INSERM U567 and CNRS UMR 8104, Institut Cochin, Paris, France. Adrenal masses can be detected in up to 4% of the population, and are mostly of adrenocortical origin. Adrenocortical tumours (ACTs) may be responsible for excess steroid production and, in the case of adrenocortical cancers, for morbidity or mortality due to tumour growth. Our understanding of the pathogenesis of ACTs is more limited than that for other tumours. However, studies of the genetics of ACTs have led to major advances in this field in the last decade. The identification of germline molecular defects in the hereditary syndrome responsible for ACTs has facilitated progress. Indeed, similar molecular defects have since been identified as somatic alterations in sporadic tumours. The familial diseases concerned are Li-Fraumeni syndrome, which may be due to germline mutation of the tumour-suppressor gene TP53 and Beckwith-Wiedemann syndrome, which is caused by dys-regulation of the imprinted IGF-II locus at 11p15. ACTs also occur in type 1 multiple endocrine neoplasia (MEN 1), which is characterized by a germline mutation of the menin gene. Cushing's syndrome due to primary pigmented nodular adrenocortical disease (PPNAD) has been observed in Carney complex patients presenting inactivating germline PRKAR1A mutations. Interestingly, allelic losses at 17p13 and 11p15 have been demonstrated in sporadic adrenocortical cancer and somatic PRKAR1A mutations have been found in secreting adrenocortical adenomas. More rarely, mutations in Gs protein (gsp) and the gene for ACTH receptor have been observed in ACTs. The genetics of another group of adrenal diseases that can lead to adrenal nodular hyperplasia -- congenital adrenal hyperplasia (CAH) and glucocorticoid-remediable aldosteronism (GRA) -- have also been studied extensively. This review summarizes recent advances in the genetics of ACTs, highlighting both improvements in our understanding of the pathophysiology and the diagnosis of these tumours. PMID: 16189167 [PubMed - indexed for MEDLINE]

epartment of Endocrinology and Diabetes, Murdoch Children's Research Institute, Royal Children's Hospital,Parkville, Victoria, Australia. garry.warne@rch.org.au. Individuals with congenital adrenal hyperplasia (CAH) are shorter, on an average, than the general population. A recent meta analysis of final height in CAH indicated that the height deficit is typically 1 to 2 standard deviations below the mean in both males and females. Growth in CAH due to 21-hydroxylase deficiency is influenced by a number of factors, related both to the underlying disease and its treatment. In general, males with the simple virilising form have the poorest height prognosis. This relates in part to late diagnosis and treatment and the bone age advancement seen in individuals with untreated postnatal androgen excess. Obesity in CAH patients also appears to be correlated with reduced height potential. Glucocorticoid treatment which is vital for cortisol replacement, prevention of adrenal crises and androgen suppression, results in growth inhibition when administered in larger doses. Current evidence suggests that infancy and peripubertal periods are the time periods where height outcome is most sensitive to glucocorticoid dose. More recent estimates of physiological cortisol secretion rates indicate that standard cortisol replacement schedules may result in overtreatment. In addition, dose titration to achieve complete androgen suppression and normalization of 17-hydroxyprogesterone is likely to result in overtreatment and consequent growth impairment. Optimization of current treatment may lead to further improvements in height prognosis. The potential benefits of more complex treatment regimes, using aromatase inhibitors and antiandrogens, in combination with a reduced glucocorticoid dose remain uncertain.

Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. Congenital adrenal hyperplasia (CAH) is primarily caused by 21-hydroxylase deficiency and leads to an accumulation of 17-hydroxyprogesterone and reduced cortisol levels. Newborn screening for CAH is traditionally based on measuring 17-hydroxyprogesterone by different immunoassays. Despite attempts to adjust cutoff levels for birth weight, gestational age, and stress factors, the positive predictive value for CAH screening remains less than 1%. To improve this situation, we developed a method using liquid chromatography-tandem mass spectrometry to measure 17-hydroxyprogesterone, androstenedione, and cortisol simultaneously in blood spots. A total of 1222 leftover blood spots from six different screening programs using different immunoassays (fluorescent immunoassay and ELISA) were reanalyzed in a blinded fashion by liquid chromatography-tandem mass spectrometry. Thirty-one samples were from babies with CAH, 190 had yielded false-positive results by immunoassay, and the remaining 1001 samples were from babies with normal screening results. Steroid profiling allowed for an elimination of 169 (89%) of the false-positive results and for an improvement of the positive predictive value from the reported 0.5 to 4.7%.Although this method is not suitable for mass screening due to the length of the analysis (12 min), it can be used as a second-tier test of blood spots with positive results for CAH by the conventional methods. This would prevent unnecessary blood draws, medical evaluations, and stress to families. PMID: 15292289 [PubMed - indexed for MEDLINE]

Department of Paediatrics, Leiden University Medical Center, Leiden, The Netherlands. H.J.van_der_Kamp@LUMC.nl Congenital adrenal hyperplasia (CAH) is well suited for newborn screening, as it is a common and potentially fatal disease which can be easily diagnosed by a simple hormonal measurement in blood. Moreover, early recognition and treatment can prevent severe salt wasting, dehydration and death and shorten the time of male sex assignment in virilised females.In screening programmes, 17alpha-hydroxyprogesterone (17OHP) is measured in filter paper blood spots obtained by a heel puncture preferably between 2 and 4 days after birth. Three assay techniques are utilised for initial screening: radio-immunoassay (USA), enzyme-linked immunosorbent assay (Japan) and time-resolved fluoro-immunoassay (Europe). Preterm newborns have higher 17OHP concentrations in serum than babies born at term. Therefore, cut-off levels are based on gestational age (in Japan and Europe) or on birth weight (in the USA). There is a considerable variation in cut-off levels from one programme to another. This is most likely due to the different antibodies and reagents used, varying thickness and density of filter paper used for sample collection and, most significantly, the characteristics of the reference population (in terms of birth weight and gestational age).More than 30 million newborns have been screened. The prevalence of CAH in the USA and Europe is approximately 1:15 000-16 000, and slightly lower in Japan (1:19 000). In general, severe salt wasting can be prevented, but there is a remarkable variation in the number of false-positives and false-negatives among the various programmes. Ongoing refinement of cut-off levels is needed to improve specificity and sensitivity. PMID: 15554889 [PubMed - indexed for MEDLINE]