Pediatric Cushing Syndrome: a unique account of a rare but important condition

Introduction

It is a pleasure to write an Editorial Commentary on the definitive and comprehensive prospective cohort study of pediatric Cushing syndrome (CS) published by Dr. Christina Tatsi et al. (1). Such articles, notably of this quality, are rarely seen in the medical literature. The series of 342 patients described by Tatsi et al. is unique in several respects. First, the size of the cohort is remarkable and spans over 30 years of knowledge and experience. Secondly, the investigation and management in a single institution, namely The Eunice Kennedy Shriver National Institute of Child Health and Human Development in Bethesda, USA, gives added value because of the conformity of investigation and management protocols. Thirdly, the comparison of clinical and biochemical data between the three etiological categories of CS, namely Cushing’s disease (CD) caused by a pituitary adrenocorticotropin hormone (ACTH)-secreting adenoma, ACTH-independent CS due to a primary adrenal-associated defect and the ectopic ACTH syndrome, is in my experience unique and very valuable.

Pediatric CS comprises a rare group of abnormalities of the hypothalamic-pituitary-adrenal axis. The current article will serve as a key reference for many years, and possibly generations, to come. The principle of centralisation of care for such a rare disorder is relevant to discuss, because the investigation of the child with possible CS is rarely practised by pediatric endocrinologists and the centre at National Institutes of Health (NIH) has become the international reference institution for this clinical problem. The accumulated clinical experience, notably that of diagnosis and treatment outcome, described by Dr. Tatsi, in my opinion, fully justifies the referral of such patients to a small number of national centres. Pediatricians seeing patients with possible CS should be encouraged to seek out the few national centers with acknowledged expertise in this condition. Such a referral pattern will take advantage of accumulated experience providing both opportunities for research and publications and a significant contribution to patient care.

Epidemiology and presenting features

There is agreement that the commonest cause of CS is CD, which was confirmed by the NIH data reporting 76% of pediatric patients to have CD, 22% had adrenal-associated, i.e., ACTH-independent, CS and 2% had ectopic ACTH syndrome (1). The incidence of pediatric CD is reported to be approximately one twentieth of that in adults (2). We reported that in prepubertal patients CD was more common in boys, but that the sex difference became equal during puberty and after puberty the majority of patients were female (3). The NIH data agree with this.

Presenting features of pediatric CS are variable and may be subtle, to the extent that the interval between onset of symptoms and diagnosis had a median length of 2 years in Tatsi’s cohort and 2.5 years in 43 pediatric patients with CD in our own centre (4). Comparison of family photographs makes a key contribution to diagnosis as the facial appearance of the child changes over time. Detailed presentation of the initial features across the range of CS etiologies emphasises the contrast between mean height standard deviation scores (SDS) being below zero and body mass index (BMI) SDS being above zero. This distinction is not present in patients presenting with simple obesity (5). Tatsi also describes that pubertal development is frequently abnormal in pediatric CS due to the combination of frequent virilization, i.e., advanced pubic hair growth, related to increased adrenal androgen secretion, combined with gonadotropin deficiency secondary to chronic hypercortisolemia (6). Mood volatility and depression with fatigue and loss of energy and behaviour changes including anxiety were frequent (1).

Investigation and diagnosis

One of the strengths of Tatsi’s article is the clear definition of biochemical diagnostic criteria. The most sensitive markers of hypercortisolemia were elevation of sleeping midnight serum cortisol, elevated urinary free cortisol and failure to suppress serum cortisol on the high-dose dexamethasone suppression test (HDDST). We have discontinued the use of the HDDST because of associated hyperglycaemia and in the low-dose dexamethasone suppression test (LDDST), cortisol suppression correlated with that during HDDST (r=+0.45, P<0.05) with >30% cortisol suppression in the LDDST predicting the diagnosis of CD (7). Plasma ACTH was predictably suppressed in adrenal-associated CS, but always detectable in CD (8). The use of the corticotropin-releasing hormone (CRH) stimulation test is described in detail, although CRH is not available in many countries.

The procedure of simultaneous inferior petrosal sinus sampling for ACTH was pioneered at the NIH. Tatsi describes this procedure, but does not appraise it critically in terms of benefit to diagnosis. The increased central to peripheral ratio of serum ACTH after stimulation with CRH demonstrates that ACTH is of central origin and therefore consistent with CD. This procedure should be performed by an interventional radiologist experienced in the investigation of adults (8). Pituitary magnetic resonance imaging (MRI) was performed in 248 NIH patients with CD and revealed a lesion of any size in 67%, thus indicating the unreliability of this investigation. Many of the corticotroph microadenomas were too small to be detected.

Primary adrenal causes of CS have strong genetic associations. Examples are; pathological variants of the PRKAR1A gene, consistent with Carney complex, in primary pigmented nodular adrenocortical disease (PPNAD), mutations of the tumor suppressor gene P53 in adrenocortical tumors and somatic mutations of the GNAS gene in McCune-Albright patients with bilateral adrenocortical hyperplasia.

Treatment and recurrence

Data on management were available for 339 NIH patients. Surgical treatment was the first line of management for all patients. Unilateral adrenalectomy was performed in patients with isolated adrenocortical tumours and bilateral adrenalectomy performed in 49 out of 57 patients with PPNAD. Eight patients had initial unilateral adrenalectomy, 6 of whom required later contralateral adrenalectomy. Transsphenoidal surgery (TSS) was the primary treatment of choice for the patients with CD. Of 203 CD patients whose first TSS was performed at the NIH, 196 (97%) achieved remission after the first operation and 12/196 achieved remission after immediate re-operation. There is no internationally agreed definition of biochemical remission following TSS for CD, however the NIH definition was a post-operative cortisol concentration of <2 µg/dL (1). In our centre, we use <1.8 µg/dL (50 nmol/L) (8).

Tatsi et al. report that of the patients operated on solely at NIH, at least 16/195 (8%), were diagnosed with recurrence of CD at a median time of 40 months (range, 0–256 months). Follow-up of the NIH patients was not consistent as many did not return to the NIH after their therapy. Overall, the prognosis was reported to be excellent after surgery for the three diagnostic sub-types of paediatric CS. Factors contributing to recurrence of CD were not specifically described in the Tatsi article. Complete removal of the microadenoma as evidenced by undetectable post-TSS serum cortisol and slow return of the functional hypothalamic-pituitary-adrenal axis have previously been reported from NIH as favorable long-term prognostic markers (9,10). Long-term follow-up of CD patients following apparent remission is however necessary because recurrence of hypercortisolaemia is clearly a possibility.

Conclusions

The article by Tatsi et al. provides a very useful account of the management of the different diagnostic components of paediatric CS. This rare and complex condition is frequently puzzling to paediatric endocrinologists who do not have the experience of investigation of such patients. The advice of adult endocrinologist colleagues is strongly recommended, with the suggestion that the adult specialist is invited to come and see the patient with the pediatrician in attendance for learning. Following investigations, referral to a pediatric surgeon for adrenal surgery and an experienced pituitary surgeon for TSS is recommended. However pituitary surgery in children is technically difficult and a surgeon with extensive practical experience and an academic interest in treatment of pediatric CD should be identified. The prognosis of pediatric CS has been shown to be excellent if diagnosis and management is performed by specialists with experience of this disorder.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Pediatrics. The article has undergone external peer review.

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-24-170/prf

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-24-170/coif). The author reports that he is chairman of the Study Steering Committee of a study organised by Recordati of Osilodrostat in pediatric Cushing disease. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

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