children | CushieBlog

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)	NA^b	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)
Bickler 1994 [54]	15.7 y (pituitary) 8.1 y (adrenal)	Pituitary (10) Adrenal (2)	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)
Gafni 2000 [39]	5–17 y	CS patients (14), Healthy controls (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%]
Batista 2007 [38]	3–18 y	Pituitary (80), Adrenal (25), Controls (20)	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)
			UFC	> 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].

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/.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

From https://www.springermedizin.de/cushing-syndrome-in-paediatric-population-who-and-how-to-screen/50061094

Filed under: Cushing's | Tagged: children, Cushing's, pediatric | Leave a comment »

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)

OA Hakami et al.

Epidemiology and mortality of Cushing’s syndrome

Best Pract Res Clin Endocrinol Metab

(2021)
HL Storr et al.

Paediatric Cushing’s syndrome: epidemiology, investigation and therapeutic advances

Trends Endocrinol Metab

(2007)
C Tatsi et al.

Neonatal Cushing syndrome: a rare but potentially devastating disease

Clin Perinatol

(2018)
CA Stratakis

An update on Cushing syndrome in pediatrics

Ann Endocrinol (Paris)

(2018)
JL Shaw et al.

Validity of establishing pediatric reference intervals based on hospital patient data: a comparison of the modified Hoffmann approach to CALIPER reference intervals obtained in healthy children

Clin Biochem

(2014)
MB Lodish et al.

Effects of Cushing disease on bone mineral density in a pediatric population

J Pediatr

(2010)
L Meloche-Dumas et al.

Role of unilateral adrenalectomy in bilateral adrenal hyperplasias with Cushing’s syndrome

Best Pract Res Clin Endocrinol Metab

(2021)
M Fleseriu et al.

Consensus on diagnosis and management of Cushing’s disease: a guideline update

Lancet Diabetes Endocrinol

(2021)
MS Broder et al.

Incidence of Cushing’s syndrome and Cushing’s disease in commercially-insured patients <65 years old in the United States

Pituitary

(2015)
O Ragnarsson et al.

The incidence of Cushing’s disease: a nationwide Swedish study

Pituitary

(2019)

From https://www.sciencedirect.com/science/article/abs/pii/S235246422300264X

Filed under: Cushing's, Rare Diseases, symptoms, Treatments | Tagged: child, children, Cushing's Syndrome, ectopic, pediatric | Leave a comment »

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

Filed under: Cushing's, pituitary, Treatments | Tagged: children, Cushing's Disease, pituitary, Transsphenoidal surgery | Leave a comment »

Pediatric Adrenal Insufficiency: Challenges and Solutions

Posted on January 14, 2022 by MaryO

Authors Nisticò D , Bossini B, Benvenuto S, Pellegrin MC, Tornese G

Received 29 October 2021

Accepted for publication 28 December 2021

Published 11 January 2022 Volume 2022:18 Pages 47—60

DOI https://doi.org/10.2147/TCRM.S294065

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Professor Garry Walsh

Download Article [PDF]

Daniela Nisticò,¹ Benedetta Bossini,¹ Simone Benvenuto,¹ Maria Chiara Pellegrin,¹ Gianluca Tornese²

¹University of Trieste, Trieste, Italy; ²Department of Pediatrics, Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy

Correspondence: Gianluca Tornese
Department of Pediatrics, Institute for Maternal and Child Health IRCCS Burlo Garofolo, Via dell’Istria 65/1, Trieste, 34137, Italy
Tel +39 040 3785470
Email gianluca.tornese@burlo.trieste.it

Abstract: Adrenal insufficiency is an insidious diagnosis that can be initially misdiagnosed as other life-threatening endocrine conditions, as well as sepsis, metabolic disorders, or cardiovascular disease. In newborns, cortisol deficiency causes delayed bile acid synthesis and transport maturation, determining prolonged cholestatic jaundice. Subclinical adrenal insufficiency is a particular challenge for a pediatric endocrinologist, representing the preclinical stage of acute adrenal insufficiency. Although often included in the extensive work-up of an unwell child, a single cortisol value is usually difficult to interpret; therefore, in most cases, a dynamic test is required for diagnosis to assess the hypothalamic-pituitary-adrenal axis. Stimulation tests using corticotropin analogs are recommended as first-line for diagnosis. All patients with adrenal insufficiency need long-term glucocorticoid replacement therapy, and oral hydrocortisone is the first-choice replacement treatment in pediatric. However, children that experience low cortisol concentrations and symptoms of cortisol insufficiency can take advantage using a modified release hydrocortisone formulation. The acute adrenal crisis is a life-threatening condition in all ages, treatment is effective if administered promptly, and it must not be delayed for any reason.

Keywords: adrenal gland, primary adrenal insufficiency, central adrenal insufficiency, Addison disease, children, adrenal crisis, hydrocortisone

Introduction

Primary adrenal insufficiency (PAI) is a condition resulting from impaired steroid synthesis, adrenal destruction, or abnormal gland development affecting the adrenal cortex.¹ Acquired primary adrenal insufficiency is termed Addison disease. Central adrenal insufficiency (CAI) is caused by an impaired production or release of adrenocorticotropic hormone (ACTH). It can originate either from a pituitary disease (secondary adrenal insufficiency) or arise from an impaired release of corticotropin-releasing hormone (CRH) from the hypothalamus (tertiary adrenal insufficiency). An underlying genetic cause should be investigated in every case of adrenal insufficiency (AI) presenting in the neonatal period or first few months of life, although AI is relatively rare at this age (1:5.000–10.000).²

Physiology of the Adrenal Gland

The adrenal cortex consists of three zones: the zona glomerulosa, the zona fasciculata, and the zona reticularis, responsible for aldosterone, cortisol, and androgens synthesis, respectively.³ Aldosterone production is under the control of the renin-angiotensin system, while cortisol is regulated by the hypothalamic-pituitary-adrenal axis (HPA).⁴ This explains why patients affected by CAI only manifest glucocorticoid deficiency while mineralocorticoid function is spared. CRH is secreted from the hypothalamic paraventricular nucleus into the hypophyseal-portal venous system in response to light, stress, and other inputs. It binds to a specific cell-surface receptor, the melanocortin 2 receptor, stimulating the release of preformed ACTH and the de novo transcription of the precursor molecule pro-opiomelanocortin (POMC). ACTH is derived from the cleavage of POMC by proprotein convertase-1.^5–9 ACTH binds to steroidogenic cells of both the zona fasciculata and reticularis, activating adrenal steroidogenesis. It also has a trophic effect on adrenal tissue; therefore, ACTH deficiency determines adrenocortical atrophy and decreases the capacity to secrete glucocorticoids. Circulating cortisol is 75% bound to corticosteroid-binding protein, 15% to albumin, and 10% free. The endogenous production rate is estimated between 6 and 10 mg/m²/day, even though it depends on age, gender, and pubertal development. Glucocorticoids have multiple effects: they regulate immune, circulatory, and renal function, influence growth, development, energy and bone metabolism, and central nervous system activity. Several studies reported higher cortisol plasma concentrations in girls than in boys and younger children.^3,4,8

Cortisol secretion follows a circadian and ultradian rhythm according to varying amplitudes of ACTH pulses. Pulses of ACTH and cortisol occur every 30–120 minutes, are highest at about the time of waking, and decline throughout the day, reaching a nadir overnight.^3,8,9 This pattern can change in the presence of serious illness, major surgery, and sleep deprivation. During stressful situations, glucocorticoid secretion can increase up to 10-fold to enhance survival through increased cardiac contractility and cardiac output, sensitivity to catecholamines, work capacity of the skeletal muscles, and availability of energy stores.³

The interaction between the hypothalamus and the two endocrine glands is essential to maintain plasma cortisol homeostasis (Figure 1). Cortisol exerts double-negative feedback on the HPA axis. It acts on the hypothalamus and the corticotrophin cells of the anterior pituitary, reducing CRH and ACTH synthesis and release.⁶ ACTH inhibits its secretion through a feedback effect mediated at the level of the hypothalamus.³ Increased androgen production occurs in the case of cortisol biosynthesis enzymatic deficits.

Figure 1 The hypothalamic–pituitary–adrenal axis.

Primary Adrenal Insufficiency

PAI affects 10–15 per 100,000 individuals and recognizes different classes of genetic causes (Table 1). Congenital adrenal hyperplasia (CAH) is the main cause of PAI in the neonatal period, being included among the disorders of steroidogenesis secondary to deficits in enzymes. It has an autosomal recessive transmission.^1,10,11 The estimated incidence ranges between 1:10,000 and 1:20,000 births. CAH phenotype depends on disease-causing mutations and residual enzyme activity. 21-hydroxylase deficiency (21OHD) accounts for more than 90% of cases, 21-hydroxylase converts cortisol and aldosterone precursors, respectively 17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol and progesterone to deoxycortisone. Less frequent forms of CAH include 11 β -hydroxylase deficiency (11BOHD, 8% of cases), 17α-hydroxylase/17–20 lyase deficiency (17OHD), 3β-hydroxysteroid dehydrogenase deficiency (3BHDS), P450 oxidoreductase deficiency (PORD).¹² Steroidogenesis may also be impaired by steroidogenic acute regulatory (StAR) protein deficiency, which is involved in cholesterol transport into mitochondria, or P450 cytochrome side-chain cleavage (P450scc) deficiency, that converts cholesterol into pregnenolone.^12,13 Of these conditions, 21OHD and 11BOHD only affect adrenal steroidogenesis, whereas the other deficits also impact gonadal steroid production. In classic CAH, enzyme activity can be absent (salt-wasting form) or low (1–2% enzyme activity, simple virilizing form). The salt-wasting form is the most severe and affects 75% of patients with classic 21OHD.^1,10,12,14 Non-classic CAH (NCCAH) is more prevalent than the classic form, in which there is 20–50% of residual enzymatic activity. Two-thirds of NCCAH individuals are compound heterozygotes with different CYP21A2 mutations in two different alleles (classic severe mutation plus mild mutation in two different alleles or homozygous with two mild mutations). Notably, 70% of NCCAH patients carry the point mutation Val281Leu.

Table 1 Causes of Primary Adrenal Insufficiency (PAI)

Central Adrenal Insufficiency

CAI incidence is estimated between 150 and 280 per million, and it should be suspected when mineralocorticoid function is preserved. When, rarely, isolated is due to iatrogenic HPA suppression secondary to prolonged glucocorticoid therapy or the removal of an ACTH- or cortisol-producing tumor (Cushing syndrome).¹⁵ Defects in POMC,¹⁶ characterized by red or auburn-haired children, pale skin (due to melanocyte stimulating hormone [MSH] – deficiency) and hyperphagia later in life, and in transcription factor TPIT,¹⁷ which regulates POMC synthesis in corticotrope cells, are the two leading genetic causes of isolated ACTH deficiency (Table 2). Mainly, it occurs as part of complex syndromes in which a combined multiple pituitary hormone deficiency (CMPD) is associated with craniofacial and midline defects, such as Prader-Willi syndrome, CHARGE syndrome, Pallister-Hall syndrome (anatomical pituitary abnormalities), white vanishing matter disease (progressive leukoencephalopathy).⁵ Individuals with an isolated pituitary deficiency, usually a growth hormone deficiency (GHD), may develop multiple pituitary hormone deficiencies over the years. Therefore, excluding a latent CAI at GHD onset and periodically monitoring of HPA axis is of utmost importance. Notably, cortisol reduction secondary to an increased basal metabolism when starting GHD or thyroxin substitutive therapy may unleash a misdiagnosed CAI. CMPD can be caused by several defective genes, such as GLI1, LHX3, LHX4, SOX2, SOX3, HESX1: in such cases, hypoglycemia or small penis with undescended testes may respectively suggest concomitant GH and gonadotropins deficits.¹⁸

Table 2 Causes of Central Adrenal Insufficiency (CAI)

Clinical Manifestations of Adrenal Insufficiency

AI is an insidious diagnosis presenting non-specific symptoms and may be mistaken with other life-threatening endocrine conditions (septic shock unresponsive to inotropes or recurrent sepsis, acute surgical abdomen).^1,19 Children can be initially misdiagnosed as having sepsis, metabolic disorders, or cardiovascular disease, highlighting the need to consider adrenal dysfunction as a differential diagnosis for an unwell or deteriorating infant. With age-related items, clinical features depend on the type of AI (primary or central) and could manifest in an acute or chronic setting (Table 3).

Table 3 Features of Isolated Adrenal Insufficiency in Pediatric Age

Clinical signs of PAI are based on the deficiency of both gluco- and mineralocorticoids. Signs due to glucocorticoid deficiency are weakness, anorexia, and weight loss. Hypoglycemia with normal or low insulin levels is frequent and often severe in the pediatric population. Mineralocorticoid deficiency contributes to hyponatremia, hyperkalemia, acidosis, tachycardia, hypotension, and salt craving. The lack of glucocorticoid-negative feedback is responsible for the elevated ACTH levels. The high levels of ACTH and other POMC peptides, including the various forms of MSH, cause melanin hypersecretion, stimulating mucosal and cutaneous hyperpigmentation. Searching for an increased pigmentation may represent an essential diagnostic tool since all the other symptoms of PAI are non-specific. However, hyperpigmentation is variable, dependent on ethnic origin, and more prominent in skin exposed to sun and in extension surface of knees, elbows, and knuckles.¹⁵ In autoimmune PAI, vitiligo may be associated with hyperpigmentation.

In the classic CAH simple virilizing form, salt wasting is absent due to the presence of aldosterone production. In males, diagnosis typically occurs between 3 and 4 years of age with pubarche, accelerated growth velocity, and advanced bone age at presentation.^1,10,12,14

NCCAH may occur in late childhood with signs of hyperandrogenism (premature pubarche, acne, adult apocrine odor, advanced bone age) or be asymptomatic. In adolescents and adult women, conditions of androgen excess (acne, oligomenorrhea, hirsutism) may underlie an NCCAH.^20,21

The clinical presentation of CAI may be more complex when caused by an underlying central nervous system disease or by CMPD. In the case of a pituitary or hypothalamic tumor, patients may present headache, vomiting, visual disturbances, short stature, delayed or precocious puberty. In the case of CMPD, manifestations vary considerably and depend on the number and severity of the associated hormonal deficiencies. In CAI, aldosterone production is spared, which means that serum electrolytes are usually normal. However, cortisol contributes to regulating free water excretion, so patients with CAI are at risk for dilutional hyponatremia, with normal serum potassium levels. Since adrenal androgen secretion is under the control of ACTH, girls with ACTH deficiency may present light pubic hair. Patients with partial and isolated ACTH defects can be “asymptomatic”, and adrenal crisis appears during stress or in case of major illness (high fever, surgery).

The acute adrenal crisis is a life-threatening condition in all ages. Patients present with profound malaise, fatigue, nausea, vomiting, abdominal or flank pain, muscle pain or cramps, and dehydration, which lead to hypotension, shock, and metabolic acidosis. Hyponatremia and hyperkalemia are less common in CAI than in PAI, but possible in acute AI. Severe hypoglycemia causes weakness, pallor, sweatiness, and impaired cognitive function, including confusion, loss of consciousness, and coma. Immediate treatment is required (see below).

Children and adolescents affected by autoimmune primary adrenal insufficiency develop a chronic AI, with an insidious onset and slow progress to an acute adrenal crisis over months or even years. Initial symptoms are decreased appetite, anorexia, nausea, abdominal pain, unintentional weight loss, lethargy, headache, weakness, and fatigue, with prominent pain in the joints and muscles. Due to salt loss through the urine and the subsequent reduction in blood volume, blood pressure decreases, and orthostatic hypotension develops together with salt craving. An increased risk of infection in AI patients is reported only in those exposed to glucocorticoids. However, in APECED (Autoimmune Polyendocrinopathy-Candidiasis- Ectodermal-Dystrophy) patients, there is an increased risk of candidiasis and splenic atrophy increases the likelihood for severe infections.

In neonates, AI classically presents with failure to thrive and hypoglycemia, commonly severe and associated with seizures. The condition can be life-threatening and, if misdiagnosed, may result in coma and unexplained neonatal death. In newborns, cortisol deficiency causes delayed bile acid synthesis and transport maturation, determining prolonged cholestatic jaundice with persistently raised serum liver enzymes. The cholestasis can be resolved within ten weeks of correct treatment. StAR deficiency and P450scc cause salt-losing AI with female external genitalia in genetically male neonates.²² In the classic CAH salt-wasting form, the mineralocorticoid deficiency presents with the adrenal crisis at 10–20 days of life. Females show atypical genitalia with signs of virilization (clitoral enlargement, labial fusion, urogenital sinus), whereas males have normal-appearing genitalia, except for subtle signs as scrotal hyperpigmentation and enlarged phallus.^1,10,12,14 Neonates with CMPD may display non-specific symptoms including hypoglycemia, lethargy, apnea, poor feeding, jaundice, seizures, hyponatremia without hyperkalemia, temperature and hemodynamic instability, recurrent sepsis, and poor weight gain. A male with hypogonadism may have undescended testes and micropenis. Infants with optic nerve hypoplasia or agenesis of the corpus callosum may present with nystagmus. Furthermore, infants with midline defects may have various neuro-psychological problems or sensorineural deafness.

Genetic Disorders and Other Conditions at Increased Risk for Adrenal Insufficiency

Among the cholesterol biosynthesis disorder, there is the Smith-Lemli-Opitz syndrome,²³ where microcephaly, micrognathia, low-set posteriorly rotated ears, syndactyly of the second and third toes, and atypical genital may, although rarely, combine with AI; this autosomal recessive disorder is due to defective 7-dehydrocholesterol reductase so that elevated 7-dehydrocholesterol is diagnostic. In lysosomal acid lipase A deficiency,²⁴ AI is due to calcification of the adrenal gland as a result of the accumulation of esterified lipids; in infantile form, that is Wolman disease, hepatosplenomegaly with hepatic fibrosis and malabsorption lead to death in the first year of life, if not treated with enzyme replacement therapy such as sebelipase alfa.²⁵

Adrenal development may be impaired in X-linked congenital adrenal hypoplasia (AHC),^13,26 a disorder caused by defective nuclear receptor DAX-1, presenting with salt-losing AI in infancy in approximately half of the cases, but also later in childhood or adolescence with two other key features such as hypogonadotropic hypogonadism and impaired spermatogenesis. Two syndromes combine adrenal hypoplasia with intrauterine growth restriction (IUGR): in IMAGe syndrome,²⁷ caused by CDKN1C gain-of-function mutations, IUGR and AI present with metaphyseal dysplasia and genitourinary anomalies; MIRAGE syndrome²⁸ is instead characterized by myelodysplasia, infections, genital abnormalities, and enteropathy, as a result of gain-of-function mutations in SAMD9, with elevated mortality rates.

In some other conditions, AI is due to ACTH resistance. Familial Glucocorticoid Deficiency type 1 (FGD1)^13,29 and type 2 (FGD2)³⁰ derive from defective ACTH receptor (MC2R) or its accessory protein MRAP, and both present with early glucocorticoid insufficiency (hypoglycemia, prolonged jaundice) and pronounced hyperpigmentation; there is usually an excellent response to cortisol replacement therapy, even though ACTH levels remain elevated.

In Allgrove or Triple-A Syndrome,^13,31 defective Aladin protein (an acronym for alacrimia-achalasia-adrenal insufficiency) leads to primary ACTH-resistant adrenal insufficiency with achalasia and absent lacrimation, often combined with neurological dysfunction, either peripheral, central, or autonomic. It is an autosome recessive condition, phenotypically characterized by microcephaly, short stature, and skin hyperpigmentation.^32,33

Among metabolic disorders associated with AI, Sphingosine-1-Phosphate Lyase (SGPL1) Deficiency³⁴ is a sphingolipidosis with various features such as steroid-resistant nephrotic syndrome, primary hypothyroidism, undescended testes, neurological impairment, lymphopenia, ichthyosis; interestingly, in cases where nephrotic syndrome develops before AI, the latter may be masked by glucocorticoid treatment.

Adrenoleukodystrophy (ALD)^35–37 is an X-linked recessive proximal disorder of beta-oxidation due to defective ABCD1, where the accumulation of very-long-chain fatty acids (VLCFA) affects in almost all cases adrenal gland among other tissues. Most patients present with progressive neurological impairment, but in some, AI is the only (approximately 10%) or first manifestation, so that every unexplained AI in boys should receive plasma VLCFA evaluation to diagnose ALD and reduce cerebral involvement through a low VLCFAs diet (Lorenzo’s oil) and allogeneic bone marrow transplantation. Early disease-modifying therapies have been developed. Gene therapy adds new functional copies of the ABCD1 gene in hematopoietic stem cells through a lentiviral vector reinfusing the modified cells in the patient’s bloodstream. Recent trials show encouraging results.³⁸

In Zellweger syndrome, caused by mutations in peroxin genes (PEX), peroxisomes are absent, and disease presentation occurs in the neonatal period, with low survival rates after the first year of life. Finally, mitochondrial disorders have been described to occasionally develop AI: Pearson syndrome (sideroblastic anemia, pancreatic dysfunction), MELAS syndrome (encephalopathy with stroke-like episodes), and Kearns-Sayre syndrome (external ophthalmoplegia, heart block, retinal pigmentary changes) belong to this class.³⁹

Autoimmune pathogenesis (Addison disease) accounts for approximately 15% of cases of primary AI in children, in contrast with adolescents and adults where it is the most common mechanism; half of these children present other glands involvement as well. Two syndromes recognize specific combinations: in Autoimmune Polyglandular Syndrome Type 1 (APS1, or APECED)⁴⁰ defective autoimmune regulator AIRE causes AI, hypoparathyroidism, hypogonadism, malabsorption, chronic mucocutaneous candidiasis; APS2 usually present later in life (third-fourth decades) with AI, thyroiditis, and type 1 diabetes mellitus (T1DM). Antibodies against 21-hydroxylase enzyme are the hallmark of APS.

Apart from a genetic disorder, a strong link between autoimmune conditions and autoimmune primary AI has been established, with more than 50% of patients with the latter also having one or more other autoimmune endocrine disorders; on the other hand, only a few patients with T1DM or autoimmune thyroiditis or Graves’ disease develop AI. As an example, in a study of 629 patients with T1DM, only 11 (1.7%) presented 21-hydroxylase autoantibodies, with three of them having AI.⁴¹ Nevertheless, these patients are to be considered at increased risk for a condition that is potentially fatal yet easy to diagnose and treat; that is why it is reasonable to screen for autoimmune AI at least patients with T1DM, significantly if associated with DQ8 HLA combined with DRB*0404 HLA alleles, who have been observed to develop AI in 80% of cases if also 21-hydroxylase autoantibodies positive.⁴²

Regarding immunological disruption, the link with celiac disease is instead well established: celiac patients have an 11-fold increased risk for AI, while in a study, 6 of 76 patients with AI had celiac disease, so that mutual evaluation should be granted in these patients.^43,44

Subclinical Adrenal Insufficiency

Subclinical AI is a particularly insidious challenge for a pediatric endocrinologist. It represents the preclinical stage of Addison disease when 21-hydroxylase autoantibodies are already detectable but still absent from evident symptoms. 21-hydroxylase autoantibodies positivity carries a greater risk to develop overt AI in children than in adults: in a study, estimated risk was 100% in children versus 32% in adults on a medium six-year period of follow-up.⁴⁵ As the adrenal crisis is a potentially lethal condition, it is essential to recognize and adequately manage subclinical AI.

Although asymptomatic by definition, subclinical AI may present with non-specific symptoms such as fatigue, lethargy, gastrointestinal symptoms (nausea, vomiting, diarrhea, constipation), hypotension; physical or psychosocial stresses may sometimes exacerbate these symptoms. When symptoms lack, subclinical AI may be identified thanks to the co-occurrence with other autoimmune endocrinopathies.⁴⁶

21-hydroxylase autoantibodies titer is considered a marker of autoimmune activity and correlates with disease progression.⁴⁷ Other reported risk factors for the disease evolution include young age, male sex, hypoparathyroidism or candidiasis coexistence, increased renin activity, or an altered synacthen test with normal baseline cortisol and ACTH.⁴⁵ ACTH elevation has been reported as the best predictor of progression to the clinical stage in 2 years (94% sensitivity and 78% specificity).⁴⁸

Management of patients with subclinical AI should include serum cortisol, ACTH, renin measurement, and a synacthen test. If normal, cortisol and ACTH should be repeated in 12–18 months, while synacthen test every two years. After synacthen test results are subnormal, cortisol and ACTH should be assessed every 6–9 months if ACTH remains in range or every six months if ACTH becomes elevated.⁴⁹ In the latter case, therapy with hydrocortisone should be started.¹⁹ This strategy will prevent acute crises and possibly improve the quality of life in patients reporting non-specific symptoms.

Diagnosis

Laboratory evaluation of a stable patient with suspected AI should start with combined early morning (between 6 and 8 AM) serum cortisol and ACTH measurements (Figure 2).

Figure 2 Diagnostic algorithm for adrenal insufficiency.

Although often included in the extensive work-up of an unwell child, a single cortisol value is usually challenging to interpret: circadian cortisol rhythm is highly variable and morning peak is unpredictable; morning cortisol levels in children with diagnosed AI may range up to 706 nmol/L (97th percentile); several factors, such as exogenous estrogens, may alter total serum cortisol values by influencing the free cortisol to cortisol binding globulin or albumin-bound cortisol ratio.⁷

Significant variability is also observed depending on the specific type of cortisol assay; therefore, it is recommended to check the reference ranges with the laboratory. Mass spectrometry analysis and the new platform methods (Roche Diagnostics Elecsys Cortisol II)⁵⁰ have more specificity because it detects lower cortisol concentrations than standard immunoassays.¹⁵ Low serum cortisol with normal or low ACTH levels is compatible with CAI. In such cases, morning serum cortisol levels below 3 µg/dL (83 nmol/L) best predict AI, while greater than 13 µg/dL (365 nmol/L) values tend to exclude it.⁵¹ This is why in most cases, a dynamic test is required for diagnosis and has been introduced to assess the hypothalamic-pituitary-adrenal (HPA) axis in case of intermediate values.⁵

The insulin tolerance test (ITT) is considered the gold standard for CAI diagnosis as hypoglycemia results in an excellent HPA axis activation; moreover, it allows simultaneous growth hormone evaluation in patients with suspected CPHD. Serum cortisol is measured at baseline and 15, 30, 45, 60, 90, and 120 minutes after intravenous administration of 0.1 UI/Kg regular insulin; the test is valid if serum glucose is reduced by 50% or below 2.2 mmol/L (40 mg/dL).⁵² CAI is diagnosed for a <20 µg/dL (550 nmol/L) cortisol value at its peak.¹⁵ Hypoglycemic seizures and hypokalemia (due to glucose infusion) are the main risks of this test so that it is contraindicated in case of a history of seizures or cardiovascular disease.

Glucagon stimulation test (GST, 30 µg/Kg up to 1 mg i.m. glucagon with cortisol measurements every 30 min for 180 min) allows both CAI and growth hormone deficiency evaluation as well but is characterized by frequent gastrointestinal side effects and poor specificity.⁸

Metyrapone is an 11-hydroxylase inhibitor, thereby decreasing cortisol synthesis and removing its negative feedback on ACTH release. Overnight metyrapone test is based on oral administration of 30 mg/Kg metyrapone at midnight, and 11-deoxycortisol measurement on the following morning: in case of CAI, its level will not reach 7 µg/dL (200 nmol/L). This test may, however, induce an adrenal crisis so that it is rarely performed.

Given their safety profile and accuracy, corticotropin analogs such as tetracosactrin (Synacthen^®) or cosyntropin (Cortrosyn^®) are recommended as first-line stimulation tests. Nevertheless, false-negative results are probable in the case of recent or moderate ACTH deficiency, which would not have induced adrenal atrophy. The standard dose short synacthen test (SDSST) is based on a 250 µg Synacthen vial administration with serum cortisol measurement at baseline and 30 and 60 minutes after. CAI is diagnosed if peak cortisol level is <16 µg/dL (440 nmol/L), or excluded if >39 µg/dL (1076 nmol/L). However, the cut-offs for both the new platform immunoassay and mass spectrometry serum cortisol assays are 13.5 to 14.9 mcg/dL (373 to 412 nmol/L).⁵³ The 250 µg Synacthen dose is considered a supraphysiological stimulus since it is 500 times greater than the minimum ACTH dose reported to induce a maximal cortisol response (500 ng/1.73 m²). The low dose short synacthen test (LDSST) has been introduced as a more sensitive first-line test in children greater than two years.⁵⁴ The recommended dose is 1 µg⁵⁵, which is contained in 1 mL of the solution obtained by diluting a 250 µg vial into 250 mL saline. Serum cortisol level is then measured at baseline and after 30 minutes, resulting in diagnose of CAI if <16 µg/dL (440 nmol/L), otherwise ruling it out if >22 µg/dL (660 nmol/L). Using these thresholds, LDSST is more precise than SDSST in children, with an area under the ROC curve of 0.99 (95% CI 0.98–1.00).⁵⁶ LDSST has not been validated in acutely ill patients, pituitary acute disorders or surgery or radiation therapy, and impaired sleep-wake cycle. Patients with an indeterminate LDSST result should be furtherly studied with ITT or metyrapone test.

Finally, the CRH test is based on 1 µg/Kg human CRH (Ferring^®) administration and may differentiate secondary from tertiary AI, but its thresholds are still not precisely defined.⁵⁷

Once CAI is diagnosed, other pituitary hormones should be assessed (prolactin, IGF1, LH, FSH, fT4, TSH), and an MRI of the pituitary region should be performed to exclude neoplastic or infiltrative processes.

Primary adrenal insufficiency (PAI) should be suspected in case of low serum cortisol with elevated ACTH levels. When hypocortisolemia has been confirmed, ACTH levels >66 pmol/L or greater than twice the upper limit best predict PAI. Nevertheless, a confirmatory dynamic test is always recommended for diagnosis.¹⁹ Given the comparable accuracy between standard and low dose SST reported in these patients, SDSST is recommended as the most feasible test.⁵⁸ Moreover, suspected PAI cases should receive plasma renin activity or direct renin and aldosterone assessment to evaluate mineralocorticoid deficiency.

Etiologic work-up of confirmed PAI should start from 21-hydroxylase antibodies assessment: if positive, differential diagnosis will include Addison disease and APS1 or APS2. Adrenal autoantibody negative patients should instead be screened for CAH by measuring 17-hydroxyprogesterone, ALD (if young male) by assessing VLCFA, and tuberculosis if endemic; adrenal glands imaging will complete the work-up in order to exclude infection, hemorrhage, or tumor.⁶

While universal newborn screening is already implemented for CAH in many countries, allowing a timely replacement therapy, basal salivary cortisol, and salivary cortisone measurements could improve CAI screening in the future: this technique is simple, cost-effective, and independent of binding proteins.¹⁵

Treatment

All patients with adrenal insufficiency need long-term glucocorticoid replacement therapy. Individuals with PAI also require mineralocorticoids replacement, together with salt intake as required (Table 4). Otherwise, guidelines do not recommend androgen replacement.^5,9,19

Table 4 Management of Adrenal Insufficiency (AI)

Oral hydrocortisone is the first-choice replacement treatment in children due to its short half-life, rapid peak in plasma concentration, lower potency, and fewer adverse effects than prednisolone and dexamethasone.^5,8 Based on endogenous production, dosing replacement regimens vary from 7.5 to 15 mg/m2/day, divided into two, three, or four doses.¹⁹ The first and largest dose should be taken at awakening, the next in the early afternoon to avoid sleep disturbances. Small and frequent dosing mimic the physiological rhythm of cortisol secretion, but high peak cortisol levels after drug assumption and prolonged periods of hypocortisolemia between doses are described.^8,9 Some children experience low cortisol concentrations and symptoms of cortisol insufficiency (eg, fatigue, nausea, headache) despite modifications in dosing. This cohort of patients can take advantage of using a modified-release hydrocortisone formulation, such as Chronocort^® and Plenadren^®. Plenadren^®, approved for adults, consists of a coating of hydrocortisone released rapidly, followed by a slow release of hydrocortisone from the tablet center. It is available as 5 and 20 mg tablets. Park et al demonstrate smoother cortisol profiles and normal growth and weight gain patterns using Plenadren^® in children.⁵⁹ In a few cases, the continuous subcutaneous infusion of hydrocortisone using insulin pump technology proved to be a feasible, well-tolerated and safe option for selected patients with poor response to conventional therapy.¹⁹

Monitoring glucocorticoid therapy is based on growth, weight gain, and well-being. Cortisol measurements are usually not useful, apart from cases when a discrepancy between daily doses and patient symptoms exists.¹⁵ The concomitant use of hydrocortisone and CYP3A4 inducers, such as Rifampicin, Phenytoin, Carbamazepine, requires an increased dose of glucocorticoids. Conversely, the inhibition of CYP3A4 impairs hydrocortisone metabolism.⁵

Mineralocorticoid replacement is unnecessary if the patient has a normal renin-angiotensin-aldosterone axis and, hence, normal aldosterone secretion, as well as in CAI. By contrast, patients with PAI and confirmed aldosterone deficiency need fludrocortisone at the dosage of 0.1–0.2 mg/day when given together with hydrocortisone, which has some mineralocorticoid activity. When using other synthetic glucocorticoids for replacement, higher fludrocortisone doses may be needed. Infants younger than one year should also be supplemented with sodium chloride due to their relatively low dietary sodium intake and relative renal resistance to mineralocorticoids. The dose is approximately 1 gram (17 mEq) daily.¹⁹

Surgery and anesthesia increase the glucocorticoid requirement during the pre-, intra-, and post-operative periods (Table 4). All children with AI should receive an intravenous dose of hydrocortisone at induction (2 mg/kg for minor or major surgery under general anesthesia). For minor procedures or sedation, the child should receive a double morning dose of hydrocortisone orally.⁶⁰

Adrenal crisis is a life-threatening condition, treatment is effective if administered promptly, and it must not be delayed for any reason. Hydrocortisone should be administered as soon as possible with an intravenous bolus of 4 mg/kg followed by a continuous infusion of 2 mg/kg/day until stabilization. In the alternative, it can be administered as a bolus every four hours intravenous or intramuscular. In difficult peripheral venous access, the intramuscular route must be used as the first choice. In order to counteract hypotension, a bolus of normal saline 0.9% should be given at a dose of 20 mL/kg; it can repeat up to a total of 60 mL/kg within one hour for shock. If there is hypoglycemia, 10% dextrose at a 5 mL/kg dose should be administered.^5,19,61,62

Patients with AI require additional doses of glucocorticoids in case of physiologic stress such as illness or surgical procedures to avoid an adrenal crisis. Home management of illness with a fever (> 38°C), vomiting or diarrhea, is based on the increase from two to three times the usual dose orally. If the child is unable to tolerate oral therapy, intramuscular injection of hydrocortisone should be administered (Table 4).

Education for caregivers and patients (if adolescent) is crucial to prevent adrenal crisis. They should recognize signs and symptoms of adrenal crisis and should receive a steroid emergency card with the sick day rules. Prescribing doctors should provide for additional oral glucocorticoids and adequate training in hydrocortisone emergency self-injection.

Abbreviations

AI, adrenal insufficiency; PAI, primary adrenal insufficiency; CAI, central adrenal insufficiency; HPA, hypothalamic-pituitary-adrenal axis; CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone; POMC, pro-opiomelanocortin; CAH, congenital adrenal hyperplasia; STAR, steroidogenic acute regulatory; 21OHD, 21-hydroxylase deficiency; 11BOHD, 11-B-hydroxylase deficiency; P450scc, P450 cytochrome side-chain cleavage deficiency; 17-OHP, 17-hydroxyprogesterone; NCCAH, non-classic congenital adrenal hyperplasia; ALD, adrenoleukodystrophy; VLCFA, very long-chain fatty acids; CMPD, combined multiple pituitary hormone deficiency; GHD, growth hormone deficiency; MSH, melanocyte stimulating hormone; IUGR, intrauterine growth restriction; APS1, autoimmune polyglandular syndrome type 1; SDSST, standard dose short synacthen test; LDSST, low dose short synacthen test.

Take Home Messages

In neonates and infants CAH is the commonest cause of PAI, causing almost 71.8% of cases.
Adrenoleukodystrophy should be considered in any male with hypoadrenalism.
Unexplained hyponatremia, hyperpigmentation and the loss of pubic and axillary hair should raise the suspicion of AI.
Adrenal insufficiency can present with non-specific clinical features; therefore a single cortisol measurement should be included in the biochemical work-up of an unwell child.
Patients and parents should be well-trained in adrenal crisis recognition and management.

Disclosure

The authors report no conflicts of interest in this work.

References

1. Charmandari E, Nicolaides N, Chrousos G. Adrenal insufficiency. Lancet. 2021;383(9935):2152–2167. doi:10.1016/S0140-6736(13)61684-0

2. White PC. Adrenocortical insufficiency. In: Nelson Textbook of Pediatrics. Elsevier. 2019:11575–11617.

3. White PC. Physiology of the adrenal gland. Nelson Textbook of Pediatrics. Elsevier. 2019.

4. Butler G, Kirk J. Adrenal gland disorders. In: Paediatric Endocrinology and Diabetes. Oxford University Press. 2020:274–288.

5. Patti G, Guzzeti C, Di Iorgi N, Loche S. Central adrenal insufficiency in children and adolescents. Best Pract Res Clin Endocrinol Metab. 2018;32(4):425–444. doi:10.1016/j.beem.2018.03.012

6. Martin-grace J, Dineen R, Sherlock M, Thompson CJ. Adrenal insufficiency: physiology, clinical presentation and diagnostic challenges. Clin Chim Acta. 2020;505:78–91. doi:10.1016/j.cca.2020.01.029

7. Shaunak M, Blair JC, Davies JH. How to interpret a single cortisol measurement. Arch Dis Child Educ Pract. 2020;105:347–351. doi:10.1136/archdischild-2019-318431

8. Park J, Didi M, Blair J. The diagnosis and treatment of adrenal insuf fi ciency during childhood and adolescence. Arch Dis Child. 2016;101:860–865. doi:10.1136/archdischild-2015-308799

9. Husebye ES, Pearce SH, Krone NP, Kämpe O. Adrenal insufficiency. Lancet. 2021;397:613–629. doi:10.1016/S0140-6736(21)00136-7

10. Speiser P, Azziz R, Baskin L, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(9):4133–4160. doi:10.1210/jc.2009-2631

11. Buonocore F, McGlacken-Byrne S, Del Valle I, Achermann J. Current insights into adrenal insufficiency in the newborn and young infant. Front Pediatr. 2020;8:619041. doi:10.3389/fped.2020.619041

12. Bacila I, Elder C, Krone N. Update on adrenal steroid hormone biosynthesis and clinical implications. Arch Dis Child. 2019;104(12):1223–1228. doi:10.1136/archdischild-2017-313873

13. Buonocore F, Maharaj A, Qamar Y, et al. Genetic analysis of pediatric primary adrenal insufficiency of unknown etiology: 25 years’ experience in the UK. J Endocr Soc. 2021;5(8):1–15. doi:10.1210/jendso/bvab086

14. Balsamo A, Baronio F, Ortolano R, et al. Congenital adrenal hyperplasias presenting in the newborn and young infant. Front Pediatr. 2020;8:593315. doi:10.3389/fped.2020.593315

15. Hahner S, Ross RJ, Arlt W, et al. Adrenal insufficiency. Nat Rev Dis Prim. 2021;7(1):1–24. doi:10.1038/s41572-021-00252-7

16. Krude H, Biebermann H, Luck W, et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet. 1998;19:155–157. doi:10.1038/509

17. Vallette-Kasic S, Brue T, Pulichino A-M, et al. Congenital isolated adrenocorticotropin deficiency: an underestimated cause of neonatal death, explained by TPIT gene mutations. J Clin Endocrinol Metab. 2005;90:1323–1331. doi:10.1210/jc.2004-1300

18. Alatzoglou K, Dattani M. Genetic forms of hypopituitarism and their manifestation in the neonatal period. Early Hum Dev. 2009;85:705–712. doi:10.1016/j.earlhumdev.2009.08.057

19. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2016;101:364–389. doi:10.1210/jc.2015-1710

20. Kurtoğlu S, Hatipoğlu N. Non-classical congenital adrenal hyperplasia in childhood. J Clin Res Pediatr Endocrinol. 2017;9(1):1–7. doi:10.4274/jcrpe.3378

21. Livadas S, Bothou C. Management of the female with non-classical congenital adrenal hyperplasia (NCCAH): a patient-oriented approach. Front Endocrinol. 2019;10:366. doi:10.3389/fendo.2019.00366

22. Miller W. Disorders in the initial steps of steroid hormone synthesis. J Steroid Biochem Mol Biol. 2017;165:18–37. doi:10.1016/j.jsbmb.2016.03.009

23. Nowaczyk M, Irons M. Smith–Lemli–Opitz syndrome: phenotype, natural history, and epidemiology. Am J Med Genet Part C Semin Med Genet. 2012;160:250–262. doi:10.1002/ajmg.c.31343

24. Anderson R, Byrum R, Coates P, Sando G. Mutations at the lysosomal acid cholesteryl ester hydrolase gene locus in Wolman disease. Proc Natl Acad Sci USA. 1994;91:2718. doi:10.1073/pnas.91.7.2718

25. Jones S, Rojas-Caro S, Quinn A. Survival in infants treated with sebelipase Alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study. Orphanet J Rare Dis. 2017;12:25. doi:10.1186/s13023-017-0587-3

26. Muscatelli F, Strom T, Walker A, et al. Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Nature. 1994;372:672–676. doi:10.1038/372672a0

27. Vilain E, Merrer M, Lecointre C, et al. IMAGe, a new clinical association of Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, and Genital anomalies. J Clin Endocrinol Metab. 1999;84(12):4335–4340. doi:10.1210/jcem.84.12.6186

28. Narumi S, Amano N, Ishii T, et al. SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7. Nat Genet. 2016;48:792–797. doi:10.1038/ng.3569

29. Maharaj A, Maudhoo A, Chan L, et al. Isolated glucocorticoid deficiency: genetic causes and animal models. J Steroid Biochem Mol Biol. 2019;189:73–80. doi:10.1016/j.jsbmb.2019.02.012

30. Metherell L, Chapple J, Cooray S, et al. Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2. Nat Genet. 2005;37:166–170. doi:10.1038/ng1501

31. Prpic I, Huebner A, Persic M, et al. Triple A syndrome: genotype-phenotype assessment. Clin Genet. 2003;63:415. doi:10.1034/j.1399-0004.2003.00070.x

32. Kurnaz E, Duminuco P, Aycan Z, et al. Clinical and genetic characterisation of a series of patients with triple A syndrome. Eur J Pediatr. 2018;177(3):363–369. doi:10.1007/s00431-017-3068-8

33. Brett E, Auchus R. Genetic forms of adrenal insufficiency. Endocr Pract. 2015;21(4):395–399. doi:10.4158/EP14503.RA

34. Prasad R, Hadjidemetriou I, Maharaj A, et al. Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome. J Clin Invest. 2017;127:942–953. doi:10.1172/JCI90171

35. Moser H, Moser A, Smith K, et al. Adrenoleukodystrophy: phenotypic variability and implications for therapy. J Inherit Metab Dis. 1992;15:645. doi:10.1007/BF01799621

36. Bradbury A, Ream M. Recent advancements in the diagnosis and treatment of leukodystrophies. Semin Pediatr Neurol. 2021;37:100876. doi:10.1016/j.spen.2021.100876

37. Engelen M, Kemp S. X-linked adrenoleukodystrophy: pathogenesis and treatment. Curr Neurol Neurosci Rep. 2014;14(10):486. doi:10.1007/s11910-014-0486-0

38. Federico A, de Visser M. New disease modifying therapies for two genetic childhood-onset neurometabolic disorders (metachromatic leucodystrophy and adrenoleucodystrophy). Neurol Sci. 2021;42(7):2603–2606. doi:10.1007/s10072-021-05412-x

39. Artuch R, Pavía C, Playán A, et al. Multiple endocrine involvement in two pediatric patients with Kearns-Sayre syndrome. Horm Res. 1998;50:99. doi:10.1159/000023243

40. Peterson P, Pitkänen J, Sillanpää N, et al. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED): a model disease to study molecular aspects of endocrine autoimmunity. Clin Exp Immunol. 2004;135:348. doi:10.1111/j.1365-2249.2004.02384.x

41. Brewer K, Parziale VS, Eisenbarth GS, et al. Screening patients with insulin-dependent diabetes mellitus for adrenal insufficiency. New Engl J Med. 1997;337:202. doi:10.1056/NEJM199707173370314

42. Yu L, Brewer K, Gates S, et al. DRB1*04 and DQ alleles: expression of 21-hydroxylase autoantibodies and risk of progression to Addison’s disease. J Clin Endocrinol Metab. 1999;84:328. doi:10.1210/jcem.84.1.5414

43. Myhre A, Aarsetøy H, Undlien D, et al. High frequency of coeliac disease among patients with autoimmune adrenocortical failure. Scand J Gastroenterol. 2003;38:511. doi:10.1080/00365520310002544

44. Elfström P, Montgomery S, Kämpe O, et al. Risk of primary adrenal insufficiency in patients with celiac disease. J Clin Endocrinol Metab. 2007;92:3595. doi:10.1210/jc.2007-0960

45. Coco G, Dal Pra C, Presotto F, et al. Estimated risk for developing autoimmune Addison’s disease in patients with adrenal cortex autoantibodies. J Clin Endocrinol Metab. 2006;91(5):1637–1645. doi:10.1210/jc.2005-0860

46. Yamamoto YT. Latent adrenal insufficiency: concept, clues to detection, and diagnosis. Endocr Pract. 2018;24(8):746–755. doi:10.4158/EP-2018-0114

47. Laureti S, De Bellis A, Muccitelli V, et al. Levels of adrenocortical autoantibodies correlate with the degree of adrenal dysfunction in subjects with preclinical Addison’s disease. J Clin Endocrinol Metab. 1998;83:3507–3511. doi:10.1210/jcem.83.10.5149

48. Baker P, Nanduri P, Gottlieb P, et al. Predicting the onset of Addison’s disease: ACTH, renin, cortisol and 21-hydroxylase autoantibodies. Clin Endocrinol. 2012;76:617–624. doi:10.1111/j.1365-2265.2011.04276.x

49. Thuillier P, Kerlan V. Subclinical adrenal diseases: silent pheochromocytoma and subclinical Addison’s disease. Ann Endocrinol. 2012;73(Suppl 1):S45–S54. doi:10.1016/S0003-4266(12)70014-8

50. Raverot V, Richet C, Morel Y, Raverot G, Borson-Chazot F. Establishment of revised diagnostic cut-offs for adrenal laboratory investigation using the new Roche Diagnostics Elecsys^® Cortisol II assay. Ann Endocrinol. 2016;77(5):620–622. doi:10.1016/j.ando.2016.05.002

51. Grossman A. The diagnosis and management of central hypoadrenalism. J Clin Endocrinol Metab. 2010;95:4855e63. doi:10.1210/jc.2010-0982

52. Petersenn S, Quabbe HJ, Schöfl C, et al. The rational use of pituitary stimulation tests. Dtsch Arztebl Int. 2010;107(25):437–443. doi:10.3238/arztebl.2010.0437

53. Kline GA, Buse J, Krause RD. Clinical implications for biochemical diagnostic thresholds of adrenal sufficiency using a highly specific cortisol immunoassay. Clin Biochem. 2017;50(9):475–480. doi:10.1016/j.clinbiochem.2017.02.008

54. Agwu JC, Spoudeas H, Hindmarsh PC, Pringle PJ, Brook CGD. Tests of adrenal insufficiency. Arch Dis Child. 1999;80(4):330–333. doi:10.1136/adc.80.4.330

55. Maghnie M, Uga E, Temporini F, et al. Evaluation of adrenal function in patients with growth hormone deficiency and hypothalamic-pituitary disorders: comparison between insulin-induced hypoglycemia, low-dose ACTH, standard ACTH and CRH stimulation tests. Eur J Endocrinol. 2005;152:735–741. doi:10.1530/eje.1.01911

56. Kazlauskaite R, Maghnie M. Pitfalls in the diagnosis of central adrenal insufficiency in children. Endocr Dev. 2010;17:96e107.

57. Chanson P, Guignat L, Goichot B, et al. Group 2: adrenal insufficiency: screening methods and confirmation of diagnosis. Ann Endocrinol. 2017;78:495e511. doi:10.1016/j.ando.2017.10.005

58. Ospina N, Al Nofal A, Bancos I, et al. ACTH stimulation tests for the diagnosis of adrenal insufficiency: systematic review and meta-analysis. J Clin Endocrinol Metab. 2016;101(2):427–434. doi:10.1210/jc.2015-1700

59. Park J, Das U, Didi M, et al. The challenges of cortisol replacement therapy in childhood: observations from a case series of children treated with modified-release hydrocortisone. Pediatr Drugs. 2018;20(6):567–573. doi:10.1007/s40272-018-0306-0

60. Woodcock T, Barker P, Daniel S, et al. Guidelines for the management of glucocorticoids during the peri-operative period for patients with adrenal insuf fi ciency Guidelines from the Association of Anaesthetists, the Royal College of Physicians and the Society for Endocrinology UK. Anaesthesia. 2020;75:654–663. doi:10.1111/anae.14963

61. Rushworth R, Torpy DJ, Falhammar H. Adrenal crisis. N Engl J Med. 2019;381(9):852–861. doi:10.1056/NEJMra1807486

62. Miller BS, Spencer SP, Geffner ME, et al. Emergency management of adrenal insufficiency in children: advocating for treatment options in outpatient and field settings. J Investig Med. 2020;68:16–25. doi:10.1136/jim-2019-000999

Creative Commons License This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

Download Article [PDF]

From https://www.dovepress.com/pediatric-adrenal-insufficiency-challenges-and-solutions-peer-reviewed-fulltext-article-TCRM

Filed under: Addison's disease, adrenal crisis | Tagged: Addison's disease, adrenal crisis, adrenal insufficiency, children, hydrocortisone, pediatric | Leave a comment »

Severe COVID-19 risks greatly increased for children with adrenal insufficiency

Posted on March 24, 2021 by MaryO

Adrenal insufficiency increases the risk for severe outcomes, including death, 23-fold for children who contract COVID-19, according to a data analysis presented at the ENDO annual meeting.

“Adrenal insufficiency in pediatrics does increase risk of complications with COVID-19 infections,” Manish Gope Raisingani, MD, assistant professor in the department of pediatrics in the division of pediatric endocrinology at Arkansas Children’s Hospital, University of Arkansas for Medical Sciences, told Healio. “The relative risk of complications is over 20 for sepsis, intubation and mortality, which is very significant.”

Adrenal transparent _Adobe — Source: Adobe Stock

Using the TriNetX tool and information on COVID-19 from 54 health care organizations, Raisingani and colleagues analyzed data from children (aged 0-18 years) with COVID-19; 846 had adrenal insufficiency and 252,211 did not. The mortality rate among children with adrenal insufficiency was 2.25% compared with 0.097% for those without, for a relative risk for death of 23.2 (P < .0001) for children with adrenal insufficiency and COVID-19. RRs for these children were 21.68 for endotracheal intubation and 25.45 for sepsis.

“Children with adrenal insufficiency should be very careful during the pandemic,” Raisingani said. “They should take their steroid medication properly. They should also be appropriately trained on stress steroids for infection, other significant events.”

From https://www.healio.com/news/endocrinology/20210321/severe-covid19-risks-greatly-increased-for-children-with-adrenal-insufficiency

Filed under: Addison's disease, Rare Diseases | Tagged: adrenal insufficiency, children, COVID-19 | Leave a comment »

	38 Years Cushing… on In Memory: Edward H. Oldfield,…
	Voices from the Past… on Looking at your Doctor’s…
	Basics: Meds: Recorl… on FDA Approval for Endogenous Cu…
	What’s on Your Med… on Medical ID Jewelry Often Lacks…
	Day 26, Cushing’s Aw… on Day 6: Cushing’s Awareness Cha…

Translate to…

Recent Posts

Enjoying the Free Content?

Recent Comments

Categories

Meta

Introduction

Methods

Clinical presentation of CS in children

Diagnostic workup for CS

Screening for endogenous hypercortisolism

24-h Urinary free cortisol (UFC)

Late night cortisol

Low-dose dexamethasone suppression tests (DST)

Etiological diagnosis of endogenous CS

Basal electrolytes and ACTH

CRH stimulation test

Desmopressin test

Standard high dose dexamethasone suppression test (HDDST)

Imaging

Pituitary magnetic resonance imaging (MRI)

Bilateral petrosal sinus sampling (BIPSS)

Radiological anatomic imaging

Functional imaging

Algorithm approach

Conclusions

Declarations

Ethical approval

Informed consent

Conflict of interest

Publisher’s note

Share this:

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Data sharing

Declaration of interests

Best Pract Res Clin Endocrinol Metab

Trends Endocrinol Metab

Clin Perinatol

Ann Endocrinol (Paris)

Clin Biochem

J Pediatr

Best Pract Res Clin Endocrinol Metab

Lancet Diabetes Endocrinol

Incidence of Cushing’s syndrome and Cushing’s disease in commercially-insured patients <65 years old in the United States

Pituitary

The incidence of Cushing’s disease: a nationwide Swedish study

Pituitary

Share this:

Abstract

Objective

Design

Patients

Measurements

Results

Conclusions

Share this:

Introduction

Physiology of the Adrenal Gland

Primary Adrenal Insufficiency

Central Adrenal Insufficiency

Clinical Manifestations of Adrenal Insufficiency

Genetic Disorders and Other Conditions at Increased Risk for Adrenal Insufficiency

Subclinical Adrenal Insufficiency

Diagnosis

Treatment

Abbreviations

Take Home Messages

Disclosure

References

Share this: