raise the question about the misclassification bias based on GH response to stimulation tests where false-negative results have been recently reported in patients with structural hypothalamic–pituitary abnormalities (38).

Due to the small size of the pituitary structures and in the absence of systematic use of contrast medium enhancement (13, 25), it may not always be possible to obtain a complete image of the pituitary stalk, particularly at the given resolution of the images and even in the presence of small moving artefacts. Thus, the diagnoses of ES and HME are not always absolutely certain. This observation is strengthened by the fact that the frequency of MPHD among patients with ES was not dissimilar to that of patients with HME. Certainly, ectopic posterior pituitary and pituitary stalk agenesis are more commonly associated with severe pituitary hormone defects compared with those with either pituitary hypoplasia or ES who had a more preserved hypothalamic–pituitary region and function (3, 12, 13, 14, 17, 18, 22). In addition, the higher frequency of breech presentation in patients with HME is in line with what has been previously reported in the presence of structural hypothalamic–pituitary abnormalities (1, 3, 10, 11).

There is no doubt that MRI investigations play a major role in the diagnostic process of GHD. However, anatomical and functional findings a priori do not always mirror each other. Biochemical investigations to define partial pituitary deficits are probably even less standardized than MRI. Consequently, there is a constant debate about which investigations, be they anthropometrical, biochemical, imaging or genetic, are required to firmly establish the diagnosis of GHD, particularly permanent GHD, in childhood and adolescence (39). Although genetic analyses may in the future help define an aetiological diagnosis when anatomical abnormalities in the CNS are observed (40, 41, 42), it is probably the case that all investigations complement each other and need to be done in a standardized manner according to the best available techniques and with the greatest possible expertise.

Declaration of interest

M Maghnie has no conflict of interest to declare. M-K Häggström and A Lindberg are full-time employees of Pfizer Health AB. M B Ranke is a member of the International KIGS Board and received lecture fees from Pfizer, Eli Lilly, Novo Nordisk and Ipsen.

Funding

KIGS database is funded by Pfizer, Inc. No authors were paid for their contributions to this manuscript.

Acknowledgements

The authors express their thanks and appreciation to the clinicians who provided the data on their patients.

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    • Export Citation
  • 20

    Maghnie M, Ghirardello S, Genovese E. Magnetic resonance imaging of the hypothalamus–pituitary unit in children suspected of hypopituitarism: who, how and when to investigate. Journal of Endocrinological Investigation 2004 27 496509.

    • Search Google Scholar
    • Export Citation
  • 21

    Tauber M, Chevrel J, Diene G, Moulin P, Jouret B, Oliver I, Pienkowski C, Sevely A. Long-term evolution of endocrine disorders and effect of GH therapy in 35 patients with pituitary stalk interruption syndrome. Hormone Research 2005 64 266273. (doi:10.1159/000089425).

    • Search Google Scholar
    • Export Citation
  • 22

    Maghnie M, di Iorgi N, Rossi A, Gastaldi R, Tortori-Donati P & Lorini R. Neuroimaging in growth hormone deficiciency. In Growth Hormone Therapy in Pediatrics – 20 Years of KIGS, 1st edn, ch 9, pp 93–107. Eds MB Ranke, DA Price & EO Reiter. Basel: Karger, 2007

  • 23

    Murray PG, Hague C, Fafoula O, Patel L, Raabe AL, Cusick C, Hall CM, Wright NB, Amin R, Clayton PE. Associations with multiple pituitary hormone deficiency in patients with an ectopic posterior pituitary gland. Clinical Endocrinology 2008 69 597602. (doi:10.1111/j.1365-2265.2008.03236.x).

    • Search Google Scholar
    • Export Citation
  • 24

    Murray PG, Hague C, Fafoula O, Gleeson H, Patel L, Banerjee I, Raabe AL, Hall CM, Wright NB, Amin R. Likelihood of persistent GH deficiency into late adolescence: relationship to the presence of an ectopic or normally sited posterior pituitary gland. Clinical Endocrinology 2009 71 215219. (doi:10.1111/j.1365-2265.2009.03554.x).

    • Search Google Scholar
    • Export Citation
  • 25

    Di Iorgi N, Allegri AE, Napoli F, Bertelli E, Olivieri I, Rossi A, Maghnie M. The use of neuroimaging for assessing disorders of pituitary development. Clinical Endocrinology 2012 76 607. (doi:10.1111/j.1365-2265.2012.04360.x).

    • Search Google Scholar
    • Export Citation
  • 26

    Wilton P. KIGS: structure and organization. In Growth Hormone Therapy in Pediatrics – 20 Years of KIGS, 1st edn, ch 1, pp 1–5. Eds MB Ranke, DA Price & EO Reiter. Basel: Karger, 2007

  • 27

    Riis P. Thirty years of bioethics: the Helsinki Declaration 1964–2003. New Review of Bioethics 2003 1 1525. (doi:10.1080/1740028032000131396).

    • Search Google Scholar
    • Export Citation
  • 28

    Ranke MB. The KIGS aetiology classification system. In Growth Hormone Therapy in Pediatrics – 20 Years of KIGS, 1st edn, ch 5, pp 29–37. Eds MB Ranke, DA Price & EO Reiter. Basel: Karger, 2007

  • 29

    Lindberg A & Ranke MB. Data analyses within KIGS. In Growth Hormone Therapy in Pediatrics – 20 Years of KIGS, 1st edn, ch 4, pp 23–28. Eds MB Ranke, DA Price & EO Reiter. Basel: Karger, 2007

  • 30

    Barkovich JA. Pediatric Neuroimaging, Techniques and methods in pediatric neuroimaging, pp 1–14. Philadelphia, USA: Lippincott Williams & Wilkins, 2005

  • 31

    Delman BN, Fatterpekar GM, Law M, Naidich TP. Neuroimaging for the pediatric endocrinologist. Pediatric Endocrinology Reviews 2008 5 (Suppl 2) 708719.

    • Search Google Scholar
    • Export Citation
  • 32

    Binder G, Nagel BH, Ranke MB, Mullis PE. Isolated GH deficiency (IGHD) type II: imaging of the pituitary gland by magnetic resonance reveals characteristic differences in comparison with severe IGHD of unknown origin. European Journal of Endocrinology 2002 147 755760. (doi:10.1530/eje.0.1470755).

    • Search Google Scholar
    • Export Citation
  • 33

    Freda PU, Beckers AM, Katznelson L, Molitch ME, Montori VM, Post KD, Vance ML, Endocrine Society . Pituitary incidentaloma: an endocrine society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2011 96 894904. (doi:10.1210/jc.2010-1048).

    • Search Google Scholar
    • Export Citation
  • 34

    Bjerre P. The empty sella. A reappraisal of etiology and pathogenesis. Acta Neurologica Scandinavica. Supplementum 1990 130 125.

  • 35

    Cacciari E, Zucchini S, Ambrosetto P, Tani G, Carlà G, Cicognani A, Pirazzoli P, Sganga T, Balsamo A, Cassio A. Empty sella in children and adolescents with possible hypothalamic–pituitary disorders. Journal of Clinical Endocrinology and Metabolism 1994 78 767771. (doi:10.1210/jc.78.3.767).

    • Search Google Scholar
    • Export Citation
  • 36

    Degnan AJ, Levy LM. Pseudotumor cerebri: brief review of clinical syndrome and imaging findings. AJNR. American Journal of Neuroradiology 2011 32 19861993. (doi:10.3174/ajnr.A2404).

    • Search Google Scholar
    • Export Citation
  • 37

    Jordan LC, McKinstry RC III, Kraut MA, Ball WS, Vendt BA, Casella JF, DeBaun MR, Strouse JJ. Incidental findings on brain magnetic resonance imaging of children with sickle cell disease. Pediatrics 2010 126 5361. (doi:10.1542/peds.2009-2800).

    • Search Google Scholar
    • Export Citation
  • 38

    Secco A, di Iorgi N, Napoli F, Calandra E, Ghezzi M, Frassinetti C, Parodi S, Casini MR, Lorini R, Loche S. The glucagon test in the diagnosis of growth hormone deficiency in children with short stature younger than 6 years. Journal of Clinical Endocrinology and Metabolism 2009 94 42514257. (doi:10.1210/jc.2009-0779).

    • Search Google Scholar
    • Export Citation
  • 39

    Tenenbaum-Rakover Y, Hujeirat Y, Admoni O, Khayat M, Allon-Shalev S, Hess O. Can auxology, IGF-I and IGFBP-3 measurements followed by MRI and genetic tests replace GH stimulation tests in the diagnosis of GH deficiency in children? Journal of Pediatric Endocrinology and Metabolism 2010 23 387394. (doi:10.1515/jpem.2010.060).

    • Search Google Scholar
    • Export Citation
  • 40

    McCabe MJ, Alatzoglou KS, Dattani MT. Septo-optic dysplasia and other midline defects: the role of transcription factors: HESX1 and beyond. Best Practice & Research. Clinical Endocrinology & Metabolism 2011 25 115124. (doi:10.1016/j.beem.2010.06.008).

    • Search Google Scholar
    • Export Citation
  • 41

    Pfäffle R, Klammt J. Pituitary transcription factors in the aetiology of combined pituitary hormone deficiency. Best Practice & Research. Clinical Endocrinology & Metabolism 2011 25 4360. (doi:10.1016/j.beem.2010.10.014).

    • Search Google Scholar
    • Export Citation
  • 42

    Kelberman D, Dattani MT. Hypopituitarism oddities: congenital causes. Hormone Research 2007 68 (Suppl 5) 138144. (doi:10.1159/000110610).

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    Flow chart showing the distribution of patients analysed.

  • View in gallery

    Normal sellar region. (A) Sagittal T1-weighted image. The posterior pituitary lobe (PPL), physiologically bright on T1-weighted image, anterior pituitary lobe (APL), pituitary stalk (PS), median eminence (ME), optic chiasm (OC), tuber cinereum (TC), and mammillary bodies (MB) are clearly visible. (B) Anterior pituitary hypoplasia Small anterior pituitary lobe housed within a small pituitary fossa (arrow). Normal posterior lobe (arrowhead) and pituitary stalk (double arrowheads). (C) Hypoplastic anterior lobe (arrow). Small and ectopic posterior lobe, located at the level of the median eminence (arrowhead). The pituitary stalk is not visible (double arrowheads).

  • 1

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    Cacciari E, Zucchini S, Ambrosetto P, Tani G, Carlà G, Cicognani A, Pirazzoli P, Sganga T, Balsamo A, Cassio A. Empty sella in children and adolescents with possible hypothalamic–pituitary disorders. Journal of Clinical Endocrinology and Metabolism 1994 78 767771. (doi:10.1210/jc.78.3.767).

    • Search Google Scholar
    • Export Citation
  • 13

    Maghnie M, Genovese E, Villa A, Spagnolo L, Campan R, Severi F. 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 1996 45 281290. (doi:10.1046/j.1365-2265.1996.00789.x).

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    Nagel BH, Palmbach M, Petersen D, Ranke MB. Magnetic resonance images of 91 children with different causes of short stature: pituitary size reflects growth hormone secretion. European Journal of Pediatrics 1997 156 758763. (doi:10.1007/s004310050707).

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    Arrigo T, De Luca F, Maghnie M, Blandino A, Lombardo F, Messina MF, Wasniewska M, Ghizzoni L, Bozzola M. Relationships between neuroradiological and clinical features in apparently idiopathic hypopituitarism. European Journal of Endocrinology 1998 139 8488. (doi:10.1530/eje.0.1390084).

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  • 18

    Chen S, Leger J, Garel C, Hassan M, Czernichow P. 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. Journal of Clinical Endocrinology and Metabolism 1999 84 24082413. (doi:10.1210/jc.84.7.2408).

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  • 19

    Arends NJ, V d Lip W, Robben SG, Hokken-Koelega AC. MRI findings of the pituitary gland in short children born small for gestational age (SGA) in comparison with growth hormone-deficient (GHD) children and children with normal stature. Clinical Endocrinology 2002 57 719724. (doi:10.1046/j.1365-2265.2002.01605.x).

    • Search Google Scholar
    • Export Citation
  • 20

    Maghnie M, Ghirardello S, Genovese E. Magnetic resonance imaging of the hypothalamus–pituitary unit in children suspected of hypopituitarism: who, how and when to investigate. Journal of Endocrinological Investigation 2004 27 496509.

    • Search Google Scholar
    • Export Citation
  • 21

    Tauber M, Chevrel J, Diene G, Moulin P, Jouret B, Oliver I, Pienkowski C, Sevely A. Long-term evolution of endocrine disorders and effect of GH therapy in 35 patients with pituitary stalk interruption syndrome. Hormone Research 2005 64 266273. (doi:10.1159/000089425).

    • Search Google Scholar
    • Export Citation
  • 22

    Maghnie M, di Iorgi N, Rossi A, Gastaldi R, Tortori-Donati P & Lorini R. Neuroimaging in growth hormone deficiciency. In Growth Hormone Therapy in Pediatrics – 20 Years of KIGS, 1st edn, ch 9, pp 93–107. Eds MB Ranke, DA Price & EO Reiter. Basel: Karger, 2007

  • 23

    Murray PG, Hague C, Fafoula O, Patel L, Raabe AL, Cusick C, Hall CM, Wright NB, Amin R, Clayton PE. Associations with multiple pituitary hormone deficiency in patients with an ectopic posterior pituitary gland. Clinical Endocrinology 2008 69 597602. (doi:10.1111/j.1365-2265.2008.03236.x).

    • Search Google Scholar
    • Export Citation
  • 24

    Murray PG, Hague C, Fafoula O, Gleeson H, Patel L, Banerjee I, Raabe AL, Hall CM, Wright NB, Amin R. Likelihood of persistent GH deficiency into late adolescence: relationship to the presence of an ectopic or normally sited posterior pituitary gland. Clinical Endocrinology 2009 71 215219. (doi:10.1111/j.1365-2265.2009.03554.x).

    • Search Google Scholar
    • Export Citation
  • 25

    Di Iorgi N, Allegri AE, Napoli F, Bertelli E, Olivieri I, Rossi A, Maghnie M. The use of neuroimaging for assessing disorders of pituitary development. Clinical Endocrinology 2012 76 607. (doi:10.1111/j.1365-2265.2012.04360.x).

    • Search Google Scholar
    • Export Citation
  • 26

    Wilton P. KIGS: structure and organization. In Growth Hormone Therapy in Pediatrics – 20 Years of KIGS, 1st edn, ch 1, pp 1–5. Eds MB Ranke, DA Price & EO Reiter. Basel: Karger, 2007

  • 27

    Riis P. Thirty years of bioethics: the Helsinki Declaration 1964–2003. New Review of Bioethics 2003 1 1525. (doi:10.1080/1740028032000131396).

    • Search Google Scholar
    • Export Citation
  • 28

    Ranke MB. The KIGS aetiology classification system. In Growth Hormone Therapy in Pediatrics – 20 Years of KIGS, 1st edn, ch 5, pp 29–37. Eds MB Ranke, DA Price & EO Reiter. Basel: Karger, 2007

  • 29

    Lindberg A & Ranke MB. Data analyses within KIGS. In Growth Hormone Therapy in Pediatrics – 20 Years of KIGS, 1st edn, ch 4, pp 23–28. Eds MB Ranke, DA Price & EO Reiter. Basel: Karger, 2007

  • 30

    Barkovich JA. Pediatric Neuroimaging, Techniques and methods in pediatric neuroimaging, pp 1–14. Philadelphia, USA: Lippincott Williams & Wilkins, 2005

  • 31

    Delman BN, Fatterpekar GM, Law M, Naidich TP. Neuroimaging for the pediatric endocrinologist. Pediatric Endocrinology Reviews 2008 5 (Suppl 2) 708719.

    • Search Google Scholar
    • Export Citation
  • 32

    Binder G, Nagel BH, Ranke MB, Mullis PE. Isolated GH deficiency (IGHD) type II: imaging of the pituitary gland by magnetic resonance reveals characteristic differences in comparison with severe IGHD of unknown origin. European Journal of Endocrinology 2002 147 755760. (doi:10.1530/eje.0.1470755).

    • Search Google Scholar
    • Export Citation
  • 33

    Freda PU, Beckers AM, Katznelson L, Molitch ME, Montori VM, Post KD, Vance ML, Endocrine Society . Pituitary incidentaloma: an endocrine society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2011 96 894904. (doi:10.1210/jc.2010-1048).

    • Search Google Scholar
    • Export Citation
  • 34

    Bjerre P. The empty sella. A reappraisal of etiology and pathogenesis. Acta Neurologica Scandinavica. Supplementum 1990 130 125.

  • 35

    Cacciari E, Zucchini S, Ambrosetto P, Tani G, Carlà G, Cicognani A, Pirazzoli P, Sganga T, Balsamo A, Cassio A. Empty sella in children and adolescents with possible hypothalamic–pituitary disorders. Journal of Clinical Endocrinology and Metabolism 1994 78 767771. (doi:10.1210/jc.78.3.767).

    • Search Google Scholar
    • Export Citation
  • 36

    Degnan AJ, Levy LM. Pseudotumor cerebri: brief review of clinical syndrome and imaging findings. AJNR. American Journal of Neuroradiology 2011 32 19861993. (doi:10.3174/ajnr.A2404).

    • Search Google Scholar
    • Export Citation
  • 37

    Jordan LC, McKinstry RC III, Kraut MA, Ball WS, Vendt BA, Casella JF, DeBaun MR, Strouse JJ. Incidental findings on brain magnetic resonance imaging of children with sickle cell disease. Pediatrics 2010 126 5361. (doi:10.1542/peds.2009-2800).

    • Search Google Scholar
    • Export Citation
  • 38

    Secco A, di Iorgi N, Napoli F, Calandra E, Ghezzi M, Frassinetti C, Parodi S, Casini MR, Lorini R, Loche S. The glucagon test in the diagnosis of growth hormone deficiency in children with short stature younger than 6 years. Journal of Clinical Endocrinology and Metabolism 2009 94 42514257. (doi:10.1210/jc.2009-0779).

    • Search Google Scholar
    • Export Citation
  • 39

    Tenenbaum-Rakover Y, Hujeirat Y, Admoni O, Khayat M, Allon-Shalev S, Hess O. Can auxology, IGF-I and IGFBP-3 measurements followed by MRI and genetic tests replace GH stimulation tests in the diagnosis of GH deficiency in children? Journal of Pediatric Endocrinology and Metabolism 2010 23 387394. (doi:10.1515/jpem.2010.060).

    • Search Google Scholar
    • Export Citation
  • 40

    McCabe MJ, Alatzoglou KS, Dattani MT. Septo-optic dysplasia and other midline defects: the role of transcription factors: HESX1 and beyond. Best Practice & Research. Clinical Endocrinology & Metabolism 2011 25 115124. (doi:10.1016/j.beem.2010.06.008).

    • Search Google Scholar
    • Export Citation
  • 41

    Pfäffle R, Klammt J. Pituitary transcription factors in the aetiology of combined pituitary hormone deficiency. Best Practice & Research. Clinical Endocrinology & Metabolism 2011 25 4360. (doi:10.1016/j.beem.2010.10.014).

    • Search Google Scholar
    • Export Citation
  • 42

    Kelberman D, Dattani MT. Hypopituitarism oddities: congenital causes. Hormone Research 2007 68 (Suppl 5) 138144. (doi:10.1159/000110610).