Childhood acromegaly due to X-linked acrogigantism: long term follow-up

Purpose

Acromegaly in infancy is extremely rare. We describe a 32 year old woman who presented at 6 months of age with isolated macrocephaly, followed by accelerated linear growth. At 21 months of age, her head circumference was 55 cm (+5.5 SD), height was 97.6 cm (+4.4 SD) and weight was 20.6 kg (+6.2 SD). She had markedly elevated levels of growth hormone (GH) (135 ng/ml), IGF-1 (1540 ng/ml) and prolactin (370 ng/ml). A pituitary macroadenoma was surgically resected. Immunohistochemical staining was positive for GH. Post-operatively, she developed ACTH and TSH deficiency and diabetes insipidus.

Methods

Long term clinical follow-up and genetic testing with chromosomal microarray analysis.

Results

Despite GH deficiency, she grew well until 7 ½ years old, with subsequent decline in growth velocity, and received GH therapy for 5 years. Puberty was initiated with estrogen therapy. As an adult, she has no stigmata of acromegaly, with a height of 164.5 cm and non-acromegalic features. IGF-1 has remained in the low normal range. Prolactin has been mildly elevated. Serial MRIs have shown no evidence of tumor recurrence. She receives replacement therapy with hydrocortisone, levothyroxine and DDAVP. Chromosomal microarray analysis revealed that she has X-linked acrogigantism (X-LAG) due to a de novo duplication of Xq26.3 (516 kb). She recently became pregnant following ovarian stimulation and chorionic villus sampling revealed that she is carrying a male with the same duplication.

Conclusion

This report provides detailed long term clinical follow-up of a patient with X-LAG syndrome.

     

A randomized study of SMS 201-995 versus bromocriptine treatment in acromegaly: clinical and biochemical effects

Twenty-six acromegalic patients were randomized to treatment with either SMS 201-995 or bromocriptine in increasing doses and were investigated before treatment, after 2, 4, and 8 weeks of treatment, and 2 weeks after discontinuation of treatment. There were two dropouts from the bromocriptine group and one from the SMS 201-995 group. Amelioration of clinical signs and symptoms was seen in both groups during treatment. After 8 weeks mean 12-h GH concentrations had declined from 13.8 +/- 5.2 to 2.9 +/- 4.4 (mean +/- SEM) in SMS 201-995-treated and from 18.8 +/- 7.5 to 5.4 +/- 1.2 micrograms/L in bromocriptine-treated patients. Somatomedin-C concentrations fell from 3.04 +/- 0.36 to 1.43 +/- 0.36 in SMS 201-995-treated and from 2.93 +/- 0.40 to 2.13 +/- 0.27 U/mL in bromocriptine-treated patients. Size reduction of the pituitary tumor was seen in one patient receiving bromocriptine. Gastrointestinal glucose absorption was delayed, and insulin secretion suppressed during treatment with SMS 201-995. Hemoglobin-A1 concentrations remained unchanged in SMS 201-995-treated patients, but declined in the bromocriptine group. Side-effects were common, but usually tolerable, with both treatments. It is concluded that both drugs are of benefit in the treatment of acromegaly.     

Bromocriptine treatment in acromegaly: clinical and biochemical effects.

Eight selected patients with active acromegaly and elevated GH levels without other endocrine disturbances were submitted to long-term treatment and acute dose-response trials with bromocriptine. Seven patients showed clinical improvement and lowering of GH levels in response to long-term treatment, however, two of these showed only minor changes in GH levels during the acute dose-response trial. Glucose tolerance and heel pad thickness remained unchanged, while urinary hydroxyproline excretion and blood, plasma and erythrocyte volumes decreased. Using daily doses of 20 mg bromocriptine, side effects were generally minor. Severe vasovagal reactions were, however, observed in two patients, in one at the start of treatment, in the other after ingestion of 25 mg bromocriptine. Bromocriptine represents a valuable treatment alternative in acromegaly, but only long-term treatment will separate responders from nonresponders.     

Long-term treatment of acromegaly with bromocriptine.

Treatment with bromocriptine, 30-55 mg daily, in 13 acromegalics for 1-15 months, resulted in a 60% decrease in growth hormone secretion, as judged from the excretion of growth hormone in 24-h urine. Normal excretion was obtained in 10 patients, while 1 patient showed no response. The plasma growth hormone response to O-GTT was improved, but not normalized, in 4 of 7 patients treated for more than 6 months, and marked glucosuria disappeared in two diabetics. While the secretion of TSH, LH and FSH was unchanged, the prolactin secretion was inhibited. The urine excretion of free cortisol showed a 30% decrease, possibly due to a direct effect of bromocriptine on the ACTH-secretion. Hypercalcaemia was never seen, but the initial hypercalcuria showed a modest decrease without measurable changes in the creatinine clearance. The subjective relief during long-term treatment was marked in 10 of 11 patients and the dominating symptoms disappeared in 40-67%, whereas heal-pad thickness, enlarged sellae, and visual fields remained unchanged. No serious side effects were observed. Treatment with bromocriptine seems effective and should be considered as a remedy amongst others, in suitable cases of acromegaly.     

Changes in plasma GH levels and clinical activity during bromocriptine therapy in acromegaly. The value of predictive tests

Twenty-seven patients with active acromegaly despite previous treatment by surgery and/or radiotherapy received bromocriptine in a dose of 10-20 mg daily for a period of 6-9 months. The results of chronic bromocriptine treatment were evaluated by measurement of plasma growth hormone (GH) levels during the day and by subjective and objective criteria of clinical activity. The results of chronic bromocriptine treatment were also compared with four biochemical criteria obtained before treatment e.g. basal plasma prolactin (Prl) levels and the plasma GH response to oral administration of 2.5 mg bromocriptine respectively iv administration of 200 micrograms TRH and 500 micrograms somatostatin. The main observations may be summarized as follows: 1) The mean pre-treatment GH levels during the day ranged from 6-207 mU/1. Hyperprolactinaemia was present in 6 patients. 2) During bromocriptine treatment mean plasma GH levels decreased to less than 50% in 11 patients (GH responders) whereas in 19 patients changes of mean plasma GH and of subjective criteria of clinical activity were concordant. 3) Glucose tolerance improved significantly (P less than 0.01) in 10 GH-responders and the urinary hydroxyproline/creatinine ratio decreased significantly (P less than 0.05) in 8 GH-responders. 4) Five out of 6 patients with hyperprolactinaemia belonged to the group of GH-responders. 5) A single dose of 2.5 mg bromocriptine induced a more than 50% decrease of plasma GH in 8 of 11 GH-responders and in 5 of 16 GH non-responders.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acromegaly: biochemical assessment of cure after long term follow-up of transsphenoidal selective adenomectomy

This study reports the clinical and biological follow-up 5-11 yr after transsphenoidal selective adenomectomy in 25 patients with acromegaly. Eight patients had microadenomas, and 17 had macroadenomas. Initial normalization of plasma GH levels (basal values, less than 5 ng/ml; glucose-suppressed concentrations, less than 2.5 ng/ml) was achieved in all 8 patients with microadenomas and in 13 patients with macroadenomas. Of these, 3 patients with normal GH levels and dynamics had relapse of GH hypersecretion after intervals between 1-6 yr after microadenoma removal. Recurrence of pituitary adenoma was documented by surgery in 1 patient and by computed tomographic scanning in 2 others. Normal basal and glucose-suppressed plasma GH concentrations were maintained 7.4 +/- 0.5 (+/- SEM) yr after adenomectomy in 7 patients with microadenomas and in all 10 patients with macroadenomas. Thus, 88% of the patients with microadenomas and 59% of the patients with macroadenomas were cured, and the overall cure rate was 68%. We conclude that recurrence of acromegaly after successful surgery may occur late after adenoma removal and that it cannot be predicted by normal postoperative GH levels and dynamics. However, in view of the overall cure rate, transsphenoidal adenomectomy remains a most valuable treatment for acromegaly.     

GSPalpha mutations in Mexican patients with acromegaly: potential impact on long term prognosis.

OBJECTIVE: The frequency of activating mutations of the GSPalpha gene as the etiology of GH-secreting pituitary adenomas has been the subject of important ethnogenetic variability. Whereas up to 40% of Caucasian patients with acromegaly have tumors which harbor these somatic mutations, their prevalence among Asian populations is much lower. The correlation between the presence of these mutations and the clinical and biological behavior of these tumors has also been a matter of controversy. In the present study, we investigated the prevalence of GSPalpha mutations in GH-secreting tumors obtained from a genetically homogenous population of Mexican patients with acromegaly. We also sought to establish whether or not the presence of these mutations correlates in any way with the clinical or biochemical characteristics of the disease. STUDY DESIGN AND METHODS: Fifty eight GH-secreting pituitary adenomas were examined for the presence of point mutations in either codon 201 or 227 of the GSPalpha gene, using PCR and direct sequencing of DNA extracted from either fresh or paraffin-embedded tissues. Patients were prospectively followed clinically and biochemically for up to nine years after pituitary surgery. RESULTS: Heterozygous point mutations in exon 8 (codon 201) were found in 11 patients (19%), and no molecular alterations were evident in exon 9. The frequency and severity of the different clinical features of acromegaly did not differ between patients with and without GSPalpha mutations. Patients with and without mutations had pre-operative GH and IGF-I elevations of similar magnitude, and although microadenomas appeared to be more frequent among patients with GSPalpha mutations, this did not reach statistical significance. Upon short-term follow-up, biochemical cure (normal age- and gender-adjusted IGF-I and post-glucose GH below 1 ng/mL) was similarly achieved in both groups. After 3-9 years of post-operative follow up however, a significantly greater proportion of patients with the mutation achieved a "safe" basal GH value (100% vs 33%, p=0.001) as well a lower nadir post-glucose GH (0.53+/-0.5 vs 2.9+/-6.2 ng/mL, p=0.04) although the rate of IGF-1 normalization did not differ between the 2 groups. CONCLUSIONS: Our results show that the prevalence of GSPalpha mutations in Mexican patients with acromegaly is intermediate between that found in Asian and Caucasian populations. In this well-defined genetic population the presence of codon 201 mutations appeared to be associated with a greater probability of achieving a "safe" GH value upon long-term follow-up.     

拉米夫定治疗儿童和青少年慢性乙型肝炎的长期临床观察

目的观察拉米夫定治疗儿童和青少年慢性乙型肝炎的疗效及安全性。方法27例5—18岁的慢性乙型肝炎患者给予拉米夫定片剂每天3mg／kg,最大剂量100mg／d,疗程不少于12个月。观察治疗前后肝功能、HBVDNA、HBeAg／抗一HBe变化;有HBVDNA复升者检测YMDD变异;记录不良事件;停药后定期随访。结果治疗12、24、36和48个月的生化应答率分别为92．6％、84．6％、100％和100％;HBVDNA阴转率为92,6％;HBeAg阴转率为60％;HBeAg血清学转换率为55％。YMDD变异见于治疗12个月后,累积变异发生率为14．8％。达到停药标准终止治疗者,复发率为21．4％。无严重不良反应事件。结论拉米夫定治疗儿童和青少年慢性乙肝安全有效,YMDD发生率低。可以扩大样本进一步观察。     

Current concepts in the biochemical assessment of the patient with acromegaly.

Biochemical assessment of a patient for acromegaly aims to definitively establish or exclude the presence of growth hormone excess. Whether applied to a newly recognized patient or to detect residual disease after therapy, this assessment is best accomplished by measurement of both the degree of GH suppression after oral glucose administration (OGTT) and levels of the GH dependent peptide, insulin-like growth factor I (IGF-I). When measured properly and compared to a well-characterized, age-adjusted normative database, elevation of the serum IGF-I level is a sensitive and specific indicator for the presence of acromegaly or persistent disease after therapy. The diagnosis of acromegaly can be confirmed by documenting an elevated IGF-I level in combination with failure of GH to suppress after oral glucose to below 0.3 microg/l, when GH is measured with a highly sensitive and specific assay. Persistently, normal IGF-I levels along with a nadir GH <0.3 microg/l should exclude the diagnosis. In assessing disease status during or after treatment, normalization of IGF-I is an essential criterion for biochemical control. It is important to recognize that nadir GH levels are >0.3 microg/l in some healthy subjects, so this criterion alone is not diagnostic of acromegaly. Also, because of heterogeneity of clinically available GH assays, this GH criterion, which was developed with a research assay, may not be applicable to use with all other assays. A nadir GH cut off of 1 microg/l has been found to be reliable for use with some standard immunoassays. It is recommended that glucose-suppressed GH levels be interpreted in conjunction with those of IGF-I and with consideration of conditions other than acromegaly that can alter them. With greater assay standardization and the use of IGF-I levels along with new rigorous criteria for interpretation of GH suppression during a OGTT we can improve our identification of patients with acromegaly in earlier stages of the disease as well as better recognize residual disease during therapy.     

Primary oxalosis: clinical and biochemical response to high-dose pyridoxine therapy.

Although pyridoxine hydrochloride (vitamin B6) is known to reduce the endogenous production of oxalate in some individuals with primary oxalosis, the dose for a satisfactory trial of treatment is not established. We report two cases of primary oxalosis on a daily regimen of 1 g pyridoxine hydrochloride, in which 24-hr urinary oxalate excretion decreased by 60% and 70%, respectively, with corresponding clinical benefit. The responses have been sustained up to 2.5 yr in one case, and 20 mo in the other. In the patient with renal failure, serum creatinine decreased from 243 to 146 mumole/liter after 15 mo of treatment. The decrease in glycollic acid excretion in both patients was consistent with an increase of glyoxalate transaminase activity by the vitamin. Supranormal levels of erythrocyte glutamic oxaloacetate transaminase (egot) activity were observed during therapy, and these may be useful as a measure of the effective dose of pyridoxine.     

Treatment of Chinese acromegaly with a combination of bromocriptine and octreotide

Background : Good results have been reported with combined use of octreotide and bromocriptine in acromegalic Caucasians. Data concerning the efficacy and tolerability of this combination treatment in Chinese acromegalic patients are scanty.
Aim : The aim of this study was to assess the efficacy and tolerability of combined therapy using bromocriptine and octreotide in the treatment of acromegaly in Chinese patients and to compare the cost-effectiveness of various regimes.
Methods : Sixteen Chinese acromegalic patients with growth hormone (GH) concentration not suppressible to below 5 mU/L (2 μg/L) during an extended OGTT were recruited to undergo four phases of the study. During the study period, the patients were given bromocriptine alone, bromocriptine and low dose octreotide, bromocriptine and medium dose octreotide, and medium dose octreotide alone. Plasma concentrations of GH and insulin-like growth factor-1 (IGF-1) were measured before and after the completion of each phase.
Results : The number of patients reaching target GH concentrations was significantly higher when treated with octreotide compared to baseline ( p <0.05). Bromocriptine alone had a significant effect but not to the extent of octreotide alone. A combination of low dose octreotide and bromocriptine is as efficacious in the treatment of acromegaly as high dose octreotide. None of the patients suffered from serious adverse effects.
Conclusion : The results confirmed the usefulness and tolerability of bromocriptine and octreotide in Chinese acromegalics. The most cost-effective regime in this study was a combination of low dose octreotide and bromocriptine.     

Hyperthyroidism and acromegaly due to a thyrotropin- and growth hormone-secreting pituitary tumor. Lack of hormonal response to bromocriptine

A 47-year-old woman with acromegaly and hyperthyroidism was found to have an inappropriately normal serum thyrotropin level (1.5 to 2.5 microU/ml) that responded poorly to thyrotropin-releasing hormone but showed partial responsiveness to changes in circulating thyroid hormones. Serum alpha-subunit levels were high-normal and showed a normal response to thyrotropin-releasing hormone. Growth hormone and thyrotropin hypersecretion persisted despite radiotherapy and bromocriptine treatment. Selective trans-sphenoidal removal of a pituitary adenoma led to normalization of both growth hormone and thyrotropin levels. Both thyrotropes and somatotropes were demonstrated in the adenoma by the immunoperoxidase technique and electron microscopy.     

Very long term follow-up of cardiac resynchronization therapy: clinical outcome and predictors of mortality

BACKGROUND: Cardiac resynchronization therapy (CRT) improves symptoms, left ventricular ejection fraction (LVEF) and survival in patients with heart failure and wide QRS, however, long term clinical outcome is unknown. AIMS: To identify predictors of mortality and evaluate the effects of CRT after long term follow-up. METHODS: Consecutive patients treated with CRT between 1997 and 2002 were included. We collected clinical information from patient files. Patients who were still alive underwent echocardiography and clinical evaluation. RESULTS: We included 179 patients (median age 65.5 years, 144 male). Median follow-up for survival was 4.0 years. Mortality at one and five years was 15% and 53%, respectively. Predictors of mortality were, ischaemic heart disease (IHD), higher NYHA class and lower LVEF (<22.5%) at baseline, and no improvement in NYHA class at early follow-up. NYHA class remained stable from early to long term follow-up after a median of 5.1 years. In patients with non-IHD median LVEF increased significantly from early to long term follow-up (39% vs. 50% p=0.007). CONCLUSION: Predictors of mortality in patients with CRT are IHD, lower LVEF and higher NYHA class at baseline, and no symptomatic response to CRT. After 5 years follow-up, clinical effects are sustained, and in patients with non-IHD further improvements in LVEF are observed.     

Mitral annuloplasty--a long term clinical and haemodynamic study.

One hundred and thirteen hospital survivors with mitral annuloplasty have been followed-up from 3--19 years. Actuarially 82.4 +/- 12.1% and 65.1 +/- 18.1% of all patients are expected to be alive at 10 and 19 years respectively. 90.1 +/- 5.9% of patients were predicted to be free from reoperation at 5 years postop, while at 10 and 15 years the figures are 77.2 +/- 13.9% and 53.8 +/- 23.9% respectively. Postoperative haemodynamic investigations, performed in 18 patients at a mean duration of 8.5 (range 4--11) years, showed significant reduction in both mean pulmonary artery and wedge pressures as compared to pre-operative values. 92% of patients were in grade I and II (NYHA) clinically at the latest evaluation as compared to 84% being in grade III and IV pre-operatively. Mitral annuloplasty provides statisfactory long term clinical and haemodynamic improvement in a selected group of patients and should always be considered in the management of mitral regurgitation.     

Lymphocytic colitis: clinical presentation and long term course

Background—Lymphocytic colitis is characterised bychronic watery diarrhoea with normal endoscopic or radiologicalfindings and microscopic evidence of pronounced infiltration of thecolonic mucosa with lymphocytes.
Aim—To investigate the long term clinical andhistological evolution of the disease in a large group of patients withwell characterised lymphocytic colitis.
Methods—Between 1986 and 1995 the histologicaldiagnosis of lymphocytic colitis was obtained in 35 patients; 27 ofthese agreed to a follow up examination. All clinical, endoscopic, andhistopathological records were reviewed at that time and the patientshad a second endoscopic examination with follow up biopsies.
Results—The patients initially presented with thetypical findings of lymphocytic colitis. After a mean (SD) follow up of 37.8 (27.5) months, diarrhoea subsided in 25 (93%) and histological normalisation was observed in 22 (82%) of the 27 patients. Progression from lymphocytic colitis to collagenous colitis was not observed.
Conclusions—Lymphocytic colitis is characterisedby a benign course with resolution of diarrhoea and normalisation ofhistology in over 80% of patients within 38 months. Considering thebenign course of the disease, the potential benefit of any drugtreatment should be carefully weighed against its potential side effects.

Keywords:lymphocytic colitis; colitis; diarrhoea

     

Psoriatic spondyloarthropathy: a long term prospective study.

Fifty two patients with psoriatic spondyloarthropathy were monitored prospectively over a mean of 57 months (range 30-107). A comprehensive protocol was used to assess clinical and radiological features of disease activity and severity. Serial radiographs showed a significant increase in the number of patients with syndesmophyte formation and sacroiliitis. In contrast, there was no significant increase in the number of patients with inflammatory neck pain or stiffness, back pain or stiffness, cervical spine limitation, or sacroiliac tenderness. Similarly, there were no significant changes in any of the direct or indirect measurements of thoracolumbar spine mobility. The presence of HLA-B27 did not appear to influence disease progression. These results suggest that although patients with psoriatic spondyloarthropathy have radiological progression of their disease, this remains clinically silent and does not compromise spinal mobility.     

Comparison of an oxygen concentrator and wall oxygen in the assessment of patients undergoing long term oxygen therapy assessment

Long term oxygen therapy (LTOT) is a recognised management option for hypoxaemic patients with chronic respiratory disease. Formal assessment is required which is usually conducted in the hospital and performed on piped oxygen to ensure correction of the hypoxaemia. However, an oxygen concentrator is the standard oxygen source for the patient at home who requires LTOT. The oxygen concentration delivered is lower from a concentrator than piped oxygen. Here, we present a study of ten hypoxaemic patients using both delivery sources in a cross-over design. The partial pressure of oxygen was lower in patients when receiving oxygen from a concentrator, p < 0.05. This encourages the Clinician to consider formal assessments on an oxygen concentrator in order to ensure that the hypoxaemia will be corrected when they are prescribed a concentrator for home use.