Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency.

Over the last two decades, we have extensively studied the genetics of congenital adrenal hyperplasia caused by 21-hydroxylase deficiency (CAH) and have performed 8,290 DNA analyses of the CYP21A2 gene on members of 4,857 families at risk for CAH--the largest cohort of CAH patients reported to date. Of the families studied, 1,507 had at least one member affected with one of three known forms of CAH, namely salt wasting, simple virilizing, or nonclassical CAH. Here, we report the genotype and phenotype of each affected patient, as well as the ethnic group and country of origin for each patient. We showed that 21 of 45 genotypes yielded a phenotypic correlation in our patient cohort. In particular, contrary to what is generally reported in the literature, we found that certain mutations, for example, the P30L, I2G, and I172N mutations, yielded different CAH phenotypes. In salt wasting and nonclassical CAH, a phenotype can be attributed to a genotype; however, in simple virilizing CAH, we observe wide phenotypic variability, particularly with the exon 4 I172N mutation. Finally, there was a high frequency of homozygous I2G and V281L mutations in Middle Eastern and Ashkenazi Jewish populations, respectively. By identifying the predominant phenotype for a given genotype, these findings should assist physicians in prenatal diagnosis and genetic counseling of parents who are at risk for having a child with CAH.

[Contemporary diagnosis and therapy in women with congenital adrenal hyperplasia]. / Wspólczesna diagnostyka i terapia kobiet z wrodzonym przerostem nadnerczy.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive defect in steroidogenesis, mostly affecting 21-hydroxylase enzyme deficiency. The other seldom cortisol synthesis abnormalities include deficiencies of: 11beta-hydroxylase, 3beta-hydroxysteroid dehydrogenase, 17beta-hydroxylase, 17,20-lase and 11 beta-hydroxysteroid dwehydrogenase type 1. There are three main types, depending on the clinical level of 21-hydroxylase deficiency: (1) classical form--salt-wasting CAH (2) the classical form non- salt-wasting (3) non-classical form. CAH incidence is estimated at 1/14 000-1/10 000, of which about 70% is the classic salt-wasting form. The clinical picture varies considerably depending on the form. In the classic salt-wasting CAH may develop into the a shock. In classic CAH without loss of salt dominates virilization in girls and precocious puberty in boys. A non-classical forms usually presents as hyperandrogenisation and fertility. CAH treatment is mainly based on the use of glucocorticoid therapy, and if necessary supplemented mineralocorticoids. There is also potential to consider prenatal treatment (female fetuses diagnosed as CAH) with the use of dexamethason. However this kind of treatment is related to some medical and ethical controversies.

Molecular testing in congenital adrenal hyperplasia due to 21α-hydroxylase deficiency in the era of newborn screening.

Newborn screening (NBS) identifies the majority of classical [salt-wasting (SW) and simple-virilizing (SV)] cases of congenital adrenal hyperplasia (CAH) due to 21α-hydroxylase (21α-OHase) during the first days of life. Diagnosis of classical CAH is confirmed by follow-up serum 17-hydroxyprogesterone and/or the adrenocorticotropin stimulation test; however, neither test definitively distinguishes between the classical subtypes. After confirmation, all newborns are started on hydrocortisone (glucocorticoid) and fludrocortisone (mineralocorticoid) treatment. While initiating fludrocortisone treatment in classical CAH patients, independent of subtype and before SW signs or symptoms occur, prevents a life-threatening SW crisis, it may later complicate distinguishing between the classical subtypes. Genotype-phenotype correlations in 21α-OHase deficiency are excellent; however, molecular testing is not a regular part of the diagnostic workup. Molecular testing on 39 patients (25 identified by NBS) with an already established diagnosis of CAH identified 11 SW patients (8 identified by NBS) whose mutations suggested further biochemical and clinical reassessment of their subtype. Overall, SW accounted for 57.6% of our classical CAH patients, below the generally accepted figure that >75% of classical CAH are comprised of the SW form. In the era of NBS, molecular testing is a valuable supplemental tool identifying patients who may benefit from reassessment of their salt-retaining ability.

A Multiclassifier System to Identify and Subtype Congenital Adrenal Hyperplasia Based on Circulating Steroid Hormones.

CONTEXT: Measurement of plasma steroids is necessary for diagnosis of congenital adrenal hyperplasia (CAH). We sought to establish an efficient strategy for detection and subtyping of CAH with a machine-learning algorithm. METHODS: Clinical phenotype and genetic testing were used to provide CAH diagnosis and subtype. We profiled 13 major steroid hormones by liquid chromatography-tandem mass spectrometry. A multiclassifier system was established to distinguish 11ß-hydroxylase deficiency (11ßOHD), 17α-hydroxylase/17,20-lyase deficiency (17OHD), and 21α-hydroxylase deficiency (21OHD) in a discovery cohort (n = 226). It was then validated in an independent cohort (n = 111) and finally applied in a perspective cohort of 256 patients. The diagnostic performance on the basis of area under receiver operating characteristic curves (AUCs) was evaluated. RESULTS: A cascade logistic regression model, we named the "Steroidogenesis Score", was able to discriminate the 3 most common CAH subtypes: 11ßOHD, 17OHD, and 21OHD. In the perspective application cohort, the steroidogenesis score had a high diagnostic accuracy for all 3 subtypes, 11ßOHD (AUC, 0.994; 95% CI, 0.983-1.000), 17OHD (AUC, 0.993; 95% CI, 0.985-1.000), and 21OHD (AUC, 0.979; 95% CI, 0.964-0.994). For nonclassic 21OHD patients, the tool presented with significantly higher sensitivity compared with measurement of basal 17α-hydroxyprogesterone (17OHP) (0.973 vs 0.840, P = 0.005) and was not inferior to measurement of basal vs stimulated 17OHP (0.973 vs 0.947, P = 0.681). CONCLUSIONS: The steroidogenesis score was biochemically interpretable and showed high accuracy in identifying CAH patients, especially for nonclassic 21OHD patients, thus offering a standardized approach to diagnose and subtype CAH.

Congenital adrenal hyperplasia: an Indian experience.

AIMS: Data regarding the presentation and course of patients with congenital adrenal hyperplasia (CAH) is scarce in South Asia. We aimed to fill that gap by collating our experience with CAH and comparing it with findings from few other centres around the world for pertinent differences. METHODS: We retrospectively analysed the records of 86 CAH patients seen at our tertiary care centre in Eastern-India from 1996 to 2010. RESULTS: Forty-five patients (52.3%) had classic disease and 41 (47.7%) had non-classic disease (NC CAH). In the classic CAH group, 18 (20.9%) had salt wasting CAH (SW CAH) while 27 (31.4%) had simple virilising disease (SV CAH). Ten (11.6%) had a 46,XY karyotype. Patients with SW CAH were diagnosed earlier in infancy at a median age of 0.5 year, than those with SV type, who were diagnosed at 9 years (P < 0.05). The NC CAH patients were diagnosed still later, at 20.4 years. In patients with SW CAH, boys were diagnosed at an earlier median age of 0.1 year than girls who were diagnosed at 6.4 years (P < 0.05). Sixteen girls (21% of the girls) underwent vaginoplasty of whom four required additional clitoroplasty. One girl needed bilateral laparoscopic adrenalectomy. One NC CAH patient had a successful assisted pregnancy. Hypothyroidism, found in seven (8.1%) was the commonest coexisting abnormality. CONCLUSION: The skewed male : female ratio suggested that a substantial proportion of males were being missed and consequently may die. Majority of the diagnosed patients (n= 55, 64%) have been lost to follow-up. Remaining patients could be reasonably controlled with standard therapy.

Assessment of Facial Morphologic Features in Patients With Congenital Adrenal Hyperplasia Using Deep Learning.

Importance: Congenital adrenal hyperplasia (CAH) is the most common primary adrenal insufficiency in children, involving excess androgens secondary to disrupted steroidogenesis as early as the seventh gestational week of life. Although structural brain abnormalities are seen in CAH, little is known about facial morphology. Objective: To investigate differences in facial morphologic features between patients with CAH and control individuals with use of machine learning. Design, Setting, and Participants: This cross-sectional study was performed at a pediatric tertiary center in Southern California, from November 2017 to December 2019. Patients younger than 30 years with a biochemical diagnosis of classical CAH due to 21-hydroxylase deficiency and otherwise healthy controls were recruited from the clinic, and face images were acquired. Additional controls were selected from public face image data sets. Main Outcomes and Measures: The main outcome was prediction of CAH, as performed by machine learning (linear discriminant analysis, random forests, deep neural networks). Handcrafted features and learned representations were studied for CAH score prediction, and deformation analysis of facial landmarks and regionwise analyses were performed. A 6-fold cross-validation strategy was used to avoid overfitting and bias. Results: The study included 102 patients with CAH (62 [60.8%] female; mean [SD] age, 11.6 [7.1] years) and 59 controls (30 [50.8%] female; mean [SD] age, 9.0 [5.2] years) from the clinic and 85 controls (48 [60%] female; age, <29 years) from face databases. With use of deep neural networks, a mean (SD) AUC of 92% (3%) was found for accurately predicting CAH over 6 folds. With use of classical machine learning and handcrafted facial features, mean (SD) AUCs of 86% (5%) in linear discriminant analysis and 83% (3%) in random forests were obtained for predicting CAH over 6 folds. There was a deviation of facial features between groups using deformation fields generated from facial landmark templates. Regionwise analysis and class activation maps (deep learning of regions) revealed that the nose and upper face were most contributory (mean [SD] AUC: 69% [17%] and 71% [13%], respectively). Conclusions and Relevance: The findings suggest that facial morphologic features in patients with CAH is distinct and that deep learning can discover subtle facial features to predict CAH. Longitudinal study of facial morphology as a phenotypic biomarker may help expand understanding of adverse lifespan outcomes for patients with CAH.

Classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency in Croatia between 1995 and 2006.

AIMS: To evaluate the incidence, gender, symptoms and age at diagnosis of patients with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency in Croatia. METHODS: Data were collected retrospectively for all classical CAH patients born or electively aborted following prenatal diagnosis between January 1, 1995 and December 31, 2006 and were compared with the data of a previously conducted study evaluating CAH patients discovered between 1964 and 1984. RESULTS: During a 12-year period 34 classical CAH patients were born. There were 20 salt-wasting (SW; 12 female/8 male) and 14 simple-virilizing (SV; 7 female/7 male) patients. If 3 female, electively aborted fetuses were added, there would be a total of 37 CAH patients. With 532,942 live births and 34 CAH patients born over this period, the incidence of classical CAH was estimated at 1:15,574 or 1:14,403 if the 3 electively aborted fetuses were included. The lower incidence of SW boys compared to SW girls (8:12) and similar number of SW and SV boys (8:7) indicate that a substantial proportion of SW boys die unrecognized. Owing to better healthcare, the diagnosis was established significantly earlier in SW and SV girls compared to the period of 1964-1984 (p < 0.003). During 1995-2006, none of the patients died following the diagnosis of CAH and there was no erroneous sex assignment. CONCLUSION: Despite improvements in healthcare, the diagnosis of CAH in Croatia is still delayed and some of the patients go unrecognized or die. Therefore, the results of our study support the need to introduce newborn screening.

Age-specific changes in sex steroid biosynthesis and sex development.

Normal male sex development requires the SRY gene on the Y chromosome, the regression of Müllerian structures via anti-Müllerian hormone (AMH) signalling, the development of the Wolffian duct system into normal male internal genital structures consequent to testosterone secretion by the testicular Leydig cells, and finally, sufficient activation of testosterone to dihydrotestosterone by 5alpha-reductase. All these events take place during weeks 8-12 of gestation, a narrow window of sexual differentiation. Recent studies in human fetal development have demonstrated the early fetal expression of the adrenocorticotrophic hormone (ACTH) receptor and all steroidogenic components necessary for the biosynthesis of cortisol. These findings provide compelling evidence for the assumed pathogenesis of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, diminished feedback to the pituitary due to glucocorticoid deficiency, subsequent ACTH excess, and up-regulation of adrenal androgen production with subsequent virilization. Another CAH variant, P450 oxidoreductase deficiency, manifests with 46,XX disorder of sex development (DSD), i.e., virilized female genitalia, despite concurrently low circulating androgens. This CAH variant illustrates the existence of an alternative pathway toward the biosynthesis of active androgens in humans which is active in human fetal life only. Thus CAH teaches important lessons from nature, providing privileged insights into the window of human sexual differentiation, and particularly highlighting the importance of steroidogenesis in the process of human sexual differentiation.

Nouveautés dans l'hyperplasie congénitale des surrénales: New insights in congenital adrenal hyperplasia.

Congenital adrenal hyperplasia is an autosomal recessive disease due to functional abnormalities of adrenal steroid enzymes. The most common form of the disease is due to a 21-hydroxylase deficiency. The classical forms (most severe) are characterized by a deficiency in cortisol and sometimes in aldosterone, which may compromise the vital prognosis of neonates, and by an increase in androgen synthesis, leading to the virilization of girls' external genitalia at birth, followed by clinical signs of hyperandrogenism during childhood and adolescence. Neonatal screening has improved management and reduced morbidity and mortality in the neonatal period, but its performance could be broadly optimised by adjusting the assay techniques or the biomarkers used. The genetic diagnosis is difficult owing to the large genetic heterogeneity of the 6p21.3 region, which contains the CYP21A2 gene, especially with respect to the use of new-generation techniques of sequencing. Prenatal diagnosis is now possible as early as 6 weeks of gestation, but prenatal treatment remains controversial, awaiting results from prospective cohorts evaluating its long-term impact. Since conventional therapies have limitations, new therapies are currently being developed to allow better control of androgen synthesis and a substitutive treatment that respects the physiological rhythm of cortisol secretion, which would limit the development of long-term complications.

Non-Classical Congenital Adrenal Hyperplasia in Childhood.

Congenital adrenal hyperplasia (CAH) is classified as classical CAH and non-classical CAH (NCCAH). In the classical type, the most severe form comprises both salt-wasting and simple virilizing forms. In the non-classical form, diagnosis can be more confusing because the patient may remain asymptomatic or the condition may be associated with signs of androgen excess in the postnatal period or in the later stages of life. This review paper will include information on clinical findings, symptoms, diagnostic approaches, and treatment modules of NCCAH.

Adrenal cortical hyperplasia: diagnostic workup, subtypes, imaging features and mimics.

Adrenal cortical hyperplasia manifests radiologically as a non-malignant growth, or enlargement, of the adrenal glands, specifically the cortex, although the cortex cannot be definitively identified by conventional imaging. Controlled by the pituitary gland, the adrenal cortex drives critical processes, such as the production of cortisol, mineralocorticoid and sex hormones. Any disruption in the multiple enzymes and hormones involved in these pathways may cause serious or life-threatening symptoms, often associated with anatomical changes in the adrenal glands. Diagnosis and treatment of adrenal cortical hyperplasia requires a thorough clinical evaluation. As imaging has become more robust so has its role in the diagnosis and treatment of adrenal conditions. CT has been the primary modality for adrenal imaging owing to reproducibility, temporal and spatial resolution and broad access. MRI serves a complimentary role in adrenal imaging and can be used to further evaluate indeterminate CT findings or serve as an adjunct tool without the use of ionizing radiation. Ultrasound and fluoroscopy (genitography) are most commonly used in children and foetuses to evaluate congenital adrenal hyperplasia. This article will discuss the clinical presentation, laboratory workup and imaging features of adrenal cortical hyperplasia, both congenital and acquired.

[Total urogenital sinus mobilization in the repair of ambiguous genitalia in children with congenital adrenal hyperplasia]. / Mobilização total do seio urogenital para tratamento da genitália ambígua em crianças com hiperplasia adrenal congênita.

The surgical approach to patients with congenital adrenal hyperplasia (CAH) has been a challenge and it is still controversial. The aim of this study was to review 10 children with 46,XX CAH who underwent one-stage total urogenital sinus mobilization (TUM). Age at operation ranged from 11 to 78 months (mean= 32) and the follow-up from 15 to 36 months (mean= 26). Cosmetic results were good in 7 patients and satisfactory in 3. After a mean follow-up of 26 months, our results showed that TUM was a good option to repair ambiguous genitalia in children with CAH.

Spatial function in adolescents and young adults with congenital adrenal hyperplasia: clinical phenotype and implications for the androgen hypothesis.

Females with the classic form of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency are said to perform better than unaffected female controls on tests of mental rotation or other visuospatial abilities, but findings are conflicting. We studied 31 adolescents and young adults with CAH and 19 unaffected sibling controls, who were given standardized spatial tests and tests of other sexually differentiated cognitive functions (verbal fluency, perceptual speed). The possible role of CAH subtype (salt-wasting or simple-virilizing) was evaluated. Only females with the more severe, salt-wasting form of CAH, but not females with the simple-virilizing form, performed significantly better than sex-matched sibling controls on measures of mental rotation. Subtype differences were not significant for verbal fluency or perceptual speed. Severity of prenatal genital virilization, but not postnatal age when medication was started, predicted accuracy on the Mental Rotations Test. Results are consistent with the possibility of an organizational effect of androgens in the central nervous system that impacts the development of spatial abilities. Implications for the timing of the hypothetical critical period are discussed.

The spectrum of molecular defects of the CYP21 gene in the Hellenic population: variable concordance between genotype and phenotype in the different forms of congenital adrenal hyperplasia.

Defective steroid synthesis due to 21-hydroxylase deficiency is the most common form of congenital adrenal hyperplasia. Knowledge of the molecular defects causing 21-hydroxylase deficiency in different populations is of both theoretical and practical interest. The types and the relative frequencies of molecular defects and the correlation between the genotype and the phenotype were examined in the Hellenic population. We searched for deletions, conversions, and 11 of the most frequent mutations of the CYP21 gene by Southern blot and allele-specific PCR in 222 chromosomes from 111 unrelated subjects and their parents. The most frequent molecular defects were 1) in the salt wasting form, I(2) splice (42.9%), deletions and conversions (24.5%), and Q318stop (14.3%); 2) in the simple virilizing form, I172N (35.3%), I(2) splice (29.4%), and P30L (19.1%); and 3) in the nonclassical form, V281L (41.1%), P30L (21.4%), and P453S (14.3%). Compared with other populations, Greek patients had a higher frequency of Q318stop in the salt-wasting form, of P30L in both simple virilizing and nonclassical forms and of P453S in the nonclassical form. The concordance of genotype to phenotype in the total sample was 87%. However, the concordance rate was different in the three forms of the disease. Thus, complete concordance was detected in the genotypes predicting the salt-wasting phenotype, a slightly lower concordance (95.2%) was detected in the genotypes predicting the simple virilizing phenotype, and the lowest concordance (67.6%) was observed in genotypes predicting the nonclassical phenotype. In conclusion, the concordance between genotype and phenotype decreases as the severity of the disease diminishes. This should be taken into consideration in genetic counseling and antenatal intervention.

Genetic differences between the salt-wasting, simple virilizing, and nonclassical types of congenital adrenal hyperplasia.

Human leukocyte antigen (HLA) alleles and plasma 17-hydroxyprogesterone levels after ACTH stimulation were studied in 134 German families of patients with the salt-wasting (SW), simple virilizing (SV), or nonclassical (NC) late-onset form of congenital adrenal hyperplasia (CAH). Unexpected hormonal evidence for CAH was found in 6 otherwise healthy members of the relatives' group, who, therefore, were considered to be NC cryptic cases. HLA typing revealed a genetic difference between the 2 classical disease forms; SW CAH was strongly associated with Bw47, whereas SV CAH was closely linked to B5(w51). It also confirmed the nearly complete connection of NC CAH with B14. These alleles, especially Bw47 and B14, are mostly components of normally rare haplotypes: A3,Bw47,DR7 and Aw33,B14,DR1, respectively. They do not occur in the families' disease-unaffected haplotypes. Thus, it may be that all or almost all individuals from the general population bearing 1 of them are in fact CAH heterozygotes. Moreover, it seems possible to predict the severity of an infant's disease from his genomic type. The HLA linkage data were consistent with those obtained from ACTH testing, which showed significantly higher 17-hydroxyprogesterone increases in the genetically defined heterozygous relatives of SW patients than in the respective members of SV families. Of the families, 2 were also informative for mapping of the CAH disease gene(s) within the HLA-B to Glo interval.

Phenotype-genotype correlation in 56 women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Complete analysis of the CYP21 gene was performed in 56 unrelated French women with symptomatic nonclassical congenital adrenal hyperplasia. The mutational spectrum and the phenotype-genotype correlation were examined. The overall predominant mutation was V281L, which was present on 51% of alleles and in 80% of women. Three novel mutations were found: L317M, R435C, and a 5'-end gene conversion. Sixty-three percent of the women were carrying a severe mutation of the CYP21 gene, and hence risk giving birth to children with a classical form of the disease. In such cases, screening for heterozygosity in the partner is crucial. Potential genotype/phenotype correlations were examined by classifying the patients into three groups according to the CYP21 allelic combinations: A (mild/mild), B (mild/severe), and C (severe/severe). Primary amenorrhea was more frequent, and mean basal and stimulated 17-hydroxyprogesterone levels were higher in compound heterozygotes for mild and severe mutations (group B) compared with women with two mild mutations (group A), but there was a considerable overlap for individual values. Surprisingly, in two women, a severe mutation was found on both alleles (group C). Therefore, the phenotype cannot be accurately predicted from the genotype. Variability in phenotypic expression may be conditioned by mechanisms other than genetic heterogeneity at the CYP21 locus.

No mutation in cytochrome P450 side chain cleavage in a patient with congenital lipoid adrenal hyperplasia.

Molecular basis of lipoid adrenal hyperplasia (lipoid CAH) in a Japanese patient was investigated. A 46XY Japanese female patient was clinically diagnosed as having lipoid CAH based on her clinical history of adrenal crisis at birth and the low basal concentrations of cortisol, aldosterone, adrenal androgens and testosterone in serum. In vitro studies of testicular mitochondrial enzymes confirmed a specific impairment of cholesterol side chain cleavage (SCC) activity. However, in spite of the virtual reduction of SCC activity, the amounts of immunodetectable P450scc, adrenodoxin reductase, and adrenodoxin in testicular mitochondria were almost same as those of normal testis. Furthermore, the size of each protein was similar to that of normal testis. Enzymatic amplification of the complementary DNA encoding P450scc from the patient's testis RNA and its nucleotide analysis by direct sequencing revealed no mutation. These results indicate that defective P450scc is not the lesion in this patient, confirming a previous report showing no P450scc mutations in patients with lipoid CAH. The exact lesion causing lipoid CAH in this patient is currently unknown.

Follow-up of 68 children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: relevance of genotype for management.

The phenotype of congenital adrenal hyperplasia (CAH) varies greatly. The purpose of this study was to optimize diagnosis and follow-up by comparing phenotype with genotype. Sixty-eight patients with CAH due to 21-hydroxylase deficiency were studied by clinical, hormonal, and molecular genetic methods. Patients were classified according to predicted mutation severity: group 0, null mutation (17.6%); group A, homozygous for IVS2 splice mutation or compound heterozygous for IVS2 and null mutations (33.8%); group B, homozygous or compound heterozygous for I172N mutation (14.7%); group C, homozygous or compound heterozygous for V281L or P30L mutations (26.5%); and group D, mutations with unknown enzyme activity (7.4%). All group 0 and A patients had the salt-wasting form, and group C had nonclassical forms. Group B included five salt-wasting and five simple virilizing forms. Groups 0 and A were younger at diagnosis (P < 0.02), and females were more virilized than those in group B. Group B had higher basal plasma 17-hydroxyprogesterone (564 +/- 162 nmol/liter) and testosterone (11 +/- 3 nmol/liter) levels than group C [59 +/- 13 nmol/liter (P < 0.001) and 1.4 +/- 0.2 nmol/liter (P < 0.005), respectively]. Hydrocortisone doses given to groups 0, A, and B were similar at all ages, but lower in group C (P < 0.01). Final height was below target height in classical (n = 16; -2 +/- 0.2 SD score; P < 0.02) and nonclassical (n = 11; -1.2 +/- 0.4 SD score; P < 0.03) forms. The severity of the genetic defects and the clinical-laboratory features are well correlated. Genotyping, combined with neonatal screening and optimal medical and surgical treatment, can help in the management of CAH.

Primary adrenocortical nodular dysplasia, a distinct subtype of Cushing's syndrome. Case report and review of the literature.

Non-iatrogenic Cushing's syndrome has been associated primarily with three entities: pituitary-dependent processes due to pituitary adenomas or microadenomas causing adrenal hyperplasia; pituitary-independent primary adrenal causes, predominantly unilateral adenomas, rarely multiple adenomas or adrenal carcinoma; ectopic sources of adrenocorticotropic hormone (ACTH) production. Although non-neoplastic bilateral adrenal disease generally has been ascribed to extra-adrenal stimulation, a rare cause of Cushing's syndrome that involves bilateral adrenal nodule formation independent of pituitary stimulation has been identified. Nodular adrenal diseases represent a confusion of terms in the literature, but one subgroup of Cushing's syndrome has most frequently--and, perhaps, most appropriately--been designated primary adrenocortical nodular dysplasia. A case of this unusual entity is presented, and previous case reports pertaining to this confusing area of adrenal hyperfunction are reviewed. The characteristic manifestations that separate this diagnosis from other types of nodular adrenal disease are also discussed. Recognition of this diagnosis, although rare, is important, as bilateral adrenalectomy in the treatment of choice.

Results of screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia.

OBJECTIVE: To assess results of newborn screening for 21-hydroxylase-deficient congenital adrenal hyperplasia (CAH) in Texas over 6 years of screening 1.9 million infants. METHODS: In 1989, CAH was incorporated into the ongoing Texas Newborn Screening Program, which requires two screens on each newborn. 17-Hydroxyprogesterone was assayed, without extraction, by radioimmunoassay of blood collected from heel sticks onto filter paper collection cards. Infants with elevated levels of 17-hydroxyprogesterone were referred for evaluation, and those considered to have CAH were studied with respect to disease characteristics. Data were collected by pediatric endocrinologists using standardized forms that included type of CAH, results of laboratory tests, treatment regimen, disease symptoms and signs, and, for girls, degree of genital virilization. RESULTS: The incidence of classic CAH in Texas is 1:16 008, with a ratio of salt-wasting to simple-virilizing of 2.7:1. A majority of infants detected were undiagnosed until screened, despite signs of salt-wasting or ambiguous genitalia. It was difficult to differentiate salt-wasting from simple-virilizing CAH in infants who were identified before the onset of adrenal insufficiency or electrolyte abnormalities. A substantial number of infants with nonclassic (NC) CAH also were detected. Not all infants were detected on the initial screen; 14% of infants with classic CAH and 87% with NC CAH were detected on the second routine screening test. CONCLUSIONS: Our findings confirm the benefits of newborn screening for CAH and the importance of a second screening test, and suggest that programs for newborn CAH screening must consider complex issues in diagnosis and treatment. These results also confirm that CAH is a continuum of disorders, rather than a disorder with discrete subtypes. In addition, the difficulties in differentiating CAH subtypes in newborns, and thus deciding appropriate treatment, and the high incidence of NC CAH suggest that standard diagnostic criteria and treatment regimens for CAH may need modification. Where screening exists, physicians will encounter more cases of CAH than in the past.