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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

Pediatric Endocrinology-Diabetology, and Radiology (C.G., M.H.) Units, Hôpital Robert Debré, 75019 Paris, France

Address all correspondence and requests for reprints to: Juliane Leger, M.D., Pediatric Endocrinology and Diabetes Unit, Hôpital Robert Debré, 48 boulevard Sérurier, 75019 Paris, France.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
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.

	Introduction

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ECTOPIC posterior pituitary hyperintense signal (EPP) is a marker of the so-called pituitary stalk transection syndrome, which was described after the introduction of magnetic resonance imaging (MRI). This syndrome is also characterized by the absence of pituitary stalk visibility and hypoplasia of the anterior hypophysis (1, 2). EPP may also be associated with a visible pituitary stalk (3). It has been shown that the sensitivity of MRI for visualizing the pituitary stalk is increased by gadolinium injection and that the presence of an extremely thin pituitary stalk cannot be definitely excluded without enhancement (4, 5).

Clinical data concerning this syndrome are limited, and it has been shown to be associated with either isolated GH deficiency (IGHD) or multiple anterior pituitary hormone deficiency (MPHD), but normal posterior pituitary function (6, 7, 8, 9, 10). Previous studies have suggested that MPHD is more frequent in cases showing EPP in association with the absence of pituitary stalk visibility, whereas IGHD is more common in cases showing EPP associated with visible pituitary stalk (3, 4, 5, 10, 11).

This study was therefore undertaken to 1) carefully investigate the anatomy of the pituitary hypothalamic region in a large group of GHD patients with EPP by MRI using gadolinium injection and 2) correlate the presence or the absence of visibility of the pituitary stalk with anterior pituitary function.

	Subjects and Methods

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All 25 children studied were selected from a large group of patients with GH deficiency (GHD) as having an ectopic hyperintense signal of the neurohypophysis on MRI. At the time of diagnosis, their mean chronological age was 4.9 ± 3.6 yr (from 0.1–11.8 yr; 9 females and 16 males) with a mean height of -2.9 ± 1.5 SD score and a mean height velocity of -2.5 ± 1.4 SD score. The mean bone age retardation over chronological age was 1.7 ± 1.2 yr. MRI evaluation was performed at the age of 8.7 ± 5.0 yr (range, 0.9–17.4 yr). Patients were 9.6 ± 4.8 yr old (range, 1–17.4 yr) at the last evaluation.

GHD was established by a GH peak of less than 10 ng/mL after two pharmacological tests. Complete evaluation of the other anterior pituitary functions was performed in all of the patients at diagnosis and was repeated during the follow-up if deemed necessary from clinical examination. TSH deficiency was diagnosed by a plasma T₄ level below 10 pmol/L and/or abnormal TSH stimulation after TRH administration (normal values for TSH were, respectively, 0.5–6, 14 ± 7, and <8 mU/L for basal, peak, and 120 min post-TRH administration). ACTH deficiency was diagnosed by morning basal plasma cortisol values below 60 ng/mL and below 150 ng/mL during insulin-induced hypoglycemia. When the morning cortisol value was higher than 100 ng/mL, the corticotropin reserve was not systematically evaluated. Hyperprolactinemia was defined as basal plasma PRL levels above 25 ng/mL. Evaluation of the pituitary-gonadal axis was mainly clinical. Patients were either prepubertal or considered nondeficient when spontaneous pubertal development occurred. Gonadotropin deficiency was suspected in patients who showed no pubertal development at a normal pubertal age, and this was assessed by measurement of plasma sex steroid levels and FSH and LH after GnRH treatment or after induced puberty. Diabetes insipidus was excluded in all patients by a 12-h water deprivation test.

MPHD was defined as GHD associated with abnormality of at least one of the other anterior pituitary hormones.

All MRI readings (0.5 Tesla Magnet, Gyrex, Elscint, Haïfa, Israël) were reviewed by the same investigator who was not aware of the endocrinological data. Three-millimeter thick slices were obtained on sagittal and coronal views of the pituitary area using a gradient echo T1-weighted sequence (TR = 400, TE = 18, = 90°), and axial slices of encephalus using a T2-weighted sequence (fast spin echo TR = 4000, TE = 100) were made.

Gadolinium injection was performed in 23 of 25 patients, as the pituitary stalk was visible without injection in 2 cases. The absence or presence of the pituitary stalk was recorded before and after gadolinium treatment as normal, absent, or thin. Patients were classified into 2 groups according to the presence (group 1) or the absence (group 2) of pituitary stalk visibility after gadolinium injection.

The height and surface aspect of the anterior pituitary were recorded, and its height was measured on a sagittal T1-weighted image, perpendicular to the sella turcica base and was judged to be either normal or small, according to previously published normative data in children (12). The precise localization of EPP was also established by MRI.

Associated brain abnormalities and adverse perinatal events, such as breech or forceps delivery, caesarean, prematurity, or neonatal distress (low Apgar score), and other associated malformations were also recorded.

Statistical analysis

Results were expressed as the mean ± SD. The Mann-Whitney U test was performed for comparison between groups. The percentages within the two groups were compared by the ² test.

	Results

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Patients were classified into 2 groups (groups I and II) according to the visibility of the pituitary stalk. As shown in Table 1, the pituitary stalk was identified in 14 patients (group I). In 2 of the 14 patients, the pituitary stalk was visible only after gadolinium injection. In 11 of the 14 cases, the pituitary stalk was described as thin, and this was particularly true for the 2 patients in whom the stalk was only visible after gadolinium injection. In 11 patients (group II), the pituitary stalk was not visible even after enhancement. The ectopic posterior hyperintense signal was found at the median eminence level in all group II patients and 6 of the 14 group I patients. Interestingly, the EPP was located at various points along the pituitary stalk in the other 8 patients (60%) of group I, at a lower proximal level of the pituitary stalk (n = 4), at the distal level of the pituitary stalk (n = 2; Fig. 1), or in the middle of the pituitary stalk (n = 2). The height of the adenohypophysis differed between the 2 groups (3.3 ± 1.3 vs. 2.2 ± 1.7 mm for groups I and II, respectively; P = 0.07), and when correlated with age and pubertal status, the prevalence of anterior pituitary hypoplasia was higher in group II than in group I patients (91% vs. 50%; P < 0.05).

View larger version (135K): [in this window] [in a new window]   Figure 1. Cerebral MRI (T1-weighted images). a, Sagittal slice; b, coronal slice: normal morphology of anterior pituitary and pituitary stalk is seen. The hyperintense signal of the posterior pituitary is in the normal location. The neurohypophysis is not visible on the coronal slice because the slice is anterior to it. c, Sagittal slice; d, coronal slice: a small anterior pituitary with no visible pituitary stalk after gadolinium injection is seen. The ectopic posterior pituitary hyperintense signal is at the median eminence (arrow). e, Sagittal slice; f, coronal slice: a small anterior pituitary with normal visibility of the pituitary stalk is seen. The ectopic posterior pituitary hyperintense signal is at a distal level of the pituitary stalk (arrow). The cerebellar vermis is small (star). A posterior callosal agenesis was found in this case (only the anterior part of the corpus callosum is seen; arrowhead).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Our study demonstrated in a large group of children with GHD and EPP that this anatomical abnormality may be associated in more than half of the cases with a visible pituitary stalk. Although excellent definition of the hypothalamic pituitary region is obtained with MRI, gadolinium injection is necessary for a better description of the stalk. In our series, two patients were classified in group I after gadolinium injection only, because the stalk was not visible without enhancement. In addition, the pituitary stalk was thin in several patients, and although visible without injection, the characterization was better after enhancement. Moreover, when the pituitary stalk was visible, the adenohypophysis was hypoplasic in only 50% of cases, but was hypoplasic in the vast majority of patients showing no visibility of the pituitary stalk. This classification by careful imaging is important because the pituitary anatomy and function were clearly different in the two groups. Only two patients with a visible pituitary stalk had MPHD, whereas it was the rule for most patients with no pituitary stalk visibility. Thus visualized by MRI using gadolinium, the pituitary stalk may be a sensitive marker of IGHD in EPP, whereas its absence constitutes a predictive factor of MPHD. These results are in accordance with those of previous studies that suggest, in a limited group of GH-deficient children with EPP, a correlation between anterior pituitary function and morphological anomalies of the hypothalamic-pituitary region on MRI, with a functional prognostic value of the visibility of the pituitary stalk (3, 4, 5, 10, 11). Although MRI has been proved to be a helpful tool in the diagnosis and prognosis of GHD (13, 14), the use of MRI with gadolinium injection has not been mentioned in most previous reports of patients with pituitary stalk transection syndrome (2, 7, 8, 9, 14), and consequently, it has been shown that one third of these patients present IGHD (9). Therefore, these data are not useful in correlating the status of the stalk with anterior pituitary function.

Moreover, we have shown that in cases with a visible pituitary stalk, the EPP is not always at the median eminence, but can be located at different levels (proximal, middle, or distal level) of the pituitary stalk, as was seen in 8 of the 14 group I patients (60% of cases). Anatomical variations in the location of the high intensity signal of the posterior pituitary seen on T1-weighted MRI may occur infrequently (11, 15) and have to be differentiated from a stalk-located lipoma (15, 16).

According to the present data, when the pituitary stalk is visible in EPP cases, the malformation generally does not affect the adenohypophysis and pituitary stalk. Whether this type of developmental anomaly is due to associated vascular change (8, 9) only or to a subtype of genetic defect (17) remains unclear. An ectopic posterior pituitary could result from defective neural migration during embryogenesis (7, 8, 10). The migration abnormality may be complete or partial, which could explain why EPP can be located at different parts of the stalk, as seen in some group I patients. This hypothesis of abnormal embryonic development is supported by the presence in our patients of associated midline structure malformations in both the brain and the rest of the body or by the presence of other malformations and/or a familial form of GHD (n = 1). Moreover, adverse perinatal events are not found consistently in our study, and the hypothesis of a traumatic origin during delivery for the syndrome (1, 2, 6), although possible in some patients, is not unanimously supported.

In conclusion, EPP represents an important marker of anterior pituitary structure and function, and patients should be investigated with a precise imaging technique. Those with the absence of pituitary stalk visibility are afflicted with a more severe form of adenohypophysis hypoplasia and with MPHD. These children need repeated reassessment of pituitary function when MPHD is not demonstrated at the first evaluation, as progression to complete anterior pituitary deficiency may occur progressively, even during the second or the third decade of life (4, 18). Those showing pituitary stalk visibility and IGHD during childhood seem to have a better endocrinological prognosis. Nevertheless, careful follow-up of these latter patients is also necessary, as the natural history of the disease is not established until adulthood. It should also be noted that this description results from a cross-sectional approach at one given time point. It may be that in some cases the pituitary stalk and adenohypophysis may undergo a secondary atrophy. If this is the case, our description is valid at a certain moment in the evolution of the disease, and groups I and II would thus not represent different entities.

Several transcription factors are implicated in early pituitary development and are involved in different developmental stages (17). Inactivating mutations of the genes for pituitary-specific transcription factor PIT 1 and Prophet of PIT 1 (PROP 1) have been identified in humans with combined pituitary hormone deficiency (19). We believe that in the near future a better knowledge of the different transcription factors involved in pituitary development will elucidate these profound abnormalities of the hypothalamo-pituitary axis. Therefore, a more precise description of patient phenotypes will aid in the future description of the disease at the molecular level.

Received January 25, 1999.

Revised April 1, 1999.

Accepted April 8, 1999.

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