Endokrynologia Pediatryczna Pediatric Endocrinology

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1 Vol. 3/2003 Nr 2(3) Endokrynologia Pediatryczna Pediatric Endocrinology Pituitary size and growth hormone (GH) secretion in short children; a relationship between pituitary size and the first-year response to GH therapy in children with GH deficiency Wielkość przysadki i wydzielanie hormonu wzrostu u dzieci z niedoborem wzrostu; zależność pomiędzy wielkością przysadki a odpowiedzią na hormon wzrostu w pierwszym roku leczenia u dzieci z niedoborem hormonu wzrostu 1 Maciej Hilczer, 1 Joanna Smyczyńska, 2 Danuta Kaniewska, 1 Renata Stawerska, 1 Andrzej Lewiński 1 Department of Endocrinology and Isotope Therapy, Institute of Endocrinology, Medical University of Łódź at Polish Mother`s Memorial Hospital Research Institute 2 Magnetic Resonance and Computer Tomography Division, Polish Mother`s Memorial Hospital Research Institute, Łódź, Poland Adres do korespondencji: Maciej Hilczer, Department of Endocrinology and Isotope Therapy, Institute of Endocrinology, Medical University of Łódź at Polish Mother`s Memorial Hospital Research Institute Key words: pituitary height, growth hormone deficiency, growth hormone therapy Słowa kluczowe: wysokość przysadki, niedobór hormonu wzrostu, leczenie hormonem wzrostu STRESZCZENIE/ABSTRACT Introduction: Pituitary height (PHt) determination in magnetic resonance imaging (MRI) provides convenient information for pituitary size assessment. Objective: The aim of the study was an evaluation of GH secretion, depending on pituitary size in short children, and relations between the pituitary size and the first-year response to GH therapy in children with GH deficiency (GHD). Material and methods: The analysis comprised 135 children (104 boys) with short stature. In all the patients GH secretion was assessed, and PHt was measured. Pituitary hypoplasia was diagnosed when PHt was < -2.0 SD for the chronological age (CA) and/or for height age (HA). The patients were classified according to GH secretion, PHt and anatomical details of hypothalamic-hypophyseal region (HHR). Results: Significant differences in PHt SDS were observed among all the groups of patients with multiple pituitary hormone deficiency (MPHD), severe isolated GHD (SIGHD), partial isolated GHD (PIGHD) and idiopathic short stature (ISS), except that between MPHD and SIGHD. A correlation between PHt SDS (for both CA and HA) and GH peak was observed. Significant differences in both GH peak and height SDS before treatment were observed among particular groups of patients, divided, according to PHt. After one year of GH therapy, the observed differences in height SDS became insignificant. Growth improvement was greater in patients with more severe pituitary hypoplasia. In patients with complete form of PSIS, GH secretion and PHt SDS were the lowest, and MPHD was observed in the majority of cases, whereas most children in other gro- Vol. 2/2003, Nr 1(2) 9

2 Praca oryginalna Endokrynol. Ped., 3/2003;2(3):9-19 ups presented with isolated GHD. After one year of GH therapy the obtained growth improvement was the highest in patients with PSIS. Conclusion: In children with short stature, a strong positive correlation is observed between the pituitary size and GH secretion, together with a negative correlation between GH secretion rate and GH therapy effectiveness. The absence of pituitary stalk visibility in MRI is connected with the most severe forms of anterior pituitary hypoplasia and the most severe GH deficiency, and is, generally, associated with MPHD. The best first-year effects of GH therapy were observed in children with complete form of PSIS. Celem pracy była ocena związku pomiędzy wielkością przysadki i wydzielaniem hormonu wzrostu (GH) u dzieci z niedoborem wzrostu oraz ocena zależności pomiędzy wysokością przysadki a przyrostem wysokości ciała w pierwszym roku leczenia preparatem GH u pacjentów z somatotropinową niedoczynnością przysadki. Pacjenci i metody: Analizą objęto 135 dzieci (104 chłopców) z niedoborem wzrostu, u których oceniono wydzielanie GH oraz dokonano pomiaru wysokości przysadki w badaniu MRJ. Hipoplazję przysadki rozpoznawano, gdy wysokość przysadki była < -2,0 SD dla wieku metrykalnego i wieku wzrostowego. Pacjentów podzielono na grupy zależności od wydzielania GH, wysokości przysadki oraz anatomicznych zmian w okolicy podwzgórzowo-przysadkowej. Wyniki: Obserwowano statystycznie znamienne różnice w wysokości przysadek w grupach pacjentów z: wielohormonalną niedoczynnością przysadki, ciężką i częściową somatotropinową niedoczynnością przysadki oraz z idiopatycznym niskim wzrostem. Stwierdzono korelacje pomiędzy wysokością przysadki (PHt SDS) a szczytem wydzielania GH zarówno w odniesieniu do wieku chronologicznego, jak i wzrostowego. Wydzielanie GH i SDS wzrostu różniły się znamiennie w grupach pacjentów wyodrębnionych ze względu na PHt SDS. Po rocznym leczeniu preparatem GH obserwowane różnice SDS wzrostu uległy zmniejszeniu, a największą poprawę wzrastania zanotowano w grupie pacjentów z zespołem przerwania szypuły przysadki (PSIS). Wnioski: Stwierdzono silną dodatnią korelację pomiędzy wysokością przysadki a wydzielaniem GH u dzieci z niedoborem wzrostu, a także ujemną korelację pomiędzy wydzielaniem GH i efektywnością terapii hormonem wzrostu w przypadku dzieci z niedoborem GH. Przerwanie szypuły przysadki wiąże się z najcięższą formą hipoplazji przysadki i skojarzone jest zazwyczaj z wielohormonalną niedoczynnością przysadki. Największą skuteczność leczenia hormonem wzrostu uzyskano u pacjentów z PSIS. Introduction Magnetic resonance imaging (MRI) has become a selected technique in neuroradiological evaluation of the anatomy of the hypothalamic-hypophyseal region (HHR) and of its possible alterations, like hypoplasia of the anterior pituitary gland, interruption of the pituitary stalk (PS), the absence of posterior pituitary hyperintensity in the posterior part of the sella turcica and the presence of high signal intensity in the region of the infundibular recess of the third ventricle (at the level of infundibular stump), considered as posterior pituitary ectopia [1, 2]. The most complete form of the observed abnormalities in HHR is the pituitary stalk interruption syndrome (PSIS), including pituitary stalk invisibility (PS interruption), ectopic posterior pituitary (EPP), and the anterior pituitary hypoplasia (HP). In some cases, however, EPP may be associated with visible pituitary stalk [3, 4]. Pituitary hypoplasia may also occur without other features of PSIS. It was shown in previous studies that PSIS could be associated with growth hormone deficiency (GHD), either isolated (ighd) or multiple anterior pituitary hormone deficiency (MPHD), but with normal posterior pituitary function [4]. Moreover, previous studies have suggested that MPHD is commonly associated with EPP and PS interruption, whereas ighd is observed in cases of EPP with visible PS [3]. Pituitary height (PHt) measurement allows assessing the pituitary size, since the age-dependent size progression of this gland appears to be mainly related to changes in its height, but not in its length or width. There is a strong correlation between PHt and the pituitary volume [5]. The associations between the morphological features of the pituitary and its size and function have been a controversial matter. In the observations conducted by Abrahams et al. [6] and Cacciari et al. [7], no link could be found between PHt and GH secretion. The first investigation, confirming the correlation between PHt and GH secretion, was presented in 1997 [8]. Objective The aim of the study was an evaluation of GH secretion, depending on pituitary size in short children, and relations between the pituitary size and 10

3 Hilczer M. et all Pituitary size and growth hormone (GH) secretion in short children... the first-year response to GH therapy in children with GH deficiency (GHD). Patients and method The analysis comprised 135 children (104 boys, 31 girls) with short stature. At the diagnosis, the patients age was 12.6 ± 3.2 years (mean ± SD). Two GH stimulation tests (with clonidine 0.15 mg/m2 orally and with insulin 0.1 U/kg i.v. or glucagon 30 μg/kg i.m.) were performed in each patient. Blood samples for human GH (hgh) estimation were collected every 30 min (from 0 to 120 min) in clonidine and insulin tests. In the glucagon test, blood samples were collected at 0, 90, 120, 150, 180 min. Growth hormone deficiency (GHD) was diagnosed on the basis of decreased GH secretion in two stimulation tests (GH peak in both tests <10.0 ng/ml). According to the highest GH peak in the stimulation tests, the patients were classified into the following groups: severe isolated GH deficiency (SIGHD, GH < 5 ng/ml; n = 19), partial isolated GH deficiency (PIGHD, GH 5-10 ng/ml; n = 58), multiple pituitary hormone deficiency (MPHD; n = 15), idiopathic short stature (ISS; GH 10 ng/ml; n = 43). The concentration of GH was measured by the two-site chemiluminescent enzyme immunometric assay hgh IMMULITE, DPC) with a sensitivity of 0.01 ng/ml, with intraassay coefficients of variation of % and interassay coefficients of variation of %. GH standards were calibrated, according to the WHO reference standard 80/505. In order to identify MPHD, further pituitary stimulation tests (GnRH, TRH, ACTH) were considered necessary. Patients body height was expressed in standard deviation scores (SDS), according to national reference values for age and sex [9]. The criterion of short stature was height SDS (H SDS) < In all the patients, MRI of the HHR was performed before GH therapy, and the height of the pituitary gland was assessed. All the MRI scans of HHR were carried out with a 1.5-Tesla MRI unit (Picker, model Edge), with sagittal and coronal slices, their thickness of 2 3 mm, depicted as midline images on T1-weighted, before and after gadolinium injection. The height of the pituitary gland (PHt), defined as the greatest distance between the base and the top of the gland, was measured on the mid-sagittal T1-weighted image, in a plane perpendicular to the base of the sella turcica, after magnification through an overhead projector and using the scaling provided on the films (the accuracy of measurement: 0.1 mm). Pituitary height measurements were compared with the published normal values for given age [10] and expressed in SDS, with reference to the chronological age (CA) and to the height age (HA). The pituitary gland was considered hypoplastic when PHt SDS was below -2.0 for CA and for HA. In short children, HA is below CA, so, in certain cases, the pituitary gland, classified as hypoplastic with reference to normative data for CA, turned out to be normal for HA. In some cases, other abnormalities, included in PSIS may be observed as well. Results In the analysed group of patients, H SDS was ± 0.86 and GH peak was 10.4 ± 8.6 ng/ml. The detailed data of particular subgroups of patients, divided, according to GH peak and to the type of pituitary insufficiency (ighd or MPHD), are shown in Table I. Height SDS was significantly lower in MPHD than in either PIGHD (p < 0.001) or ISS (p < 0.05). Significant differences in PHt SDS for CA were observed among all the groups, except the difference between MPHD and SIGHD. In PHt SDS, assessed for HA, significant differences were found among all the groups, except the differences between MPHD and SIGHD and between SIGHD and PI- GHD (the last two differences were close to significance, p = 0.07). The values of PHt SDS for CA and for HA and the incidence of HP for CA and for HA were compared in particular groups of the patients (Figures 1 and 2). There was a very strong (r = 0.99) correlation between PHt SDS for CA and PHt SDS for HA (Fig. 3). A correlation was also observed between PHT SDS (for both CA and HA) and GH peak (r = 0.41 and r = 0.43, respectively) (Fig. 4). Next, all the patients were classified, according to the pituitary size (PHt SDS for CA and for HA). The following groups of patents were created: HA patients with pituitary hypoplasia for HA (n = 42); CA patients with pituitary hypoplasia for CA but not for HA (n = 29); NORMAL patients with normal pituitary height (n = 64). 11

4 Praca oryginalna Endokrynol. Ped., 3/2003;2(3):9-19 Table. I. Selected data of subgroups of patients divided according to GH peak and to the type of pituitary insufficiency. Tabela. I. Wybrane dane grup pacjentów, podzielonych w zależności od szczytu wydzielania hormonu wzrostu i typu niedoczynności przysadki n CA [years] HSDS GH peak [ng/ml] PHt SDS Frequency of pituitary hypoplasia [%] for CA for HA for CA for HA MPHD ± ±1.06 ab 1,7±1,6-4.29±1,22 cd -3.81±1.29 hi SIGHD ± ± ± ±2.36 ef -2.23±2.54 k PIGHD ± ±0.70 a 7.5± ±1.70 ceg -1.06±1.74 hl ISS ± ±0.86 b 19.9± ±1.47 dfg -0.51±1.49 ikl Significant differences: a p<0.001; b, e, g, l p<0.05; c, d, h, i p< ; f, k p<0.01 Fig. 1. Pituitary height in particular subgroups of patients, divided according to GH peak and to the type of pituitary insufficiency Ryc. 1. Wysokość przysadki w poszczególnych podgrupach pacjentów, podzielonych w zależności od szczytu wydzielania hormonu wzrostu i typu niedoczynności przysadki Fig. 2. The incidence of pituitary hypoplasia for CA and HA in particular groups of patients. Ryc.2. Częstość hipoplazji przysadki dla wieku chronologicznego i wzrostowego w poszczególnych grupach pacjentów 12

5 Hilczer M. et all Pituitary size and growth hormone (GH) secretion in short children... Fig. 3. Correlation between PHt SDS for CA and PHt SDS for HA in children with short stature Ryc. 3. Korelacja pomiędzy SDS wysokości przysadek dla wieku chronologicznego i wzrostowego u dzieci z niedoborem wzrostu Fig. 4. Correlation between PHt SDS for HA and GH peak in stimulation tests in children with short stature Ryc. 4. Korelacja pomiędzy SDS wysokości przysadki dla wieku wzrostowego i szczytem wydzielania hormonu wzrostu u dzieci z niedoborem hormonu wzrostu Table. II. Age, height SDS and GH secretion inpatients with short stature, classified according to the pituitary size Tabela II. Wiek, SDS wzrostu I wydzielanie hormonu wzrostu u pacjentów z niedoborem wzrostu klasyfikowanych w zależności od wielkości przysadki w badaniu MRJ Age [years] HSDS GH peak [ng/ml] HA 11.1±3.8 a -2.92±0.96 b 6.0±5.9 cd CA 12.9± ± ±4.6 ce NORMAL 13.4±2.7 a -2.42±0.74 b 14.1±9.8 de Significant differences: a, c p<0.005; b p<0.01; d p< ; e p<

6 Praca oryginalna Endokrynol. Ped., 3/2003;2(3):9-19 Fig. 5. Height SDS of the patients with short stature, divided according to PHt SDS Ryc. 5. SDS wzrostu pacjentów z niedoborem wzrostu, klasyfikowanych w zależności od SDS wysokości przysadki Fig. 6. GH secretion in the patients with short stature, divided according to PHt SDS Ryc. 6. Wydzielanie GH u pacjentów z niedoborem wzrostu klasyfikowanych w zależności od SDS wysokości przysadki Table III. Age, H SDS and GH secretion in patients with GHD, classified according to the pituitary size Tabela III. Wiek, SDS wzrostu i wydzielanie hormonu wzrostu u pacjentów z niedoborem hormonu wzrostu, klasyfikowanych w zależności od wielkości przysadki Age [years] HSDS GH peak [ng/ml] HA 10.9± ±0.98 a 4.4±2.7 bc CA 12.7± ± ±2.0 b NORMAL 13.1± ±0.64 a 7.6±1.5 c Significant differences: a, b p<0.005; c p<

7 Selected data of patients with short stature, classified according to the pituitary size in MRI, are shown in Table II. Significant differences in GH peak were observed among all the groups, while for H SDS, the difference achieved significance only for HPFOR- HA and Normal (Fig. 5 and 6). The patients with HPFORHA were also significantly younger than the Normal. The second part of the analysis comprised 96 short children (72 boys, 24 girls) with GHD; patients with ISS were excluded from further studies. All the patients with GHD were classified into the following groups, according to the pituitary size again: HPFORHA patients with pituitary hypoplasia for HA (n = 36), including 9 patients with the complete form of PSIS; HPFORCA patients with pituitary hypoplasia for CA but not for HA (n = 23); Normal patients with normal pituitary height (n = 37). Selected data of the patients with short stature, classified according to the pituitary size in MRI, are shown in Table III. Significant differences were observed in GH peak between HPFORHA and Normal (p < 0.005), and between HPFORHA and HPFORCA (p < ), but no between HPFORCA and Normal. All the patients with GHD were treated with GH for at least one year, with the mean dose of 0.5 IU/kg/week. At the onset of the therapy, the patients H SDS was ± Before the treatment, height velocity (HV) was < 4 cm/year in all the patients. The first-year effectiveness of GH therapy was assessed as H SDS gain after one year of the therapy. Selected data of particular groups of patients before GH therapy and after one year of the therapy are shown in Table IV and on Fig. 7 and 8. Hilczer M. et all Pituitary size and growth hormone (GH) secretion in short children... After one year of GH therapy, the differences in H SDS became insignificant (NS). The obtained growth improvement (expressed as H SDS gain) was insignificantly higher in HPFORHA group than in other groups. There was a negative correlation (r = -0.34) between GH peak and height SDS gain (Fig. 9). Further observation is necessary for an accurate assessment of long-term effectiveness of GH therapy in particular groups of the patients. In the final part of the study, relations between GH secretion and morphological features of HHR in MRI (the visibility of pituitary stalk and the ectopy of posterior pituitary) were evaluated in children with pituitary hypoplasia. The analysis comprised 36 patients, classified according to the anatomical details of HHR, into the following groups: Group A: patients with complete form of PSIS, including HP and EPP and PS interruption (n = 9); Group B: patients with HP and EPP and with visible PS (n = 12); Group C: patients with HP only without EPP and with visible PS (n = 15). Selected parameters of patients, classified into particular groups, are shown in the Table V. Both GH peak values and PHt SDS were significantly lower in the patients with complete form of PSIS (Group A) than in other groups of patients. The patients H SDS was also the lowest in those with complete form of PSIS. Multiple pituitary hormone deficiency was observed in the majority of children with the complete form of PSIS, whereas most children in the other groups presented with isolated GH deficiency. The incidence of ighd and MPHD in particular groups of the patients is shown on the graph (Fig. 10). The first-year effectiveness of GH therapy in particular groups of patients was assessed as H SDS gain after one year of the therapy. No significant differences were observed in both H0SDS and H1SDS Table IV. Selected data of patients with GHD before GH therapy (H 0 SDS) and after 1 year of its application (H 1 SDS) Tabela IV. Wybrane dane pacjentów z niedoborem hormonu wzrostu przed (H 0 SDS) i po roku leczenia (H 1 SDS) H 0 SDS H 1 SDS Height SDS gain HA -2.90± ± ±0.53 CA -2.42± ± ±0.36 NORMAL -2.28± ± ±

8 Praca oryginalna Endokrynol. Ped., 3/2003;2(3):9-19 Fig. 7. Height SDS of the patients with GHD, classified according to the pituitary size before GH therapy and after 1 year of its application Ryc.7. SDS wzrostu pacjentów z niedoborem hormonu wzrostu klasyfikowanych w zależności od wielkości przysadki przed leczeniem i po roku leczenia hormonem wzrostu Fig. 8. Height SDS gain after 1 year of GH therapy in particular groups of the patients with GHD Ryc. 8. Przyrost SDS wzrostu po roku leczenia hormonem wzrostu w poszczególnych grupach pacjentów z niedoborem hormonu wzrostu Fig. 9. Correlation between GH peak and height SDS gain in first year of GH therapy in children with GHD Ryc. 9. Korelacja pomiędzy szczytem wydzielania hormonu wzrostu a przyrostem SDS wzrostu w pierwszym roku leczenia hormonem wzrostu u dzieci z GHD 16

9 Hilczer M. et all Pituitary size and growth hormone (GH) secretion in short children... Table V. Selected data of patients, classified into particular groups, according to anatomical details of HHR Tabela V. Wybrane dane pacjentów klasyfikowanych w zależności od anatomicznych wariantów zaburzeń okolicy podwzgórzowo-przysadkowej n MPHD [%] height SDS GH peak [ng/ml] PHt SDS Group A ± ± 0.4 a,b ± 1.23 c,d Group B ± ± 1.9 a ± 1.44 c Group C ± ± 2.8 b ± 1.01 d a, b, c, d significant differences (p<0.05) Fig. 10. The incidence of ighd and MPHD in particular groups of patients Ryc. 10. Częstość izolowanego GHD oraz MPHD w poszczególnych grupach pacjentów among the groups, probably due to relatively small number of patients in particular groups. In spite of this, significant (p < 0.01) differences were found in H SDS gain between Group A and Group B and between Group A and Group C. The obtained growth improvement was significantly higher in patients with the complete form of PSIS than in remaining groups of patients. Selected data of particular groups of patients before GH therapy and after one year of the therapy are shown in Table VI and on the graphs (Fig. 11 and 12). Discussion A high incidence of morphological abnormalities in the hypothalamic-hypophyseal region, as revealed in MRI, has been reported in patients with GHD [2, 7, 8]. The pituitary stalk interruption and ectopy of the posterior lobe of the pituitary gland may be considered as diagnostic markers of permanent GHD, since they have been more frequently reported in patients with MPHD than in those with isolated GHD [2, 7, 8]. Pellini et al. [11] described an invisible stalk in all of their subjects with MPHD and in 44.4% of subjects with isolated GHD; similarly, further investigation of the same group revealed the above abnormalities in 95% of subjects with MPHD and in 39% of subjects with isolated GHD [12]. On the other hand, MRI-diagnosed abnormalities, e.g., ectopy of the neurohypophysis, are not invariably associated with MPHD, as they are also observed in healthy children [13]. Since normal subjects display a fairly broad spectrum of hypophysis shapes, a markedly concave hypophysis 17

10 Praca oryginalna Endokrynol. Ped., 3/2003;2(3):9-19 Table VI. Selected data of particular groups of patients before GH therapy (H 0 SDS) and after 1 year of the therapy (H 1 SDS) Tabela IV. Wybrane dane poszczególnych grup pacjentów przed leczeniem GH (H 0 SDS) i po roku leczenia (H 1 SDS) H 0 SDS H 1 SDS Height SDS gain Group A ± ± ±0.54 a,b Group B ± ± ±0.93 a Group C ± ± ±0.29 b significant differences: a,b p<0.01 Fig. 11. Height SDS of particular groups of patients pituitary hypoplasia before GH therapy and after 1 year of the therapy Ryc.11. SDS wzrostu w poszczególnych grupach pacjentów z hipoplazją przysadki przed leczeniem hormonem wzrostu i po roku leczenia Fig. 12. Height SDS gain after 1 year of GH therapy in particular groups of patients Ryc. 12. Przyrost SDS wzrostu po roku leczenia hormonem wzrostu w poszczególnych grupach pacjentów 18

11 Hilczer M. et all Pituitary size and growth hormone (GH) secretion in short children... with the normal volume can be wrongly mistaken too short, while the values for convex shape would, analogously, be too high. It is very important to maintain careful attention while measuring PHt [14]. Low GH secretion is then highly probable in patients with marked hypoplasia of the anterior pituitary (PHt SDS < -2.0). In our data, anterior pituitary hypoplasia for height age was observed in 93.3% of the patients with MPHD and in 68.4% of the patients with SIGHD. A significant correlation was found between PHt SDS and GH peak in stimulation tests in children with GHD [10]. Our findings also revealed that PHt of the patients with MPHD and SIGHD was significantly lower from the respective one in all the other groups. Therefore, MRI seems to be an indispensable tool in the diagnosis of GHD, providing that the endocrinological diagnosis is more precise. Pituitary height is a reliable measurement for the assessment of pituitary size, although the limits of this method must be kept in mind. Patients with PSIS are diagnosed as having either MPHD or SIGHD. Lower GH secretion is thus to be expected in patients with significantly reduced PHt. PIŚMIENNICTWO/REFERENCES [1] Triulzi F., Scotti G., di Natale B. et al.: Evidence of congenital midline brain anomaly in pituitary dwarfs: a magnetic resonance imaging study in 101 patients. Pediatrics, 1994:93, [2] Bozzola M., Adamsbaum C., Biscaldi I. et al.: Role of magnetic resonance imaging in the diagnosis and prognosis of growth hormone deficiency. Clin. Endocrinol., 1996:45, [3] Ultmann M.C., Siegel S.F., Hirsch W.L. et al.: Pituitary stalk and ectopic hyperintense T1 signal on magnetic resonance imaging: implications for anterior pituitary dysfunction. Am. J. Dis. Child., 1993:147, [4] Pinto G., Netchine I., Sobrier M.L. et al.: Pituitary stalk interruption syndrome: a clinical-biological-genetic assessment of its pathogenesis. J. Clin. Endocrinol. Metab., 1997:82, [5] Lurie S.N., Doraiswamy P.M., Hussain M.M. et al.: In vivo assessment of pituitary gland volume with magnetic resonance imaging: the effect of age. J. Clin. Endocrinol. Metab., 1990:71, [6] Abrahams J.J., Trefelner E., Boulware S.D.: Idiopathic growth hormone deficiency: MR findings in 35 patients. Am. J. Neuroradiol., 1991:12, [7] Cacciari E., Zucchinni S., Carla G. et al.: Endocrine function and morphological findings in patients with disorders of the hypothalamo-pituitary area: a study with magnetic resonance. Arch. Dis. Child., 1990:65, [8] Nagel B.H. P., Palmbach M., Petersen D. et al.: Magnetic resonance images of 91 children with different causes of short stature: pituitary size reflects growth hormone secretion. Eur. J. Pediatr., 1997:156, [9] Palczewska J., Niedźwiecka Z.: Centile charts for body height and mass. Institute of Mother and Child, Warsaw [10] Argyropoulu M., Prignon F., Brauner R. et al.: Magnetic resonance imaging in the diagnosis of growth hormone deficiency. J. Pediatr., 1992:120, [11] Pellini C., di Natale B., de Angelis et al.: Growth hormone deficiency in children: Role of magnetic resonance imaging in assessing aetiopathogenesis and prognosis in idiopathic hypopituitarism. Eur. J. Pediatr., 1990:149, [12] Bressani N., di Natale B., Pellini C. et al.: Evidence of morphological and functional abnormalities in the hypothalamus of growth deficient children: A combined magnetic resonance imaging and endocrine study. Horm. Res., 1990:34, [13] Benshoff E.F., Katz B.H.: Ectopia of the posterior pituitary gland as a normal variant: assessment with MR imaging. Am. J. Neuroradiol., 1990:11, [14] Marwaha R., Menon P.S.N., Jena A. et al.: Hypothalamo-pituitary axis by magnetic resonance imaging in isolated growth hormone-deficient patients born by normal delivery. J. Clin. Endocrinol. Metab., 1992:74, [15] Chen S., Leger J., Garel C. et al.: Growth hormone deficiency with ectopic neurohypophysis: anatomical variations and relationship between visibility of the pituitary stalk asserted by magnetic resonance imaging and anterior pituitary function. J. Clin. Endocrinol. Metab., 1999:84,