Cushing's syndrome resulting from primary pigmented nodular adrenocortical disease

In a 10-year-old boy with Cushing's syndrome, the dexamethasone suppression test, the metyrapone test, and both basal and corticotropin-releasing factor-stimulated corticotropin levels all indicated a primary adrenal disorder. However, a computed tomographic scan failed to detect an adrenal tumor. At surgery, the adrenal glands were not enlarged but were studded with small pigmented nodules composed of enlarged nonmalignant adrenocortical cells. This unusual abnormality, referred to as primary pigmented nodular adrenocortical disease, is associated with autonomous hypersecretion of cortisol primarily in children and young adults. Our patient was cured by total bilateral adrenalectomy and corticosteroid replacement therapy, the treatment of choice for this condition.     

Cushing's disease in children: report of three cases

Cushing's disease is rare in children and adolescents. We report the clinical presentations of three children with Cushing's disease. All three exhibited the typical symptoms and signs of weight gain and growth retardation. Tw o also demonstrated personality changes, hypertension and hypokalemia, the last of these being rarely reported in patients with Cushing's disease. Lack of diurnal changes in serum cortisol levels was the most common biochemical finding. Serum cortisol levels were suppressed by low-dose dexamethasone in one patient, which is not typical for patients with Cushing's disease. Imaging studies are essential for localizing the tumor. Transsphenoidal surgery remains the treatment of choice, and pituitary irradiation should be considered for those patients whose tumors cannot be totally removed. Careful follow-up of these patients with awareness of the possibilities of relapse and the complications of hypopituitarism is indicated.     

Adrenal axis function after high-dose steroid therapy for childhood acute lymphoblastic leukemia

Background A 4‐week course of high‐dose glucocorticoids may cause prolonged adrenal suppression even after a 9‐day tapering phase. In this study, adrenal function and signs and symptoms of adrenal insufficiency were prospectively assessed in children with acute lymphoblastic leukemia (ALL) after induction treatment including high‐dose prednisone (PDN) or dexamethasone (DXM). Procedures Sixty‐four children with ALL, treated according to the AIEOP ALL 2000 Study protocol, underwent low dose ACTH (LD‐ACTH) stimulation 24 hr after the last tapered steroid dose. In those with impaired cortisol response, additional LD ACTH tests were performed every 1–2 weeks until cortisol levels normalized. Signs and symptoms of adrenal insufficiency were recorded during the observation period. Results All patients had normal basal cortisol values at diagnosis. Twenty‐four hours after last glucocorticoid dose, morning cortisol was reduced in 40/64 (62.5%) patients. LD‐ACTH testing showed adrenal suppression in 52/64 (81.5%) patients. At the following ACTH test 7–14 days later, morning cortisol values were reduced in 8/52 (15.4%) patients and response to the test was impaired in 12/52 (23%). Adrenal function completely recovered in all patients within 10 weeks. No difference was found between patients treated with PDN or DXM. Almost 35% of children with impaired cortisol values at the first test developed signs or symptoms of adrenal insufficiency. One child developed a severe adrenal crisis during adrenal suppression. Conclusions High‐dose glucocorticoid therapy in ALL children may cause prolonged adrenal suppression and related clinical symptoms. Laboratory monitoring of cortisol levels and steroid coverage during stress episodes may be indicated. Pediatr Blood Cancer 2008;50:537–541. © 2007 Wiley‐Liss, Inc.     

Hypercortisolism in childhood: shortcomings of conventional diagnostic criteria.

Two patients are described in whom hypercortisolism occurred prepubertally as a consequence of bilateral adrenocortical hyperplasia. In contrast with the manifestations of Cushing's syndrome in adults, these children presented with obesity and reduced stature and no other symptoms. Both patients excreted amounts of urinary 17-OHCS before and during a conventional suppression test with dexamethasone (0.5 mg every six hours) which were within the usual normal range. However, when urinary 17-OHCS excretion was expressed per gram of urinary creatinine or per square meter of surface area, and when the dose of dexamethasone was tailored to body mass (20mug/kg/day) the results were clearly abnormal, as were plasma corticoids and (in one patient) cortisol secretion rate. Resumption of linear growth occurred after bilateral adrenalectomy in both patients and was associated, in the one patient so studied, by a return of hypoglycemia-stimulated increases in plasma growth hormone levels from previously suppressed values to the normal range, and by a slight increase in the fasting plasma somatomedin concentration. The observations suggest that pediatric patients with hypercortisolism are likely to be overlooked when conventional criteria for laboratory diagnosis are used, but can be recognized by the simple diagnostic modifications used in these studies.     

Cushing's disease in an 11-month-old child

Cushing's disease (Pituitary tumor causing bilateral adrenal hyperplasia) is very rare in children and more so in infants. Cushing's syndrome in pediatric patients is usually due to adrenal tumors.We report a case of an 11-month-old child with Cushing's disease caused by a Pituitary macroadenoma.     

Salivary cortisol determination in the diagnosis of pediatric Cushing's disease

Endogenous Cushing's syndrome in children is a very rare entity. Diagnosis is complex due to the wide variety of tests available. Recently, the utility of salivary cortisol has been proposed for the diagnosis of this entity, although greater evidence is required, especially in pediatric patients. We report a 14-year-old girl with Cushing's disease due to a pituitary microadenoma in whom salivary cortisol determination was very useful for the diagnosis.     

Enfermedad de Addison. Formas de presentación en pediatría

Addison's disease or primary adrenal insufficiency is a rare disease in children. The signs and symptoms at diagnosis are frequently non-specific and insidious. Since adrenal crisis represents an emergency, it is important to be aware and to have a high degree of suspicion of the disorder in order to achieve an early diagnosis and treatment.We present a retrospective study describing the epidemiological, clinical and etiological data at diagnosis of five patients with Addison's disease followed up in our hospital. Dehydration, hyponatremia and skin hyperpigmentation were the most prevalent signs and symptoms at onset of the disease. The patients had low serum cortisol levels and positive adrenal antibodies. One patient with negative antibodies presented with a polyglandular syndrome.     

Cushing's syndrome or obesity

A rare case of the Cushing syndrome, due to bilateral adrenal hyperplasia is described. Because of generalized obesity, normal height, normal bone age and family history of obesity, a boy 10 years of age had at first been misdiagnosed as simple obesity. A reduction in height velocity, advancement of bone age and development of precocious pseudopuberty led to a more detailed biochemical investigation and to the correct diagnosis. The clinical picture can be misleading in the differential diagnosis of Cushing's disease versus simple obesity. From a comparison of reports on pediatric Cushing's syndrome, it is obvious that in most pediatric cases fat distribution differs from that of adult Cushing's syndromes. Stunted growth is reported to be more frequent, but normal and excessive height in Cushing's syndrome is not uncommon. In adrenal hyperplasia a retardation of bone age is usually expected. Interpretation of endocrine functions must take into account that simple obesity leads to secondary endocrinopathies, which are similar to the findings in Cushing's syndromes.Plasma cortisol at midnight and 12 hourly excretion of free cortisol in urine as well as overnight Dexamethasone suppression of morning plasma cortisol are judged to be good screning parameters. Plasma ACTH assays can help in the initial diagnosis and are mandatory during the follow up for an early detection of Nelson's syndrome.     

Disturbed adrenal function in adolescents with chronic fatigue syndrome

OBJECTIVE: To investigate adrenal function in children and adolescents with chronic fatigue syndrome (CFS) compared with age-matched controls. METHODS: Case-control study of low dose (500 ng/m2) synacthen tests (LDST) in 23 adolescents with CFS and 17 age-matched controls. Serum cortisol concentrations were measured at 5-min intervals from 10 to 45 minutes. Peak serum cortisol concentration, time to peak, rise in cortisol and area under the curve (AUC) were derived. RESULTS: Patients with CFS had significantly lower mean cortisol levels during the LDST (p <0.001), lower peak cortisol (p <0.025), reduced cortisol AUC (p <0.005) and longer time to peak cortisol (p <0.05). Abnormalities were seen in both sexes but were more pronounced in females. Unstimulated adrenal androgen and 17-hydroxyprogesterone concentrations were normal. CONCLUSIONS: Adolescents with CFS have subtle alterations in adrenal function suggesting a reduction in central stimulation of the adrenal glands. The more pronounced effects in females may reflect differential central effects of stress on hypothalamic-pituitary-adrenal axis regulation between the sexes.     

Treatment of Cushing's disease in childhood and adolescence by stereotactic pituitary irradiation

Eight children with Cushing's disease aged 6-18 years were treated with external radiation to the pituitary gland using 60Co gamma radiation given with stereotactic technique. The dose given varied between 50 and 70 Gy. The observation time was 2.6 to 6.75 years. Seven children had a clinical remission with normal urinary cortisol excretion. One child had insufficient effect of two irradiations and underwent bilateral adrenalectomy. In the patients in remission the growth velocity increased during the first year after treatment but growth retardation occurred again during the second year. Insufficient growth hormone secretion was demonstrated in all subjects. Two patients were given thyroxine substitution and three showed evidence for secondary hypogonadism. In conclusion, stereotactic pituitary irradiation was effective in normalizing the excessive glucocorticoid production in children with Cushing's disease. However, with the doses used, it was not possible to maintain a normal anterior pituitary function.     

Cushing's syndrome caused by Ewing's sarcoma secreting corticotropin releasing factor-like peptide.

Procedures were carried out in a 12-year-old girl to relate Ewing's sarcoma of the left tibia with Cushing's syndrome. Computed tomography revealed a normal pituitary and hypothalamus but bilateral adrenal hyperplasia without focal enlargement, thus readily excluding hypothalamic-pituitary-adrenal tumor. Negative results from a high-dose dexamethasone suppression test do not support pituitary-dependent Cushing's disease. Ewing's sarcoma was diagnosed on tibial biopsy. The regression of the physical and biochemical findings of Cushing's syndrome subsequent to amputation of the left lower leg strongly suggests ectopic Cushing's syndrome caused by Ewing's sarcoma. Immunohistochemical studies of the resected bone were negative for corticotropin but positive for corticotropin releasing factor-like peptide. We conclude that this is the first reported case of ectopic Cushing's syndrome in a child that is caused by Ewing's sarcoma secreting corticotropin releasing factor-like peptide.     

Prenatal Cushing's syndrome secondary to nodular adrenocortical hyperplasia with unsuppressed plasma ACTH levels

We report a newborn girl (36th week of gestation, birth weight 1,054 g) with Cushing's syndrome secondary to nodular adrenocortical hyperplasia with normal plasma ACTH levels. From birth she was hypertensive, hyperglycaemic and slightly hirsuit. Hypercortisolaemia (>1,380 nmol/l) was accompanied by normal plasma ACTH levels (8.64-23.9 pg/ml). A 48-h dexamethasone suppression test decreased plasma cortisol by 35%, indicating some degree of ACTH dependency. However, there was no ACTH rise on CRF test. MRI showed enlarged adrenal glands with a possible cyst on the right; the pituitary gland was normal. At the age of 6 weeks she underwent bilateral adrenalectomy. Histology showed enlarged adrenals with multiple non-pigmented nodules (up to 5 mm) in both glands. However, over the next few weeks she developed liver failure and sepsis. She died at the age of 3 months. Post mortem examination confirmed the diagnosis. Nodular adrenocortical hyperplasia may present at birth with severe Cushing's syndrome and unsuppressed ACTH levels, indicating some degree of ACTH dependency in this condition.     

Diagnosis,treatment and long-term outcome in Cushing's disease

Cushing's disease is uncommon in childhood. It is usually caused by the oversecretion of adrenocorticotrophic hormone (ACTH) by a pituitary corticotroph adenoma. Clinical abnormality is often undetected for long periods of time. The principal clinical features are growth retardation and obesity. We present four patients who were diagnosed with Cushing's disease in a tertiary hospital from January 1995 to December 2002. There were two boys and two girls, aged 10-15 years. The main clinical features at presentation were growth failure and excessive weight gain. The interval between onset of symptoms and diagnosis ranged from 2.5 to 5 years. All patients presented moon face and increased fat around the neck. In all patients, 24-hour urinary free cortisol was high and loss of normal serum cortisol circadian rhythm (3/3) and suppression of cortisol to less than 50 % of the basal level with high-dose but not with low-dose dexamethasone (2/2) were observed. Pituitary microadenoma was detected by magnetic resonance imaging in three patients; no tumor was detected in the fourth patient and inferior petrosal sinus sampling was performed, showing left lateralization of ACTH central secretion. Therapy consisted of transsphenoidal surgery in all patients. Two patients are in remission, one patient presented disease recurrence requiring total hypophysectomy because the tumor could not be completely removed and one patient had persistent disease after a second intervention and required pituitary radiotherapy. Two patients showed pituitary hormone deficiency after therapy.     

Glucocorticosteroids and growth hormone secretion under physiological conditions and in states of steroid excess

Cortisol and growth hormone (GH) secretion (spontaneous variations at night and the release induced by insulin hypoglycaemia) were investigated in 69 children and adolescents. Statistical analysis of approximately 600 pairs of cortisol and GH values in this study demonstrated that physiological fluctuations of cortisol do not alter GH secretion.A review of the literature shows that GH secretion is consistently depressed in Cushing's disease of central origin and in Cushing's syndrome due to adrenal carcinoma. When acutely administered, doses higher than 100 mg of cortisol (or equivalent amounts of other steroids) per adult are necessary to block GH secretion and the hormones have to be given several hours previously. In long-term steroid treatment, suppression of GH is observed in only 1 out of 3 patients. The effect apparently does not persist beyond elimination of the last dose, i.e. generally not longer than 12 to 24 h. These data can be taken as a rationale for intermittent or alternating dosage schedules, and for the use of short acting derivatives if long-term, high-dose steroid treatment is necessary in children.It remains to be established whether growth deficiency in exogenous hypercortisolism is due to suppression of GH secretion, decreased production of somatomedins, direct antagonism of the action of somatomedins on growing cartilage, or a combination of these mechanisms.Supported by Deutsche Forschungsgemeinschaft (Mu 254/5)In part presented at the Joint meeting, ESPR, ESPE, WGMM, Rotterdam, 1976Dedicated to Professor H. Bickel on the occasion of his 60th birthday     

Partial glucocorticoid resistance in obese children detected by very low dose dexamethasone suppression test

The effects of glucocorticoids (GC) are mediated by the activation of specific receptors that can be quantified in vitro by several laboratory tests. In vivo, other tests to determine GC sensitivity have been described, but only employing pharmacological doses. In this study, we used a very low dose of dexamethasone, an in vivo model to assess individual GC sensitivity. Fifty-five obese children and adolescents and 17 controls were studied. The patients were submitted to four 12-h urine collections, starting at 22:00 h; dexamethasone was administered orally at the end of the second urine sample. Patients were divided in the following groups: group Ob75 (n = 29) and the control group (n = 17) received dexamethasone 75 microg/m2, and group Ob150 (n = 26) received dexamethasone 150 microg/m2. Urinary cortisol was determined by RIA and expressed as microg/m2/12 h. All patients and controls showed a circadian rhythm before GC, which was maintained after dexamethasone only in controls. In the obese patients the circadian rhythm was abolished following both doses of dexamethasone, but more prominently with the dose of 150 microg/m2. In the obese group given 75 microg/m2, urinary cortisol inhibition was only observed in the first 12 h after dexamethasone, suggesting a partial and shorter suppression of the hypothalamic-pituitary axis. In both control and obese patients, the very low dose of dexamethasone was able to create a gradient of cortisol suppression that could be useful to identify an individual's sensitivity to glucocorticoids.     

An adolescent with food-dependent Cushing's syndrome secondary to ectopic expression of GIP receptor in unilateral adrenal adenoma

ACTH-independent Cushing's syndrome may be secondary to the expression of ectopic hormone receptors in adrenal tissue. In food-dependent Cushing's syndrome the adrenals aberrantly express receptors for gastric inhibitory polypeptide (GIP). We present the first case of food- and GIP-dependent adrenal adenoma in an adolescent. A 15 year-old girl presented with signs of hypercortisolism. Urinary cortisol excretion was clearly elevated. Upon the finding of very low fasting plasma cortisol levels with a rise during the morning, food-dependent cortisol secretion was suspected. Hourly measurements of plasma cortisol and GIP levels during a day with and a day without meals showed meal- and GIP-related cortisol secretion. Plasma ACTH levels were undetectable. Abdominal computed tomography showed a tumor of 2.5 x 2.5 x 2 cm in the left adrenal. Unilateral adrenalectomy was performed and microscopic examination of the tumor showed an adrenocortical adenoma. Incubation of adenomatous cells prepared from this tumor with GIP resulted in increased cortisol secretion. Using RT-PCR amplification and cDNA hybridization, the GIP receptor was found to be overexpressed in the adenoma tissue but not in the adjacent adrenal tissue. Twelve months after the operation, hourly measurements of plasma cortisol, GIP and ACTH levels on a day with and a day without meals no longer showed GIP-related cortisol production. The present report shows that in an adolescent with corticotrophin-independent Cushing's syndrome, food-dependent hypercortisolism is a possible diagnosis.     

小儿库欣病的诊断和经蝶窦显微外科手术

目的：总结小儿库欣病的诊断和经蝶窦显微外科手术经验。方法：男7例，女8例。年龄8～14岁，平均12．7岁。平均病程2．6年。14例有典型库欣综合征，高血压7例，发育迟缓6例。内分泌检查均有皮质醇增高，地塞米松抑制试验符合小剂量不能抑制、大剂量能抑制者12例，不符合者3例。MRI的阳性发现率为69％。均行经蝶窦显微外科手术。结果：随诊6个月～10年，痊愈12例，复发3例。结论：经蝶窦显微外科手术是治疗儿童库欣病的最佳方法。对于内分泌学检查符合库欣病而蝶鞍区MRI无异常，或MRI显示垂体腺瘤而内分泌学检查不支持库欣病者都应积极地进行经蝶窦手术探查。垂体腺瘤复发者可再经蝶窦手术。     

Nine cases of childhood adrenal tumour presenting with hypertension and a review of the literature

AIM: To describe the clinical features, treatment and outcome of children adrenal tumors presenting with hypertension. METHODS: The records of nine children under 16 years of age with adrenal tumours presenting with hypertension were analysed. Details were recorded for family history, clinical presentation, biochemistry, imaging, histology, treatment and outcome. RESULTS: Abdominal mass was palpable only in one patient at diagnosis. Besides hypertension-associated symptoms, Cushing's syndrome was the common presentation form (n = 4). Abdominal computed topography showed adrenal mass in all patients. Tumours were completely resected for each patient. The median tumour weight was 73 g (11-530 g) and the size ranged from 1.5 x 1.5 to 12 x 14 cm2. Pheochromocytoma (n = 2), adrenocortical adenoma (n = 3), adrenocortical carcinoma (n = 1), neuroblastoma (n = 2) and ganglioneuromas (n = 1) were found. In one case, adrenal pheochromocytoma first occurred and non-functioning islet cell tumour successively occurred at pancreas. A better status is common at a median follow-up time of 3.5 years. CONCLUSIONS: Childhood adrenal tumours presented with hypertension showed an atypical course, variable presentation. We report a unique case of adrenal pheochromocytoma followed by the occurrence of non-functioning islet cell tumour. Reversal of hypertension by surgery is crucial. Imaging techniques are important to detect adrenal tumours.     

Cushing's disease in a 5-month infant due to a basophilic microadenoma of the pituitary gland

We report a female patient who developed severe Cushing's disease during the fifth month of life due to a basophilic pituitary adenoma Histological findings showed a basophilic microadenoma of the pituitary gland, leading to the diagnosis of Cushing's disease. The infant died because of untreatable septic shock. The importance of the present report resides in the age of the child at diagnosis, and that it was the necropsy finding of microadenoma which clarified the cause of the Cushing's syndrome, since it was not diagnosed during life. Cushing's disease is most often diagnosed in children older than 7 years, and our patient was only 5 months old when we detected the pituitary adenoma, the earliest case diagnosed so far. Cushing's syndrome in pediatric patients has been rarely reported and most cases are due to functioning adrenal tumors, usually a malignant carcinoma but occasionally a benign adenoma. The present case shows that the pituitary of these patients should be investigated with important implications in terms of therapeutic approaches, such as pituitary radiotherapy, which can cure the patient when treatment is started very soon.     

Clinical impact of corticosteroid-induced adrenal suppression during treatment for acute lymphoblastic leukemia in children: a prospective observational study using the low-dose adrenocorticotropin test

OBJECTIVES: To investigate how frequently adrenal function fails to recover after corticosteroid therapy in children with acute lymphoblastic leukemia and to explore the clinical impact of slow adrenal recovery without steroid substitution. STUDY DESIGN: Low-dose (1 microg) adrenocorticotropic hormone tests were performed before and after steroid courses and during infectious episodes in 24 children. Test results were not available during the study. RESULTS: All 13 patients tested before treatment had normal adrenal responses. Adrenal suppression was found in 8 (47%) of 17 patients 5 days after discontinuation of a 5-week induction course of prednisolone and in 1 (20%) of 5 patients 7 days after a 3-week intensification course of dexamethasone, both courses being tapered over 9 days, as well as in all 13 patients tested 2 days after a 1-week prednisolone course. Clinically significant manifestations of adrenal suppression were noted in 3 (12%) patients. Of 204 scheduled tests, 131 were performed. CONCLUSIONS: High-dose glucocorticoid therapy may cause adrenal suppression lasting more than 1 week in children with acute lymphoblastic leukemia, even after tapering the dose. We suggest steroid replacement during stress episodes within 1 to 2 weeks after discontinuation and thereafter testing adrenal function selectively in accordance with symptoms.