MRI Insights into the Hypothalamic-Pituitary Axis in Children with Central puberty related disorders

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Abumota, Tarek M. Rashad, Shaymaa E. AbdelMeguid, Ahmed Adel ElBeheiry This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7437028/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Magnetic resonance imaging of the brain and pituitary gland has become an exceedingly helpful tool in the evaluation of children suffering from central precocious or delayed puberty with a high capability of detecting possible causative intra cranial pathologies, however the routine use of MRI for the evaluation of all children suffering these conditions has longly been debatable. Objective To determine the incidence of abnormal hypothalamic-pituitary axis imaging findings in children with puberty related disturbances and correlate between the imaging findings and the clinical and hormonal profile of the affected children Materials and methods A total of 75 children suffering from central disturbance of their pubertal timing were evaluated by MRI; 44 children diagnosed with precocious puberty and 31 children diagnosed with delayed puberty. MRI results were correlated with basal LH level and basal LH/FSH ratio in both groups and with Tanner stage in children with precocious puberty and with the pattern of pituitary hormonal disturbance in children with delayed puberty. Results A high prevalence of abnormal MRI results was detected in both groups; 63.6% in precocious puberty group (group I) and 67.7% in delayed puberty group (group II). The highest proportion of abnormalities was detected in the hypothalamic-pituitary axis in both groups; 92.9% and 100% respectively. Remarkably the prevalence of abnormal MRI results in females aged 6–8 years old in precocious puberty group was higher than both males and females aged less than 6 years old and the only detected case of supra sellar adamantinomatous craniopharyngioma was detected in a female aged 6–8 years old. Abnormal MRI results did not correlate with basal LH level or LH/FSH ratio in both groups, neither with Tanner stage in precocious puberty group but they had a strong positive correlation with combined hormonal disturbance/pan hypopituitarism in cases with delayed puberty. Conclusion MRI of the hypothalamic-pituitary axis is recommended in all cases with precocious puberty including females aged 6–8 years old and all cases of delayed puberty suffering from combined hormonal disturbance/pan hypopituitarism. MRI evaluation of delayed puberty cases with isolated hypogonadotrophic hypogonadsism can be watchfully postponed until males are older than 15 and females are older than 14 years old. Central precocious puberty Delayed puberty Hypothalamic-pituitary axis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction Puberty can be a stressful and concerning time for adolescents and their families, as it is a sensitive period of growth marked by significant emotional and physical changes and the disturbance of its timing whether precocious or delayed can have significant diverse effects on physical and mental health. ( 1 – 3 ) Puberty normally occurs between the ages of 8 to 13 years for females and 9 to 14 years for males. In females, the first sign of true puberty is breast development or thelarche, while in males, the first sign is testicular enlargement, by which testicular size increases to a volume of 4 ml or a length of 2.5 cm or greater. ( 1 , 4 , 5 ) Precocious puberty is defined as the development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys, while delayed puberty, in females, is the lack of breast development by 13 years old, a delay of more than 4 years between thelarche and completion of puberty, or a lack of menarche by the age of 16 years. In males, a pubertal delay is evident by a lack of testicular enlargement by 14 years or more than 5 years between testicular enlargement and completion of puberty.( 4 – 6 ) Puberty represents the maturation of the hypothalamic-pituitary-gonadal (HPG) axis and pathologies affecting this axis can result in either precocious or delayed puberty. Both precocious and delayed puberty can result from central or peripheral causes. Pathologies affecting the hypothalamic-pituitary axis result in central disturbance of the pubertal process, while pathologies affecting the gonads result in peripheral disturbance of the pubertal process. ( 4 – 6 ) Gonadotropin-dependent precocious puberty and hypogonadotrophic hypogonadism are a very common pediatric endocrinological problem and are a common cause of referral to a pediatric endocrinologist. Evaluation of these cases usually includes magnetic resonance imaging of the brain and sella searching for an underlying structural cause causing disturbance of their hypothalamic-pituitary axis.( 7 ) Routine evaluation by MRI of the brain and sella in these cases has longly been a point of debate. In precocious puberty the North American and European Pediatric Endocrinology societies in 2007 came to the conclusion that brain MRIs should be performed on all boys with central precocious puberty (CPP) and all girls with CPP who are younger than six years old. It is unclear, nevertheless, if females with CPP who are 6 to 8 years old should have the same procedure and their routine assessment by MRI is an established point of disagreement owing to the fact that several studies have shown that the incidence of unsuspected intra cranial lesions in these cases is low while other studies have shown that significant unsuspected pathologies still occur and can not otherwise be predicted. ( 8 – 11 ) In contrast to CPP, studies assessing the incidence of intra cranial pathologies in children with delayed puberty are scarce and a consensus regarding their routine imaging is not established, yet many authors agree upon routine imaging of males who are older than 15 and females who are older than 14 years old owing to the high incidence of constitutional delay of growth and puberty in children younger than that age, particularly males aged 14 to 15 years old. ( 12 ) In this study we tried to evaluate the prevalence of intra cranial pathologies in children with central disturbance of the pubertal process and tried to establish a correlation between different variables including the clinical status or hormonal profile and the occurrence of intra cranial pathologies to finally reach a recommendation regarding hypothalamic-pituitary axis routing imaging assessment. Materials and methods · Study population: This ambispective observational study was conducted during the period between April and December 2024 and included children who presented with central disturbance of the pubertal timing, referred to our institution and who had MRI examination of the brain and sella during the period between 2021 and 2024. Approval for this study was obtained from the Research Ethics Committee of our institution. (Ethics committee’s reference number: 0108174, IRB No: 00012098, FWA No: 00018699) All study procedures were carried out in accordance with the Declaration of Helsinki regarding research involving human subjects. Informed consent was waived from retrospectively collected cases, while informed consent was obtained from the parents of prospectively collected cases. The diagnosis of precocious or delayed puberty was made based on clinical evaluation, plasma hormonal investigations (LH, FSH and testosterone/ oestradiol levels), and assessment of bone age. Syndromic cases or cases with functional delayed puberty were excluded, such as those suffering from malnutrition, chronic illness or those with previous history of CNS irradiation. Finally, seventy five cases were included in our study, 44 cases with precocious puberty (group I) and 31 cases with delayed puberty (group II). All the cases with delayed puberty (31 patients) and 30 out of 44 cases with precocious puberty were collected prospectively, while the remaining 14 cases with precocious puberty were collected retrospectively. · Pre-imaging clinical assessment: Body weight was measured using a digital body-weighing scale, and height was measured in the standing position using a Harpenden stadiometer. The height standard deviation scores (SDSs) for chronological age and bone age were calculated. Tanner staging was used to determine pubertal stage. Tanner stage is also known as Sexual Maturity Ratings (SMR), which is a standardized system used to assess and classify pubertal development based on external secondary sex characteristics including breast development in females, genital development in males, and pubic hair in both sexes. The stages are numbered 1 through 5:Stage 1: Prepubertal, Stage 2: Early pubertal, Stage 3: Midpubertal, Stage 4: Late pubertal and Stage 5: Adult (postpubertal) maturity.(13,14) Bone age was determined by a pediatric endocrinologist, according to Greulich and Pyle. (15) · MRI imaging protocol: All the cases prospectively and retrospectively collected had MRI evaluation of the brain and sella. In case of retrospectively collected cases, MRI examinations were included if performed on a closed magnet (at least 1.5 Tesla). In case of prospectively collected cases, MRI examinations were performed on one of the following machines: a- 3T Philips MR system (Ingenia, Philips, Health care, Best, the Netherlands). b- 3T GE Discovery MR 750 system (GE Discovery, Madison, WI, USA). Acquisition protocol: Young children were offered sedation to improve MRI data quality, and scans were acquired under standard sedation administered and monitored by an on-site professional anesthesiologist. MR images were acquired with the following sequences: A-Routine MRI brain protocol : Fast spin echo (FSE) T2- weighted axial (TR 4400, TE 120, NEX 2, Matrix 384 x 320, 6 mm slice thickness, 1.0 mm gap), coronal (TR 5000, TE 122, NEX 2, Matrix 384 x 320, 6 mm slice thickness, 1 mm gap) and sagittal (TR 3400, TE 100, FOV 23, 5.5 mm slice thickness 0.5 mm gap, Matrix 256 x 224, NEX 3) sequences, 3D fast spoiled gradient-echo (FSPGR) T1-weighted sequences (TR 6.6, TE 2.6, TI 600, NEX 1, flip angle 25, matrix 192 x 192, 1.2 mm slice thickness, 0 mm gap) acquired in an axial plane and reconstructed in coronal and sagittal planes, Fluid-attenuated inversion-recovery (FLAIR) axial sequences (TR 10000, TE 95, TI 2575, NEX 1, matrix 350 x 192, 6 mm slice thickness, 0.6 mm gap), Diffusion Weighted Images; DWI (single shot, b value = 1,000 mm2/s, TR 8000, TE 78.8, NEX 1, field of view (FOV) 220 x 220, matrix 140 x 140, slice thickness 6 mm with 0.6 mm gap) and Susceptibility Weighted Images; SWI (TR 38.5ms, TE 22.9 ms, 320x224 acquisition matrix, field of view 240x192 mm, slice thickness 3 mm and a gap of 0.2 mm). B- Imaging of the pituitary gland including: a) Pre-contrast sequences included sagittal and coronal T1 thin sections (2.5 mm) pre-contrast (TR 400-500ms, TE 15ms, 256x256 acquisition matrix, NEX 4, field of view 100-120mm, slice thickness 2.5 mm and a gap of 0.5mm) and Sagittal and coronal T2 thin sections (2.5 mm) (TR 4000-5000ms, TE 110ms, 256x256 acquisition matrix, NEX4, field of view 100-120mm, slice thickness 2.5 mm and a gap of 0.5 mm) b) Post -contrast sequences included 1- Dynamic MRI of the pituitary gland (TR 280-350ms, TE 15ms, 192x192 acquisition matrix, NEX2, field of view 130-160mm, 2 mm slice thickness and a gap of 0.3mm). Dynamic Contrast Protocol: · IV contrast : Gadolinium-based contrast agent ( Magnevist ). · Injection rate : 1.5–2 ml/sec using a power injector. · Total dose : 0.1 mmol/kg. (This is equivalent to: 0.1 mL/kg) · Dynamic Acquisition Timing : Average of eight phases are acquired. The first phase is non contrast. The following post contrast phases start immediately after injection. Each phase time averages 20 seconds. · Sequence Type: T1-weighted fast spin echo (FSE) or turbo spin echo (TSE) sequence. Preferably fat-saturated sequences for better lesion contrast. 2- Coronal and sagittal T1 thin section (2.5 mm) post-contrast (TR 400-500ms, TE 15ms, 256x256 acquisition matrix, NEX4, field of view 100-120mm, slice thickness 2.5 mm and a gap of 0.5mm) · MRI data analysis and imaging evaluation: Examination of the acquired imaging sequences was performed by two experienced pediatric neuroradiologists to assess the brain scans to exclude any abnormality, followed by assessment of the size of the anterior pituitary gland (volume and three dimensions), the morphology of hypothalamic-pituitary axis to detect possible presence and then location, signal pattern and potential occurrence of contrast enhancement of focal lesions or any other abnormalities. · Clinico-Imaging correlation. Possible correlations between collected clinical data and imaging findings were sought by correlating data such as Tanner stage or clinical status and hormonal profile, LH level and LH/FSH ratio with the imaging results. Tailored correlation between gender specific age group and imaging in cases with precocious puberty was performed to tackle the popular argument regarding the imaging recommendation of those cases. · Statistical analysis of the data The statistical analysis of the data was performed using IBM SPSS software version 20.0 (Armonk, NY: IBM Corp, released 2011). Categorical data were summarized as numbers and percentages. For continuous data, normality was assessed using the Shapiro-Wilk test. Quantitative data were described using range (minimum and maximum), mean, standard deviation, median and interquartile range (IQR). Significance of the obtained results was judged at the 5% level. Results Patients’ Demographics Group I (Precocious puberty group) included 44 children with precocious puberty; 36 girls and 8 boys coming along the ages between 9 months & 9 years old. Overall, the median age was 7.75 years while the mean age was 6.65±2.27 years. Group II (Delayed puberty group) included 31 children with delayed puberty; 9 girls and 22 boys, coming along the ages between 14 and 17.5 years old. Overall, the median age was 17 years while the mean age was 16.61±1.28 years. Clinical and endocrinal presentation of included children: Group I (Precocious puberty): According to their Tanner stage, precocious puberty children were subdivided into; children with early pubertal Tanner stages (stages 2&3) and children with late pubertal Tanner stages (stages 4&5); representing 46.7% and 53.3% respectively. Apart from two cases who had short stature and one case who had gigantism, all of the remaining cases had isolated precocious puberty with normal hormonal profile apart from elevated gonadotropins. Group II (Delayed puberty): All of the cases in this study group were arrested in Tanner stage 1 and hence their clinical categorization was based on whether they had another accompanying clinical/hormonal disturbance. According to their clinical status and hormonal profile, the children in this group were subdivided into; children with isolated gonadotropins deficiency and children with combined or pan hormonal disturbance; representing 48.4% (15 cases) and 51.6% (16 cases) respectively. Imaging assessment results: Group I (Precocious puberty): This group with a total number of 44 included 16 cases with normal MRI of the brain and sella (36.4%) and 28 cases with abnormal imaging findings (63.6%), 26 of them had an abnormality of the hypothalamic-pituitary axis (HPA) with or without other extra HPA findings (92.9) and 2 had isolated extra HPA abnormal findings (7.1%). The most common imaging finding was anterior pituitary hyperplasia (14 cases representing 31.8% of the total number of cases and 50% of cases with abnormal imaging findings) followed by pituitary microadenoma (detected in 8 cases, representing 18.8% of the total number of cases and 28.6% of cases with abnormal imaging findings) and tuber cinereum hamartoma (detected in two cases, representing 4.5% of the total number of cases and 7.1% of cases with abnormal imaging findings). Smaller number of cases showed anterior pituitary hypoplasia, craniopharyngioma and Rathke’s cleft cyst (one case each). (Figures 1-4) Group II (Delayed puberty): This group with a total number of 31 included 10 cases with normal MRI findings (32.3%) and 21 cases with abnormal imaging findings (67.7%), all of them had an abnormality of the hypothalamic-pituitary axis with or without other extra HPA findings and none had isolated extra HPA abnormal findings. The most common imaging findings in this group were anterior pituitary hypoplasia (detected in nine cases representing 29% of the total number of cases and 42.8% of cases with abnormal imaging findings) followed by Pituitary stalk interruption syndrome (detected in five cases, representing 16.1% of the total number of cases and 23.8% of the cases with abnormal imaging finding). Pituitary microadenoma and Rathke’s cleft cyst were detected in two cases each while craniopharyngioma, pituitary hyperplasia and partial empty sella were detected in one cases each. ( Figures 5-7) Clinico-Imaging correlation results: For such aim, we assessed the clinical status and pattern of hormonal profile abnormality of each child as well as their basal gonadotropins levels and ratio. We then proceeded to statistically analyze their changes with MRI findings. Group I: (Precocious puberty) In this group, we correlated their Tanner stage, basal LH level and basal LH/FSH ratio with their MRI findings. No relation was found between MRI findings and Tanner stage, basal LH level or basal LH/FSH ratio. The prevalence of abnormal MRI results didn’t differ in accordance with the child’s Tanner stage or with his basal LH level or basal gonadotropins ratio. Also of note is that most of our cases suffered from precocious puberty solely, apart from three cases who had accompanying hormonal disturbance in the form of growth hormone excess or deficiency and all the cases had free neurological examination apart from two cases who suffered from sequelae of previous MCA stroke and meningo-encephalitis. The three cases with accompanying hormonal disturbance were an 8-year-old girl who suffered from growth hormone deficiency and also rapid progression of pubertal stages and she had an anterior pituitary microadenoma on MRI. The other two children were males, one aged 5 years old with associated GH deficiency and Chiari 1 malformation on MRI and the other was 9 years old with growth hormone excess and pituitary hyperplasia on MRI. So, MRI results couldn't be predicted from the child’s clinical status or basal LH level or basal gonadotropins ratio and the only helpful clue was accompanying hormonal disturbance which occurred only in a minority of cases and couldn't be relied upon. Tailored correlation between MRI findings and gender-specific age group in precocious puberty group Tackling the popular argument of whether females with central precocious puberty and aged 6 to 8 years old should perform magnetic resonance imaging of the brain and sella routinely or not, we compared the prevalence of abnormal imaging findings in that particular group and the remaining study population; comprised of females younger than 6 years old and all the males. Surprisingly the prevalence of abnormal MRI findings was slightly higher in that group compared to the rest of the study population; 64.3% versus 62.5% respectively, moreover, the prevalence of neoplastic lesions was even higher; 25% versus 12.5%, though that difference wasn’t statistically significant. (Table 1) Table 1: Relation between MRI findings and age and gender in precocious puberty group (n = 44) Age (years) p Female (6 – ≥8) (n = 28) Female (<6) or males (n = 16) No. % No. % MRI findings Normal 10 35.7 6 37.5 0.906 Abnormal 18 64.3 10 62.5 Hypothalamic-pituitary axis abnormality Hypoplasia 0 0.0 1 6.3 FE p=0.364 Microadenoma 6 21.4 2 12.5 FE p=0.689 Hyperplasia 10 35.7 4 25.0 FE p=0.314 Craniopharyngioma 1 3.6 0 0.0 FE p=1.000 Hamartoma 0 0.0 2 12.5 FE p=0.127 RCC 1 3.6 0 0.0 FE p=1.000 Extra HPA abnormality Temporal arachnoid cyst 1 3.6 0 0.0 FE p=1.000 CHIARI 1 0 0.0 1 6.3 FE p=0.364 MCA infarct 1 3.6 0 0.0 FE p=1.000 Cerebellar atrophy 1 3.6 0 0.0 FE p=1.000 PVL 1 3.6 0 0.0 FE p=1.000 χ 2 Chi square test, FET: Fisher Exact test, p: p value for Relation between Age with MRI findings. PVL: periventricular leukomalicia, RCC: Rathke’s cleft cyst, *: Statistically significant at p ≤ 0.05 Group II: (Delayed puberty) A significant positive correlation was found between abnormal MRI findings and combined hormonal disturbance/panhypopituitarism; abnormal MRI findings were significantly higher in children with combined hormonal disturbance/ panhypopituitarism in comparison to children with isolated gonadotropins deficiency. In contrast to precocious puberty, combined hormonal disturbance occurred in a significant proportion of the cases with delayed puberty and it can be relied upon as a predictive factor for abnormal MRI results. No correlation was found between MRI findings and basal LH level or basal LH/FSH ratio. Similar to precocious puberty, the prevalence of abnormal MRI results didn’t differ in accordance with the child’s gonadotropins level or ratio. (Table 2) Table 2: Relation between MRI findings and pattern of hormonal disturbance, basal LH level and basal LH/FSH ratio in delayed puberty group (n = 31) MRI p Abnormal (n = 21) Normal (n = 10) No. % No. % Hormonal disturbance Isolated gonadotropin deficiency 7 33.3 8 80.0 FE p= 0.023 * Combined hormonal disturbance/Panhypopitu-itarism 14 66.7 2 20.0 Basal LH Min. – Max. 0.01 – 3.74 0.10 – 6.90 0.118 Mean ± SD. 0.86 ± 0.97 2.35 ± 2.59 Median (IQR) 0.45 (0.20 – 1.30) 0.73 (0.60 – 4.30) Basal LH/FSH Min. – Max. 0.09 – 2.17 0.06 – 4.94 0.145 Mean ± SD. 0.61 ± 0.65 1.66 ± 1.67 Median (IQR) 0.32 (0.15 – 0.83) 1.19 (0.46 – 1.77) IQR: Inter quartile range , SD: Standard deviation, U: Mann Whitney test χ 2 : Chi square test , p: p value for Relation between MRI with different parameters , *: Statistically significant at p ≤ 0.05 Discussion In this study we focused on assessment of the brain and hypothalamic pituitary axis in children with central precocious or delayed puberty in a trial to estimate the prevalence of intracranial abnormalities detected by MRI and to stratify these data by gender and age. Particular attention was given to females suffering from precocious puberty and aged 6 to 8 years old, whose routine imaging assessment is debatable with emphasis on significant pathologies which may impact their management plan to eventually reach a solid recommendation regarding the routine imaging assessment of each group individualized to our pediatric population. Additionally we tried to correlate the imaging results with the child’s clinical status and hormonal profile to find out if these inputs can predict the imaging results or alter the radiologic assessment recommendation. So, in the current study we tried to answer three main questions and then use the answers in formulating an imaging recommendation for children presenting with central disturbance of pubertal timing. The three questions were; what is the nature and prevalence of abnormal intra cranial MRI findings?, the second question was, is there a correlation between the clinical data and the imaging results through which the occurrence of abnormal imaging findings could be predicted clinically ? and the third question was, what is the impact of the imaging results on the child’s management plan?. Precocious puberty group: In the current study we tried to avoid the routinely followed categorization method of abnormal intra cranial findings in previous studies which divided them into pathological, incidental and findings of questionable relationship with precocious puberty in which the distribution of the individual abnormalities are not standardized and what was considered to be incidental in one study was considered to be pathological in another. In our study we categorized our results as abnormalities of the hypothalamic pituitary axis (HPA) with or without extra HPA abnormalities and isolated extra HPA abnormalities with normal HPA. We found this pattern of categorization as the most reproducible and the most consistent with the continued study and research by which the previously unrevealed relation of certain pathologies to precocious puberty is established. What was the nature and prevalence of abnormal intra cranial MRI findings? Abnormal imaging findings were detected in 63.6% (28 in number) of the cases, 92.9% (26 in number) of which were detected in the hypothalamic-pituitary axis (HPA) with or without other extra HPA abnormal findings with anterior pituitary hyperplasia representing the most predominantly detected abnormality present in 50% of the cases (14 in number) with abnormal imaging results. Anterior pituitary microadenoma comes second followed by tuber cinereum hamartoma representing 28.6% and 7.1% of the cases respectively. Anterior pituitary hypoplasia, supra sellar craniopharyngioma as well as isolated extra hypothalamic-pituitary axis findings represented by temporal arachnoid cyst and Chiari 1 represent 3.6% of the cases each. All of the detected abnormalities in our study were also reported in similar previous studies ( 9 , 16 , 17 ), although the detected abnormalities differed between the studies and still several previously reported abnormalities weren’t detected in our study at all. Similar to previous studies ( 16 ), the two cases of tuber cinereum hamartomas occurred in females at very young age before the age of four years old and were associated with advanced bone age and very high gonadotropins levels. The high prevalence of abnormal imaging findings in our study in comparison to previous studies may be related to the high proportion of cases with anterior pituitary hyperplasia in our study which is usually not reported in other studies as anterior pituitary hyperplasia itself is considered as a manifestation or proof of central precocious puberty rather than its cause and these cases are still considered to have idiopathic CPP ( 18 , 19 ), furthermore this finding doesn’t impact the child’s management plan. In our study we reported anterior pituitary hyperplasia to demonstrate its high prevalence which in so many cases is misdiagnosed as anterior pituitary macroadenoma or other pathology. Taking this into consideration and reevaluating our cases, abnormal imaging findings -excluding anterior pituitary hyperplasia- were present in 38.6% of the cases (17 in number); 37.5% of the males (3 in number) and 38.9% of the females (14 in number). The prevalence of CNS abnormalities in boys in our study was lower than what is previously reported to be as high as 75% and 92% by Choi et al and Faizah et al respectively ( 20 , 21 ) , but higher than what is reported to be as low as 7% by Yoon et al ( 22 ). In contrast to the previously reported low prevalence of intra cranial abnormalities in females in several studies as shown by the meta analysis performed by Cantas-Orsdemir et al ( 9 ), Faizah et al ( 21 ) reported high prevalence of intra cranial pathologies in females similar to our study reaching 45% but they reported an exceedingly high prevalence of intra cranial abnormalities in boys reaching 92% in contrast to ours. The females aged 6 to 8 years old (28 in number) were further evaluated to detect the prevalence of abnormal imaging findings in this particular age group whose routine imaging assessment is debatable. Abnormal imaging findings were detected in 39.3% of these cases and neoplastic lesions were detected in 25%, compared to only 37.5% and 12.5% respectively in the males and females younger than 6 years old. The overall prevalence of abnormal imaging findings as well as the prevalence of neoplastic lesions in girls aged 6 to 8 years old was higher in our study relative to previous studies conducted by Pedicelli et al ( 10 )and Yoon et al ( 11 ). Was there a correlation between the child’s clinical data and his imaging result? In our study abnormal imaging findings couldn't be predicted based on the child’s age, gender, Tanner stage or basal gonadotropins level or ratio which goes in agreement with the previous results reported by Ng et al ( 23 ) but contrasting the results reported by Bajpai et al ( 24 ). Choi et al ( 25 ) similar to our results reported no correlation between MRI findings and Tanner stage or LH level, but they reported a correlation with age of onset of the pubertal disturbance. Oh et al ( 26 ) reported very similar results to our study with positive brain MRI findings observed in 37.7%, no significant differences in sex or age were found in incidence of pituitary abnormalities or non pituitary incidental findings as well as no significant differences in laboratory findings were identified between patients with CPP and abnormal versus normal MRI findings. None of the clinical characteristics including puberty stage or bone age − chronological age, were significantly correlated with pituitary abnormalities on MRI. What was the impact of imaging results on the child’s management plan? The standard management plan for cases with idiopathic CPP is medical treatment which can be modified to surgical management in certain cases with organic causes detected on imaging. At least two of our cases diagnosed with microadenomas were surgically managed and unfortunately the case of craniopharyngioma was lost to follow up. The two cases with tuber cinereum hamartomas didn’t require surgical management and were adequately controlled on medical treatment with imaging follow up. Our recommendation for routine imaging assessment in cases of precocious puberty Based on the previously discussed results showing high prevalence of organic causes of CPP and which couldn't be predicted based on the child’s clinical status or gonadotropins level and which were also very high in the females aged 6 to 8 years old, we recommend performing routine magnetic resonance imaging of the brain and sella in all children presenting with central precocious puberty including girls aged 6 to 8 years old irrespective of their Tanner stage or Gonadotropins level. Though other researchers as Pedicelli et al ( 10 ) didn’t recommend routine MRI screening in females with CPP aged 6 to 8 years old, our recommendations are consistent with those of several other researchers including Mogensen et al ( 27 ) who reported that a high frequency of their 6–8 year old girls with early or precocious puberty had a pathological brain MRI, which could not be predicted from any clinical or biochemical parameters in their study and hence they -similar to us- believed that girls with precocious pubertal development of central origin before 8 years of age should continue to be screened by MRI. Delayed puberty group What was the nature and prevalence of abnormal intra cranial MRI findings? Abnormal imaging findings had a high prevalence and were detected in 67.7% (21 in number) of the cases (63.6% of the males and 70% of the females), all of them involved the hypothalamic-pituitary axis with or without other extra HPA findings. The most prevalent imaging finding was anterior pituitary hypoplasia (42.8%) followed by pituitary stalk interruption syndrome (23.8%) and three cases (two females and one male) representing 14.3% had neoplastic lesions; two cases had microadenomas (9.5%) and one case had craniopharyngioma (4.8%). Two cases with RCCs (9.5%), a case with partial empty sella and another with anterior pituitary hyperplasia were detected (4.8% each). Unfortunately, we couldn't adequately study male children aged 14 to 15 years old and whose routine imaging assessment is controversial owing to the fact that most males at that age have constitutional delay of growth and puberty. Our study included only two males aged 14 to 15 years, one of them with isolated gonadotropins deficiency and whose imaging assessment was normal and the other had combined hormonal deficiency and his imaging assessment revealed anterior pituitary hypoplasia and absent posterior pituitary bright spot. In contrast to precocious puberty which is vastly studied with estimation of the prevalence of intra cranial pathology in affected children with attention given to both males and females- though higher attention is of course given to females owing to the much higher incidence of such pubertal disturbance in them-, delayed puberty didn’t get the same attention considering studying the prevalence of intra cranial pathology in affected children. Though our study is different in its design from the previous studies studying hypogonadotrophic hypogonadism or delayed puberty, still the intra cranial abnormalities detected in our study were also detected in previous studies assessing hypogonadotrophic hypogonadism, multiple pituitary hormone deficiencies or in case reports of cases presenting with delayed puberty.( 28 – 34 ) Was there a correlation between the child’s clinical data and his imaging result? Similar to precocious puberty, imaging results couldn’t be predicted based on the level of basal gonadotropins or their ratio, but the incidence of abnormal imaging findings was significantly higher in children with combined hormonal disturbance or panhypopituitarism (87.5%) in comparison to children with isolated gonadotropins deficiency (46.7%) and also it is worth noting that the incidence of combined hormonal disturbance or panhypopituitarism occurred in a significant proportion of the cases with delayed puberty in contrast to precocious puberty which makes it a reliable predictor of the imaging results. What was the impact of imaging results on the child’s management plan? As in the case of precocious puberty, the standard management plan for cases with hypogonadotrophic hypogonadism is either medical treatment or watchful observation for spontaneous occurrence of puberty as most of the cases suffer from constitutional delay of growth and puberty. The typical management plan was altered in certain cases in our study resorting to surgical management in the cases with craniopharyngioma and one of the cases with Rathke’s cleft cysts which was large in size with significant mass effect resulting in panhypopituitarism. The other significant impact of the imaging results on the management plan was the possible prediction of the occurrence of persistent hypogonadotrophic hypogonadism in certain cases as those with pituitary stalk interruption syndrome or marked anterior pituitary hypoplasia which would necessitate initiation of therapy without residing to a period of observation as spontaneous occurrence of puberty in those cases is unlikely and it also may predict the need for long term replacement therapy. Our recommendation for routine imaging assessment in cases of primary hypogonadotrophic delayed puberty Based on the previously discussed results showing very high incidence of intra cranial pathologies in cases with primary hypogonadotrophic delayed puberty and their significant impact on the child’s management plan but also taking into consideration that the mean age of the cases assessed in this study was relatively advanced which may have played a significant role in the occurrence of such high prevalence of intra cranial pathologies in our study and also considering the well established fact that most cases of primary hypogonadotrophic delayed puberty at younger age are due to constitutional delay of growth and puberty and the limited resources, we recommend watchful postponing imaging assessment for one year after the onset of delayed puberty in cases with isolated hypogonadotrophic delayed puberty and with free neurological exam and then routinely performing magnetic resonance imaging of the brain and sella in all the cases. The significantly high incidence of abnormal imaging findings in cases presenting with combined hormonal disturbance or panhypopituitarism, warrants imaging assessment of children presenting early and suffering such a condition. Our recommendation is similar to the recommendation of Harrington et al ( 12 ) who stated that MRI should be obtained in any patient with suggestive clinical features of intracranial pathology. Absent such concerns, they balance between potential for undiagnosed disorders and resource utilization by waiting until youth are older (girls > 14 years and boys > 15 years) but then routinely perform MRI in youth without evidence of endogenous puberty. Points of strength of the current study Studying both aspects of pubertal timing disturbance illustrated the difference in the overall prevalence of abnormal imaging findings as well as the difference in the prevalence of individual abnormalities between both disorders. Studying the prevalence of intra cranial abnormalities in primary hypogonadotrophic delayed puberty which in contrast to central precocious puberty is scarcely studied, including both sexes and taking into consideration the pattern of their hormonal disturbance whether isolated or combined. Performing our imaging studies using 1.5 & 3 Tesla closed magnet machines and with administration of contrast material to all the cases avoided the underestimation of the prevalence of certain pathologies such as microadenomas which may otherwise have been missed and also allowed for a firmer diagnosis of tuber cinereum hamartomas differentiating them from hypothalamic gliomas. Studying the prevalence and nature of imaging abnormalities in the female population aged 6 to 8 years with precocious puberty as well as their adequate representation in our study population allowed reviewing and changing the mainstream recommendation denying the need for their imaging assessment. Limitations The relatively small sample size and advanced mean age of the cases of delayed puberty which prevented better assessment of the prevalence of abnormal imaging findings in males aged 14 to 15 years. The prospective collection of most of our cases which didn’t allow for an adequate period of follow up for the cases to adequately assess the impact of the reported imaging results on the child’s management plan. Conclusions Abnormal hypothalamic pituitary axis MRI findings are prevalent in children with precocious puberty, including females aged 6 to 8 years old with even a higher prevalence of abnormal imaging findings in general and neoplastic lesions in particular in this group compared to other groups in contrast to the common assumption. Such findings can’t be predicted from the child’s age, gender, basal gonadotropins level/ratio or Tanner stage. Abnormal hypothalamic pituitary axis MRI findings are also highly prevalent in children with delayed puberty and they can significantly impact the child’s management plan. A higher incidence of abnormal imaging results could be predicted from accompanying clinic-hormonal disturbance and it can be reliably used as a marker for imaging recommendation. MRI of the brain and sella is recommended in all delayed puberty children with combined hormonal disturbance or panhypopituitarism. In absence of such urging factors for imaging assessment, watchful postponing of imaging until females are older than 14 and males are older than 15 years old is recommended. Abbreviations CPP central precocious puberty HPA Hypothalamic pituitary axis RCC Rathke’s cleft cyst Declarations -Ethics approval and consent to participate Approval for this study was obtained from the Research Ethics Committee of Alexandria Faculty of Medicine. (Ethics committee’s reference number: 0108174, IRB No: 00012098, FWA No: 00018699) All study procedures were carried out in accordance with the Declaration of Helsinki regarding research involving human subjects. Informed consent was waived from retrospectively collected cases, while informed consent was obtained from the parents of prospectively collected cases. -Consent for publication : 'Not applicable' -Disclosures The authors have nothing to disclose. -Availability of data and material The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request. -Competing interests : The authors declare that they have no competing interests. -Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Author Contribution AA, TR and AB drafted the manuscript. AA, AB and SE collected the data. AA and AB edited the images. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7437028","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":530759624,"identity":"f4967001-f7ba-4913-be29-fa1a11df1ba6","order_by":0,"name":"Aya A. Abumota","email":"","orcid":"","institution":"Alexandria University","correspondingAuthor":false,"prefix":"","firstName":"Aya","middleName":"A.","lastName":"Abumota","suffix":""},{"id":530759625,"identity":"f8a3d154-0145-4ad6-bab8-62fc55effb40","order_by":1,"name":"Tarek M. 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2","display":"","copyAsset":false,"role":"figure","size":257873,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAnterior pituitary hyperplasia. \u003c/strong\u003eMRI of a child (range of age 6-9 years) with precocious puberty (Tanner stage 5), A: axial T2 , B: sagittal T1 pre-contrast, C: coronal T2 and D: coronal T1 post contrast showing enlarged anterior pituitary gland for patient’s age, notably its height with supra sellar extension stretching the optic chiasm, still with homogeneous post contrast enhancement and no focal lesions. Also noted mild effacement of the normally located posterior pituitary bright spot by the enlarged anterior pituitary gland. The supra tentorial white matter shows marked reduction in volume with approximation of cortico-ventricular distance and ectatic supra tentorial ventricular system which shows undulated borders with mild thinning of the splenium of the corpus callosum…\u003cstrong\u003e.Features matching with anterior pituitary hyperplasia associated with periventricular leukomalacia.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7437028/v1/83a5d068ed2f862ee7b8aa93.png"},{"id":93777079,"identity":"5bed3cb3-e57f-418e-98a7-b3bfeb1a33bf","added_by":"auto","created_at":"2025-10-17 12:39:00","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":98755,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAnterior pituitary microadenoma.\u003c/strong\u003e MRI sella of a child (range of age 6-9 years) with central precocious puberty\u003cstrong\u003e; \u003c/strong\u003ecoronal T1 early phase dynamic post contrast showing a small hypo enhancing lesion (arrow) noted at the left side of the anterior pituitary gland, still with preserved central location of the pituitary stalk….\u003cstrong\u003efeatures matching with\u003c/strong\u003e \u003cstrong\u003eanterior pituitary microadenoma.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7437028/v1/fc3013c4151ac52132feb54e.png"},{"id":93777102,"identity":"dead6b95-83a7-445d-a4b0-d3c00b2e2594","added_by":"auto","created_at":"2025-10-17 12:39:01","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":133577,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTuber cinereum hamartoma\u003c/strong\u003e. MRI sella of a child (range of age 3-6 years) with central precocious puberty; A\u0026amp;B: Sagittal T1 pre and post contrast showing a small pedunculated lesion seen arising from the tuber cinereum (arrows), expressing iso intense signal to the gray matter with no post contrast enhancement….\u003cstrong\u003efeatures matching with\u003c/strong\u003e \u003cstrong\u003eTuber cinereum hamartoma.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7437028/v1/13ad3443c6f44f5e8967d0f6.png"},{"id":93777101,"identity":"d399e8e1-5d62-4452-b562-84460f18aae4","added_by":"auto","created_at":"2025-10-17 12:39:01","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":94321,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMRI findings in delayed puberty group\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-7437028/v1/6b633cca31b56f17a88e0751.png"},{"id":93777082,"identity":"dbf41ffc-ddac-4441-afd9-65a49f9dcd55","added_by":"auto","created_at":"2025-10-17 12:39:00","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":219205,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAnterior pituitary hypoplasia.\u003c/strong\u003e MRI sella of a child (range of age 14-17 years) presenting with delayed puberty and isolated hypogonadotrophic hypogonadism. A: sagittal T1 pre-contrast, B: coronal T2, C\u0026amp;D: sagittal and coronal T1 post-contrast showing small size of the anterior pituitary gland for patient’s age with pituitary height of 2.5mm and concave upper border, otherwise it shows normal enhancement pattern and no focal lesions, the pituitary stalk is of normal thickness and centrally located, the posterior pituitary bright spot is preserved and normally located with free supra sellar cistern and normal appearance of the hypothalamus and optic chiasm\u003cstrong\u003e….Features are matching with anterior pituitary hypoplasia.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-7437028/v1/beb39793942c51fc6c78a4f6.png"},{"id":93777098,"identity":"38035bf9-0d45-446c-b039-d4c1c0e56b01","added_by":"auto","created_at":"2025-10-17 12:39:01","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":100847,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePituitary stalk interruption syndrome.\u003c/strong\u003e MRI sella of a child (range of age 14-17 years) with panhypopituitarism. A\u0026amp;B: sagittal T1 pre and post contrast showing abnormally located posterior pituitary bright spot noted at median eminence, the pituitary stalk is absent with markedly hypoplastic anterior pituitary gland for patient’s age showing concave upper border, otherwise it shows normal enhancement pattern and no focal lesions with free supra sellar cistern and normal appearance of the optic chiasm…\u003cstrong\u003e.Features are matching with pituitary stalk interruption syndrome.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-7437028/v1/b199d4c287c703237c96623a.png"},{"id":102409584,"identity":"a7d73c64-8f7a-4934-872d-060a29aebaa2","added_by":"auto","created_at":"2026-02-11 11:42:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3697434,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7437028/v1/ce55d61e-bcfc-4bc4-83e3-7e5149b356de.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"MRI Insights into the Hypothalamic-Pituitary Axis in Children with Central puberty related disorders","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePuberty can be a stressful and concerning time for adolescents and their families, as it is a sensitive period of growth marked by significant emotional and physical changes and the disturbance of its timing whether precocious or delayed can have significant diverse effects on physical and mental health. (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\u003cp\u003ePuberty normally occurs between the ages of 8 to 13 years for females and 9 to 14 years for males. In females, the first sign of true puberty is breast development or thelarche, while in males, the first sign is testicular enlargement, by which testicular size increases to a volume of 4 ml or a length of 2.5 cm or greater. (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e\u003cp\u003ePrecocious puberty is defined as the development of secondary sexual characteristics before the age of 8 years in girls and 9 years in boys, while delayed puberty, in females, is the lack of breast development by 13 years old, a delay of more than 4 years between thelarche and completion of puberty, or a lack of menarche by the age of 16 years. In males, a pubertal delay is evident by a lack of testicular enlargement by 14 years or more than 5 years between testicular enlargement and completion of puberty.(\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\u003cp\u003ePuberty represents the maturation of the hypothalamic-pituitary-gonadal (HPG) axis and pathologies affecting this axis can result in either precocious or delayed puberty. Both precocious and delayed puberty can result from central or peripheral causes. Pathologies affecting the hypothalamic-pituitary axis result in central disturbance of the pubertal process, while pathologies affecting the gonads result in peripheral disturbance of the pubertal process. (\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eGonadotropin-dependent precocious puberty and hypogonadotrophic hypogonadism are a very common pediatric endocrinological problem and are a common cause of referral to a pediatric endocrinologist. Evaluation of these cases usually includes magnetic resonance imaging of the brain and sella searching for an underlying structural cause causing disturbance of their hypothalamic-pituitary axis.(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eRoutine evaluation by MRI of the brain and sella in these cases has longly been a point of debate. In precocious puberty the North American and European Pediatric Endocrinology societies in 2007 came to the conclusion that brain MRIs should be performed on all boys with central precocious puberty (CPP) and all girls with CPP who are younger than six years old. It is unclear, nevertheless, if females with CPP who are 6 to 8 years old should have the same procedure and their routine assessment by MRI is an established point of disagreement owing to the fact that several studies have shown that the incidence of unsuspected intra cranial lesions in these cases is low while other studies have shown that significant unsuspected pathologies still occur and can not otherwise be predicted. (\u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eIn contrast to CPP, studies assessing the incidence of intra cranial pathologies in children with delayed puberty are scarce and a consensus regarding their routine imaging is not established, yet many authors agree upon routine imaging of males who are older than 15 and females who are older than 14 years old owing to the high incidence of constitutional delay of growth and puberty in children younger than that age, particularly males aged 14 to 15 years old. (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eIn this study we tried to evaluate the prevalence of intra cranial pathologies in children with central disturbance of the pubertal process and tried to establish a correlation between different variables including the clinical status or hormonal profile and the occurrence of intra cranial pathologies to finally reach a recommendation regarding hypothalamic-pituitary axis routing imaging assessment.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003e\u0026middot; \u003cstrong\u003e\u003cu\u003eStudy population:\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis ambispective observational study was conducted during the period between April and December 2024 and included children who presented with central disturbance of the pubertal timing, referred to our institution and who had MRI examination of the brain and sella during the period between 2021 and 2024.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eApproval for this study was obtained from the Research Ethics Committee of our institution. (Ethics committee\u0026rsquo;s reference number: 0108174, IRB No: 00012098, FWA No: 00018699) All study procedures were carried out in accordance with the Declaration of Helsinki regarding research involving human subjects. Informed consent was waived from retrospectively collected cases, while informed consent was obtained from the parents of prospectively collected cases.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe diagnosis of precocious or delayed puberty was made based on clinical evaluation, plasma hormonal investigations (LH, FSH and testosterone/ oestradiol levels), and assessment of bone age. Syndromic cases or cases with functional delayed puberty were excluded, such as those suffering from malnutrition, chronic illness or those with previous history of CNS irradiation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFinally, seventy five cases were included in our study, 44 cases with precocious puberty (group I) and 31 cases with delayed puberty (group II). All the cases with delayed puberty (31 patients) and 30 out of 44 cases with precocious puberty were collected prospectively, while the remaining 14 cases with precocious puberty were collected retrospectively.\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003e\u003cu\u003ePre-imaging clinical assessment:\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBody weight was measured using a digital body-weighing scale, and height was measured in the standing position using a Harpenden stadiometer. The height standard deviation scores (SDSs) for chronological age and bone age were calculated. Tanner staging was used to determine pubertal stage. Tanner stage is also known as Sexual Maturity Ratings (SMR), which is a standardized system used to assess and classify pubertal development based on external secondary sex characteristics including breast development in females, genital development in males, and pubic hair in both sexes. The stages are numbered 1 through 5:Stage 1: Prepubertal, Stage 2: Early pubertal, Stage 3: Midpubertal, Stage 4: Late pubertal and Stage 5: Adult (postpubertal) maturity.(13,14) Bone age was determined by a pediatric endocrinologist, according to Greulich and Pyle. (15)\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003e\u003cu\u003eMRI imaging protocol:\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the cases prospectively and retrospectively collected had MRI evaluation of the brain and sella. In case of retrospectively collected cases, MRI examinations were included if performed on a closed magnet (at least 1.5 Tesla). In case of prospectively collected cases, MRI examinations were performed on one of the following machines:\u003c/p\u003e\n\u003cp\u003ea- 3T Philips MR system (Ingenia, Philips, Health care, Best, the Netherlands).\u003c/p\u003e\n\u003cp\u003eb- 3T GE Discovery MR 750 system (GE Discovery, Madison, WI, USA).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcquisition protocol:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYoung children were offered sedation to improve MRI data quality, and scans were acquired under standard sedation administered and monitored by an on-site professional anesthesiologist.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMR images were acquired with the following sequences:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA-Routine MRI brain protocol\u003c/strong\u003e: Fast spin echo (FSE) T2- weighted axial (TR 4400, TE 120, NEX 2, Matrix 384 x 320, 6 mm slice thickness, 1.0 mm gap), coronal (TR 5000, TE 122, NEX 2, Matrix 384 x 320, 6 mm slice thickness, 1 mm gap) and sagittal (TR 3400, TE 100, FOV 23, 5.5 mm slice thickness 0.5 mm gap, Matrix 256 x 224, NEX 3) sequences, 3D fast spoiled gradient-echo (FSPGR) T1-weighted sequences (TR 6.6, TE 2.6, TI 600, NEX 1, flip angle 25, matrix 192 x 192, 1.2 mm slice thickness, 0 mm gap) acquired in an axial plane and reconstructed in coronal and sagittal planes, Fluid-attenuated inversion-recovery (FLAIR) axial sequences (TR 10000, TE 95, TI 2575, NEX 1, matrix 350 x 192, 6 mm slice thickness, 0.6 mm gap), Diffusion Weighted Images; DWI (single shot, b value = 1,000 mm2/s, TR 8000, TE 78.8, NEX 1, field of view (FOV) 220 x 220, matrix 140 x 140, slice thickness 6 mm with 0.6 mm gap) and Susceptibility Weighted Images; SWI (TR 38.5ms, TE 22.9 ms, 320x224 acquisition matrix, field of view 240x192 mm, slice thickness 3 mm and a gap of 0.2 mm).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eB- \u0026nbsp; Imaging of the pituitary gland including:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea) \u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ePre-contrast sequences included\u0026nbsp;\u003c/strong\u003esagittal and coronal T1 thin sections (2.5 mm) pre-contrast (TR 400-500ms, TE 15ms, 256x256 acquisition matrix, NEX 4, field of view 100-120mm, slice thickness 2.5 mm and a gap of 0.5mm) and Sagittal and coronal T2 thin sections (2.5 mm) (TR 4000-5000ms, TE 110ms, 256x256 acquisition matrix, NEX4, field of view 100-120mm, slice thickness 2.5 mm and a gap of 0.5 mm)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eb) \u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ePost -contrast sequences included\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1- \u003cem\u003eDynamic MRI of the pituitary gland\u003c/em\u003e\u003c/strong\u003e (TR 280-350ms, TE 15ms, 192x192 acquisition matrix, NEX2, field of view 130-160mm, 2 mm slice thickness and a gap of 0.3mm).\u003c/p\u003e\n\u003ch4\u003e\u003cstrong\u003eDynamic Contrast Protocol:\u003c/strong\u003e\u003c/h4\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eIV contrast\u003c/strong\u003e: Gadolinium-based contrast agent (\u003cstrong\u003eMagnevist\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eInjection rate\u003c/strong\u003e: 1.5\u0026ndash;2 ml/sec using a power injector.\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eTotal dose\u003c/strong\u003e: 0.1 mmol/kg. (This is equivalent to: \u003cstrong\u003e0.1 mL/kg)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eDynamic Acquisition Timing\u003c/strong\u003e: Average of eight phases are acquired. The first phase is non contrast. The following post contrast phases start immediately after injection. Each phase time averages 20 seconds.\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003eSequence Type:\u003c/strong\u003e \u003cstrong\u003eT1-weighted fast spin echo (FSE) or turbo spin echo (TSE) sequence.\u003c/strong\u003e Preferably fat-saturated sequences for better lesion contrast.\u003c/p\u003e\n\u003cp\u003e2- \u003cstrong\u003e\u003cem\u003eCoronal and sagittal T1 thin section (2.5 mm) post-contrast\u003c/em\u003e\u003c/strong\u003e (TR 400-500ms, TE 15ms, 256x256 acquisition matrix, NEX4, field of view 100-120mm, slice thickness 2.5 mm and a gap of 0.5mm)\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003e\u003cu\u003eMRI data analysis and imaging evaluation:\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eExamination of the acquired imaging sequences was performed by two experienced pediatric neuroradiologists to assess the brain scans to exclude any abnormality, followed by assessment of the size of the anterior pituitary gland (volume and three dimensions), the morphology of hypothalamic-pituitary axis to detect possible presence and then location, signal pattern and potential occurrence of contrast enhancement of focal lesions or any other abnormalities.\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003e\u003cu\u003eClinico-Imaging correlation.\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePossible correlations between collected clinical data and imaging findings were sought by correlating data such as Tanner stage or clinical status and hormonal profile, LH level and LH/FSH ratio with the imaging results. Tailored correlation between gender specific age group and imaging in cases with precocious puberty was performed to tackle the popular argument regarding the imaging recommendation of those cases.\u003c/p\u003e\n\u003cp\u003e\u0026middot; \u003cstrong\u003e\u003cu\u003eStatistical analysis of the data\u0026nbsp;\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe statistical analysis of the data was performed using IBM SPSS software version 20.0 (Armonk, NY: IBM Corp, released 2011). Categorical data were summarized as numbers and percentages. For continuous data, normality was assessed using the Shapiro-Wilk test. Quantitative data were described using range (minimum and maximum), mean, standard deviation, median and interquartile range (IQR). Significance of the obtained results was judged at the 5% level.\u003c/p\u003e"},{"header":"Results","content":"\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003e\u003cu\u003ePatients\u0026rsquo; Demographics\u003c/u\u003e\u003c/strong\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eGroup I (Precocious puberty group)\u0026nbsp;\u003c/strong\u003eincluded 44 children with precocious puberty; 36 girls and 8 boys coming along the ages between 9 months \u0026amp; 9 years old. Overall, the median age was 7.75 years while the mean age was 6.65\u0026plusmn;2.27 years. \u003cstrong\u003eGroup II (Delayed puberty group)\u0026nbsp;\u003c/strong\u003eincluded 31 children with delayed puberty; 9 girls and 22 boys, coming along the ages between 14 and 17.5 years old. Overall, the median age was 17 years while the mean age was 16.61\u0026plusmn;1.28 years.\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003e\u003cu\u003eClinical and endocrinal presentation of included children:\u003c/u\u003e\u003c/strong\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eGroup I (Precocious puberty):\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAccording to their Tanner stage, precocious puberty children were subdivided into; children with early pubertal Tanner stages (stages 2\u0026amp;3) and children with late pubertal Tanner stages (stages 4\u0026amp;5); representing 46.7% and 53.3% respectively. Apart from two cases who had short stature and one case who had gigantism, all of the remaining cases had isolated precocious puberty with normal hormonal profile apart from elevated gonadotropins.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGroup II (Delayed puberty):\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll of the cases in this study group were arrested in Tanner stage 1 and hence their clinical categorization was based on whether they had another accompanying clinical/hormonal disturbance. According to their clinical status and hormonal profile, the children in this group were subdivided into; children with isolated gonadotropins deficiency and children with combined or pan hormonal disturbance; representing 48.4% (15 cases) and 51.6% (16 cases) respectively.\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003e\u003cu\u003eImaging assessment results:\u003c/u\u003e\u003c/strong\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eGroup I\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e(Precocious puberty):\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis group with a total number of 44 included 16 cases with normal MRI of the brain and sella (36.4%) and 28 cases with abnormal imaging findings (63.6%), 26 of them had an abnormality of the hypothalamic-pituitary axis (HPA) with or without other extra HPA findings (92.9) and 2 \u0026nbsp;had isolated extra HPA abnormal findings (7.1%). The most common imaging finding was anterior pituitary hyperplasia (14 cases representing 31.8% of the total number of cases and 50% of cases with abnormal imaging findings) followed by pituitary microadenoma (detected in 8 cases, representing 18.8% of the total number of cases and 28.6% of cases with abnormal imaging findings) and tuber cinereum hamartoma (detected in two cases, representing 4.5% of the total number of cases and 7.1% of cases with abnormal imaging findings). Smaller number of cases showed anterior pituitary hypoplasia, craniopharyngioma and Rathke\u0026rsquo;s cleft cyst (one case each). \u003cstrong\u003e(Figures 1-4)\u003c/strong\u003e\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGroup II\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e(Delayed puberty):\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis group with a total number of 31 included 10 cases with normal MRI findings (32.3%) and 21 cases with abnormal imaging findings (67.7%), all of them had an abnormality of the hypothalamic-pituitary axis with or without other extra HPA findings and none had isolated extra HPA abnormal findings. The most common imaging findings in this group were anterior pituitary hypoplasia (detected in nine cases representing 29% of the total number of cases and 42.8% of cases with abnormal imaging findings) followed by Pituitary stalk interruption syndrome (detected in five cases, representing 16.1% of the total number of cases and 23.8% of the cases with abnormal imaging finding). Pituitary microadenoma and Rathke\u0026rsquo;s cleft cyst were detected in two cases each while craniopharyngioma, pituitary hyperplasia and partial empty sella were detected in one cases each. (\u003cstrong\u003eFigures 5-7)\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u003cstrong\u003e\u003cu\u003eClinico-Imaging correlation results:\u003c/u\u003e\u003c/strong\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eFor such aim, we assessed the clinical status and pattern of hormonal profile abnormality of each child as well as their basal gonadotropins levels and ratio. We then proceeded to statistically analyze their changes with MRI findings.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGroup I: (Precocious puberty)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this group, we correlated their Tanner stage, basal LH level and basal LH/FSH ratio with their MRI findings. \u003cstrong\u003eNo relation\u003c/strong\u003e was found between MRI findings and Tanner stage, basal LH level or basal LH/FSH ratio.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe prevalence of abnormal MRI results didn\u0026rsquo;t differ in accordance with the child\u0026rsquo;s Tanner stage or with his basal LH level or basal gonadotropins ratio. Also of note is that most of our cases suffered from precocious puberty solely, apart from three cases who had accompanying hormonal disturbance in the form of growth hormone excess or deficiency and all the cases had free neurological examination apart from two cases who suffered from sequelae of previous MCA stroke and meningo-encephalitis.\u003c/p\u003e\n\u003cp\u003eThe three cases with accompanying hormonal disturbance were an 8-year-old girl who suffered from growth hormone deficiency and also rapid progression of pubertal stages and she had an anterior pituitary microadenoma on MRI. The other two children were males, one aged 5 years old with associated GH deficiency\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eand Chiari 1 malformation on MRI and the other was 9 years old with growth hormone excess and pituitary hyperplasia on MRI. \u0026nbsp;So, MRI results couldn\u0026apos;t be predicted from the child\u0026rsquo;s clinical status or basal LH level or basal gonadotropins ratio and the only helpful clue was accompanying hormonal disturbance which occurred only in a minority of cases and couldn\u0026apos;t be relied upon.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTailored correlation between MRI findings and gender-specific age group in precocious puberty group\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTackling the popular argument of whether females with central precocious puberty and aged 6 to 8 years old should perform magnetic resonance imaging of the brain and sella routinely or not, we compared the prevalence of abnormal imaging findings in that particular group and the remaining study population; comprised of females younger than 6 years old and all the males. Surprisingly the prevalence of abnormal MRI findings was slightly higher in that group compared to the rest of the study population; 64.3% versus 62.5% respectively, moreover, the prevalence of neoplastic lesions was even higher; 25% versus 12.5%, though that difference wasn\u0026rsquo;t statistically significant. \u003cstrong\u003e(Table 1)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1: Relation between MRI findings and age and gender in precocious puberty group (n = 44)\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"532\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 261px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 75px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 130px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFemale (6 \u0026ndash; \u0026ge;8)\u003cspan dir=\"RTL\"\u003e\u003cbr\u003e\u0026nbsp;\u003c/span\u003e(n = 28)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 131px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFemale \u0026nbsp;(\u0026lt;6) or males (n = 16)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMRI findings\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 195px;\"\u003e\n \u003cp\u003eNormal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e35.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e37.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 75px;\"\u003e\n \u003cp\u003e0.906\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 195px;\"\u003e\n \u003cp\u003eAbnormal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e64.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e62.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHypothalamic-pituitary axis abnormality\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003eHypoplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e6.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u003csup\u003eFE\u003c/sup\u003ep=0.364\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMicroadenoma\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e21.4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e12.5\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003csup\u003eFE\u003c/sup\u003e\u003c/strong\u003e\u003cstrong\u003ep=0.689\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003eHyperplasia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e35.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e25.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u003csup\u003eFE\u003c/sup\u003ep=0.314\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCraniopharyngioma\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e3.6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003csup\u003eFE\u003c/sup\u003e\u003c/strong\u003e\u003cstrong\u003ep=1.000\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003eHamartoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e12.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u003csup\u003eFE\u003c/sup\u003ep=0.127\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003eRCC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u003csup\u003eFE\u003c/sup\u003ep=1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eExtra HPA abnormality\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003eTemporal arachnoid cyst\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u003csup\u003eFE\u003c/sup\u003ep=1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003eCHIARI 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e6.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u003csup\u003eFE\u003c/sup\u003ep=0.364\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003eMCA infarct\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u003csup\u003eFE\u003c/sup\u003ep=1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003eCerebellar atrophy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u003csup\u003eFE\u003c/sup\u003ep=1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 195px;\"\u003e\n \u003cp\u003ePVL\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 65px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u003csup\u003eFE\u003c/sup\u003ep=1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u0026chi;\u003csup\u003e2\u003c/sup\u003e\u003cstrong\u003e\u0026nbsp;Chi square test, FET: Fisher Exact test,\u0026nbsp;\u003c/strong\u003ep: p value for Relation between Age with MRI findings.\u003cstrong\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/strong\u003ePVL: periventricular leukomalicia, RCC: Rathke\u0026rsquo;s cleft cyst, \u0026nbsp;*: Statistically significant at p \u0026le; 0.05\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGroup II: (Delayed puberty)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA \u003cstrong\u003esignificant positive correlation\u0026nbsp;\u003c/strong\u003ewas found between abnormal MRI findings and combined hormonal disturbance/panhypopituitarism; abnormal MRI findings were significantly higher in children with combined hormonal disturbance/ panhypopituitarism in comparison to children with isolated gonadotropins deficiency. In contrast to precocious puberty, combined hormonal disturbance occurred in a significant proportion of the cases with delayed puberty and it can be relied upon as a predictive factor for abnormal MRI results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNo correlation\u0026nbsp;\u003c/strong\u003ewas found between MRI findings and basal LH level or basal LH/FSH ratio. Similar to precocious puberty, the prevalence of abnormal MRI results didn\u0026rsquo;t differ in accordance with the child\u0026rsquo;s \u0026nbsp;gonadotropins level or ratio. \u003cstrong\u003e(Table 2)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2: Relation between MRI findings and pattern of hormonal disturbance, basal LH level and basal LH/FSH ratio in delayed puberty group (n = 31)\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"575\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 302px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMRI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 158px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbnormal\u003cbr\u003e\u0026nbsp;(n = 21)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNormal\u003cbr\u003e\u0026nbsp;(n = 10)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 193px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 193px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHormonal disturbance\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 193px;\"\u003e\n \u003cp\u003eIsolated gonadotropin deficiency\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e33.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e80.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 79px;\"\u003e\n \u003cp\u003e\u003csup\u003eFE\u003c/sup\u003ep=\u003cbr\u003e0.023\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 193px;\"\u003e\n \u003cp\u003eCombined hormonal disturbance/Panhypopitu-itarism\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 84px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e66.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e20.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 193px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBasal LH\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 158px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 193px;\"\u003e\n \u003cp\u003eMin. \u0026ndash; Max.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 158px;\"\u003e\n \u003cp\u003e0.01 \u0026ndash; 3.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 144px;\"\u003e\n \u003cp\u003e0.10 \u0026ndash; 6.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0.118\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 193px;\"\u003e\n \u003cp\u003eMean \u0026plusmn; SD.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 158px;\"\u003e\n \u003cp\u003e0.86 \u0026plusmn; 0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 144px;\"\u003e\n \u003cp\u003e2.35 \u0026plusmn; 2.59\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 193px;\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 158px;\"\u003e\n \u003cp\u003e0.45 (0.20 \u0026ndash; 1.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 144px;\"\u003e\n \u003cp\u003e0.73 (0.60 \u0026ndash; 4.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 193px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBasal LH/FSH\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 158px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 79px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 193px;\"\u003e\n \u003cp\u003eMin. \u0026ndash; Max.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 158px;\"\u003e\n \u003cp\u003e0.09 \u0026ndash; 2.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 144px;\"\u003e\n \u003cp\u003e0.06 \u0026ndash; 4.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 79px;\"\u003e\n \u003cp\u003e0.145\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 193px;\"\u003e\n \u003cp\u003eMean \u0026plusmn; SD.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 158px;\"\u003e\n \u003cp\u003e0.61 \u0026plusmn; 0.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 144px;\"\u003e\n \u003cp\u003e1.66 \u0026plusmn; 1.67\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 193px;\"\u003e\n \u003cp\u003eMedian (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 158px;\"\u003e\n \u003cp\u003e0.32 (0.15 \u0026ndash; 0.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 144px;\"\u003e\n \u003cp\u003e1.19 (0.46 \u0026ndash; 1.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eIQR:\u003cstrong\u003e\u0026nbsp;Inter quartile range\u003c/strong\u003e , SD: \u003cstrong\u003eStandard deviation, U: Mann Whitney test \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026chi;\u0026nbsp;\u003c/strong\u003e\u003csup\u003e2\u003c/sup\u003e: \u003cstrong\u003eChi square test\u003c/strong\u003e, p: p value for Relation between MRI with different parameters\u003cstrong\u003e,\u0026nbsp;\u003c/strong\u003e*: Statistically significant at p \u0026le; 0.05 \u0026nbsp;\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study we focused on assessment of the brain and hypothalamic pituitary axis in children with central precocious or delayed puberty in a trial to estimate the prevalence of intracranial abnormalities detected by MRI and to stratify these data by gender and age. Particular attention was given to females suffering from precocious puberty and aged 6 to 8 years old, whose routine imaging assessment is debatable with emphasis on significant pathologies which may impact their management plan to eventually reach a solid recommendation regarding the routine imaging assessment of each group individualized to our pediatric population.\u003c/p\u003e\u003cp\u003eAdditionally we tried to correlate the imaging results with the child\u0026rsquo;s clinical status and hormonal profile to find out if these inputs can predict the imaging results or alter the radiologic assessment recommendation.\u003c/p\u003e\u003cp\u003eSo, in the current study we tried to answer three main questions and then use the answers in formulating an imaging recommendation for children presenting with central disturbance of pubertal timing. The three questions were; what is the nature and prevalence of abnormal intra cranial MRI findings?, the second question was, is there a correlation between the clinical data and the imaging results through which the occurrence of abnormal imaging findings could be predicted clinically ? and the third question was, what is the impact of the imaging results on the child\u0026rsquo;s management plan?.\u003c/p\u003e\u003cdiv id=\"Sec24\" class=\"Section2\"\u003e\u003ch2\u003ePrecocious puberty group:\u003c/h2\u003e\u003cp\u003e In the current study we tried to avoid the routinely followed categorization method of abnormal intra cranial findings in previous studies which divided them into pathological, incidental and findings of questionable relationship with precocious puberty in which the distribution of the individual abnormalities are not standardized and what was considered to be incidental in one study was considered to be pathological in another.\u003c/p\u003e\u003cp\u003eIn our study we categorized our results as abnormalities of the hypothalamic pituitary axis (HPA) with or without extra HPA abnormalities and isolated extra HPA abnormalities with normal HPA.\u003c/p\u003e\u003cp\u003eWe found this pattern of categorization as the most reproducible and the most consistent with the continued study and research by which the previously unrevealed relation of certain pathologies to precocious puberty is established.\u003c/p\u003e\u003cdiv id=\"Sec25\" class=\"Section3\"\u003e\u003ch2\u003eWhat was the nature and prevalence of abnormal intra cranial MRI findings?\u003c/h2\u003e\u003cp\u003eAbnormal imaging findings were detected in 63.6% (28 in number) of the cases, 92.9% (26 in number) of which were detected in the hypothalamic-pituitary axis (HPA) with or without other extra HPA abnormal findings with anterior pituitary hyperplasia representing the most predominantly detected abnormality present in 50% of the cases (14 in number) with abnormal imaging results.\u003c/p\u003e\u003cp\u003eAnterior pituitary microadenoma comes second followed by tuber cinereum hamartoma representing 28.6% and 7.1% of the cases respectively. Anterior pituitary hypoplasia, supra sellar craniopharyngioma as well as isolated extra hypothalamic-pituitary axis findings represented by temporal arachnoid cyst and Chiari 1 represent 3.6% of the cases each.\u003c/p\u003e\u003cp\u003eAll of the detected abnormalities in our study were also reported in similar previous studies (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e), although the detected abnormalities differed between the studies and still several previously reported abnormalities weren\u0026rsquo;t detected in our study at all.\u003c/p\u003e\u003cp\u003eSimilar to previous studies (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e), the two cases of tuber cinereum hamartomas occurred in females at very young age before the age of four years old and were associated with advanced bone age and very high gonadotropins levels.\u003c/p\u003e\u003cp\u003eThe high prevalence of abnormal imaging findings in our study in comparison to previous studies may be related to the high proportion of cases with anterior pituitary hyperplasia in our study which is usually not reported in other studies as anterior pituitary hyperplasia itself is considered as a manifestation or proof of central precocious puberty rather than its cause and these cases are still considered to have idiopathic CPP (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e), furthermore this finding doesn\u0026rsquo;t impact the child\u0026rsquo;s management plan.\u003c/p\u003e\u003cp\u003eIn our study we reported anterior pituitary hyperplasia to demonstrate its high prevalence which in so many cases is misdiagnosed as anterior pituitary macroadenoma or other pathology.\u003c/p\u003e\u003cp\u003eTaking this into consideration and reevaluating our cases, abnormal imaging findings -excluding anterior pituitary hyperplasia- were present in 38.6% of the cases (17 in number); 37.5% of the males (3 in number) and 38.9% of the females (14 in number). The prevalence of CNS abnormalities in boys in our study was lower than what is previously reported to be as high as 75% and 92% by Choi et al and Faizah et al respectively (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e)\u003csup\u003e,\u003c/sup\u003e but higher than what is reported to be as low as 7% by Yoon et al (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn contrast to the previously reported low prevalence of intra cranial abnormalities in females in several studies as shown by the meta analysis performed by Cantas-Orsdemir et al (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e), Faizah et al (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) reported high prevalence of intra cranial pathologies in females similar to our study reaching 45% but they reported an exceedingly high prevalence of intra cranial abnormalities in boys reaching 92% in contrast to ours.\u003c/p\u003e\u003cp\u003eThe females aged 6 to 8 years old (28 in number) were further evaluated to detect the prevalence of abnormal imaging findings in this particular age group whose routine imaging assessment is debatable.\u003c/p\u003e\u003cp\u003eAbnormal imaging findings were detected in 39.3% of these cases and neoplastic lesions were detected in 25%, compared to only 37.5% and 12.5% respectively in the males and females younger than 6 years old. The overall prevalence of abnormal imaging findings as well as the prevalence of neoplastic lesions in girls aged 6 to 8 years old was higher in our study relative to previous studies conducted by Pedicelli et al (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)and Yoon et al (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec26\" class=\"Section3\"\u003e\u003ch2\u003eWas there a correlation between the child\u0026rsquo;s clinical data and his imaging result?\u003c/h2\u003e\u003cp\u003eIn our study abnormal imaging findings couldn't be predicted based on the child\u0026rsquo;s age, gender, Tanner stage or basal gonadotropins level or ratio which goes in agreement with the previous results reported by Ng et al (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) but contrasting the results reported by Bajpai et al (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eChoi et al (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) similar to our results reported no correlation between MRI findings and Tanner stage or LH level, but they reported a correlation with age of onset of the pubertal disturbance.\u003c/p\u003e\u003cp\u003eOh et al (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) reported very similar results to our study with positive brain MRI findings observed in 37.7%, no significant differences in sex or age were found in incidence of pituitary abnormalities or non pituitary incidental findings as well as no significant differences in laboratory findings were identified between patients with CPP and abnormal versus normal MRI findings. None of the clinical characteristics including puberty stage or bone age\u0026thinsp;\u0026minus;\u0026thinsp;chronological age, were significantly correlated with pituitary abnormalities on MRI.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec27\" class=\"Section3\"\u003e\u003ch2\u003eWhat was the impact of imaging results on the child\u0026rsquo;s management plan?\u003c/h2\u003e\u003cp\u003eThe standard management plan for cases with idiopathic CPP is medical treatment which can be modified to surgical management in certain cases with organic causes detected on imaging. At least two of our cases diagnosed with microadenomas were surgically managed and unfortunately the case of craniopharyngioma was lost to follow up.\u003c/p\u003e\u003cp\u003eThe two cases with tuber cinereum hamartomas didn\u0026rsquo;t require surgical management and were adequately controlled on medical treatment with imaging follow up.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec28\" class=\"Section2\"\u003e\u003ch2\u003eOur recommendation for routine imaging assessment in cases of precocious puberty\u003c/h2\u003e\u003cp\u003eBased on the previously discussed results showing high prevalence of organic causes of CPP and which couldn't be predicted based on the child\u0026rsquo;s clinical status or gonadotropins level and which were also very high in the females aged 6 to 8 years old, we recommend performing routine magnetic resonance imaging of the brain and sella in all children presenting with central precocious puberty including girls aged 6 to 8 years old irrespective of their Tanner stage or Gonadotropins level.\u003c/p\u003e\u003cp\u003eThough other researchers as Pedicelli et al (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) didn\u0026rsquo;t recommend routine MRI screening in females with CPP aged 6 to 8 years old, our recommendations are consistent with those of several other researchers including Mogensen et al (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e) who reported that a high frequency of their 6\u0026ndash;8 year old girls with early or precocious puberty had a pathological brain MRI, which could not be predicted from any clinical or biochemical parameters in their study and hence they -similar to us- believed that girls with precocious pubertal development of central origin before 8 years of age should continue to be screened by MRI.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec29\" class=\"Section2\"\u003e\u003ch2\u003eDelayed puberty group\u003c/h2\u003e\u003cdiv id=\"Sec30\" class=\"Section3\"\u003e\u003ch2\u003eWhat was the nature and prevalence of abnormal intra cranial MRI findings?\u003c/h2\u003e\u003cp\u003eAbnormal imaging findings had a high prevalence and were detected in 67.7% (21 in number) of the cases (63.6% of the males and 70% of the females), all of them involved the hypothalamic-pituitary axis with or without other extra HPA findings.\u003c/p\u003e\u003cp\u003eThe most prevalent imaging finding was anterior pituitary hypoplasia (42.8%) followed by pituitary stalk interruption syndrome (23.8%) and three cases (two females and one male) representing 14.3% had neoplastic lesions; two cases had microadenomas (9.5%) and one case had craniopharyngioma (4.8%). Two cases with RCCs (9.5%), a case with partial empty sella and another with anterior pituitary hyperplasia were detected (4.8% each).\u003c/p\u003e\u003cp\u003eUnfortunately, we couldn't adequately study male children aged 14 to 15 years old and whose routine imaging assessment is controversial owing to the fact that most males at that age have constitutional delay of growth and puberty. Our study included only two males aged 14 to 15 years, one of them with isolated gonadotropins deficiency and whose imaging assessment was normal and the other had combined hormonal deficiency and his imaging assessment revealed anterior pituitary hypoplasia and absent posterior pituitary bright spot.\u003c/p\u003e\u003cp\u003eIn contrast to precocious puberty which is vastly studied with estimation of the prevalence of intra cranial pathology in affected children with attention given to both males and females- though higher attention is of course given to females owing to the much higher incidence of such pubertal disturbance in them-, delayed puberty didn\u0026rsquo;t get the same attention considering studying the prevalence of intra cranial pathology in affected children.\u003c/p\u003e\u003cp\u003eThough our study is different in its design from the previous studies studying hypogonadotrophic hypogonadism or delayed puberty, still the intra cranial abnormalities detected in our study were also detected in previous studies assessing hypogonadotrophic hypogonadism, multiple pituitary hormone deficiencies or in case reports of cases presenting with delayed puberty.(\u003cspan additionalcitationids=\"CR29 CR30 CR31 CR32 CR33\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e)\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec31\" class=\"Section2\"\u003e\u003ch2\u003eWas there a correlation between the child\u0026rsquo;s clinical data and his imaging result?\u003c/h2\u003e\u003cp\u003eSimilar to precocious puberty, imaging results couldn\u0026rsquo;t be predicted based on the level of basal gonadotropins or their ratio, but the incidence of abnormal imaging findings was significantly higher in children with combined hormonal disturbance or panhypopituitarism (87.5%) in comparison to children with isolated gonadotropins deficiency (46.7%) and also it is worth noting that the incidence of combined hormonal disturbance or panhypopituitarism occurred in a significant proportion of the cases with delayed puberty in contrast to precocious puberty which makes it a reliable predictor of the imaging results.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec32\" class=\"Section2\"\u003e\u003ch2\u003eWhat was the impact of imaging results on the child\u0026rsquo;s management plan?\u003c/h2\u003e\u003cp\u003eAs in the case of precocious puberty, the standard management plan for cases with hypogonadotrophic hypogonadism is either medical treatment or watchful observation for spontaneous occurrence of puberty as most of the cases suffer from constitutional delay of growth and puberty.\u003c/p\u003e\u003cp\u003eThe typical management plan was altered in certain cases in our study resorting to surgical management in the cases with craniopharyngioma and one of the cases with Rathke\u0026rsquo;s cleft cysts which was large in size with significant mass effect resulting in panhypopituitarism.\u003c/p\u003e\u003cp\u003eThe other significant impact of the imaging results on the management plan was the possible prediction of the occurrence of persistent hypogonadotrophic hypogonadism in certain cases as those with pituitary stalk interruption syndrome or marked anterior pituitary hypoplasia which would necessitate initiation of therapy without residing to a period of observation as spontaneous occurrence of puberty in those cases is unlikely and it also may predict the need for long term replacement therapy.\u003c/p\u003e\u003cdiv id=\"Sec33\" class=\"Section3\"\u003e\u003ch2\u003eOur recommendation for routine imaging assessment in cases of primary hypogonadotrophic delayed puberty\u003c/h2\u003e\u003cp\u003eBased on the previously discussed results showing very high incidence of intra cranial pathologies in cases with primary hypogonadotrophic delayed puberty and their significant impact on the child\u0026rsquo;s management plan but also taking into consideration that the mean age of the cases assessed in this study was relatively advanced which may have played a significant role in the occurrence of such high prevalence of intra cranial pathologies in our study and also considering the well established fact that most cases of primary hypogonadotrophic delayed puberty at younger age are due to constitutional delay of growth and puberty and the limited resources, we recommend watchful postponing imaging assessment for one year after the onset of delayed puberty in cases with isolated hypogonadotrophic delayed puberty and with free neurological exam and then routinely performing magnetic resonance imaging of the brain and sella in all the cases.\u003c/p\u003e\u003cp\u003eThe significantly high incidence of abnormal imaging findings in cases presenting with combined hormonal disturbance or panhypopituitarism, warrants imaging assessment of children presenting early and suffering such a condition.\u003c/p\u003e\u003cp\u003eOur recommendation is similar to the recommendation of Harrington et al (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) who stated that MRI should be obtained in any patient with suggestive clinical features of intracranial pathology. Absent such concerns, they balance between potential for undiagnosed disorders and resource utilization by waiting until youth are older (girls \u0026gt; 14 years and boys \u0026gt; 15 years) but then routinely perform MRI in youth without evidence of endogenous puberty.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec34\" class=\"Section3\"\u003e\u003ch2\u003ePoints of strength of the current study\u003c/h2\u003e\u003cp\u003eStudying both aspects of pubertal timing disturbance illustrated the difference in the overall prevalence of abnormal imaging findings as well as the difference in the prevalence of individual abnormalities between both disorders.\u003c/p\u003e\u003cp\u003eStudying the prevalence of intra cranial abnormalities in primary hypogonadotrophic delayed puberty which in contrast to central precocious puberty is scarcely studied, including both sexes and taking into consideration the pattern of their hormonal disturbance whether isolated or combined.\u003c/p\u003e\u003cp\u003ePerforming our imaging studies using 1.5 \u0026amp; 3 Tesla closed magnet machines and with administration of contrast material to all the cases avoided the underestimation of the prevalence of certain pathologies such as microadenomas which may otherwise have been missed and also allowed for a firmer diagnosis of tuber cinereum hamartomas differentiating them from hypothalamic gliomas.\u003c/p\u003e\u003cp\u003eStudying the prevalence and nature of imaging abnormalities in the female population aged 6 to 8 years with precocious puberty as well as their adequate representation in our study population allowed reviewing and changing the mainstream recommendation denying the need for their imaging assessment.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\n\u003ch3\u003eLimitations\u003c/h3\u003e\n\u003cp\u003eThe relatively small sample size and advanced mean age of the cases of delayed puberty which prevented better assessment of the prevalence of abnormal imaging findings in males aged 14 to 15 years.\u003c/p\u003e\u003cp\u003eThe prospective collection of most of our cases which didn\u0026rsquo;t allow for an adequate period of follow up for the cases to adequately assess the impact of the reported imaging results on the child\u0026rsquo;s management plan.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eAbnormal hypothalamic pituitary axis MRI findings are prevalent in children with precocious puberty, including females aged 6 to 8 years old with even a higher prevalence of abnormal imaging findings in general and neoplastic lesions in particular in this group compared to other groups in contrast to the common assumption. Such findings can\u0026rsquo;t be predicted from the child\u0026rsquo;s age, gender, basal gonadotropins level/ratio or Tanner stage.\u003c/p\u003e\u003cp\u003eAbnormal hypothalamic pituitary axis MRI findings are also highly prevalent in children with delayed puberty and they can significantly impact the child\u0026rsquo;s management plan. A higher incidence of abnormal imaging results could be predicted from accompanying clinic-hormonal disturbance and it can be reliably used as a marker for imaging recommendation. MRI of the brain and sella is recommended in all delayed puberty children with combined hormonal disturbance or panhypopituitarism. In absence of such urging factors for imaging assessment, watchful postponing of imaging until females are older than 14 and males are older than 15 years old is recommended.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eCPP\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ecentral precocious puberty\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eHPA\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eHypothalamic pituitary axis\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003e\u003cb\u003eRCC\u003c/b\u003e\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eRathke\u0026rsquo;s cleft cyst\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cb\u003e-Ethics approval and consent to participate\u003c/b\u003e\u003c/p\u003e\u003cp\u003e Approval for this study was obtained from the Research Ethics Committee of Alexandria Faculty of Medicine. (Ethics committee\u0026rsquo;s reference number: 0108174, IRB No: 00012098, FWA No: 00018699) All study procedures were carried out in accordance with the Declaration of Helsinki regarding research involving human subjects. Informed consent was waived from retrospectively collected cases, while informed consent was obtained from the parents of prospectively collected cases.\u003c/p\u003e\u003cp\u003e\u003cb\u003e-Consent for publication\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e'Not applicable'\u003c/p\u003e\u003cp\u003e\u003cb\u003e-Disclosures\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe authors have nothing to disclose.\u003c/p\u003e\u003cp\u003e\u003cb\u003e-Availability of data and material\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\u003cp\u003e\u003cb\u003e-Competing interests\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\u003cp\u003e\u003ch2\u003e-Funding:\u003c/h2\u003e\u003cp\u003eThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAA, TR and AB drafted the manuscript. AA, AB and SE collected the data. AA and AB edited the images. SE performed the clinical assessment and management for the patients. All authors read and approved the final manuscript\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eViner RM, Allen NB, Patton GC. Puberty, developmental processes, and health interventions. In: Bundy DAP, de Silva N, Horton S, Jamison DT, Patton GC, editors. Disease Control Priorities, Third Edition: Volume 8. Child and Adolescent Health and Development [Internet]. Washington (DC): International Bank for Reconstruction and Development / The World Bank; 2017. Nov 20. 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J Pediatr Endocrinol Metab. 2002;15(8):1173\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChoi JH, Shin YL, Yoo HW. Predictive factors for organic central precocious puberty and utility of simplified gonadotropin-releasing hormone tests. Pediatr Int. 2007;49(6):806\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOh YR, Kim YJ, Oh KE, Park GH, Kang E, Nam H-K, et al. Brain magnetic resonance imaging (MRI) findings in central precocious puberty patients: is routine MRI necessary for newly diagnosed patients? Ann Pediatr Endocrinol Metab. 2023;28(3):200\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMogensen SS, Aksglaede L, Mouritsen A, S\u0026oslash;rensen K, Main KM, Gideon P, et al. Pathological and incidental findings on brain MRI in a single-center study of 229 consecutive girls with early or precocious puberty. PLoS ONE. 2012;7(1):e29829.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMaione L, Sarfati J, Gonfroy-Leymarie C, Salenave S, Brailly-Tabard S, Chanson P, et al. Reproductive phenotypes in men with acquired or congenital hypogonadotropic hypogonadism: a comparative study. J Clin Endocrinol Metab. 2022;107(7):e2812\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBrioude F, Bouligand J, Trabado S, Francou B, Salenave S, Kamenicky P, et al. Non-syndromic congenital hypogonadotropic hypogonadism: clinical presentation and genotype\u0026ndash;phenotype relationships. Eur J Endocrinol. 2010;162(5):835\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eVarimo T, Miettinen PJ, K\u0026auml;ns\u0026auml;koski J, Raivio T, Hero M. Congenital hypogonadotropic hypogonadism, functional hypogonadotropism or constitutional delay of growth and puberty? An analysis of a large patient series from a single tertiary center. Hum Reprod. 2017;32(1):147\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang F, Han J, Shang X, Li G. Distinct pituitary hormone levels of 184 Chinese children and adolescents with multiple pituitary hormone deficiency: a single-centre study. BMC Pediatr. 2019;19(1):113.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMabreh LQ, Al Rabab\u0026rsquo;ah AM. Pituitary stalk interruption syndrome (PSIS) presenting in a Jordanian male patient with short stature and delayed puberty: a case report. Egypt J Radiol Nucl Med. 2023;54(1):56.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGutch M, Kumar S, Razi SM, Saran S, Gupta KK. Pituitary stalk interruption syndrome: case report of three cases with review of literature. J Pediatr Neurosci. 2014;9(2):188\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eİnci MF, \u0026Ouml;zkan F, Bozkurt S, Demir CF. A rare presentation of craniopharyngioma: delayed puberty. Case Rep. 2012;2012:bcr2012007519.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Central precocious puberty, Delayed puberty, Hypothalamic-pituitary axis","lastPublishedDoi":"10.21203/rs.3.rs-7437028/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7437028/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eMagnetic resonance imaging of the brain and pituitary gland has become an exceedingly helpful tool in the evaluation of children suffering from central precocious or delayed puberty with a high capability of detecting possible causative intra cranial pathologies, however the routine use of MRI for the evaluation of all children suffering these conditions has longly been debatable.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003eTo determine the incidence of abnormal hypothalamic-pituitary axis imaging findings in children with puberty related disturbances and correlate between the imaging findings and the clinical and hormonal profile of the affected children\u003c/p\u003e\u003ch2\u003eMaterials and methods\u003c/h2\u003e\u003cp\u003eA total of 75 children suffering from central disturbance of their pubertal timing were evaluated by MRI; 44 children diagnosed with precocious puberty and 31 children diagnosed with delayed puberty. MRI results were correlated with basal LH level and basal LH/FSH ratio in both groups and with Tanner stage in children with precocious puberty and with the pattern of pituitary hormonal disturbance in children with delayed puberty.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eA high prevalence of abnormal MRI results was detected in both groups; 63.6% in precocious puberty group (group I) and 67.7% in delayed puberty group (group II). The highest proportion of abnormalities was detected in the hypothalamic-pituitary axis in both groups; 92.9% and 100% respectively. Remarkably the prevalence of abnormal MRI results in females aged 6\u0026ndash;8 years old in precocious puberty group was higher than both males and females aged less than 6 years old and the only detected case of supra sellar adamantinomatous craniopharyngioma was detected in a female aged 6\u0026ndash;8 years old. Abnormal MRI results did not correlate with basal LH level or LH/FSH ratio in both groups, neither with Tanner stage in precocious puberty group but they had a strong positive correlation with combined hormonal disturbance/pan hypopituitarism in cases with delayed puberty.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eMRI of the hypothalamic-pituitary axis is recommended in all cases with precocious puberty including females aged 6\u0026ndash;8 years old and all cases of delayed puberty suffering from combined hormonal disturbance/pan hypopituitarism. MRI evaluation of delayed puberty cases with isolated hypogonadotrophic hypogonadsism can be watchfully postponed until males are older than 15 and females are older than 14 years old.\u003c/p\u003e","manuscriptTitle":"MRI Insights into the Hypothalamic-Pituitary Axis in Children with Central puberty related disorders","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-17 12:38:55","doi":"10.21203/rs.3.rs-7437028/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ef561fb5-e458-4df0-8649-7d3b9886f4a5","owner":[],"postedDate":"October 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-11T11:42:08+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-17 12:38:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7437028","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7437028","identity":"rs-7437028","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}