1 Carney JA, Gordon H, Carpenter PC, Shenoy BV, Go VLW. Medicine (Balt) 1985;64(4):270-83. 2 Carney J. The complex of myxomas, spotty pigmentation and.
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manufacturers and the Committee on Safety of Medicines are not aware of this particular side effect. It is interesting to speculate as to the aetiology. DIOS is more common in CF complicated by chronic liver disease5. This patient had liver disease with cirrhosis and portal hypertension, her nutritional state was poor and Golytely may have caused hypoglycaemia by inducing intestinal hurry so depleting her residual energy intake during that period. Limited glycogen stores and impaired gluconeogenesis may have been contributed to the problem. This patient developed profound hypoglycaemia despite a fast for only 2 h. No other metabolic problems were found and she had two subsequent periods of fast which she tolerated very well. It is suggested that Golytely or other colonic cleaning agents should be used cautiously in young CF patients, especially those on special feeding regimes in whom there is also evidence of associated liver disease. A continuous energy supply should be given intravenously throughout this treatment period.
References 1 Cleghorn GJ, Stringer DA, Forstner GG, Durie PR. Treatment of distal intestinal obstruction syndrome in cystic fibrosis with balanced intestinal lavage solution. Lancet 1986;i:8-11 2 Batten JC, Matthew DJ. The respiratory system. In: Hodson ME, Norman AP, Batten JC, eds. Cystic fibrosis. London: BailliereTindall, 1983:209-18 3 Koletzko S, Stringer DA, Cleghorn GO, Durie P. Lavage treatment of distal intestinal obstruction syndrome in children with cystic fibrosis. Paediatrics 1989;83:727-33 4 Tolia V, Fleming S, Dubois RS. Use of Golytely in children and adolescents. J Paediatr Gastroenterol Nutr 1984;3:468-70 5 Maurage C, Lenaerts C, Weber A, Brochu P, Yousef I, Roy CR. Meconium ileus and its equivalent as a risk factor for the development of cirrhosis: An autopsy study in cystic fibrosis. J Paediatr Gastroenterol Nutr 1989;9:17-20
Primary pigmented nodular adrenocortical dysplasia: a rare form of a rare disorder
Imaging Chest X-ray PA - normal. Computerized tomography (CT) and magnetic resonance imaging (MRI) scan pituitary and hypothalamus - normal sized pituitary gland, no lesion identified. CT adrenals - normal sized adrenal glands. Seleno-cholesterol scans of adrenals - slight bilateral adrenal uptake. CT thorax - normal. A diagnosis of PPNAD was made on clinical and biochemical grounds; an echocardiogram was obtained and was reported normal with no evidence of myxoma or intra-cardiac lesion. The patient was therefore pre-treated with metyrapone for 6 weeks in order to normalize his serum cortisol in preparation for surgery, and then underwent bilateral adrenalectomy. On gross pathology, both adrenal glands appeared normal-sized weighing 5.6 and 5.8 g and had a grey mottled multinodular appearance, the nodules being 1-2 mm in diameter. On histology, they showed well-circumscribed cortical nodules; some of the nodules had a brown pigment deposition. The intervening cortical tissue showed crowded fasciculata with shrinkage of cells. These appearances were consistent with PPNAD.
A Jabbar MRCP1 D Grant FRCP' M Savage FRCP1 A Grossman FRCP1 'Department of Endocrinology, St Bartholomew's Hospital, London and 2The Hospital for Sick Children, Great Ormond Street, London, UK
Keywords: Cushing's syndrome; primary pigmented nodular adrenocortical disease; Carney complex
Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of Cushing's syndrome which may be familial and usually presents in childhood or young adults.
Case report Our patient was a 17-year-old boy who at the age of 12 years was noted to be markedly obese and short, with a low growth velocity. He gained about 12 kg of weight over 6 to 8 months. On examination, he was short with plethoric face, truncal obesity, buffalo hump, purple striae, gynaecomastia, some proximal muscle wasting and bruise marks. Numerous brown lentigines were noted on the trunk. At the age of 14 years, he had stage IV pubic hair but his testes were only 4 ml in volume. Laboratory investigations. His plasma electrolytes were in normal range. Plasma glucose 4.9 mmol/l, serum T4 95 nmol/l, TSH 1.6 MU/ml, and prolactin 133 iu/l. Serum cortisol was 309 nmol/l at 0900 h (normal 200-600 nmol/l), but circadian rhythmicity was absent with midnight (sleeping) values at 109-326 nmol/l (normal < 50 nmol/l). Serum cortisol at 0900 h failed to suppress with either low-dose or high-dose dexamethasone suppression tests according to standard criteria (Trainer and Grossman, 1991). Following human corticotrophin-releasing hormone 100 yg iv, plasmic adrenocorticotrophic hormone (ACTH) was undetectable (< 10 yg/l) in all samples and serum cortisol remained unchanged.
Correspondence to: Dr Abdul Jabbar, Department of Medicine, The Aga Khan University, Stadium Road, PO Box 3500, Karachi 74800, Pakistan
(Accepted 21 July 1993)
Follou-up. Post-operatively the patient is currently well on hydrocortisone and fludro cortisone replacement therapy, and has restarted his college course. Disscussion PPNAD is a rare cause of Cushing's syndrome, and was initially reported in 1984 by Carney et al. 1. In the initial review of 24 cases of PPNAD, three were familial; as Carney had noted the coincidence of two PPNAD with cardiac myxomas in one family, he explored the Mayo clinic records and literature for reports of patients with the combination of Cushing's syndrome, cardiac myxomas and other myxoid tumours and spotty skin pigmentation. This review revealed that these diverse lesions are possibly pathogenetically related and constitute a specific clinical syndrome now referred to as the 'Carney complex'. The complex includes: (1) myxomas; (2) spotty skin pigmentation; (3) endocrine overactivity; and (4) peripheral nerve tumours (Schwannomas)14. Our patient did not have a family history of either of these lesions, but did have spotty skin pigmentation with Cushing's syndrome due to PPNAD. Cushing's syndrome due to PPNAD differs from other causes in its early presentation (mean age 19 years), and being ACTH - independent in the absence of any gross adrenal lesion. The disease involves both adrenal glands as opposed to functional adrenal adenoma or carcinoma which may show similar laboratory findings. Macronodular adrenocortical hyperplasia is yet another cause of bilateral adrenal involvement presenting as Cushing's syndrome, but this usually presents in adults and on imaging shows enlarged adrenal glands; in PPNAD the adrenal glands are
Case presented to Section of Endocrinology, 28 October 1992
Journal of the Royal Society of Medicine Volume 87 February 1994 either normal-sized or even small. When familial, PPNAD shows autosomal dominant inheritance5. The other components of the Carney complex include pigmented skin lesions (lentigines, blue naevi, cutaneous myxomas), breasts (myxoid fibroadenomas, gynaecomastia), testicular tumours and pituitary tumours (producing gigantism or acromegaly). In our patient only the pigmented skin lesions were present, there were no atrial myxomas, and there was no family history. As any component of the Carney complex may present many years before others, these patients need regular follow-up and echocardiogram for the early diagnosis of cardiac myxomas. It is recommended that first degree relatives of affected person have a complete physical examination, including examination of the cardiovascular system study of skin in natural and ultraviolet light, and palpation of the testes. An echocardiogram and 24 h urinary free cortisol should be carried out annually for screening. The pathogenesis of PPNAD is suggested to be a circulating adrenal stimulating immunoglobulin. There are recent reports7`9 in which serum from these patients has been shown to stimulate cortisol production in-vitro from adrenals in guinea pigs.
2 Carney J. The complex of myxomas, spotty pigmentation and endocrine overactivity. Arch Intern Med 1987;14:418-19 3 Danoff A, Jormark S, Lorber D, Fleischer N. Adrenocortical micronodular dysplasia, cardiac myxomas, lentigines and spindle cell tumours. Arch Intern Med 1987;147:443-8 4 Bain J. Carney complex. Mayo Clin Proc 1986;61:508 5 Carney J, Hruska L, Beakchamp G, Gordon H. Dominant inheritance of myxomas, spotty pigmentation and endocrine overactivity. Mayo Clin Proc 1986;61:165-72 6 Keyano T, Satoh T, Ohtaki N. Familial cases of cutaneous myxomas and spotty pigmentation (Carney's complex) [ Japanese]; Japan J Dermatol 1990;100(10):1047-52 7 Young WF Jr, Carney JA, Musa BW, Wulffraat NM, Lens JW, Drexhage HA. Familial Cushing's syndrome due to Primary pigmented nodular adrenocortical disease. N Engl J Med 1989;321:1659-64 8 Teding Van Berkhout F, Croughs RJ, Wulffraat NM, Drexhage HA. Familial Cushing's syndrome due to nodular adrenocortical dysplasia is an inherited disease of immunological origin. Clin Endocrin 1989;31(2):185-91 9 Carstense H, Krabbe S, Wulffraat NM, Neilson MD, Ralf-Klaer E, Drexhage HA. Autoimmune involvement in Cushing's syndrome due to primary adrenocortical nodular dysplasia. Eur J Pediatr 1989;149(2):84-7
References 1 Carney JA, Gordon H, Carpenter PC, Shenoy BV, Go VLW. Medicine (Balt) 1985;64(4):270-83
(Accepted 19 October 1993)
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Meeting reports
The impact of the European Community's 1992 regulations on medical treatments
Keywords: European Community; drug development
In his opening address of welcome to delegates, Sir George Pinker (President, RSM), reminded them that among the important changes introduced into our Society of Membership of the European Community, its regulations on medical treatments would have a major impact, and influence the lives of us all. Dr John Griffin (Director, ABPI, London, UK), in his keynote lecture, reviewed the development of EC regulatory intervention on community and national medical treatment. Important in this development was the establishment of the Committee on Proprietary Medicinal Products (CPMP) in 1976, which has already achieved much to harmonise evaluation of drugs and medicines in terms of animal toxicology and clinical safety and efficacy. The Community is now working towards a centralized community procedure through a single European Medicines Evaluation Agency (EMEA), and a decentralized procedure by which a pharmaceutical company which has obtained marketing authorization in one member state could, if it wished, apply for the acceptance of this authorization in one or more other member states of the Community. Such a system has profound legal and logistic problems, and Griffin expressed uncertainty about its ability to enable important new medicines to be made available within reasonable time scales to patients who would benefit from them. He also provocatively suggested that regulations governing 'good regulatory practice' should be introduced in addition to GLP and GCP!
Professor A T Florence (School of Pharmacy, London, UK), in a discussion of quality issues involving both drug substances and their formulations, stressed that its assessment in the new Europe should not be a matter of routine bureaucracy, if problems are to be avoided with complex therapeutic entity, particularly those involving biotechnology. Similar concerns were expressed by Professor E F Hvidberg (Copenhagen, Denmark) in his review of regulations regarding efficacy, in which he stressed the importance of high scientific standards and professional skill, combined with strict adherence to good clinical practice guidelines, in evaluation of relative efficacy and cost-benefit judgements. Dr K Olejniczak (Berlin, Germany) discussed attempts between EC, Japanese and US authorities to harmonize their requirements for toxicological testing. Many problems still await resolution, some of the most important involving interspecies pharmacokinetic data in relation, for example, to carcinogenicity studies.
Professor V K Lepakhin (Moscow, Russia) pointed out that Europe is much larger than the European Community. Although disintegration rather than integration appears to be dominant in the politics of the old USSR, the newly emerging states want integration of drug evaluation and regulation, and are watching carefully the experience of the Community. Their first priority will be towards regulation of important, life-saving drugs. In opening the discussion, Professor K Strandberg (Uppsala, Sweden) spoke for the EFTA countries, regretting delays and problems in integrating their drug regulatory procedures with that of the European Community. It was evident from the following discussion that there was general agreement that the community will be poorer if EFTA expertise was not to be welcomed into the CPMP. Particular reference
Report of joint meeting of Society and Forum on Clinical Pharmacology & Therapeutics, 16-17 September 1993
