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.     

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。     

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.     

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.     

Recurrence of Cushing's disease in childhood after radiotherapy-induced remission

A 16-year-old female patient with recurrent Cushing's disease (CD) underwent successful treatment with pituitary irradiation. Within one year after radiotherapy, cortisol levels had returned to normal (but with continued absence of diurnal variation), growth velocity improved, and puberty ensued. Five years after treatment, the patient developed clinical and biochemical evidence of recurrent CD. The high baseline evening corticotropin level (9 pmol/L [40 pg/mL]) was unresponsive (maximum level, 10 pmol/L [46 pg/mL]) to stimulation with ovine corticotropin-releasing hormone (CRF). In patients with CD treated with radiotherapy, the corticotropin response to CRF stimulation may not be reliably compared with that of normal control values. After pituitary adenomectomy, the corticotropin concentration was still unresponsive to CRF. We suggest that the pituitary tumor was secondary to abnormal hypothalamic CRF regulation not corrected by pituitary irradiation; therefore, CD may recur despite pituitary irradiation.     

Home parenteral nutrition in chronic intestinal diseases: its effect on growth and development

Nine children and adolescents with chronic intestinal diseases and growth failure were treated with home parenteral nutrition (HPN) for 7-63 months. All patients improved their growth velocities on HPN, with an average height gain of 9 cm. The mean growth velocity in six patients with Crohn's disease increased more than fivefold (from 0.67 +/- 0.4 cm/year to 3.8 +/- 1.09 cm/year), and they gained a mean of 11.4 +/- 3.4 kg/year. The three patients without Crohn's disease [intestinal pseudo-obstruction (two), severe short bowel (one)] increased growth velocity from an average of 2.9 +/- 1.1 cm to 6.1 +/- 1.34 cm/year and gained a mean of 10 +/- 2.84 kg/year. Patients without Crohn's disease grew faster on HPN than age comparable patients with Crohn's disease. Also, the two patients with Crohn's disease who were younger and had their disease for a shorter period (less than 3 years) grew better than older patients with Crohn's disease who had their disease for a mean of 8 +/- 1.3 years. All patients improved clinically, and three with Crohn's disease achieved complete remission. Five of the nine patients had psychosocial adjustment problems while on HPN. In conclusion, HPN is a relatively safe and effective means to stimulate growth in children and adolescents who cannot meet nutritional needs by the enteral route.     

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.     

Cushing's syndrome in childhood and adolescence

Objective: To review the diagnosis, management and outcome of Cushing's syndrome in children and adolescents.
Methods: We conducted a retrospective review of nine cases treated between 1976 and 1996 at the Royal Children's Hospital, Melbourne, Australia.
Results: Six children with Cushing's disease and three with primary adrenal disease were identified. Mean age at diagnosis in the Cushing's disease patients was 11.3 years and in the children with primary adrenal disease 9.5 years. The most common presenting symptoms were weight gain and delayed growth. Two children had the unusual presenting symptoms of an eating disorder and hemihypertrophy, respectively. Laboratory diagnosis of Cushing's syndrome was established by demonstration of elevated urine free cortisol, loss of normal diurnal variation of serum cortisol, and loss of suppressibility of cortisol secretion by low dose dexamethasone. Investigations used to determine the aetiology of hypercortisolism included serum adrenocorticotropic hormone (ACTH) levels, high dose dexamethasone suppression tests, imaging studies, and inferior petrosal sinus sampling. Four patients with Cushing's disease had successful transphenoidal adenomectomies. Two patients with bilateral primary pigmented nodular adrenocortical dysplasia underwent bilateral adrenalectomies. One child with an adrenal adenoma was treated by left adrenalectomy.
Conclusions: Cushing's syndrome in children and adolescents remains a diagnostic challenge. Successful treatment often requires the use of multiple tests to achieve the correct diagnosis, appropriate surgery and a good long-term outcome.     

Evaluation of growth hormone release and human growth hormone treatment in children with cranial irradiation-associated short stature

We studied nine children who had received cranial irradiation for various malignancies and subsequently experienced decreased growth velocity. Their response to standard growth hormone stimulation and release tests were compared with that in seven children with classic GH deficiency and in 24 short normal control subjects. With arginine and L-dopa stimulation, six of nine patients who received radiation had a normal GH response (greater than 7 ng/ml), whereas by design none of the GH deficient and all of the normal children had a positive response. Only two of nine patients had a normal response to insulin hypoglycemia, with no significant differences in the mean maximal response of the radiation and the GH-deficient groups. Pulsatile secretion was not significantly different in the radiation and GH-deficient groups, but was different in the radiation and normal groups. All subjects in the GH-deficient and radiation groups were given human growth hormone for 1 year. Growth velocity increased in all, with no significant difference in the response of the two groups when comparing the z scores for growth velocity of each subject's bone age. We recommend a 6-month trial of hGH in children who have had cranial radiation and are in prolonged remission with a decreased growth velocity, as there is no completely reliable combination of GH stimulation or release tests to determine their response.     

Growth impairment in children treated for brain tumours.

Growth and growth hormone (GH) secretion were studied in 14 children with brain tumours before radiation and chemotherapy and at various time intervals afterwards. The peak GH response to hypoglycaemia was normal in all patients before radiation. In 6 patients the peak GH response was impaired 1 year after radiation, and in a seventh it was normal at 1 year but impaired 2 years after radiation. In 12 of 13 patients the growth velocity during the first year of chemotherapy was below the 3rd centile, although none of these had an initial standing height below the 3rd centile. Thus it appears that poor growth in such children occurs irrespective of whether radiation-induced GH deficiency develops. The cause of this impaired growth is unknown.     

CHAPTER XIII Treatment of pituitary dwarfism with human growth hormone

Two mg HGH has been given twice a week to nine patients with pituitary dwarfism and to four children in whom pituitary dwarfism was suspected. All nine patients with proved hypopituitarism increased their growth velocity, the mean height increment during the first year of treatment being 10.5 cm. During the following years the growth velocity approached normal growth. None of the patients became resistant to the treatment and regular tests for antibodies were negative. None of four patients with doubtful hypopituitarism responded to the treatment.     

Cushing's syndrome,growth impairment,and occult adrenal suppression associated with intranasal steroids

We have previously described iatrogenic Cushing's syndrome secondary to intranasal steroids. This report further highlights the potential deleterious effects of intranasal steroids. Nine cases (including the original two cases) are reviewed to show the varied clinical manifestations of adrenal suppression caused by intranasal steroids. Four presented with Cushing's syndrome, three with growth failure, while two asymptomatic patients were discovered in the course of pituitary function testing. Four children had dysmorphic syndromes--Down's, Treacher-Collins, CHARGE association, and campomelic dysplasia--reflecting the vulnerability of such children to ENT problems, together with the difficulty of interpreting steroid induced growth failure in this context. Adrenal suppression was seen not only with betamethasone but also with budesonide, beclomethasone and flunisolide nasal preparations. A careful enquiry as to the use of intranasal steroids should be routine in children presenting with unexplained growth failure or Cushing's syndrome. Particular vigilance/awareness is required in children with dysmorphic syndromes.     

Cushing's syndrome, growth impairment, and occult adrenal suppression associated with intranasal steroids.

We have previously described iatrogenic Cushing's syndrome secondary to intranasal steroids. This report further highlights the potential deleterious effects of intranasal steroids. Nine cases (including the original two cases) are reviewed to show the varied clinical manifestations of adrenal suppression caused by intranasal steroids. Four presented with Cushing's syndrome, three with growth failure, while two asymptomatic patients were discovered in the course of pituitary function testing. Four children had dysmorphic syndromes--Down's, Treacher-Collins, CHARGE association, and campomelic dysplasia--reflecting the vulnerability of such children to ENT problems, together with the difficulty of interpreting steroid induced growth failure in this context. Adrenal suppression was seen not only with betamethasone but also with budesonide, beclomethasone and flunisolide nasal preparations. A careful enquiry as to the use of intranasal steroids should be routine in children presenting with unexplained growth failure or Cushing's syndrome. Particular vigilance/awareness is required in children with dysmorphic syndromes.     

United Kingdom multicentre clinical trial of somatrem.

In a multicentre clinical trial 54 children aged 4.0 to 17.3 years, who had growth hormone deficiency that had not previously been treated, were given biosynthetic methionyl growth hormone (somatrem) 4 units three times a week by subcutaneous or intramuscular injection for one year. Height was measured every three months for at least one year before and during treatment. Forty two patients responded to treatment with an increase in growth of greater than 1.5 cm/year. The remaining 12 who grew more slowly were less obviously short and had a higher pretreatment growth than those who responded. The three who responded and the one who did not had undergone therapeutic spinal irradiation before starting the drug. If a whole year''s pretreatment growth rate of less than 5 cm/year had been used as a diagnostic criterion the prediction of those who responded would have slightly improved. About two thirds of the patients developed antibodies against growth hormone and Escherichia coli protein; these were, however, of low and fluctuating titre and binding capacity, and did not influence the response to treatment. No adverse side effects were encountered. We conclude that somatrem is a safe and effective alternative to pituitary growth hormone.     

Role of stereotactic radiosurgery with a linear accelerator in treatment of intracranial arteriovenous malformations and tumors in children

Between 1986 and 1988, 16 children were treated for 10 arteriovenous malformations and 6 recurrent intracranial tumors with stereotactic radiation therapy using a modified Clinac 6/100 linear accelerator. The median age of our patients was 10.5 years. For the group with arteriovenous malformation, follow-up ranged from 6 months to 37 months (median was 20 months). No patient bled during the follow-up period. Five of eight patients with follow-up longer than 12 months have achieved complete obliteration of their arteriovenous malformation by angiogram. The four remaining patients who have not achieved a complete obliteration are awaiting their 2-year posttreatment angiogram. The other patient has been treated within the year and have not yet been studied. Five of the six recurrent tumor patients are alive with a median follow-up of 8 months. The remaining patient was controlled locally, but he died of recurrent disease outside the area treated with radiosurgery. The radiographic responses of these patients have included three complete responses, two substantial reductions in tumor volume (greater than 50%) and one stabilization. Despite previous radiotherapy, there have been no significant complications in these patients. We conclude that stereotactic radiation therapy using a standard linear accelerator is an effective and safe technique in the treatment of selected intracranial arteriovenous malformations and tumors in children. In addition, stereotactic radiosurgery may have unique applications in the treatment of localized primary and recurrent pediatric brain tumors.     

Long-term control of central nervous system leukaemia.

Seventy-four children with acute lymphoblastic leukaemia had one or more episodes of central nervous system (CNS) leukaemia. 5 children had CNS involvement at diagnosis; 4 survived for less than one year. In 35 children who had not had a previous bone marrow relapse on treatment and who received combination chemotherapy, the median duration of haematological remission from the time of first CNS relapse was almost 3 years. 5 children received full dose (2400 rads) craniospinal irradiation after their first CNS relapse; 4 have remained in CNS and haematological remission for 2 1/2 years or more. 18 children who had a CNS relapse after irradiation received 4-weekly intrathecal methotrexate; in 8 children this was given via an intraventricular reservoir. The median duration of CNS remission in children receiving intrathecal methotrexate was 2 years. Systemic and intrathecal treatment was stopped in 7 children after 2 1/2 years in continuous remission and in 2 children after 2 years. 4 of these 9 children remain in remission at intervals from 41 to 69 weeks off treatment but one is severely retarded. These results show that CNS disease is compatible with prolonged survival, but illustrate the difficulties of eradicating established CNS leukaemia.     

ACTH IN NORMAL CHILDREN AND CHILDREN WITH PITUITARY AND ADRENAL DISEASES. I: Measurement in Plasma by Radioimmunoassay–Basal Values

ABSTRACT. Petersen, K. E. (The Children's Hospital Fuglebakken, University of Copenhagen). ACTH in normal children and children with pituitary and adrenal diseases. I. Acta Paediatr Scand, 70:341, 1981.–Plasma ACTH was measured by radioimmunoassay including preliminary extraction onto adsorbent glass particles. Normal basal values for children 4–16 years of age were 11–82 pg/ml, corresponding to values found in the literature. Normal values were found in girls with precocious puberty, children with McCune-Albright and Beckwith-Wiedemann's syndromes. Values between 233 and 305 pg/ml were found in untreated children with congenital adrenal hyperplasia. In primary Addison's disease, very high levels (654–1 413 pg/ml) before cortisone therapy and their decline to nearly normal values during therapy are described. ACTH values in a case of pituitary Cushing's syndrome was just above the normal range (104–163 pg/ml).     

Children cured of acute lymphoid leukemia. Long-term follow-up studies, including progeny

The subject of analysis is a group of 111 children with acute lymphoid leukemia (ALL) whose remission has lasted at least 4 years since stopping treatment. Patients were observed from 4 to 18 years after ALL therapy. No symptoms of disease were observed in 110 children; one child had leukemic infiltration of the testes during the fifth year after stopping treatment. In this group of children no changes in physical development have been recorded, but a growth deficiency is sometimes noted. No symptoms of intrinsic organ lesions have been ascertained in most of the patients. All of the patients, except one with schizophrenia, lead normal lives and either attend school or go to work. Seven patients have healthy children, who were born 6-24 years after the beginning of the disease and 3-16 years after cessation of therapy.     

Cushing's disease presenting with growth failure: clinical remission during cyproheptadine therapy.

A 14.7 year-old boy had almost complete suppression of growth as a result of mild pituitary-dependent Cushing's disease. There was complete clinical remission during treatment with cyproheptadine (12 mg/day) and this was maintained when treatment was stopped after 18 months.     

青春期前后支气管哮喘患者病情缓解状况调查

目的 了解支气管哮喘(哮喘)患儿青春期前后病情缓解基本状况.方法 对501例8 ～ 26岁的哮喘患者进行有关青春期前后病情缓解基本状况的问卷调查.结果 501例哮喘患者青春期后病情缓解率为67.5％(338/501例).男性患者(66.0％)与女性患者(69.9％)缓解率比较差异无统计学意义.在青春期病情未缓解的哮喘患者哮喘首次发作年龄及末次发作年龄与缓解组比较有统计学差异(=5.82、9.90,Pa=0.00).8岁后哮喘发作仍频繁者(年最多发作6次以上)的病情在青春期后缓解的概率更小,与年发作＜6次的患者比较差异有统计学意义(x2=20.69,P=0.00).变应性鼻炎症状越严重(中-重度)的哮喘患者,青春期前后的缓解率越低,与轻度或无明显鼻炎患者比较,差异有统计学意义(x2=8.25,P=0.02).个人高发季节在春夏秋季者在青春期前后哮喘病情缓解率更低,与高发季节在冬季的患者比较差异有统计学意义(x2 =7.71,P=0.04).血总IgE水平越高的哮喘患者,青春期后哮喘病情缓解率越低(t=2.16,P=0.03).规范化吸入激素联合特异性免疫治疗的哮喘患者在青春期前后缓解率较高,与吸入激素组及未规范治疗组比较,差异有统计学意义(x2=10.25,P=0.01).经常运动健身的哮喘患者在青春期前后缓解率更高,达75.3％,与不常运动健身的哮喘患者比较,差异有统计学意义(x2=8.76,P=0.00).结论 青春期前后哮喘患者病情缓解率较高,哮喘首次发作年龄越大、8岁后哮喘急性发作仍频繁、并变应性鼻炎越严重以及血总IgE越高,其在青春期前后的哮喘病情越不易缓解.给予积极的干预治疗措施如特异性免疫治疗及运动健身等,能使青春期前后哮喘的缓解率提高.