Abstract
Cushing's disease (CD) is the commonest form of ACTH-dependent Cushing's syndrome and is a rare clinical diagnosis in paediatric and adolescent patients. CD is caused by an ACTH-secreting pituitary corticotroph adenoma and is associated with significant morbidity in children; therefore, early diagnosis and treatment are critical for optimal therapeutic outcome. This review highlights the key clinical and biochemical features of paediatric CD and appraises current practices in diagnosis and management. A close liaison with adult endocrinology colleagues, particularly, for interpretation of investigations and definition of therapeutic strategy is strongly advised.
Invited Author's profile
Dr Helen Storr is Reader and Honorary Consultant in Paediatric Endocrinology at Queen Mary University of London and Barts and the Royal London Hospital. Her major clinical and research interests include paediatric Cushing's syndrome, the genetics of growth hormone insensitivity (GHI) and the molecular basis of adrenal disorders. She has published widely on many aspects of the investigation and management of Cushing's disease.
Introduction
Endogenous Cushing's syndrome (CS) is a rare life-threatening disorder caused by prolonged exposure to excess glucocorticoid hormone concentrations. CS can be divided into adrenocorticotrophic hormone (ACTH)-dependent and ACTH-independent aetiological categories. Approximately, 10% of new CS cases each year occur in the paediatric age range up to 18 years, and Cushing's disease (CD) caused by an ACTH-secreting pituitary adenoma is responsible for 75–80% of cases. Once CS is suspected, the paediatric patient requires investigation using a formal protocol to ensure an accurate diagnosis and definition of the aetiology. Once CD has been diagnosed, the primary aim of treatment is rapid normalisation of serum cortisol, which is particularly important in children due to the adverse effects of prolonged hypercortisolaemia on growth and development. Once remission of the CD has been established, post-treatment management also presents challenges for optimisation of growth, pubertal development and body composition.
In this review, we discuss epidemiology, pathogenesis, clinical features, investigations and treatment of paediatric CD. The recommendations are based on published data and our experience from the management of 47 cases of paediatric CD at St Bartholomew's and the Royal London Hospitals during the past 30 years.
Epidemiology
CD is the commonest cause of CS in children over 5 years of age (1, 2, 3), accounting for 75–80% of paediatric CS cases compared with 49–71% of adult cases (1, 4). ACTH-secreting corticotroph adenomas in childhood account for 54.8% of all pituitary adenomas from age 0 to 11 years and 29.4% from 12 to 17 years (5). Therefore, CD is the commonest cause of CS after the pre-school years, accounting for more than half of pituitary adenomas under the age of 11 years. CD accounts for ∼75% of all cases of CS in children over 5 years. In children under 5 years, primary adrenal causes (adenoma, carcinoma or bilateral adrenal hyperplasia) are the most common causes of CS (6).
In 182 cases of paediatric CD taken from the literature, the median age of presentation was 14.1 years (7). The mean age at presentation in our own series was slightly younger at 12.3±3.5 years (range 5.7–17.8) (8). In adults, CD has a female preponderance, however male predominance is now established in prepubertal subjects (3, 9), with an overall prevalence of males (63%) compared with females (79%) in paediatric and adult series respectively (8). The incidence in males and females during puberty was equal, with an increasing predominance of females in post-pubertal patients (9). No clear explanation for this phenomenon exists. In addition, male paediatric patients may have more aggressive disease with elevated BMI, shorter height and higher ACTH levels compared with females (10). The basis for this possible gender-dependent biological difference is currently unclear.
Pathogenesis
Pituitary microadenomas, frequently with diameter <5 mm (11, 12), are the commonest cause of CD in children. At surgery, corticotroph adenomas are frequently observed to have a diameter of 2 mm or less (5). Pituitary macroadenomas (defined as >1 cm in maximal diameter) account for ∼10% of adult-onset CD but are extremely rare in children. Two cases of a corticotroph macroadenomas have been identified in our series of 47 paediatric cases (4%) (8, 13).
Molecular pathogenesis
The majority of patients with paediatric CD do not have causative germline genetic defects (14). However, somatic mutations of the USP8 deubiquitinase gene in corticotroph adenomas have recently been implicated in the molecular pathogenesis of CD (15). The molecular genetic processes leading to CD are poorly understood, but an association with several rare hereditary conditions has been noted. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal-dominant disorder characterised by endocrine tumours including anterior pituitary adenomas, and MEN1-associated ACTH-producing adenomas have been reported in several young patients (16). Pituitary macroadenomas have also been reported to be an early manifestation of MEN1 (17).
Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene predispose to familial pituitary adenomas (18). However, only one out of 73 (1.4%) paediatric CD subjects were found to have an AIP mutation (19). Therefore genetic defects are extremely rare in sporadic, isolated paediatric CD. However, careful family history for features of MEN1 and familial pituitary adenomas is warranted in children presenting with CD, and genetic testing should be performed in cases with a positive family history.
Clinical features
The rarity of paediatric CS in clinical practice underlies the fact that this diagnosis may be overlooked. However, early recognition of the salient features of CD is crucial to allow prompt diagnosis and effective treatment. The features of paediatric CD are well documented (7) and have shown some interesting differences compared with adult patients (8) (Table 1). Key presenting features in children include weight gain, a change in facial appearance and growth failure. In our series of paediatric CD patients, all but one child had evidence of weight gain (mean BMI SDS at diagnosis 2.7±1.6; range 0.0–9.2) and all patients had a change in facial appearance (8). Although there is a spectrum of features, most children and adolescents have a typical Cushingoid appearance. Subtle or sub-clinical presentation or even cyclical features appear to be uncommon. The disease onset is often insidious and parents and family doctors may fail to recognise the pathological nature of the change in the child's appearance, significantly delaying diagnosis. The mean length of symptoms before diagnosis in 43 paediatric CD patients was 2.5±1.7 years (range 0.3–6.6 years) (8).
Clinical features and age at diagnosis in paediatric and adult-onset CD. Data from Storr et al. (8).
| Clinical feature | Adult CD subjects (n=183) | Paediatric CD subjects (n=41) | P value | |
|---|---|---|---|---|
| No. with symptom or sign (%) | No. with symptom or sign (%) | Mean age±s.d. (years) | ||
| Weight gain | 119 (65) | 40 (98) | 12.3±3.5 | 0.001 |
| Weight loss | 8 (4) | 1 (2) | (age 13.2) | 0.87 |
| Facial changes | 154 (81) | 41 (100) | 12.3±3.5 | 0.01 |
| Fatigue | 48 (26) | 25 (61) | 11.6±3.6 | <0.0001 |
| Virilisation | 41 (22) | 16/21 (76) | 10.5±2.8 | <0.0001 |
| Hirsutism | 125 (68) | 24 (59) | 12.6±3.3 | 0.37 |
| Emotional lability/depression | 75 (41) | 24 (59) | 11.8±3.1 | 0.006 |
| Headaches | 57 (31) | 21 (51) | 12.7±3.2 | 0.02 |
| Striae | 73 (40) | 20 (49) | 14.2±2.6 | 0.38 |
| Hypertension | 140 (77) | 20 (49) | 11.8±3.5 | 0.0009 |
| Acne | 49 (27) | 18 (44) | 13.9±2.2 | 0.05 |
CD, Cushing's disease.
Growth failure, traditionally recognised as a key clinical feature of hypercortisolaemia in children, may be less obvious. In our series, only 37% of 52 children with CS due to a range of aetiologies, actually had short stature (height ≤−2 s.d.) at diagnosis but growth velocity when available was subnormal in all patients (Fig. 1) (H Storr 2014, unpublished observations). However, at presentation, over 95% of subjects demonstrated a striking contrast between height SDS, which was almost always below 0, and BMI SDS, which was usually elevated above 1.5 SDS (7). This auxological feature distinguishes CS from subjects with simple obesity, where most children are tall (20).
Height and BMI SDS values at diagnosis in paediatric Cushing's syndrome (n=54). Circles and squares represent BMI and height SDS respectively: light and dark grey, paediatric patients with Cushing's disease (CD); white, CS of other aetiologies.
Citation: European Journal of Endocrinology 173, 1; 10.1530/EJE-15-0013
Height and BMI SDS values at diagnosis in paediatric Cushing's syndrome (n=54). Circles and squares represent BMI and height SDS respectively: light and dark grey, paediatric patients with Cushing's disease (CD); white, CS of other aetiologies.
Citation: European Journal of Endocrinology 173, 1; 10.1530/EJE-15-0013
Height and BMI SDS values at diagnosis in paediatric Cushing's syndrome (n=54). Circles and squares represent BMI and height SDS respectively: light and dark grey, paediatric patients with Cushing's disease (CD); white, CS of other aetiologies.
Citation: European Journal of Endocrinology 173, 1; 10.1530/EJE-15-0013
A further important aspect of the physical assessment in paediatric patients with CD is examination of secondary sexual development. The majority of children show signs of abnormal virilisation with advanced pubic hair and genital growth in boys in association with pre-pubertal testicular volumes or pubic hair growth in girls with pre-pubertal breast development. These features indicate abnormal exposure to adrenal androgens combined with gonadotrophin deficiency (21).
Striae and acne were present in 49 and 44% of patients respectively and were commoner in older patients (mean age 14.2±2.6 and 13.9±2.2 years). The young child with CD may present with obesity and growth failure alone, without other classical features such as plethora, hirsutism, acne and striae. Additional features commonly reported in our cohort included emotional lability (60%), fatigue (60%) and hypertension (49%). Muscle weakness and easy bruising were rare symptoms (Table 1) (8).
Therefore five key features, namely a change in facial appearance, weight gain, height SDS around or below 0 s.d., elevation of BMI and the presence of genital virilisation should alert the clinician to the possibility of CD and initiate laboratory evaluation.
Diagnostic guidelines
Biochemical evaluation
Before embarking on biochemical evaluation to confirm a diagnosis of CD, it is important to exclude other causes of CS such as excess glucocorticoid use (oral, nasal, inhaled, nasal spray and topical treatments), as exogenous CS is much more common than the endogenous form. The investigation of patients with suspected paediatric and adult CD has been extensively reviewed (1, 22, 23). A consensus statement advised that only those obese children who demonstrated slowing of their growth velocity should be investigated, as a combined reduction in height velocity and increased weight had a high sensitivity and specificity for CD (24).
The algorithm for investigations in children should be based on that performed in adults (22), and consists initially of confirmation or exclusion of the diagnosis of CS followed by investigations to determine the aetiology. The diagnosis of an ACTH-secreting pituitary adenoma follows from the investigation of suspected CS and the demonstration of ACTH-dependent hypercortisolaemia. Our published protocol for diagnosis of CD, in which the initial screening tests have a high sensitivity, is given in Table 2 (7, 25).
Protocol for diagnosis of paediatric Cushing's disease (ACTH-secreting adenomas). Data from Guaraldi et al. (25).
| Type of test | Diagnostic cut-off | Sensitivity (%) a | Specificity (%) a |
|---|---|---|---|
| A. Confirmation of Cushing's syndrome | |||
| 1. Urinary free cortisol excretion (24-h urine collection) for 3 days | >70 μg/m2 (193 nmol/24 h) | 88 | 90 |
| 2. Serum cortisol circadian rhythm study (0900 h, 1800 h, midnight (sleeping)) | ≥1.8 μg/dl (50 nmol/l) b | 100 b | 60 b |
| 3. Low-dose dexamethasone suppression test (LDDST) a. Dose 0.5 mg 6 h (0900, 1500, 2100, 0300 h) for 48 h b. Dose for patients weighing < 40 kg; 30 μg/kg per day c. Serum cortisol measured at 0, 24 and 48 h |
≥1.8 μg/dl (50 nmol/l) | 95 | 80 |
| B. Confirmation of CD | |||
| 1. Plasma ACTH (0900 h) | >5 pg/ml (1.1 pmol/l) | 68 | 100 |
| 2. CRH test (1.0 μg/kg i.v.) | Cortisol increase 14–22% | 74–91 | 88–100 |
| 3. Pituitary MRI scan | Adenoma detection | 63 | 92 |
| 4. Bilateral inferior petrosal sinus sampling for ACTH (with i.v. CRH) | Central:peripheral ACTH ratio ≥3 (after i.v. CRH) | 100 |
Confirmation or exclusion of hypercortisolaemia
Key biochemical features of hypercortisolaemia are increased 24-h urinary free cortisol (UFC) excretion, loss of serum cortisol circadian rhythm with detectable cortisol at midnight and failure of suppression of cortisol during the low-dose dexamethasone suppression test (LDDST). UFC measurements in children with hypercortisolaemia have a reported sensitivity of 88% and specificity of 90% (26), suggesting that UFC alone may not be an ideal screening test. If there is doubt about the interpretation of these values, we recommend hospitalisation for the measurement of serum cortisol at three time points (0900 h, 1800 h, and midnight (sleeping)) to assess circadian rhythm. Assessment of midnight cortisol in the sleeping child gives the highest sensitivity and specificity for the diagnosis of hypercortisolaemia (99 and 100% respectively using a cut-off of ≥121 nmol/l, ≥4.4 μg/dl) (26). Late night salivary cortisol has also been evaluated in the paediatric obese population and a high sensitivity and specificity for hypercortisolaemia (95.2 and 100%, respectively) has been reported (27); however, the influence of age has not been characterised. Following the assessment of midnight cortisol, a LDDST is performed, using the adult dose regimen of 0.5 mg every 6 h (at 0900, 1500, 2100 and 0300 h) for 48 h, unless the child weighs <40 kg when the NIH-recommended dose is 30 μg/kg per day (3). The LDDST also has a high sensitivity (>90%) for CS due to multiple causes, and is therefore a useful screening test for paediatric patients in an out-patient setting (22). The 1 mg overnight dexamethasone test has also been used in children, but there are no available data on its interpretation or reliability.
Confirmation of CD
Following confirmation of hypercortisolism, the priority is to determine its cause. CD is most easily confirmed by determination of basal plasma ACTH. In all patients with CD, ACTH is detectable, and using a cut-off value of 29 ng/l, sensitivity and specificity are reported as 70 and 100% respectively (26). In ACTH-independent CS, ACTH is always low and usually undetectable.
A CRH test using human sequence CRH (1 μg/kg i.v.) is also recommended and in 36 of 39 (92%) CD patients serum cortisol increased by >20% (range of cortisol increase from baseline 2–454%) (8). Ectopic ACTH syndrome is so rare in children that the need for a CRH test is questionable; however, an increased cortisol response contributes to the diagnosis of CD. In addition, a high sensitivity and specificity (97.5 and 100% respectively) is reported for a cortisol increase of >20% following CRH administration (26).
Radiological imaging
Magnetic resonance imaging (MRI) has superseded previous techniques for pituitary visualisation. MRI scanners currently use 3-T magnetic field strengths to improve signal-to-noise ratios, therefore further improving image quality (12, 28, 29, 30). T2-weighted imaging offers additional identification of cystic components, with post-contrast sequences improving the conspicuity of small lesions, 2–3 mm thin imaging slices being optimal for their detection. Pituitary adenomas are generally hypointense compared with the adjacent gland and take up contrast less avidly and in a more delayed fashion, and therefore fail to enhance with gadolinium (Fig. 2). On pituitary post-contrast MR scanning, 63 and 55% of the corticotroph adenomas were identified in two large paediatric series (8, 31). This relatively poor visualisation rate in children could be explained by the limited spatial resolution of MRI, i.e. small lesions within a small pituitary gland are less conspicuous. Therefore, pituitary MRI imaging alone cannot be relied upon to predict the adenoma position or to confirm the diagnosis of paediatric CD.
A left-sided pituitary corticotroph adenoma in an 8.8-year-old boy with Cushing's disease. T1 weighted coronal MRI image before gadolinium (left) and after gadolinium (right). White arrows indicate corticotroph adenoma, which typically enhances less than the background pituitary gland after contrast administration.
Citation: European Journal of Endocrinology 173, 1; 10.1530/EJE-15-0013
A left-sided pituitary corticotroph adenoma in an 8.8-year-old boy with Cushing's disease. T1 weighted coronal MRI image before gadolinium (left) and after gadolinium (right). White arrows indicate corticotroph adenoma, which typically enhances less than the background pituitary gland after contrast administration.
Citation: European Journal of Endocrinology 173, 1; 10.1530/EJE-15-0013
A left-sided pituitary corticotroph adenoma in an 8.8-year-old boy with Cushing's disease. T1 weighted coronal MRI image before gadolinium (left) and after gadolinium (right). White arrows indicate corticotroph adenoma, which typically enhances less than the background pituitary gland after contrast administration.
Citation: European Journal of Endocrinology 173, 1; 10.1530/EJE-15-0013
Bilateral simultaneous inferior petrosal sinus sampling
Bilateral simultaneous inferior petrosal sinus sampling (BSIPSS) was initially piloted in adults at the NIH (32) to enable distinction between CD and ectopic ACTH syndrome and also to provide a method of identifying a lateral vs central source of ACTH secretion within the pituitary (22). It has now become routine in adult practice unless the MRI unequivocally shows a pituitary adenoma. In children, ectopic ACTH secretion is extremely rare and so the primary aim of BSIPSS is to contribute to the localisation of the microadenoma by demonstrating lateral or midline ACTH secretion. The first paediatric data were reported in the large NIH series where a predictive value of lateralisation was 75–80% (1, 3).
BSIPSS is a highly specialised technique and should be performed by the same radiologist who regularly studies adult patients. In the majority of cases, general anaesthesia (GA) is not required so that potential alteration of ACTH secretion is avoided. However, in young children GA may be necessary. In our centre, BSIPSS has been performed in 35 paediatric CD patients without complications. The results suggest that ACTH sampling gives a better prediction of the site of the microadenoma than that by pituitary MR imaging (8, 33). A more recent study from the NIH described its further experience of BSIPSS in 94 paediatric patients and reported that localisation of ACTH secretion concurred with the site of the adenoma at surgery in 58% of cases, concluding that the technique was not an essential part of a paediatric investigation protocol (34). The percentage of predictive lateralisation, however, increased to 70% (51/73) after exclusion of 18 centrally located lesions and four bilateral lesions.
Treatment
Paediatric and adult co-operation
As mentioned previously, CD is extremely rare in the paediatric age range, and even an experienced paediatric endocrine unit may only see a handful of cases during a 20-year period. Consequently, paediatric endocrinologists may not acquire the experience to manage these patients with expertise. For this reason, collaboration with a specialised adult endocrinology unit with experience of CS is essential. The combined expertise in medical management, pituitary surgery and pituitary radiotherapy (RT) will greatly benefit the patient.
Pituitary surgery: selective microadenomectomy
Transsphenoidal surgery (TSS) is regarded as a safe and effective procedure in children (35, 36, 37, 38), and is now considered as a first-line therapy as it involves selective removal of the adenoma, maximising the potential for normal pituitary tissue to remain in situ. The small size of ACTH-secreting adenomas and the pituitary fossa in children in association with absent aeration of the sphenoid bone in young patients add to the technical difficulty of TSS. The outcome of TSS depends on the definition of post-operative ‘cure’ or remission (Table 3). In a recent report of 200 cases of paediatric CD, 98% were in remission post-surgery (12) and 97% of the subjects who were in biochemical remission had hypocortisolaemia. In all the published series where ‘remission’ is described, recurrences of post-TSS hypercortisolaemia have occurred, which were treated either by pituitary re-operation or by pituitary RT. In the two paediatric series, where ‘cure’ was defined as post-operative serum cortisol levels of <1 μg/dl (28 nmol/l) (3) or <1.8 μg/dl (50 nmol/l) (8), the reported ‘cure’ rates were 100 and 69% respectively. Follow-up data indicate that recurrence rates of CD in these patients were very low (8, 31). Initial post-operative remission in children was associated with identification of the adenoma at surgery and long-term remission correlated with younger age, smaller adenoma and morning serum cortisol level of <1 μg/dl (28 nmol/l) after surgery (12). Lasting remission in children is observed in those patients with younger age, smaller tumour size and absence of cavernous sinus or dural invasion (12). However, recurrence of CD in adults has been reported up to 15 years after apparent surgical cure, even in individuals who had very low or undetectable post-operative cortisol levels (39). Therefore lifelong follow-up for children treated for CD is essential.
Reported cure rates and long-term pituitary function following first-line transsphenoidal surgery (TSS) in childhood CD.
| Series | No. CD patients | Age (years) | No. of first-line TSS | Outcome | Long-term pituitary deficiencies |
|---|---|---|---|---|---|
| NIH, Bethesda, USA (12) | 200 | 4.0–19.0 | 173/200 (87%) | 189/200 (95%) cured a | 10/200 (5%) DI Incomplete data |
| Barts Health, London (8) | 41 (one macroadenoma) | 5.7–17.8 | 36/41 (88%) | 24/35 (69%) cured a (macroadenoma not cured) | 11/24 (46%) GH 2/24 (8%) DI 2/24 (8%) Hypopit |
| São Paulo, Brazil (67) | 15 | 6.0–18.0 | 15 | 9/15 (60%) cured a | 1/9 (11%) Hypopit 1/9 (11%) GH 1/9 (11%) DI |
| Mumbai, India (44) | 48 | 9.0–19.0 | 48 | 27/48 (56%) cured a | Not published |
| Virginia, USA (37) | 33 | 5.0–19.0 | 33 | 76% cured a | 1/33 (3%) ACTH 1/33 (3%) DI Incomplete data |
| Great Ormond Street Hospital, London (35) | 12 | 8.7–16.3 | 12 | 9/12 (75%) (clinical and biochemical remission) | 7/9 (78%) GH 4/9 (44%) ACTH 4/9 (44%) GT 3/9 (33%) TSH 1/9 (11%) DI |
| Rochester, Minnesota, USA (68) | 22 (one macroadenoma) | 10.1–18.9 | 22 | 10/22 (45%) cured a (macroadenoma not cured) | 1/22 (5%) TSH Incomplete data |
| NIH, Bethesda, USA (3) | 50 | Mean 14.4±4 | 37/50 (74%) | 35/37 (95%) cured a | 6/37 (16%) TSH 3/37 (8%) DI 3/37 (8%) GH 1/37 (3%) GT |
| Suresnes, France (69) | 36 | ≤16.0 | 33/36 (92%) (23 selective, eight subtotal) | 23/33 (69%) (hypocortisolaemia or ‘physiological’ cure) | 1/33 (3%) DI 1/33 (3%) Hypopit Incomplete data |
CD, Cushing's disease; GH, growth hormone; DI, cranial diabetes insipidus; Hypopit, pan-hypopituitarism; ACTH, adrenocorticotrophic hormone; GT, gonadotrophins; TSH, thyroid-stimulating hormone.
‘Cure’ defined as undetectable serum cortisol in the immediate post-operative period (<50 nmol/l).
Endoscopic pituitary surgery
More recently the less invasive technique of endonasal endoscopic transsphenoidal pituitary surgery (ETES) has been used in some centres, and in adult patients has shown equivalent rates of complete tumour resection, shorter hospital stays, decreased patient discomfort and reduced or equivalent surgical complications (40, 41). In children, ETES may be preferable as the first-line treatment and for recurrent lesions, being potentially advantageous in terms of efficacy and safety with reduction of surgical trauma, pain perception, paediatric intensive care unit admissions, need for blood transfusions, anterior pituitary deficiencies and incidence of diabetes insipidus (13, 42, 43). Although paediatric experience with endonasal ETES is limited, preliminary results in children with CD have recently been reported and shown an excellent outcome (13). With more experience, ETES could become the standard surgical approach in children, as has been now practised in adults.
Pituitary RT
A proportion of paediatric patients who undergo TSS for CD do not achieve post-operative cure or remission (44, 45, 46). The options for second-line therapy are repeat TSS, pituitary RT, long-term medical therapy to control hypercortisolaemia and bilateral adrenalectomy. External pituitary RT is known to be effective in children with CD with a more rapid mode of action than in adult patients. Stereotactic RT and gamma knife approaches are now available and utilised in adult CD; however, experience is limited, particularly in children. Centres using RT have administered irradiation from a 4- to 15-MeV linear accelerator, via a three-field technique (two lateral, one frontal) to deliver a total dose of 45 Gy in 25 fractions over 35 days (45). The effectiveness and rapid onset of this therapy were confirmed in three small series. In the first, seven children were treated by RT and all were cured with a mean interval of 0.94 years (range 0.25–2.86) (45). In the second series, eight subjects were treated and four were cured in 9–18 months after RT (44). In the third series, a total of 12 out of 15 patients were cured within 18 months of RT and ten of these were cured within 9 months of treatment (47). In a further series, eight children were treated with stereotactic external RT using 60 Co gamma radiation. Seven of the eight subjects were cured during the first year after completion of therapy (48).
Anterior pituitary function after RT was studied and growth hormone (GH) deficiency was present in five out of six subjects tested with peak GH <6 ng/ml at a mean interval after RT of 1.0 years (range 0.11–2.54) (49). On retesting at an interval of 9.3 years (range 7.6–11.3) in three out of four subjects, GH secretion had recovered (peak GH 6.4–16.5 ng/ml). Thyroid function, PRL and testicular volume were normal. GH deficiency and hypogonadism were also documented in seven children successfully treated with higher doses of 50–70 Gy (44, 48). Children receiving pituitary RT for CD require regular assessment of anterior pituitary function post-therapy.
Medical therapy and bilateral adrenalectomy
Definitive treatments such as surgery and/or RT, rather than long-term medical therapies, are currently recommended for the management of paediatric CD. Medical therapies for paediatric CD are currently limited (46) and not well studied, but they can be used to urgently lower cortisol levels in very sick patients, to normalise the hypercortisolaemia in preparation for surgery or whilst awaiting the effects of RT. Adrenal steroidogenesis inhibitors such as metyrapone and ketoconazole are well tolerated and can be highly effective at reducing cortisol levels either alone or in combination (6). However, control may be lost due to the oversecretion of corticotrophin and may not be effective for long-term treatment. Intravenous administration of etomidate has successfully controlled hypercortisolaemia in children with CD, who were either too unwell for TSS or presented with acute unmanageable symptoms such as respiratory failure or severe psychosis (50, 51). Bilateral adrenalectomy remains a therapeutic option for CD in life-threatening situations or where TSS is not possible or available. Although Nelson's syndrome, a potentially life-threatening complication, appears to be more frequent in children than in adults and often requires pituitary surgery or RT (52).
Post-cure growth and development and pituitary function
Growth failure is almost always seen at diagnosis in paediatric patients with CD (1, 53). Virilisation may lead to acceleration of bone age and may further compromise growth potential (54). A key article from the NIH described the abnormalities of height and GH secretion (55) together with a poor outcome for post-treatment catchup growth and adult height (56). Disappointing post-cure catchup was also reported, attributed to continuing GH deficiency, occurring either from TSS, pituitary RT or the long-standing effects of chronic hypercortisolaemia on pituitary and growth plate physiology (53). The challenge is to reverse these problems and maximise growth potential so as to achieve acceptable adult height and body composition.
In the absence of catchup growth, we recommend that GH deficiency is investigated at 3–6 months after TSS or completion of RT. If required, GH therapy should be initiated without delay and GNRH analogue therapy may be added to delay puberty and epiphyseal closure. Results demonstrate that this regime usually enables adequate catchup growth and adult height within range of target height for the majority of patients (57). Combined treatment with GH and aromatase inhibitors may also be a therapeutic alternative in pubertal patients (58).
Normal body composition is more difficult to achieve. Many patients remain obese and BMI SDS was elevated (P<0.01) at a mean interval of 3.9 years after cure in 14 patients (57). A long-term follow-up study of childhood and adolescent CD showed that total body fat and the ratio of visceral-to-subcutaneous fat remained abnormally high in the majority of patients studied 7 years after cure (59). The implications of chronic excess visceral fat in terms of risk for adult metabolic syndrome deserve future study. Bone mineral density (BMD) was closer to normal together with some patients having normal BMD at diagnosis (60).
A summary of reported long-term pituitary deficiencies following first-line TSS in children with CD is given in Table 3. Pituitary function was analysed in six patients at intervals of 6.6–16.5 years after receiving RT and have shown that although GH deficiency was frequent initially, some recovery occurred in adult life (49). Gonadotrophin secretion was generally preserved with normal or early puberty; the latter being a well-recognised complication of cranial RT (61). Thyroid-stimulating hormone and ACTH deficiencies were minimal (49). It is important to note that the risk of hypopituitarism may continue to increase in the years after radiation.
Studies of adult CS patients have reported brain atrophy, cognitive impairment and psychopathology, most commonly depression, associated with excess endogenous circulating glucocorticoids (62). A study from the NIH (63) also found significant cerebral atrophy in children with CD at diagnosis; however, there was no difference in IQ scores between patients and controls. Interestingly, this study also reported an almost complete reversal of the cerebral atrophy as has been observed in association with hypercortisolaemia-induced severe psychosis (50). However in the former study, a significant decline in cognitive function 1 year after cure by TSS was noted despite reversal of the radiological abnormalities. This is in contrast to adult studies, which report reversible cognitive impairment and reversible loss of brain volume associated with eucortisolaemia (63, 64). More recently, the NIH group reported that children with CD have impaired health-related quality of life which does not fully resolve 1 year post treatment (65).
Conclusions and future perspectives
CS rarely occurs in children and thus the paediatrician may be relatively unprepared in terms of diagnosis and management. A close liaison with adult endocrinology colleagues with more experience is strongly advised and will directly enhance the clinical care of these challenging patients. Paediatric CD manifests a number of characteristic features distinct from adult CD, most notably the significant impact on linear growth and pubertal development. Early diagnosis remains a major challenge because of the frequent lack of appreciation of the nature of the pathology by parents and family doctors.
Once suspected, the patient requires investigation using a formal protocol and the choice and interpretation of tests should be discussed with an adult specialist with experience of CD. Referral should be considered to a centre combining paediatric and adult endocrinology, BSIPSS, TSS and pituitary RT. A specialised multidisciplinary approach to define the optimal therapeutic strategy is essential. In addition, choosing a neurosurgeon experienced in TSS in children is likely to significantly improve the chance of effective and curative therapy. The less invasive technique of ETES provides an alternative to conventional transsphenoidal microscopic surgery in managing paediatric CD.
In experienced hands, the prognosis for cure is good in the majority of children and adolescents with CD, and full recovery of the hypothalamic–pituitary–adrenal axis is possible. However, post-treatment management frequently presents challenges for optimisation of growth, puberty and body composition and deserves further investigation. Longitudinal studies are also needed to formally assess potential long-term cognitive impairment and psychopathology after cure of childhood CD. In addition, further studies are warranted to identify novel genetic defects associated with pituitary corticotroph cell tumourigenesis and to assess the efficacy of new medical therapies and surgical approaches.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.
Funding
This review did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
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