Transsphenoidal Surgery Leads to Remission in Children with Cushing’s Disease

Posted on January 19, 2026 by MaryO

Transsphenoidal surgery — a minimally invasive surgery for removing pituitary tumors in Cushing’s disease patients — is also effective in children and adolescents with the condition, leading to remission with a low rate of complications, a study reports.

The research, “Neurosurgical treatment of Cushing disease in pediatric patients: case series and review of literature,” was published in the journal Child’s Nervous System.

Transsphenoidal (through the nose) pituitary surgery is the main treatment option for children with Cushing’s disease. It allows the removal of pituitary adenomas without requiring long-term replacement therapy, but negative effects on growth and puberty have been reported.

In the study, a team from Turkey shared its findings on 10 children and adolescents (7 females) with the condition, who underwent microsurgery (TSMS) or endoscopic surgery (ETSS, which is less invasive) — the two types of transsphenoidal surgery.

At the time of surgery, the patients’ mean age was 14.8 years, and they had been experiencing symptoms for a mean average of 24.2 months. All but one had gained weight, with a mean body mass index of 29.97.

Their symptoms included excessive body hair, high blood pressure, stretch marks, headaches, acne, “moon face,” and the absence of menstruation.

The patients were diagnosed with Cushing’s after their plasma cortisol levels were measured, and there was a lack of cortical level suppression after they took a low-dose suppression treatment. Measurements of their adrenocorticotropic (ACTH) hormone levels then revealed the cause of their disease was likely pituitary tumors.

Magnetic resonance imaging (MRI) scans, however, only enabled tumor localization in seven patients: three with a microadenoma (a tumor smaller than 10 millimeters), and four showed a macroadenoma.

CD diagnosis was confirmed by surgery and the presence of characteristic pituitary changes. The three patients with no sign of adenoma on their MRIs showed evidence of ACTH-containing adenomas on tissue evaluation.

Eight patients underwent TSMS, and 2 patients had ETSS, with no surgical complications. The patients were considered in remission if they showed clinical adrenal insufficiency and serum cortisol levels under 2.5 μg/dl 48 hours after surgery, or a cortisol level lower than 1.8 μg/dl with a low-dose dexamethasone suppression test at three months post-surgery. Restoration of normal plasma cortisol variation, eased symptoms, and no sign of adenoma in MRI were also requirements for remission.

Eight patients (80%) achieved remission, 4 of them after TSMS. Two patients underwent additional TSMS for remission. Also, 1 patient had ETSS twice after TSMS to gain remission, while another met the criteria after the first endoscopic surgery.

The data further showed that clinical recovery and normalized biochemical parameters were achieved after the initial operation in 5 patients (50%). Three patients (30%) were considered cured after additional operations.

The mean cortisol level decreased to 8.71 μg/dl post-surgery from 23.435 μg/dl pre-surgery. All patients were regularly evaluated in an outpatient clinic, with a mean follow-up period of 11 years.

Two patients showed pituitary insufficiency. Also, 2 had persistent hypocortisolism — too little cortisol — one of whom also had diabetes insipidus, a disorder that causes an imbalance of water in the body. Radiotherapy was not considered in any case.

“Transsphenoidal surgery remains the mainstay therapy for CD [Cushing’s disease] in pediatric patients as well as adults,” the scientists wrote. “It is an effective treatment option with low rate of complications.”

 

From https://cushingsdiseasenews.com/2019/01/15/transsphenoidal-surgery-enables-cushings-disease-remission-pediatric-patients-study/

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Skeletal Maturation in Children With Cushing’s Syndrome is Not Consistently Delayed

Posted on January 13, 2026 by MaryO

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.

J Pediatr. 2014 Jan 9. pii: S0022-3476(13)01500-X. doi: 10.1016/j.jpeds.2013.11.065. [Epub ahead of print]

The Journal of Pediatrics, 01/22/2014 Clinical Article

Lodish MB, et al. – The aim of this study is to assess skeletal maturity by measuring bone age (BA) in children with Cushing syndrome (CS) before and 1–year after transsphenoidal surgery or adrenalectomy, and to correlate BA with hormone levels and other measurements. Contrary to common belief, endogenous CS in children appears to be associated with normal or even advanced skeletal maturation. When present, BA advancement in CS is related to obesity, insulin resistance, and elevated adrenal androgen levels and aromatization. This finding may have significant implications for treatment decisions and final height predictions in these children.

Methods

  • This case series conducted at the National Institutes of Health Clinical Center included 93 children with Cushing disease (CD) (43 females; mean age, 12.3 ± 2.9 years) and 31 children with adrenocorticotropic hormone–independent CS (AICS) (22 females, mean age 10.3 ± 4.5 years).
  • BA was obtained before surgery and at follow-up.
  • Outcome measures were comparison of BA in CD vs AICS and analysis of the effects of hypercortisolism, insulin excess, body mass index, and androgen excess on BA.

Results

  • Twenty-six of the 124 children (21.0%) had advanced BA, compared with the expected general population prevalence of 2.5% (P < .0001). Only 4 of 124 (3.2%) had delayed BA.
  • The majority of children (76%) had normal BA.
  • The average BA z-score was similar in the children with CD and those with AICS (0.6 ± 1.4 vs 0.5 ± 1.8; P = .8865).
  • Body mass index SDS and normalized values of dehydroepiandrosterone, dehydroepiandrosterone sulfate, androsteonedione, estradiol, and testosterone were all significantly higher in the children with advanced BA vs those with normal or delayed BA.
  • Fifty-nine children who remained in remission from CD had follow-up BA 1.2 ± 0.3 years after transsphenoidal surgery, demonstrating decreased BA z-score (1.0 ± 1.6 vs 0.3 ± 1.4; P < .0001).

From http://www.ncbi.nlm.nih.gov/pubmed/24412141

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Cushing Syndrome in Paediatric Population

Posted on November 4, 2024 by MaryO

Introduction

Cushing’s syndrome (CS) may be defined as a clinical condition characterised by signs and symptoms resulting from excessive and prolonged exposure to glucocorticoids. CS can be differentiated into an exogenous form due to high-dose and prolonged glucocorticoid treatments and an endogenous form caused by excessive cortisol secretion.
In paediatric population, the exogenous CS represents the most frequent type of CS due to the widespread therapeutic use of glucocorticoids (given by systemic or local routes) for pulmonary, renal, haematological, or rheumatological diseases, more rarely due to an unappropriated administration of glucocorticoids by parents (medical child abuse or “Munchausen syndrome by proxy”). Endogenous CS is very rare, with an overall incidence of 1.2-5 per million per year [1‐4], of which 10% of cases occurs in paediatric age [5, 6].
According to the origin of the hypercortisolism, endogenous CS can be also differentiated into an ACTH-dependent form resulting from ACTH-secreting pituitary neuroendocrine tumours (Cushing’s disease, CD) or ACTH-and or corticotropin releasing hormone (CRH) secreting neuroendocrine tumours outside the hypothalamic-pituitary area (ectopic Cushing syndrome, ECS), and an ACTH-independent form of adrenal origin (adrenal Cushing’s syndrome, ACS) (adenoma, carcinoma or bilateral adrenal hyperplasia). Finally, there are some clinical conditions, such as psychiatric disorders, severe obesity, poorly controlled diabetes mellitus, anorexia or intense physical exercise, that are associated with non-physiological hypercortisolism (non-neoplastic hypercortisolism, NNH, formerly known as Pseudo-Cushing’s syndrome) caused by chronic stimuli on hypothalamic-pituitary-adrenal axis.
NNH, particularly when characterized by moderate hypercortisolism, have often several clinical characteristics similar to CS and the first-line tests for screening endogenous hypercortisolism may provide misleading results, making the differential diagnosis very challenging. Besides the clinical history, the duration of symptoms and the first-line tests, second-line dynamic tests can be performed to better discriminate NNH from CS [7‐9]. A recent systematic review and metanalysis provide an overview about the usefulness of the second-line tests to differentiate NNH from CS [10].
Similar to adult population, CD represents the most common form of CS in paediatric age (about 75–80%), while about 15–20% of cases are ascribed to ACS and less than 2% to ectopic origin, although there is a different distribution by age [11, 12]. In fact, CD occurs often in adolescent and pre-adolescent age, while endogenous CS in children younger than 8 years is mainly caused by adrenal tumours [13, 14]. CD in younger children with a relevant family history may be caused by rare genetic causes, since the pituitary adenomas should be the first presentation of MEN1, AIP gene mutations or more rare genetic mutations (as CDKNIB or DICER1 gene) [15].
According to some large epidemiological series studies, adrenocortical tumours present a peak incidence during the first decade, with a median age at diagnosis of 3–4 years [16] and are relatively more frequent in paediatric age than in adulthood. Paediatric adrenocortical tumours are almost always functional, presenting with virilization due to excess androgen secretion alone or in combination with hypercortisolism in about 80% of cases [16]. Adrenal tumours can be isolated or in the context of predisposing genetic syndromes as Li-Fraumeni or Beckwith-Wiedemann syndrome. Primary pigmented nodular adrenocortical disease (PPNAD) is a rare congenital disorder, occurring in late adolescence, mostly (about 95% of cases) associated with the multiple endocrine neoplasia (MEN) syndrome known as Carney complex [13]. Macronodular adrenal hyperplasia is rarely reported in the paediatric population, while another form of bilateral adrenocortical hyperplasia includes the adrenal lesions in McCune-Albright syndrome, which represents the first cause of CS in infants [5, 13, 17, 18]. ECS is extremely rare in childhood, and is associated to neuroendocrine tumours, mostly bronchial, thymic, renal and duodenal or pancreatic carcinoids [5, 13, 19, 20].

Methods

An extensive MEDLINE search was performed in 2023 for the research question by two authors (LC, GP) independently, and discrepancies were resolved by discussion. A literature search was performed from 1970 to 2023. The following search words were included: “Cushing’s Syndrome, Cushing’s disease, children, childhood, diagnosis, endogenous hypercortisolism”. Search terms were linked to the Medical Subject Headings (MeSH) when possible. Keywords and free words were used simultaneously. Additional articles were identified with manual searches and included thorough review of other meta-analyses, review articles, and relevant references.

Clinical presentation of CS in children

The diagnosis of CS is often difficult due to the insidious onset of hypercortisolism, in absence of relevant early signs of the disease, as well as the rarity of the disease in childhood. For these reasons, the time to diagnosis has been reported as a mean of 33 months (95% CI 29–38) and not dissimilar to adult population [21].
In childhood, the most common and earliest sign of CS is weight gain, which becomes pathognomonic when combined with concomitant growth failure. Generally, the discrepancy between height SDS and BMI SDS is suggestive of CS, although short stature (defined as height inferior to -2 SDS) is not always reported [22, 23]. On the other hand, decreased height velocity or growth arrest always occurs in childhood CS, due to the inhibitory action of glucocorticoids on growth plate cartilage, except for subjects presenting a concomitant hyperandrogenism in which growth may be normal or even increased. Some authors have suggested to consider children with height inferior to 0 SDS and BMI over + 1.5 SDS for CS diagnosis, allowing to differentiate from subjects with simple obesity, which often present tall stature [6, 24]. Ultimately, growth arrest could be considered the main red flag sign for paediatricians in suspected CS.
Other common signs reported in childhood and adolescence include swelling of the face (as plethora or moon face), headaches, striae rubrae, acanthosis nigricans, dorsal cervical or supraclavicular fat pads and osteopenia. The main clinical findings in paediatric CS are showed in Table 1.
Table 1

Clinical characteristics of paediatric cushing syndrome (CS)
Magiakou 1994 [23]
Devoe 1997 [25]
Storr 2011 [26]
Shah 2011 [22]
Lonser 2013 [27]
Guemes 2016 [28]
Number of patients (F/M)
59 (37/22)
42 (25/17)
41 (15/26)
48 (19/29)
200 (106/94)
30 (14/16)
Period of observation
1982–1992
1974–1993
1983–2010
1988–2008
1982–2010
1983–2013
Subtype of CS
Pituitary (50)
Adrenal (6)
Ectopic (3)
Pituitary
Pituitary
Pituitary
Pituitary
Pituitary (16), Adrenal (11), Ectopic (2), Unknown (1)
Mean age at onset (y) or duration of symptoms (m)
11±4 y
9±6 y
10±3 y
NA
NA
23.6 ± 14.2 m
10.6 ± 3.6 y
12 m (6–18)
Mean age at diagnosis (range)
14±4
10±5
11±4
13.1 y (6.5–18)a
12.3 ± 3.5 y (5.7–17.8)
14.85 ± 2.5 y (9–19)
13.7 ± 3.7 y
8.9 (0.2–15.5)a
SDS Height at diagnosis (range)
-1.3±1.5
-1.0±1.3
-0.1±0.9
-1.8 (-3.5 to + 0.3)
-1.8 ± 1.3 (-1.2 to -4.2)
NAb
NA
-0.3 (-3.2 to + 3.0)c
Signs and symptoms (%)
Weight gain
90
92
98
98
93
76.6
Growth retardation
83
84
100
83
63
36.6
Facial changes
46
100
98
63
Fatigue
44
67
61
48
40
Pubertal lack or delay
60
10
Hirsutism
78
46
59
56
56.6
Acne
47
46
44
47
50
Amenorrhea (primary or secondary
78
49
Virilization
38
76
26.6
Gynecomastia
16
Osteopenia
74
Dorsal cervical fat pad
28
69
Striae rubrae
61
36
49
58
55
26.6
Acanthosis nigricans
12
75
32
Headache
26
51
38
Hypertension
47
63
49
71
36
50
Psychiatric disorders
19
44
59
46
31
43.3
Sleep disturbances
20
Muscle weakness
48
Easy bruising
28
17
25
20
Glucose intolerance or diabetes
25
7
Abbreviation. F: female; M: male; SDS: Standard deviation score; y: years; m: months; NA: not available. a median age; b 56% of subjects presented short stature; c median SDS height
The excess of adrenal androgens is responsible for the appearance of acne, hirsutism and early secondary sexual development (i.e., precocious pubic hair growth) in prepubertal children, while the consequent inhibition of gonadotropins secretion may lead of a lack or delay of pubertal development. However, in adolescence, adrenal hyperandrogenism and hypogonadism may result in menstrual changes (as oligo- or amenorrhea), virilization or gynecomastia. Adrenocortical tumours are often characterised by severe concomitant hyperandrogenism, presenting with hirsutism, acne or virilization.
Additional clinical features reported in paediatric population include depression, behaviour disorders (as anxiety, mood swings, emotional lability) and asthenia, while other typical signs of CS in adulthood as myopathy-related fatigue, easy bruising or hypertension are less common during childhood and adolescence [6, 22, 23, 25‐29].
Considering the extreme rarity of CS and the increasing incidence of obesity in childhood, an extensive screening of the entire paediatric population with obesity is not recommended. It is however important to raise awareness amongst paediatricians to recognize few key features of CS, like facial changes, weight gain with simultaneous growth failure, prepubertal virilisation as menstrual changes or hypogonadism signs in adolescence.
Since the clinical features of NNH are often indistinguishable from neoplastic CS, a good history and examination (as individual growth charts), in addition to specific diagnostic tests, are needed to better rule out any physical or psychological causes of NNH [9].
In identify the different origin of CS based on symptoms, it should be considered that ECS is more commonly associated with catabolic signs (muscle weakness, osteoporotic fractures), little or no weight gain, hypertension and hypokalaemia due to the mineralocorticoid effect of cortisol excess. In fact, very high cortisol levels can cause the saturation of the type-2 11β-Hydroxysteroid Dehydrogenase (11βHSD-2) enzyme, expressed in renal cortex and responsive to convert cortisol into inactive cortisone, leading to spillover of cortisol to the mineralocorticoid receptor. Because of this biochemical mechanism, severe hypercortisolism may be considered as a functional mineralocorticoid excess state causing hypokalaemia, increased renal tubular sodium reabsorption, consequent intravascular volume expansion and hypertension [30‐32]. However, since the clinical spectrum of presentation of ECS may overlap with CD, the differential diagnosis is challenging and requires the combination of dynamic biochemical testing and multimodal imaging, each with its own pitfalls [17, 20, 33].

Diagnostic workup for CS

Once a possible intake of exogenous corticosteroids has been ruled out through a careful medical history, the first step in the diagnostic workup is the identification of endogenous hypercortisolism.

Screening for endogenous hypercortisolism

Endogenous hypercortisolism in the paediatric population is essentially demonstrated with the following tests: 24-h urinary free cortisol (UFC), late-night salivary or serum cortisol and dexamethasone-suppression testing. Because none of these tests has 100% of diagnostic accuracy, as for adulthood, at least two tests are usually needed to confirm endogenous CS [7]. Table 2 shows the statistical features of the three diagnostic tests reported in the paediatric population.
Table 2

Diagnostic tests performed for endogenous hypercortisolism screening in the paediatric population
Author
Population Age (mean)
Subject characteristics (N)
Test
Cut-off
Sensibility
Specificity
Bickler 1994 [54]
15.7 y (pituitary)
8.1 y (adrenal)
Pituitary (10)
Adrenal (2)
UFC
> 60 mg/m2
100% (8/8)
LDDST
< 50% of basal serum cortisol
91% (10/11)
Devoe 1997 [25]
13.1 y (6.5–18)a
Pituitary (42)
UFC
> 70 µg/m2
86% (25/29)
Martinelli 1999 [49]
10.2 ± 5 y
Pituitary (5), Adrenal (6), Obese controls (21)
Late-night salivary cortisol
> 7.5 nmol/l
100% (11/11)
95.2% (20/21)
Gafni 2000 [39]
5–17 y
CS patients (14), Healthy controls (53)
UFC
> 72 µg/m2
93% (13/14)
100% (53/53)
Late-night salivary cortisol
> 7.5 nmol/l
93% (13/14)
100% (53/53)
Davies 2005 [47]
12.2 y
Pituitary (14)
Late-night serum cortisol
> 50 nmol/l [1.8 µg/dl]
100% (14/14)
Batista 2007 [38]
3–18 y
Pituitary (80), Adrenal (25), Controls (20)
UFC
> 70 µg/m2
88% (92/105) [PPV 98%]
90% (18/20) [NPV 58%]
Late-night serum cortisol
> 4.4 µg/dl
99% (104/105)
[PPV 100%]
100% (20/20) [NPV 95%]
Shah 2011 [22]
14.85 ± 2.5 y
Pituitary (48)
Late-night serum cortisol
> 3.2 µg/dl
100% (38/38)
LDDST (30 µg/kg/day [max 2 mg/day] divided every 6 h for 48 h
≥ 1.8 µg/dl
100% (48/48)
≥ 5 µg/dl
94% (45/48)
Storr 2011 [26]
12.3 ± 3.5 y
Pituitary (41)
LDDST (30 µg/kg/day [max 2 mg/day] divided every 6 h for 48 h)
< 50 nmol/l [1.8 µg/dl]
92% (35/38)
Lonser 2013 [27]
13.7 ± 3.7 y
Pituitary (200)
UFC
Age-appropriate reference
99% (177/179)
> 70 µg/m2
88% (155/177)
Late-night serum cortisol
> 7.5 µg/dl
97% (188/193)
Shapiro 2016 [40]
11.7 y (pituitary), 12.9 y (adrenal), 11.5 y (controls)
Pituitary (39), Adrenal (8), Control (19)
UFC (different assays)
Corrected for BSA
89% (34/38)
100%
Wędrychowicz 2019 [55]
11.7 y
Pituitary (4)
UFC
> 55 µg/24 h
100% (4/4)
Late-night serum cortisol
> 4.4 µg/dl
100% (4/4)
Overnight DST (1 mg at 11.00 p.m.)
< 1.8 µg/dl
75% (3/4)
Guemes 2016 [28]
8.9 y (0.2–15.5)a
Pituitary (16), Adrenal (11), Ectopic (2), Unknown (1)
UFC
> 275 nmol [100 µg]/24 h
94% (17/18)
Late-night serum cortisol
> 138 nmol/l [5 µg/dl]
100% (27/27)
LDDST (20 µg/kg/day [max 2 mg/day] divided every 6 h for 48 h)
< 50 nmol/l [1.8 µg/dl]
100% (20/20)
Abbreviation. N: number; y: years; UFC: Urinary free cortisol; DST: dexamethasone suppression test; LDDST: low-dose DST; PPV: Positive Predictive Value; NPV: Negative Predictive Value; BSA: body surface area. a median age
Recently, some authors have reported the value of hair cortisol measurements as a good marker of hypercortisolism also in paediatric population [34], although further studies are needed to validate this test in the diagnostic workup for CS.

24-h Urinary free cortisol (UFC)

24-h UFC is a long-time used screening test for CS, widely performed in childhood for its non-invasive characteristics and the possibility to collect the 24-h samples at home, although this collection may be difficult for younger subjects. Differently from adults, in paediatric population UFC should be corrected for body surface area, conventionally used to make the normal range homogeneous despite the different cortisol secretion during childhood and puberty [35‐37]. The cut-off of 70 µg/m2/day is associated with an acceptable sensitivity and specificity (over 88% and 90% respectively) [27, 38, 39], even if the normal ranges varied among different paediatric studies, due to assay-specific reference range [25, 28, 40]. In order to reduce intra-patient variability and to provide a better diagnostic accuracy, it is now recognised that at least two UFC measurements should be performed in subjects suspected of CS [27, 38, 40, 41].
Mild forms of hypercortisolism may have a false-negative UFC assay, because free cortisol appears in the urine only when serum cortisol exceeds the plasma protein binding capacity. On the other hand, false-positive elevation of UFC measurements should be caused by NNH, as physical or emotional stress, severe obesity or depression. In fact, obese children and adolescents may present slightly elevated UFC, particularly when the obesity is associated with metabolic syndrome [42, 43].
Considering the extremely low prevalence of CS in the paediatric population, the positive predictive value of UFC measurements is considerably low. For this reason, UFC alone is not recognised as an ideal screening tool, while its use combined with another screening tests is desirable to better detect subjects with endogenous hypercortisolism.
In the last decades, liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays had demonstrated superior sensitivity and specificity compared to traditional immunoassays [44‐46], reducing a considerable analytical bias thanks to its ability to differentiate various glucocorticoid metabolites.

Late night cortisol

Abnormal circadian rhythm of cortisol secretion is a hallmark of CS. The lack of the physiological evening nadir in cortisol secretion is detectable with late-night serum or salivary cortisol tests. As for UFC, at least two late-night cortisol measurements are desirable to improve the diagnostic accuracy, particularly in patients with mild CS.
For serum cortisol measurement, an indwelling intravenous cannula should be placed before sleeping and the blood sample should be taken without waking the child. The assessment of midnight serum cortisol gives the highest sensitivity and specificity for the diagnosis of CS in childhood (99 and 100% respectively using the cut-off of 4.4 µg/dl) [38], despite different normal ranges (between 1.8 and 5 µg/dl) have been considered for paediatric subjects [22, 28, 47].
However, the late-night serum sample requires hospitalization and its use as a screening test for CS is limited.
On the other hand, late-night salivary cortisol measurement represents an easily executable, stress-free test also in outpatient setting. Conventionally, the salivary samples are collected at 11–12 pm, even if some authors suggest to performed it at usual bedtime in order to achieve unstressed levels, resulting from the request to the patient to stay awake beyond the usual bedtime [48]. This precaution, suggested for adult subjects, should be considered also for paediatric population to reduce a potential false-positive rate of the test.
Although the available data in paediatric population are limited, the sensitivity and specificity of late-night salivary cortisol assessment appear to be close to late-night serum cortisol (93–100% and 95–100% respectively) [39, 49].
For all these reasons, late-night salivary cortisol seems to be the best screening test for endogenous hypercortisolism in childhood.
Although the traditional immunoassay methods already have a very high sensitivity, LC-MS/MS assays had demonstrated an improvement of diagnostic specificity and appear to be the most accurate analytical tools also for modern salivary or serum steroid measurements [50‐52]. In fact, the use of LC-MS/MS assay allows the dosage of different cortisol metabolites (as cortisone) in order to better identify the endogenous cortisol production and consequently to reduce false-positive results [8, 51].

Low-dose dexamethasone suppression tests (DST)

In healthy individuals, a supraphysiological exogenous dexamethasone dose inhibits ACTH and consequently cortisol secretion. Therefore, a decrease of serum cortisol concentration below the value of 1.8 µg/dl after 1 or 2 mg dexamethasone dose is considered to be a normal response. The low-dose DST should be performed through two different forms: the 1 mg “overnight” (or Nugent) and the two-day 2 mg (or low-dose Liddle) test.
The “overnight” DST is performed with the administration of 1 mg (or 25 µg/kg in children with body weight < 40 kg) of dexamethasone at 11 PM to 12 AM (midnight), measuring serum cortisol at 8 AM the next morning. In order to ensure a proper DST in adult population, Ceccato et al. propose to measure also dexamethasone after 1 mg-DST with LC-MS/MS assay [53]. At present, no similar data are available among paediatric population, although dexamethasone measurement should be suggested also in children and adolescents to reduce false-positive results due to inadequate bioavailability or incorrect administration of dexamethasone.
The “low-dose Liddle” DST (LDDST) consists of the administration of 2 mg/day of dexamethasone (or 20–30 µg/kg/day in children < 30 kg), divided in 0.5 mg doses every six hours for 48 h, and measurement of serum cortisol within six hours after the last dose.
For both DST, the lack of the physiological serum cortisol suppression (< 1.8 µg/dL) is suspicious for CS. LDDST has demonstrated a good sensitivity (over 90%) for CS in paediatric patients [26, 28], whereas less data regarding the overnight DST sensitivity and specificity are available in childhood [54, 55].
For its ease analysis in an out-patient setting, LDDST is therefore a useful screening test for paediatric patients suspected of CS.
Recently, some authors have investigated the utility of salivary cortisone measurement after DST, that is characterized by a more linear relationship with serum cortisol than salivary cortisol [56]. Moreover, a prospective use of salivary cortisol/cortisone after DST in childhood should be encouraged for its non-invasive and stress-free peculiarity, avoiding venipuncture.

Etiological diagnosis of endogenous CS

Basal electrolytes and ACTH

Levels of serum electrolytes are usually normal, but potassium may be decreased, especially in children with ECS [57]. In children with CD, morning plasma ACTH is commonly detectable (> 5 pg/ml) while those with ACS showed suppressed ACTH [29]. Batista et al. showed that a cut-off of morning ACTH of 29 pg/ml had a sensitivity of 70% and specificity of 100% to differentiate ACTH-dependent from ACTH-independent CS [38]. ACTH concentrations are usually very high in patients with ECS but may be normal in patients with pituitary adenomas [17, 29, 57]. CD should be suspected in patients with biologically moderate signs, without hypokalaemia or marked plasma ACTH elevation and with progressive onset [17, 20, 33].

CRH stimulation test

The CRH test has been suggested as the best non-invasive tool for diagnosing CD. Sensitivity and specificity are reported to be around 80 and 92% (according to study in adults) [17, 58‐60]. This test consists in the intravenous injection of 1 µg/kg CRH (maximum dose 100 µg) [29]. The criterion for diagnosis of CD is a mean increase of 20% above baseline for cortisol value at 15 and 30 min and an increase in the mean ACTH concentration of at least 35% over basal value at 15 and 30 min after CRH administration [17, 29]. Some authors reported the use of ovine CRH (the only available form in the United States, until the mid-2020) in paediatric population [38, 61] as alternative to human CRH. Although it has been described as the ovine CRH can induce a stronger, more prolonged increase in ACTH and, particularly, cortisol compared with human CRH in adult subjects [62], no data are available comparing ovine and human CRH in paediatric population.
Despite children with CD seem to have a more evident cortisol response than adults, making this test more useful in the paediatric age than in adults [17, 26, 29, 63], the recent synthetic human CRH shortage [64] will make CRH test less feasible in favour of other dynamic tests as Desmopressin test [65].

Desmopressin test

Desmopressin is a preferential vasopressin receptor V2 and V3 agonist. Because of the overexpression of the V3 in human ACTH-secreting adenomas, the administration of desmopressin causes a significant rise in ACTH and cortisol levels in most patients with CD [17, 58]. This makes desmopressin administration a suitable test enabling the distinction between neoplastic from NNH [9, 10, 26]. Like CRH test, Desmopressin test results effective, well-tolerated, less expensive, and relatively non-invasive. While the sensitivity is comparable to CRH test, the specificity seems to be lower [17, 58, 60, 66]. Like the other tests, it is probabilistic: the more significant the elevation of ACTH and cortisol, the more probable the diagnosis of corticotropic adenoma [17, 58]. Different cut-off criteria were used to define a positive response. Malerbi et al. showed that the administration of Desmopressin 5–10 µg intravenous determines a cortisol increase above baseline ranging from 61 to 379% in patients with pituitary disease [67]. Sakai et al. using a high percent ACTH rise threshold of 120% reported a positive ACTH response in all 10 patients with CD, whereas all 3 patients with ECS were unresponsive to desmopressin [68]. Tsagarakis et al. showed that desmopressin test (10 µg intravenous) can produce a significant overlap of responses between CD and patients with ECS and therefore it is of limited value in the differential diagnosis of ACTH-dependent CS. This is probably due to the expression of the V2 receptors in tumours with ECS [69]. Desmopressin (10 µg intravenous) in combination with CRH may provide an improvement over the standard CRH test in the differential diagnosis of ACTH-dependent CS [70]. However, the benefit of a desmopressin-CRH combined test results limited [66]. It should be considered that all the above studies included adults [67‐69].
Desmopressin test proved to be effective in increasing the sensibility of Bilateral Petrosal Sinus Sampling (BIPSS) [71]. In a retrospective study including 16 children with CD, Chen et al. showed an increase of the sensitivity of BIPSS from 64.7% at baseline to 83.3% after desmopressin stimulation [72]. Many CD patients respond aberrantly to the desmopressin test. Loss of the desmopressin response, performed in the early post-operative period, is a good predictor for a favourable long-term outcome. Moreover, during follow-up, the return of desmopressin response is predictive of recurrence [66, 71].

Standard high dose dexamethasone suppression test (HDDST)

HDDST or high-dose Liddle test is the oldest described and it is used to differentiate CD from ECS. This test consists in the administration of dexamethasone at a dosage of 80–120µgr/kg/day divided into four doses every 6 h (maximum 2 mg/dose) for 48 h or a single cumulative dose of 80–120µgr/kg (maximum 8 mg) at 11 pm. Plasma cortisol is measured at 8–9 am the morning after the last administration of dexamethasone; the suppression of serum cortisol up to 50% of baseline is suspicious for CD as for adult population [17, 26, 28, 29, 38].
Liu et al. showed that HDDST in combination with pituitary dynamic enhanced MRI (dMRI) had a positive predictive value (98.6%), higher than that of Bilateral Petrosal Sinus Sampling (BIPSS) for the diagnosis of CD [73].
Despite HDDST had reported a good sensibility to identify CD in childhood, this test seems to have a low specificity to exclude ECS because of the high degrees of cortisol suppression after HDDST in children with ECS [19, 28, 29]. In addition, the administration of high-dose dexamethasone in CS patients with high cortisol level can cause severe side effects, including exacerbation of their hypertension and fluctuation of blood glucose. Because of the low accuracy and the risk of severe side effects, this test is less frequently used [29].

https://static-content.springer.com/image/art%3A10.1007%2Fs40618-024-02452-w/MediaObjects/40618_2024_2452_Fig1_HTML.png

Fig. 1

Diagnostic algorithm for screening and differential diagnosis of cushing syndrome in paediatric population

Imaging

Pituitary magnetic resonance imaging (MRI)

Since ACTH-secreting pituitary adenomas are very small (usually < 6 mm in diameter), it is difficult to localize these tumours. Diagnostic workup of CD includes pituitary MRI, but in many patients no tumour is identified. Conventional MRI, even with contrast enhancement, mostly failed to identify ACTH-secreting microadenomas in children with CD. Up to one-third of paediatric and adolescent patients with CD don’t have pituitary tumour detectable at brain MRI. The acquisition protocol should comprise coronal and sagittal spin-echo (SE) slices with gadolinium-enhanced T1 and T2 and millimetric 3D T1 slices [17, 29, 57, 74]. In a retrospective study including 30 children with CD (mean age 12 ± 3 years), Batista et al. showed that pre- and post-contrast spoiled gradient-recalled acquisition in the steady state (SPGR) was superior to conventional pre- and post-contrast T1-weighted SE acquisition MRI in the identification of the microadenomas. In particular, the post-contrast SPGR-MRI identified the location of the tumour in 18 of 28 patients, whereas post-contrast SE-MRI identified the location and accurately estimated the size of the tumour in only 5 of 28 patients (p < 0.001) [74].

Bilateral petrosal sinus sampling (BIPSS)

BIPSS is another powerful diagnostic tool with high sensitivity and specificity, but its invasiveness and high cost limit its wide application, and the indication for BIPSS is still controversial [7, 17, 29, 75, 76]. It consists of the placement of femoral catheters that reach the inferior petrosal sinuses. Successively, blood samples are collected for measurement of ACTH from petrosal sinuses and from peripheral pathway before and after the administration of CRH. Inferior petrosal sinus (IPS) to peripheral (P) ACTH ratio and interpetrosal sinus gradient of one of the two sides to the contralateral side are calculated [75, 76]. In order to avoid incorrect results, it is recommended to verify hypercortisolism with serum cortisol sample immediately before performing BIPSS. Detomas et al. recently described the largest study on BIPSS.
According to the authors, the cut-offs for the ACTH IPS: P ≥ 1.9 at baseline (sensitivity 82.1%, specificity 85.7%) and ≥ 2.1 at 5 min post-CRH (sensitivity 91.3%, specificity 92.9%) allow for the best discrimination between CD and ECS [77]. In a multicentre study including 16 children aged between 4 and 16.5 years, Turan et al. showed that BIPSS is a superior diagnostic work-up than MRI to confirm the diagnosis of CD. Moreover, it showed a significantly higher sensitivity (92.8%) than MRI (53.3%) in detecting adenoma localization at pituitary level, which is crucial for surgical intervention [75]. The use of desmopressin has been reported in alternative to CRH [76]. In a review including case series of children with CS [76], the overall accuracy of BIPSS was 84.1% and became 92.3% after stimulation with desmopressin. The overall lateralizing accuracy of BIPSS was 50%. While BIPSS has a high diagnostic accuracy for the localization to the pituitary gland, it is not reliable for tumour lateralization to the right or left side of the gland. BIPSS is considered the gold standard to reliably exclude ECS and should performed in a specialized centre due to potential patient risk. However, BIPSS is not routinely available in many centres, it may have decreased specificity in children, especially when the pituitary tumour is not lateralized showing misleading results [77, 78]. For these reasons and for the risks related to the invasiveness of the procedure, BIPSS should be reserved only for exceptional cases in children [17, 75, 76].

Radiological anatomic imaging

Subjects with ACS should perform an adrenal Computer Tomography (TC) or MRI to determine the adrenal cause. Despite abdominal TC with contrast-enhanced studies is the cornerstone of imaging of adrenal tumours in adults, MRI scan should be initially preferred in childhood to avoid radiation exposure [79]. Adrenocortical carcinomas are usually unilateral, larger than adenomas, with irregular margins, inhomogeneous contents (with areas of necrosis, haemorrhage and calcification) and avidly enhancement after contrast administration due to their high vascularity [80]. PPNAD is more difficult di identify with radiological studies, because it usually presents normal- or small-sized adrenal glands.
In subjects with suspected ECS, a thin-multislice neck-chest-abdomen-pelvic CT, alone or eventually followed by MRI, should be performed to identify neuroendocrine tumours that generally are very small and difficult to identify [11].

Functional imaging

Second-line functional imaging studies (as Positron Emission Tomography, PET, or scintigraphy) may be useful to provide an accurate etiological diagnosis of CS, particularly when the traditional radiological exams are inconclusive to differentiate CD from ECS. Because of the rarity of ECS, a univocal algorithm regarding the use of new molecular imaging techniques is not well established.
Whereas the ectopic ACTH-secreting tumours express the cell-surface receptors for somatostatin, 111In-pentetreotide (OCT) scintigraphy is often chosen as confirmatory exam [81].
The 68Gallium-DOTATATE PET/CT scan, using a modified octreotide molecule that also binds to somatostatin receptors, has shown a greater sensitivity for small tumours and may be useful for the tumoral identification in case of negative OCT scan [7]. Finally, 18FDG-PET/CT seems to be highly sensitive for the detection of aggressive pancreatic lesions [81].
In ACS cases, when adrenocortical carcinoma is suspected and traditional imaging studies (MRI or TC) are not diriment, 11C-metomidate-PET/CT scan allows a non-invasive characterization and staging of the adrenal lesion [82, 83].

Algorithm approach

Clinical history and the age at presentation of symptoms should guide throughout the different diagnosis of endogenous CS. A careful personal history, supported by patient growth charts, physical examination and screening tests should be able to rule out any physical or neuropsychiatric causes of NNH, even if second-line dynamic tests are sometimes needed to distinguish NNH from neoplastic CS.
Although CD is the main cause of CS in children older than 8 years, the clinical presentation of ECS may overlap with CD and the differential diagnosis of CS may be challenging, requiring the combination of dynamic biochemical tests and multimodal imaging.
Since none of the dynamic tests show a perfect sensitivity and specificity, using more than one dynamic test might improve accuracy. A non-invasive approach using a combination of three or four tests, specifically CRH and desmopressin stimulation tests plus MRI, followed by total-body CT, if biochemical and anatomical findings are discordant, correctly diagnose CD in approximately half of patients, potentially eliminating the need for BIPSS [17, 84]. If a pituitary tumour is detected on MRI and dynamic testing results are consistent with CD, BIPSS is not necessary for diagnosis. Since ECS in children is extremely rare, the algorithm approach in children may differ from the adult approach. Findings of ACTH-dependent CS, doubtful CRH test and normal pituitary MRI should be followed by extended imaging (whole-body CT/MRI or functional imaging). Considering the extremely rarity of ECS, the great majority of ACTH-dependent hypercortisolism, even with normal pituitary MRI, corresponds to CD due to a pituitary lesion not yet visible [17]. For this reason, BIPSS should be used only exceptionally in children. A diagnostic algorithm is proposed in Fig. 1.

Conclusions

We provide detailed revision on the diagnostic evaluation of children and adolescents presenting with signs and symptoms suspicious for CS and guidance on the workup from the confirmation of endogenous hypercortisolism to the etiological diagnosis of such a rare challenging condition.

Declarations

Ethical approval

This article does not include research on human participants and/or animals.
Informed consent is not required.

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://​creativecommons.​org/​licenses/​by/​4.​0/​.

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Paediatric Cushing Syndrome: Prospective, Multisite, Observational Cohort Study

Posted on January 19, 2024 by MaryO

Summary

Background

Paediatric endogenous Cushing syndrome is a rare condition with variable signs and symptoms of presentation. We studied a large cohort of paediatric patients with endogenous Cushing syndrome with the aim of describing anthropometric, clinical, and biochemical characteristics as well as associated complications and outcomes to aid diagnosis, treatment, and management.

Methods

In this prospective, multisite cohort study, we studied children and adolescents (≤18 years at time of presentation) with a diagnosis of Cushing syndrome. Patients had either received their initial diagnosis and evaluation at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Bethesda, MD, USA) or been referred from other centres in the USA or outside the USA. We collected participants’ clinical, biochemical, and imaging findings and recorded their post-operative course until their latest appointment.

Findings

Of 342 paediatric patients with a diagnosis of Cushing syndrome, 193 (56%) were female and 149 (44%) male. 261 (76%) patients had corticotroph pituitary neuroendocrine tumours (Cushing disease), 74 (22%) had adrenal-associated Cushing syndrome, and seven (2%) had ectopic Cushing syndrome. Patients were diagnosed at a median of 2 years (IQR 1·0–3·0) after the first concerning sign or symptom, and patients with adrenal-associated Cushing syndrome were the youngest at diagnosis (median 10·4 years [IQR 7·4–13·6] vs 13·0 years [10·5–15·3] for Cushing disease vs 13·4 years [11·0–13·7] for ectopic Cushing syndrome; p<0·0001). Body-mass index z-scores did not differ between the diagnostic groups (1·90 [1·19–2·34] for adrenal-associated Cushing syndrome vs 2·18 [1·60–2·56] for Cushing disease vs 2·22 [1·42–2·35] for ectopic Cushing syndrome; p=0·26). Baseline biochemical screening for cortisol and adrenocorticotropin at diagnosis showed overlapping results between subtypes, and especially between Cushing disease and ectopic Cushing syndrome. However, patients with ectopic Cushing syndrome had higher urinary free cortisol (fold change in median cortisol concentration from upper limit of normal: 15·5 [IQR 12·7–18·0]) than patients with adrenal-associated Cushing syndrome (1·5 [0·6–5·7]) or Cushing disease (3·9 [2·3–6·9]; p<0·0001). Common complications of endogenous Cushing syndrome were hypertension (147 [52%] of 281 patients), hyperglycaemia (78 [30%] of 260 patients), elevated alanine transaminase (145 [64%] of 227 patients), and dyslipidaemia (105 [48%] of 219 patients). Long-term recurrence was noted in at least 16 (8%) of 195 patients with Cushing disease.

Interpretation

This extensive description of a unique cohort of paediatric patients with Cushing syndrome has the potential to inform diagnostic workup, preventative actions, and follow-up of children with this rare endocrine condition.

Funding

Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development, National Institutes of Health.

Introduction

Paediatric endogenous Cushing syndrome is a rare disorder accounting for 5–7% of all reported cases of endogenous Cushing syndrome.1, 2, 3 In children older than 5–7 years and adolescents, endogenous Cushing syndrome is most commonly caused by corticotroph pituitary neuroendocrine tumours (PitNETs) and is termed Cushing disease. By contrast, Cushing syndrome in children younger than 5 years is often associated with adrenal disorders and is termed adrenal-associated Cushing syndrome.4 Albeit rare, a third type termed ectopic Cushing syndrome is caused by neuroendocrine tumours outside the hypothalamic–pituitary axis that secrete adrenocorticotropin or corticotropin-releasing hormone.5, 6 Thus endogenous Cushing syndrome is caused by either adrenocorticotropin-dependent sources (pituitary or ectopic) or adrenocorticotropin-independent (adrenal) hypercortisolemia.

Patients with adults-onset Cushing syndrome typically present with weight gain, skin manifestations (striae, hirsutism, acne, and easy bruising), and abnormal fat deposition.7, 8, 9 Paediatric Cushing syndrome differs from adult-onset Cushing syndrome in aspects including effects on growth (weight gain with concomitant height deceleration), atypical physical presentation (such as lack of centripetal obesity or typical striae), delayed or suppressed puberty, and variable mental health problems and neurocognitive function deficits.10 Diagnosis of paediatric Cushing syndrome is therefore challenging, and delayed evaluation is common.

Research in context

Evidence before this study

Endogenous Cushing syndrome is a rare endocrine condition. Diagnosis can be challenging and delay treatment. We searched PubMed for articles published in English on paediatric Cushing syndrome using terms “Cushing” AND “children” from database inception to May 5, 2023. Although several case series of paediatric Cushing disease were identified, only a few studies of the various causes of paediatric endogenous Cushing syndrome were available.

Added value of this study

To our knowledge, this cohort of paediatric endogenous Cushing syndrome of various causes is one of the largest sources of cumulative clinical, anthropometric, and biochemical data on the presentation, diagnosis, and management. We confirm that baseline biochemical data cannot aid differential diagnosis of Cushing syndrome subtypes. However, evidence suggests that minimally invasive stimulation tests could be a safe alternative to interventional sampling procedures such as inferior petrosal sinus sampling. We provide the prevalence of complications related to Cushing syndrome. Long-term outcomes of paediatric patients with pituitary corticotroph tumours recurrence is possible up to 8 years after initial remission.

Implications of all the available evidence

Data from this large paediatric cohort inform the evaluation, diagnosis, and long-term care of patients with paediatric Cushing syndrome. We recommend an algorithm for the diagnosis of patients and screening of complications. Screening for recurrence in patients with Cushing disease is indicated for this age group, at least for the first decade after surgery.

We have evaluated a large cohort of children and adolescents with endogenous Cushing syndrome of various causes. The aim of the study was to document anthropometric, clinical, and biochemical characteristics, complications, and outcomes of paediatric endogenous Cushing syndrome to aid clinicians in the diagnosis and management of these patients.

Section snippets

Study design and participants

In this prospective, multisite cohort study, we screened participants who, from 1995 to 2023, had enrolled in studies under protocols 97-CH-0076 (clinicaltrials.gov, NCT00001595), 95-CH-0059 (NCT00001452), and 00-CH-0160 (NCT00005927) at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD, Bethesda, MD, USA). Paediatric patients (18 years or younger at time of presentation) with a diagnosis of Cushing syndrome were eligible for inclusion in the study. We

Results

342 patients with paediatric Cushing syndrome were included in the study (table 1). 278 patients were referred from centres in the USA, and 64 patients were referred from centres outside of the USA. 261 (76%) patients were diagnosed with Cushing disease, 74 (22%) patients were diagnosed with adrenal-associated Cushing syndrome, and seven (2%) patients were diagnosed with ectopic Cushing syndrome. Patients with adrenal-associated Cushing syndrome were diagnosed at a younger age than patients

Discussion

We present extensive and unique data on presentation, diagnosis, and follow-up of paediatric patients with three diagnostic types of endogenous Cushing syndrome. Clinical and anthropometric characteristics were similar across subtypes of Cushing syndrome, but biochemical tests differed. We also present extensive information on complications; hypertension, insulin resistance, dyslipidaemia, and elevated ALT were common. Long-term follow-up of patients revealed excellent postoperative prognosis,

Data sharing

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Declaration of interests

CAS holds patents on the function of the PRKAR1A, PDE11A, and GPR101 genes and related issues; his laboratory had received research funding on GPR101, and on abnormal growth hormone secretion and its treatment by Pfizer. CAS receives support from ELPEN and has been consulting for Lundbeck Pharmaceuticals and Sync. CT reports receiving research funding on treatment of abnormal growth hormone secretion by Pfizer.

References (38)

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Clinical Features, Diagnosis and Treatment Outcomes of Cushing’s Disease In Children: a Multicenter Study

Posted on November 2, 2023 by MaryO

Abstract

Objective

Since Cushing’s disease (CD) is less common in the paediatric age group than in adults, data on this subject are relatively limited in children. Herein, we aim to share the clinical, diagnostic and therapeutic features of paediatric CD cases.

Design

National, multicenter and retrospective study.

Patients

All centres were asked to complete a form including questions regarding initial complaints, physical examination findings, diagnostic tests, treatment modalities and follow-up data of the children with CD between December 2015 and March 2017.

Measurements

Diagnostic tests of CD and tumour size.

Results

Thirty-four patients (M:F = 16:18) from 15 tertiary centres were enroled. The most frequent complaint and physical examination finding were rapid weight gain, and round face with plethora, respectively. Late-night serum cortisol level was the most sensitive test for the diagnosis of hypercortisolism and morning adrenocorticotropic hormone (ACTH) level to demonstrate the pituitary origin (100% and 96.8%, respectively). Adenoma was detected on magnetic resonance imaging (MRI) in 70.5% of the patients. Transsphenoidal adenomectomy (TSA) was the most preferred treatment (78.1%). At follow-up, 6 (24%) of the patients who underwent TSA were reoperated due to recurrence or surgical failure.

Conclusions

Herein, national data of the clinical experience on paediatric CD have been presented. Our findings highlight that presenting complaints may be subtle in children, the sensitivities of the diagnostic tests are very variable and require a careful interpretation, and MRI fails to detect adenoma in approximately one-third of cases. Finally, clinicians should be aware of the recurrence of the disease during the follow-up after surgery.

From https://onlinelibrary.wiley.com/doi/10.1111/cen.14980

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