Molecular genetics of congenital adrenal hyperplasia.

More than 95% of cases of congenital adrenal hyperplasia are attributable to steroid 21-hydroxylase (21-OH) deficiency. In normal individuals, there are usually two 21-OH genes on each chromosome 6, a functional 21-OH gene-CYP21B-and a closely related 21-OH pseudogene-CYP21A-which is defective in expression. Recent advances have shown that the pathologic mutations that contribute to 21-OH deficiency arise as a consequence of unequal crossover and gene conversion-like mechanisms that involve sequence interaction between the normally functional 21-OH gene and its pseudogene.     

Testicular adrenal rest tumors and Leydig and Sertoli cell function in boys with classical congenital adrenal hyperplasia

CONTEXT: Infertility observed in adult males with congenital adrenal hyperplasia (CAH) has been associated with testicular adrenal rest tumors (TART) that may originate during childhood. OBJECTIVE: Our objective was to describe the prevalence of TART and Sertoli and Leydig cell function in a group of boys aged 2-10 yr with CAH and to compare prevalence with that of a control group. DESIGN: From August 2005 to January 2007, 19 patients with classical CAH (CAH group) were referred from seven endocrinology centers. METHODS: We studied 19 subjects in the CAH group and, as a control group, 13 boys from the community that did not have testicular diseases. A complete physical exam was performed. High-resolution ultrasound was used to determine TART prevalence. Inhibin B and anti-Müllerian hormone were used as Sertoli cell markers. The ratio between basal testosterone levels and testosterone levels 72 h after beta-human chorionic gonadotropin (5000 U/m2) treatment [(T72- T0)/T0] was used to evaluate Leydig cell response. RESULTS: CAH and control groups were comparable in chronological age (5.9 vs. 5.6 yr; P = 0.67) and bone age/chronological age ratio (1.09 vs. 1.03; P = 0.09). TART prevalence was four of 19 (21%) in the CAH group. Lower values for inhibin B (49.2. vs. 65.2 pg/ml; P = 0.018), anti-Müllerian hormone (70.1 vs. 94.2 ng/ml; P = 0.002), and (T72- T0)/T0 (5.6 vs. 13.6; P < 0.01) were observed in the CAH group. CONCLUSION: TART in prepubertal males with classic CAH could be found during childhood. We also report differences in markers of gonadal function in a subgroup of patients, especially in those with inadequate control.     

Adenomatoid hyperplasia of pancreas presenting as tumor.

Adenomatoid hyperplasia belongs to the group of hyperplastic duct lesions of the pancreas. We report a 60-year-old man with adenomatoid hyperplasia of the pancreas, presenting as a mass lesion. The patient underwent pancreatico-duodenectomy uneventfully. The unusual location of the mass in the head of pancreas, the imaging and macroscopic appearance, dense fibrous stroma on histology and prominent expression of p21ras protein point towards a distinct subtype.     

A woman with salt-wasting congenital adrenal hyperplasia presenting with a mucinous ovarian cystadenoma during pregnancy

Women with congenital adrenal hyperplasia (CAH) caused by steroid 21-hydroxylase deficiency show reduced fertility, especially with the salt-wasting form. A 27-year-old pregnant woman with this disease underwent laparotomy and oophorectomy to remove a multilocular ovarian tumor at 14 weeks of pregnancy. This proved to be a mucinous cystadenoma. Toward the third trimester, she presented with marked elevations of 17α-hydroxyprogesterone and plasma renin activity. Careful management of endocrine and body fluid homeostasis allowed her to give birth to a healthy female infant with normal external genitalia. This case illustrates endocrinological parameters during pregnancy in a woman with classical salt-wasting CAH.     

Gastrointestinal stromal tumor presenting as a hormonally inactive adrenal mass

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Rarely, tumors with the same histological and immunohistochemical features arise in organs having no connection to the tubular gastrointestinal tract designated as extra-gastrointestinal stromal tumors (EGISTs). In this article, we report the first case of an EGIST presenting as a hormonally inactive adrenal mass. A 68-year-old woman with a 3-month history of right abdominal pain was clinically diagnosed as having a hormonally inactive right adrenal tumor sizing 15 cm in diameter. This mass and the tightly fixed right adrenal gland were resected en bloc.Histologically, the tumor was composed primarily of monomorphic spindle cells. Mitotic figure was 2–3 per 50 high power fields. Immunohistochemical analysis revealed strong positivity for CD117 (c-KIT) and smooth muscle actin (a-SMA), but negativity for beta-catenin, CD34, pan-keratin,S-100, desmin, and H-caldesmon. Genetic analysis showed no mutations in KIT gene exons 9, 11, 13, and 17,and in exon 18 of the platelet-derived growth factor-2 receptor gene (PDGFR). The patient proved to be tumor-free at the 18-month follow-up. This case under study demonstrates that EGIST should be included in the differential diagnosis of hormonally inactive adrenal tumors.CD117 (c-KIT) immunohistochemistry should be applied in the pathological workup of soft tissue adrenal tumors.This case is an additional example suggesting that the prognosis of even a very large EGIST is not definitely grave.     

Retroperitoneal schwannoma presenting as an adrenal tumor.

A retroperitoneal tumor in the region of the adrenal gland was diagnosed in a 56-year-old woman. The patient had been suffering from a dull abdominal pain for nearly four weeks before consulting her family physician. Ultrasound, CT and MRI scans revealed a giant tumor of the right adrenal gland. Endocrine activity could not be demonstrated. The size of the tumor was suggestive of an adrenal carcinoma. The patient was referred for adrenalectomy and complete exstirpation of the retroperitoneal mass. The histological examination revealed characteristical findings of a benign schwannoma.     

Prenatal treatment of congenital adrenal hyperplasia

In foetuses at risk of virilising congenital adrenal hyperplasia (CAH), prenatal treatment can be offered by administration of dexamethasone (DEX) via the mother, in order to suppress foetal adrenal androgen oversecretion and prevent genital malformations. The first treated cases were described 20 years ago, and several hundred pregnancies have been reported since. There is a consensus that the treatment effectively prevents or reduces virilisation, but opinions regarding its safety differ. Rare adverse events have been reported in treated children, but no harmful effect has been documented that can be clearly attributed to the treatment. However, few treated foetuses have been followed until adolescence. Animal studies and epidemiological data point to various adverse effects of excess glucocorticoids on the developing foetus. In order to prevent virilisation effectively in females affected with CAH, the prenatal treatment needs to be instituted in the early first trimester, before prenatal diagnosis is possible. Thus, a majority of treated foetuses will receive DEX unnecessarily. The PREDEX study was initiated in Stockholm in 1999 as an open, controlled, non-randomised, multicentre trial. Participating centres are Stockholm, Bergen, Kuopio, Warsaw, London, Lyon and Barcelona. The study has been approved by the ethics committees in each country. The purpose of PREDEX is to evaluate prospectively the prenatal treatment regarding efficacy in preventing virilisation as well as to study its safety for both mothers and treated children. Children are followed until 18 years of age and a wide range of physiological, metabolic and developmental parameters are considered. In Sweden, treatment is not offered outside the frames of the trial.     

High prevalence of testicular adrenal rest tumors, impaired spermatogenesis, and Leydig cell failure in adolescent and adult males with congenital adrenal hyperplasia.

In male patients with congenital adrenal hyperplasia, testicular tumors, or so-called adrenal rest tumors, have been described, but their presence in well controlled patients is thought to be rare. In this study, the prevalence of testicular tumors in 17 adolescent and adult male patients with congenital adrenal hyperplasia (age, 16-40 yr) was investigated. In 16 of 17 patients, one or more testicular tumors, ranging in maximal length from 0.2-4.0 cm, were found on ultrasonography. In 6 patients, the testicular tumors were palpable. Undertreatment, defined as the presence of a salivary androstenedione level (mean of 6 saliva samples collected over 24 h with intervals of 4 h) above the upper reference morning level, was found in 5 of 17 patients at the time of investigation. The other 12 patients were treated adequately or even over treated at the time of investigation. Nevertheless, 11 of these 12 patients showed testicular tumors on ultrasonography. Neither the presence of undertreatment at the time of investigation nor characteristics of the therapeutic regimen (daily dose of hydrocortisone equivalents per body surface, the use of glucocorticoid medication either two or three times a day, or the time of taking the highest glucocorticoid dose either in the morning or the evening) could predict tumor size (maximal diameter of largest tumor). In patients who were heterozygous or homozygous for the deletion or conversion of the CYP21 gene, tumor size was significantly larger than in patients who did not have this genotype. Impairment of Leydig cell function as manifested by decreased plasma levels of T was found in 6 of 17 patients. Semen analysis in 11 patients revealed azoospermia in 3 patients and poor semen quality in 4 patients. We conclude that, when carefully sought for, testicular adrenal rest tumors are frequently present in adolescent and adult males with congenital adrenal hyperplasia and are often accompanied by impaired spermatogenesis and Leydig cell failure.     

Biochemical aspects of congenital adrenal hyperplasia

The assay of 17α-hydroxyprogesterone in blood spots on filter paper forms the basis of neonatal screening programmes to detect congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. The blood concentrations of this hormone in the neonate varies with gestation age (termv preterm), age after birth, time of day and illness. Broad reference ranges for blood spot 17α-hydroxyprogesterone concentrations are therefore quoted for healthy term infants and these ranges are not appropriate for the interpretation of values in preterm and sick newborns. There is a risk of a false-negative or of a false-positive diagnosis. Many of the above difficulties may result from variations in assay performance due to changes in the pattern of steroids produced by the adrenal gland which in turn relate to morphological changes in the adrenal cortex at this age. The purpose of this presentation is to define the complex steroid milieu of the newborn human and briefly to review the factors which determine the function of the adrenal gland, since these influence the extent to which an assay for this steroid needs to be evaluated before application to neonatal screening for CAH. The data to be presented derive from the capillary column gas chromatographic analysis (GC) of steroids in urine since this provides the best method to display the overall steroid production of the organism. The GC method has itself been refined so that CAH can now be reliably diagnosed using this method, but the information from this work will also be judged for its relevance to the problems encountered in the neonatal screening for CAH by blood spot analysis.     

Neonatal screening for congenital adrenal hyperplasia

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.     

Lipid profile in congenital adrenal hyperplasia

Glucocorticoids have been reported to exert a marked effect on lipoprotein metabolism. Several studies have shown a potential risk of hyperlipidemia in patients under long-term glucocorticoid therapy. Current management of patients with congenital adrenal hyperplasia (CAH) includes the use of glucocorticoids to attenuate the increased production of undesirable adrenal hormones. A case-control study was designed to compare the serum lipid profiles of 14 patients with CAH under glucocorticoid therapy and 14 normal controls and to determine the characteristics of the profiles. A total of 9 patients (64.3%) had serum total cholesterol (TC) greater than 4.4 mmol/L (170 mg/dL), compared with 6 individuals in the control group (42.3%). Nine patients with CAH (64.3%) had serum triglycerides (TGs) more than 1.0 mmol/L (90 mg/dL), compared with only 2 in the control group (14.3%). Similarly, the mean serum TG was higher in the CAH group versus the controls, 1.33 mmol/L (118 mg/dL) versus 0.75 mmol/L (67 mg/dL), respectively. Serum low-density lipoprotein, (LDL-C) and high-density, lipoprotein (HDL-C) cholesterol were determined in 13 children with CAH and in the 14 controls. Nine CAH patients (69.2%) and 8 controls (57%) had LDL-C greater than 2.8 mmol/L (<110 mg/dL). For HDL-C, 2 children with CAH (15.4%) and 4 controls (28.6%) had levels less than 0.9 mmol/L (35 mg/dL). There were no significant differences for the cholesterol index, 0.24 for the controls and 0.22 for the CAH group. In the CAH group, the mean serum TG level and the percentage of individuals with TGs greater than 1.0 mmol/L were statistically significant compared with the controls. The mean serum TC and LDL-C, as well as the percentage of subjects with levels over the cutoff point, although slightly higher in the CAH group, were of no statistical significance. The results of this pilot study suggest that long-term glucocorticoid therapy in patients with CAH may induce abnormalities in the serum lipid profile characterized mainly by an increment in serum TGs.