Post-operative growth is different in various forms of pediatric Cushing's syndrome

in Endocrine-Related Cancer
Authors:
Evgenia Gourgari Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics (PDEGEN), Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Pediatric Endocrinology, Georgetown University School of Medicine, Biostatistics and Clinical Epidemiology Service, National Institutes of Health Clinical Center, Department of Radiology, National Institutes of Health Clinical Center, Bethesda, Maryland, USA
Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics (PDEGEN), Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Pediatric Endocrinology, Georgetown University School of Medicine, Biostatistics and Clinical Epidemiology Service, National Institutes of Health Clinical Center, Department of Radiology, National Institutes of Health Clinical Center, Bethesda, Maryland, USA
Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics (PDEGEN), Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Pediatric Endocrinology, Georgetown University School of Medicine, Biostatistics and Clinical Epidemiology Service, National Institutes of Health Clinical Center, Department of Radiology, National Institutes of Health Clinical Center, Bethesda, Maryland, USA

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Maya Lodish Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics (PDEGEN), Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Pediatric Endocrinology, Georgetown University School of Medicine, Biostatistics and Clinical Epidemiology Service, National Institutes of Health Clinical Center, Department of Radiology, National Institutes of Health Clinical Center, Bethesda, Maryland, USA
Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics (PDEGEN), Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Pediatric Endocrinology, Georgetown University School of Medicine, Biostatistics and Clinical Epidemiology Service, National Institutes of Health Clinical Center, Department of Radiology, National Institutes of Health Clinical Center, Bethesda, Maryland, USA

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Meg Keil Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics (PDEGEN), Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Pediatric Endocrinology, Georgetown University School of Medicine, Biostatistics and Clinical Epidemiology Service, National Institutes of Health Clinical Center, Department of Radiology, National Institutes of Health Clinical Center, Bethesda, Maryland, USA
Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics (PDEGEN), Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Pediatric Endocrinology, Georgetown University School of Medicine, Biostatistics and Clinical Epidemiology Service, National Institutes of Health Clinical Center, Department of Radiology, National Institutes of Health Clinical Center, Bethesda, Maryland, USA

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Robert Wesley Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics (PDEGEN), Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Pediatric Endocrinology, Georgetown University School of Medicine, Biostatistics and Clinical Epidemiology Service, National Institutes of Health Clinical Center, Department of Radiology, National Institutes of Health Clinical Center, Bethesda, Maryland, USA

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Suvimol Hill Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics (PDEGEN), Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Pediatric Endocrinology, Georgetown University School of Medicine, Biostatistics and Clinical Epidemiology Service, National Institutes of Health Clinical Center, Department of Radiology, National Institutes of Health Clinical Center, Bethesda, Maryland, USA

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Paraskevi Xekouki Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics (PDEGEN), Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Pediatric Endocrinology, Georgetown University School of Medicine, Biostatistics and Clinical Epidemiology Service, National Institutes of Health Clinical Center, Department of Radiology, National Institutes of Health Clinical Center, Bethesda, Maryland, USA

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Charalampos Lyssikatos Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics (PDEGEN), Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Pediatric Endocrinology, Georgetown University School of Medicine, Biostatistics and Clinical Epidemiology Service, National Institutes of Health Clinical Center, Department of Radiology, National Institutes of Health Clinical Center, Bethesda, Maryland, USA

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Elena Belyavskaya Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics (PDEGEN), Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Pediatric Endocrinology, Georgetown University School of Medicine, Biostatistics and Clinical Epidemiology Service, National Institutes of Health Clinical Center, Department of Radiology, National Institutes of Health Clinical Center, Bethesda, Maryland, USA

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Sierra Maria De La Luz Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics (PDEGEN), Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Pediatric Endocrinology, Georgetown University School of Medicine, Biostatistics and Clinical Epidemiology Service, National Institutes of Health Clinical Center, Department of Radiology, National Institutes of Health Clinical Center, Bethesda, Maryland, USA

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Constantine A Stratakis Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics (PDEGEN), Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Pediatric Endocrinology, Georgetown University School of Medicine, Biostatistics and Clinical Epidemiology Service, National Institutes of Health Clinical Center, Department of Radiology, National Institutes of Health Clinical Center, Bethesda, Maryland, USA
Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics (PDEGEN), Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Department of Pediatric Endocrinology, Georgetown University School of Medicine, Biostatistics and Clinical Epidemiology Service, National Institutes of Health Clinical Center, Department of Radiology, National Institutes of Health Clinical Center, Bethesda, Maryland, USA

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Dear Editor,

Cushing's syndrome (CS) is a rare disease in children it is associated with weight gain and stunting of their linear growth (McArthur et al. 1980, Magiakou et al. 1994a, Stratakis 2012). In this study, we assessed growth in pediatric patients with CS after cure, caused by either adrenocorticotropic hormone (ACTH)-dependent Cushing's disease (CD) or a form of ACTH-independent CS, and patients with micronodular adrenal hyperplasia (MAH).

We reviewed medical records of patients who had successful transsphenoidal surgery or adrenalectomy at the NIH between the years of 2002 and 2012. A total of 18 children with CD (9 F, mean age 12.2±3.0 years) and 19 children with MAH (15 F, mean age 9.8±4.4 years) were included. All patients were evaluated under the clinical protocol 97CH0076 and 95CH0059 that were approved by the NICHD Institutional Review Board. Informed consent was signed from the patients' parents. The diagnosis of CS was established as previously reported (Batista et al. 2007). Patients that were at Tanner stage 5 at the time of surgery were excluded from the analysis of annual growth velocity and insulin-like growth factor 1 (IGF1) z scores.

The mean follow-up after surgery was 402±27 days for the CD and 365±87 days for the MAH patients (P=0.09). No significant difference was found in terms of mean age (although CD patients were 2.4 years older), gender distribution, duration of symptoms, midnight cortisol levels, IGF1 z score, and mean urinary free cortisol at the time of surgery. The demographics are presented in Table 1. The baseline height (Ht) z scores and BMI z scores were not significantly different between the two groups (P=0.85 and P=0.66 respectively; Fig. 1A).

Table 1

Clinical characteristics of CS patients at time of surgery, delta height z scores and delta BMI z scores before and after surgery, growth velocities and mutations in PRKARA1A

DiagnosisAgeTannerGenderDx heightDx BMIGrowth velocity (cm/year)PRKAR1A mutation
MAH19.9Tanner 3Female1.166−1.13812Yes
MAH23.3Tanner 1Male2.485−2.4885.5No
MAH313.8Tanner 3Male0.2430.6049.1Yes
MAH49.2Female1.006−1.29812.2No
MAH56.4Tanner 1Female0.792−0.74410.9No
MAH64.5Tanner 1Female0.842−2.9657.6No
MAH716.4Tanner 5Female0.0550.117
MAH88.5Tanner 1Male0.964−1.64612No
MAH98.6Tanner 2Female1.372−0.33813.2No
MAH1017.6Tanner 5Female0.288−0.167
MAH113.8Tanner 1Female1.551−2.51912.5No
MAH1212Tanner 3Female0.527−0.87510.8No
MAH1310.7Tanner 2Female1.098−0.95714.3Yes
MAH145.8Tanner 1Female0.477−2.2499.2No
MAH1510.8Tanner 3Female0.625−1.31111Yes
MAH164.4Tanner 1Male0.1260.3415.1Yes
MAH1715.9Tanner 5Female−0.110−0.013
MAH1813.9Tanner 5Female0.0190.216
MAH1910.6Tanner 2Female0.808−1.39911.6No
CD115.1Tanner 1Male0.550−1.7218.5
CD29.2Tanner 1Male0.500−1.5488.8
CD316.4Tanner 4Female0.113−0.6450.9
CD413.2Tanner 1Male0.972−1.03514.9
CD514.3Tanner 3Male0.272−1.6467.8
CD610.9Tanner 2Male0.965−0.40912.5
CD715.7Tanner 3Male−0.2510.0410.5
CD813.4Tanner 3Male0.315−1.9478.6
CD916.7Tanner 5Female−0.239−0.565
CD1011.1Tanner 3Female−0.241−0.5145.3
CD116.8Tanner 1Female0.773−1.2439.2
CD1212.2Tanner 2Female−1.060−0.2160
CD1310.3Male0.416−0.4977.1
CD1410.8Tanner 3Female0.556−0.47210.5
CD1510.4Tanner 4Female0.349−0.7589.2
CD1610.8Tanner 1Male−0.043−1.9004.5
CD1715.3Female1.562−0.4839.3
CD187.1Tanner 1Female0.337−1.4467.4
Figure 1
Figure 1

(A) Baseline height z scores (left) and BMI z scores (right) in CD and MAH at time of surgery. (B) Before and after surgery mean height z score in CD (left) and in MAH (right); *P=0.03 and **P=0.0002. (C) Before and after surgery mean BMI z score in CD (left) and in MAH (right); both groups improved significantly; *P<0.0001 and **P=0.0003. (D) Mean delta height z score in CD and MAH group (left) and mean delta BMI z score in CD and MAH group (right); **P=0.049. (E) Delta height z score between CD and MAH when compared for the same Tanner stage; *P=0.024 between Tanner II–III group of CD and MAH. (F) Correlation of delta height z score with delta BMI z score in CD and MAH. The open squares represent MAH, with the dashed least squares fitted line; the closed circles represent CD, with the solid least squares fitted line; correlation in MAH r=-0.67, with P=0.02.

Citation: Endocrine-Related Cancer 21, 6; 10.1530/ERC-14-0405

The mean Ht z score in CD before and after surgery was −1.24±1.14 and −0.91±1.30 respectively (P=0.03). The mean Ht z score in MAH before and after surgery was −1.33±1.64 and −0.62±1.37 respectively (P=0.0002; Fig. 1B). The mean BMI z score in CD before and after surgery was 2.07±0.62 and 1.13±1.03 respectively (P<0.0001). The mean BMI z score in MAH before and after surgery was 2.17±0.76 and 1.14±0.84 respectively (P=0.0003; Fig. 1C). The mean delta Ht z score was 0.32±0.58 in the CDs vs 0.74±0.65 in the MAH group, which was significantly better in MAH (P=0.049). The mean delta BMI z score was −0.94±0.62 in the CD group and −1.04±1.0 in the MAH group (P=0.74; Fig. 1D).

We divided each group of patients into three categories, depending on their pubertal status: Tanner 1, Tanner 2–3, and Tanner 4–5. The mean delta Ht z scores in CD vs MAH were 0.51±0.35 vs 1.03±0.78 for Tanner 1 (P=0.16); 0.08±0.66 vs 0.83±0.40 for Tanner 2/3 (P=0.024); and 0.07±0.30 vs −0.01±0.07 for Tanner 4/5 (P=0.59) (Fig. 1E).

There was a strong positive correlation between BMI z score at surgery and the delta Ht z score (r=0.69, P=0.0012) in the MAH group but not in the CD group (r=0.19, P=0.44). The correlation of the delta BMI z score with delta Ht z score also showed a strong correlation in the MAH group (r=−0.67, P=0.002) but not in the CD group (r=−0.18, P=0.48) (Fig. 1F). Bone age z score was 0.8±2 and 0.6±1.4 in the MAH and CD group respectively (P=0.64), presented previously (Lodish et al. 2014).

For patients in Tanner categories 1–4 at surgery, the mean annual growth velocity was 10.47±2.69 cm in the MAH group vs 7.35±4.06 cm in the CD group (P=0.017). The mean IGF1 z score after surgery was 0.40±1.90 vs −0.77±1.33 for the MAH and CD patients respectively (P=0.050). When we excluded from the analysis the five MAH patients who are positive for a PRKAR1A mutation (patients that could have Carney complex, and thus increased IGF1 levels), we found a significant difference in the post-surgery IGF1 z score, which was 0.98±2.03 in the MAH group vs −0.77±1.33 in the CD group (P=0.012). None of the patients in this analysis received growth hormone (GH) or thyroid hormone treatment.

This is the first study to compare, after a curative surgical procedure, the growth of pediatric patients with two forms of CS: CD and MAH. Our findings show that generally patients with MAH demonstrate better post-operative growth. There are several mechanisms that could explain the above observation.

First, the surgery can have a direct effect on the pituitary somatotrophs. In cases where the ACTH-secreting pituitary adenoma requires extensive surgical exploration, it is likely that the remaining pituitary cells will lose some of their function. Also, it is likely that the ACTH-producing tumor has a pressure effect on the somatotrophs that indirectly impairs the ability of the cells to produce GH.

Another reason is related to the direct adverse effects that the glucocorticoids have on the skeleton. It is possible that CD patients, who tend to be older, are exposed for a longer period of time to glucocorticoids, suffer vertebral fractures more frequently, and thus their skeleton and, hence their overall growth potential, is more affected. Moreover, patients with MAH can have cyclical forms of CS (Batista et al. 2007, Stratakis 2012), with hypercortisolism only intermittently present and an overall milder form of CS.

It is also possible that patients with CD are exposed to higher doses of glucocorticoids than what they need during their first 12 months of recovery. Although our group has shown that 75% of patients with CD should not require any hydrocortisone replacement by 14 months after surgery, and their glucocorticoids should be tapered starting after the first 6 months (and sometimes even sooner; Lodish et al. 2012), several patients are maintained on routine replacement for much longer, although the patients in the present study were all followed under our routine replacement doses, as described by Lodish et al.

We have recently shown that patients with CD may, in some cases, have advanced bone age due to their ACTH-stimulated adrenal androgen production and the latter's increased aromatization (Lodish et al. 2014), as well as their increased obesity and adiposity (London et al. 2014) and tendency to have higher insulin resistance (London et al. 2014) than those with MAH, especially those with PRKAR1A mutations (London et al. 2014). Thus, it is also possible that patients with CD would have decreased postoperative growth rate as a function of their advanced skeletal maturation compared with that of patients with MAH. Although this may be true in general, in the subgroup of patients included in this study, the degree of skeletal maturity at surgery was not most likely a factor, because the bone age z scores were 0.8±2 and 0.6±1.4 in the MAH and CD groups respectively (P=0.64).

In addition, the patients with the greatest improvement in their BMI values had better growth after cure. This is probably because the patients with severe obesity represent the most affected patients with CS, who also get the most benefit after cure. Whether the final adult Ht compared with their target Ht is also compromised remains to be seen.

Another possible mechanism to explain our findings may be the related to the fact that CS is associated with GH suppression (Frantz & Rabkin 1964, Krieger & Glick 1972, Magiakou et al. 1994b). Previous studies have shown that longer duration and higher degree of hypercortisolism lead to greater GH suppression (Frantz & Rabkin 1964, Krieger & Glick 1972). The GH secretion profile was abnormal even 1 year after cure of CS in a study done previously at NIH (Magiakou et al. 1994b). Some of our patients with MAH also have Carney complex and germline mutations in PRKAR1A gene (Stratakis et al. 2001). Carney complex can be associated with GH excess (Stratakis et al. 2001, Boikos & Stratakis 2006, Bertherat et al. 2009). Clinically apparent acromegaly in Carney complex occurs mostly in young adulthood (Stratakis et al. 2001, Boikos & Stratakis 2006, Bertherat et al. 2009), but it is possible that abnormal GH secretion exists in early childhood (Boikos & Stratakis 2006) and this is manifested in our patients with MAH as an earlier recovery of GH secretion than one would expect. However, even when we excluded the subset of patients with PRKAR1A mutations, the MAH patients still had higher IGF1 z scores after cure when compared with CD patients.

Finally, this study demonstrated that patients with MAH grow significantly better after surgery, even when compared with a group of CD patients of the same Tanner stage at the time of surgery (Dupuis et al. 2007). A limitation of our study is that we do not have GH secretion profiles after surgery and adult final Ht in these patients.

In conclusion, there are important messages from these clinical observations: patients with MAH are less likely to need GH therapy after surgery for their CS. On the other hand, physicians should monitor patients with CD very closely and have a low threshold for considering treatment with GH to improve their final adult Ht. Finally, every effort for improvement in BMI with lifestyle modification could potentially improve growth of children with CS after they are cured.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This study was supported by the NIH Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Clinical Trial Registration Number, NCT00001595.

Author contribution statement

E Gourgari performed most of the data collection described in the manuscript and prepared the manuscript. M Lodish is currently the principal investigator for the clinical protocols. M Keil, C Lyssikatos, and E Belyavskaya participated in the clinical care of the patients. R Wesley did the statistical analysis. S Hill was responsible for the reading and interpretation of bone age films of the patients. S M De La Luz and P Xekouki participated in the genetic analysis of the patients. C A Stratakis was the principal investigator of the clinical protocol until recently, saw all the patients, and his NIH Intramural Grant provided all of the funding for this project; he also supervised the presentation of results, design of figures, and assisted in writing this manuscript.

References

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    • PubMed
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    • Export Citation
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    • PubMed
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  • (A) Baseline height z scores (left) and BMI z scores (right) in CD and MAH at time of surgery. (B) Before and after surgery mean height z score in CD (left) and in MAH (right); *P=0.03 and **P=0.0002. (C) Before and after surgery mean BMI z score in CD (left) and in MAH (right); both groups improved significantly; *P<0.0001 and **P=0.0003. (D) Mean delta height z score in CD and MAH group (left) and mean delta BMI z score in CD and MAH group (right); **P=0.049. (E) Delta height z score between CD and MAH when compared for the same Tanner stage; *P=0.024 between Tanner II–III group of CD and MAH. (F) Correlation of delta height z score with delta BMI z score in CD and MAH. The open squares represent MAH, with the dashed least squares fitted line; the closed circles represent CD, with the solid least squares fitted line; correlation in MAH r=-0.67, with P=0.02.

  • Batista DL, Riar J, Keil M & Stratakis CA 2007 Diagnostic tests for children who are referred for the investigation of Cushing syndrome. Pediatrics 120 e575e586. (doi:10.1542/peds.2006-2402).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bertherat J, Horvath A, Groussin L, Grabar S, Boikos S, Cazabat L, Libe R, Rene-Corail F, Stergiopoulos S & Bourdeau I et al. 2009 Mutations in regulatory subunit type 1A of cyclic adenosine 5′-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes. Journal of Clinical Endocrinology and Metabolism 94 20852091. (doi:10.1210/jc.2008-2333).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Boikos SA & Stratakis CA 2006 Pituitary pathology in patients with Carney complex: growth-hormone producing hyperplasia or tumors and their association with other abnormalities. Pituitary 9 203209. (doi:10.1007/s11102-006-0265-2).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dupuis CC, Storr HL, Perry LA, Ho JT, Ahmed L, Ong KK, Dunger DB, Monson JP, Grossman AB & Besser GM et al. 2007 Abnormal puberty in paediatric Cushing's disease: relationship with adrenal androgen, sex hormone binding globulin and gonadotrophin concentrations. Clinical Endocrinology 66 838843. (doi:10.1111/j.1365-2265.2007.02822.x).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Frantz AG & Rabkin MT 1964 Human growth hormone. Clinical measurement, response to hypoglycemia and suppression by corticosteroids. New England Journal of Medicine 271 13751381. (doi:10.1056/NEJM196412312712701).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Krieger DT & Glick SM 1972 Growth hormone and cortisol responsiveness in Cushing's syndrome. Relation to a possible central nervous system etiology. American Journal of Medicine 52 2540. (doi:10.1016/0002-9343(72)90005-8).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lodish M, Dunn SV, Sinaii N, Keil MF & Stratakis CA 2012 Recovery of the hypothalamic–pituitary–adrenal axis in children and adolescents after surgical cure of Cushing's disease. Journal of Clinical Endocrinology and Metabolism 97 14831491. (doi:10.1210/jc.2011-2325).

    • PubMed
    • Search Google Scholar
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  • Lodish MB, Gourgari E, Sinaii N, Hill S, Libuit L, Mastroyannis S, Keil M, Batista DL & Stratakis CA 2014 Skeletal maturation in children with Cushing syndrome is not consistently delayed: the role of corticotropin, obesity, and steroid hormones, and the effect of surgical cure. Journal of Pediatrics 164 801806. (doi:10.1016/j.jpeds.2013.11.065).

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