Form Of Congenital Adrenal Hyperplasia Research Articles

Monitoring treatment in pediatric patients with 21-hydroxylase deficiency.

21-hydroxylase deficiency (21-OHD) is the most common form of congenital adrenal hyperplasia. In most developed countries, newborn screening enables diagnosis of 21-OHD in asymptomatic patients during the neonatal period. In addition, recent advances in genetic testing have facilitated diagnosing 21-OHD, particularly in patients with equivocal clinical information. On the other hand, many challenges related to treatment remain. The goals of glucocorticoid therapy for childhood 21-OHD are to maintain growth and maturation as in healthy children by compensating for cortisol deficiency and suppressing excess adrenal androgen production. It is not easy to calibrate the glucocorticoid dosage accurately for patients with 21-OHD. Auxological data, such as height, body weight, and bone age, are considered the gold standard for monitoring of 21-OHD, particularly in prepuberty. However, these data require months to a year to evaluate. Theoretically, biochemical monitoring using steroid metabolites allows a much shorter monitoring period (hours to days). However, there are many unsolved problems in the clinical setting. For example, many steroid metabolites are affected by the circadian rhythm and timing of medication. There is still a paucity of evidence for the utility of biochemical monitoring. In the present review, we have attempted to clarify the knowns and unknowns about treatment parameters in 21-OHD during childhood.

Androgen-secreting adenoma – a possibility in hyperandrogenism differential diagnosis

Abstract Introduction Hirsutism affects almost 10% of women of reproductive age. The two most common causes of hirsutism are polycystic ovary syndrome (PCOS) and idiopathic hirsutism. Virilizing adrenocortical tumors are rare, nonetheless, it is a differential diagnosis that physicians must consider. Clinical Case We present the case of a 23-year-old woman that was referred from the Dermatology Department due to the abrupt and progressive appearance of hirsutism and facial acne. Her menstrual cycles were regular. She had a BMI of 21.7 kg/m2, facial acne, and a Ferriman-Gallwey scale of 11 points. She did not have hypertension, nor alopecia, clitoris hypertrophy or any other virilizing sign. Table 1 summarizes the analytical determinations requested in the early follicular phase of the menstrual cycle. Pelvic ultrasound scan did not revealed abnormalities. Computed tomography (CT) scan of the abdomen revealed a well-delimited and solid mass of 4.9 × 3.8 cm in the right adrenal gland, with an average density of 48 UH with enhancement on the portal phase without the presence of fat, hemorrhage or calcifications suggesting malignancy more likely (Figure 1). After multidisciplinary assessment, laparoscopic right adrenalectomy was advised. Pathology revealed an adrenal cortex adenoma which showed cytoplasmic immunoreactivity of the cells against inhibin and Melan-A with a KI-67 of 1%, negative for anti-p53 without atypical mitotic figures, necrosis, venous invasion, sinusoidal invasion nor capsular invasion. The post-surgical evolution was satisfactory with an early normalization of androgens and resolution of the virilizing signs. The most common cause of hirsutism in premenopausal women is PCOS; another cause, and far from the first, is the non-classical form of congenital adrenal hyperplasia; and even more uncommon, androgen-secreting ovarian and adrenal tumours (1,2). Adrenal tumours, unlike ovarian, usually secrete DHEAS. Most tumours are carcinomas, which commonly also secrete cortisol (3). A very high DHEAS level (>7 µg/mL) is suggestive of adrenal carcinoma. Pure virilizing adrenal tumours are extremely rare (4). Independently from hormone secretion, the suspicion of malignancy depends on radiological CT characteristics of the tumour: size (>4–6 cm), density (>10 HU with slow contrast washout), homogeneity, and shape (5). Magnetic resonance may assess local invasion (6). Adrenalectomy is the treatment of choice when virilizing adrenal tumours with malignant characteristics are found (7). In the surgical piece, it is useful to determine the Ki 67 (carcinomas: >5%) (8). Somatic mutations in the TP53 gene are associated with aggressive phenotypes(9). Conclusion Malignant ovarian and adrenal pathology should be ruled out in the scenario of new-onset hirsutism. Adrenal malignancy is usually related with tumor size, type of hormones secreted, and the velocity of the tumor progression. Exceptionally, benign adrenal tumours are producers of virilizing hormones.

Promene u dijagnostici i lečenju kongenitalne adrenalne hiperplazije - iskustvo tercijernog centra

Introduction: Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive diseases caused by a deficiency of enzymes responsible for the steroidogenesis. There are three forms of CAH due to 21-hydroxylase deficiency: the classic form with salt loss, the classic virilizing and the non-classic form. The aim of the paper was to analyze the changes in the diagnosis and treatment of children with CAH during previous 15 years. Material and methods: This retrospective cohort study includes patients who were diagnosed with CAH due to 21-hydroxylase deficiency in the period from 2007 to 2021 in endocrinology department of the Institute for Mother and Child Health Care Institute of Serbia "Dr Vukan Cupic". Respondents were divided into two groups - a group whose diagnosis was made in the period between 2007 and 2014 and another group of those whose diagnosis was made in the period between 2015 and 2021. Statistical analysis using Hi-square and Mann Whitney U test was conducted using the software IBM SPSS ver. 22, and p values <0.05 were considered significant. Results: Out of the total of 55 patients included in the study, 46 patients (83.6%) had 46, XX karyotype. The diagnosis was made in all patients on the basis of biochemical analyzes. In the second group the diagnosis was confirmed by genetic analysis in statistically significantly higher number of children (p <0.05). 49 patients (89.1%) received hydrocortisone and 16 patients received fludrocortisone. In patients from the second group a statistically significantly higher frequency of fludrocortisone therapy was noticed in patients with classic CAH. Conclusion: Having in mind the constant advancement in the field, frequent improvements in clinical care of children with CAH are needed.

Genotype-phenotype association in congenital adrenal hyperplasia due to 21-hydroxylase deficiency in children.

The purpose of this study was to investigate the clinical manifestation of various forms of congenital adrenal hyperplasia (CAH) in children of the Republic of Kazakhstan, depending on their genotype. The study analysed 50 patients diagnosed with CAH from 7 regions of Kazakhstan with different ethnic origins: 35 Kazakhs (70.0%), 8 Russians (16.0%), 2 Turks (4.0%), 2 Ukrainians (4.0%), 2 Uzbeks (4%), 1 Uighur (2%). All the children studied were from 0 to 18 years old, and their average age was 5.7 years ±3.9. In addition, all children were divided into groups depending on the form of the disease according to the phenotypic manifestation of the disease: salt-wasting (SW) and simple virile (SV) forms. Most of the patients suffered from SW - 32 (64.0%), and a smaller group had SV - 18 (36.0%), also one boy with SW was diagnosed with TART syndrome. 50 Kazakh children with the classical form of CAH were analysed. Depending on the severity of the mutations, patients were divided into 4 groups: zero groups (the most severe mutations), A, B, and C. According to the results of the study, the salt-wasting form of CAH turned out to be more common than the simple virile form. A high correlation was observed in groups with mutations of high and moderate severity - 0 and A, while group C showed a strong variability of the phenotype. Thus, the correspondence between genotype and phenotype decreased along with the decrease in the severity of the disease. The relationship between the genotype and the phenotype of both forms of CAH exists indirectly, through the activity of the 21-hydroxylase enzyme. Mutations in the CYP21A2 gene affect the level of the synthesized enzyme, which, in turn, determines the degree of hormone production in the blood.

Higher Body Fat but Similar Phase Angle Values in Patients with the Classical Form of Congenital Adrenal Hyperplasia in Comparison to a Control Group.

This study aimed to compare phase angle (PhA) and bioelectrical impedance vector analysis (BIVA) values between adult patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency (CAH21OHD) and a control group. A total of 22 patients (15 women, 22.9 ± 3.7 years) were compared with 17 controls (11 women, 27.0 ± 2.5 years). Body composition was determined by dual-energy X-ray absorptiometry. Bioelectrical impedance was used to calculate PhA, and BIVA was performed using specific software. Student’s t-test and analysis of covariance were used to compare groups. Hedges’ G and partial n2 were calculated for the effect estimates. Hotelling’s t2 test was used to compare the mean impedance vectors between the groups. The Mahalanobis test was used to determine the distance between confidence ellipses. Patients with CAH21OHD had a higher fat mass percentage than that of the control group (both sexes). There was no significant difference in PhA values between groups (CAH21OHD vs. control) in females (6.9° vs. 6.3°, p = 0.092) and males (8.2° vs. 8.1°, p = 0.849), after adjusting for covariates (age and height). BIVA analysis showed a significant difference in the mean impedance vectors between the female groups (T2 = 15.9, D = 1.58, p = 0.003) owing to the higher reactance/height (Δ = 8.5; p < 0.001) of the patients. The PhA did not significantly differ between the groups. Female patients had significantly higher reactance values. However, further studies are needed to determine the usefulness of bioimpedance parameters in evaluating the hydration status and cellular integrity of patients with CAH21OHD.

Abstract #1318425: Combined 17-Alpha Hydroxylase and 17,20 Lyase Deficiency in a Young Male

Congenital adrenal hyperplasia (CAH) is a group of disorders resulting from defect of one of the enzymes necessary for biosynthesis of cortisol. A 17-alpha hydroxylase/17,20-lyase deficiency is a rare form of CAH; accounts for about 1% of all cases. It is an autosomal recessive defect in cytochrome P450 17A1 enzyme which leads to impaired cortisol and sex steroid synthesis, with compensatory elevation of ACTH, gonadotropins, corticosterone and 11-deoxycorticosterone (DOC).

Pregnancy and Prenatal Management of Congenital Adrenal Hyperplasia.

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive diseases that may cause cortisol insufficiency together with other hormonal alterations. The most common form is 21-hydroxylase deficiency, in which the lack of pituitary negative feedback causes an increase in ACTH and adrenal androgens. Classical forms of CAHs can lead to severe adrenal failure and female virilization. To date, the appropriate management of pregnant CAH patients is still debated regarding appropriate maternal therapy modifications during pregnancy and the risks and benefits of prenatal treatment of the fetus. We conducted a literature search of relevant papers to collect current evidence and experiences on the topic. The most recent and significant articles were selected, and current international guidelines were consulted to update current recommendations and guide clinical practice. Given the lack of randomized clinical trials and other high-quality scientific evidence, the issue is still debated, and great heterogeneity exists in current practice in terms of risk/benefit evaluation and pharmacological choices for pregnancy and prenatal treatment. Glucocorticoid therapy is advised not only in classical CAH patients but also in non-classical, milder forms. The choice of which glucocorticoid to use, and the safety and benefits of dexamethasone therapy aimed at preventing genital virilization are still debated issues. Several advances, however, have been made, especially in terms of fertility and reproduction. This review aims to present the most recent scientific and real-world updates on pregnancy and prenatal management of CAH, with the presentation of various clinical scenarios and specific case-by-case recommendations.

Variant predictions in congenital adrenal hyperplasia caused by mutations in CYP21A2.

CYP21A2 deficiency represents 95% of congenital adrenal hyperplasia (CAH) cases, a group of genetic disorders that affect steroid biosynthesis. The genetic and functional analysis provide critical tools to elucidate complex CAH cases. One of the most accessible tools to infer the pathogenicity of new variants is in silico prediction. Here, we analyzed the performance of in silico prediction tools to categorize missense single nucleotide variants (SNVs) of CYP21A2. SNVs of CYP21A2 characterized in vitro by functional assays were selected to assess the performance of online single and meta predictors. SNVs were tested separately or in combination with the related phenotype (severe or mild CAH form). In total, 103 SNVs of CYP21A2 (90 pathogenic and 13 neutral) were used to test the performance of 13 single-predictors and four meta-predictors. All SNVs associated with the severe phenotypes were well categorized by all tools, with an accuracy of between 0.69 (PredictSNP2) and 0.97 (CADD), and Matthews’ correlation coefficient (MCC) between 0.49 (PoredicSNP2) and 0.90 (CADD). However, SNVs related to the mild phenotype had more variation, with the accuracy between 0.47 (S3Ds&GO and MAPP) and 0.88 (CADD), and MCC between 0.18 (MAPP) and 0.71 (CADD). From our analysis, we identified four predictors of CYP21A2 variant pathogenicity with good performance, CADD, ConSurf, DANN, and PolyPhen2. These results can be used for future analysis to infer the impact of uncharacterized SNVs in CYP21A2.

History of Adrenal Research: From Ancient Anatomy to Contemporary Molecular Biology.

The adrenal is a small, anatomically unimposing structure that escaped scientific notice until 1564 and whose existence was doubted by many until the 18th century. Adrenal functions were inferred from the adrenal insufficiency syndrome described by Addison and from the obesity and virilization that accompanied many adrenal malignancies, but early physiologists sometimes confused the roles of the cortex and medulla. Medullary epinephrine was the first hormone to be isolated (in 1901), and numerous cortical steroids were isolated between 1930 and 1949. The treatment of arthritis, Addison's disease, and congenital adrenal hyperplasia (CAH) with cortisone in the 1950s revolutionized clinical endocrinology and steroid research. Cases of CAH had been reported in the 19th century, but a defect in 21-hydroxylation in CAH was not identified until 1957. Other forms of CAH, including deficiencies of 3β-hydroxysteroid dehydrogenase, 11β-hydroxylase, and 17α-hydroxylase were defined hormonally in the 1960s. Cytochrome P450 enzymes were described in 1962-1964, and steroid 21-hydroxylation was the first biosynthetic activity associated with a P450. Understanding of the genetic and biochemical bases of these disorders advanced rapidly from 1984 to 2004. The cloning of genes for steroidogenic enzymes and related factors revealed many mutations causing known diseases and facilitated the discovery of new disorders. Genetics and cell biology have replaced steroid chemistry as the key disciplines for understanding and teaching steroidogenesis and its disorders.

Prevalence of CAH-X Syndrome in Italian Patients with Congenital Adrenal Hyperplasia (CAH) Due to 21-Hydroxylase Deficiency.

21-hydroxylase deficiency (21OHD), the most common form of congenital adrenal hyperplasia (CAH), is associated with pathogenic variants in CYP21A2 gene. The clinical form of the disease ranges from classic or severe to non-classic (NC) or mild late onset. The CYP21A2 gene is located on the long arm of chromosome 6, within the RCCX region, one of the most complex loci in the human genome. The 3′untranslated sequence of CYP21A2 exon 10 overlap the last exon of TNXB gene (these genes lie on the opposite strands of DNA and have the opposite transcriptional direction) that encodes an extracellular matrix glycoprotein tenascin-X (TNX). A recombination event between TNXB and its pseudogene TNXA causes a 30 kb deletion producing a chimeric TNXA/TNXB gene (CAH-X chimera) where both CYP21A2 and TNXB genes are impaired. This genetic condition characterizes a subset of patients with 21OHD who display the hypermobility phenotype of Ehlers–Danlos syndrome (hEDS) (CAH-X Syndrome). The aim of this study was to assess the prevalence of CAH-X syndrome in an Italian cohort of patients with 21OHD. At this purpose, 196 probands were recruited. Multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing were used to identify the CAH-X genotype. Twenty-one individuals showed the heterozygous continuous deletion involving the CYP21A2 and part of the TNXB gene. EDS-related clinical manifestations were identified in most patients carrying the CAH-X chimera. A CAH-X prevalence of 10.7% was estimated in our population.

Genotype, Mortality, Morbidity, and Outcomes of 3β-Hydroxysteroid Dehydrogenase Deficiency in Algeria.

Background3β-hydroxysteroid dehydrogenase 2 (3βHSD2) deficiency is a rare form of congenital adrenal hyperplasia (CAH), with fewer than 200 cases reported in the world literature and few data on outcomes.Patients and MethodsWe report a mixed longitudinal and cross-sectional study from a single Algerian center between 2007 and 2021. Virilization and under-masculinization were assessed using Prader staging and the external masculinization score (EMS), pubertal development staged according to the system of Tanner. Adrenal steroids were measured using mass spectrophotometry (LC-MS/MS). A genetic analysis of HSD3B2 was performed using Sanger sequencing.ResultsA 3βHSD2 defect was confirmed in 6 males and 8 females from 10 families (8 consanguineous), with p.Pro222Gln mutation in all but two siblings with a novel deletion: c.453_464del or p.(Thr152_Pro155del). Probable 3βHSD2 deficiency was diagnosed retrospectively in a further 6 siblings who died, and in two patients from two other centers. In the genetically confirmed patients, the median (range) age at presentation was 20 (0–390) days, with salt-wasting (n = 14) and genital anomaly (n = 10). The Prader stage for female patients was 2 (1–2) with no posterior fusion of the labia. The EMS for males was 6 (3–9). Median (range) values at diagnosis for 17-hydroxyprogesterone (17-OHP), dehydroepiandrosterone sulfate (DHEA-S), and 17-hydroxypregnenolone (17OHPreg) were elevated: 73.7 (0.37–164.3) nmol/L; 501.2(9.4–5441.3) nmol/L, and 139.7 (10.9–1500) nmol/l (NB >90 nmol/L diagnostic of 3βHSD2 defect). Premature pubarche was observed in four patients (3F:1M). Six patients (5F:1M) entered puberty spontaneously, aged 11 (5–13) years in 5 girls and 11.5 years in one boy. Testicular adrenal rest tumors were found in three boys. Four girls reached menarche at 14.3 (11–14.5) years, with three developing adrenal masses (surgically excised in two) and polycystic ovary syndrome (PCOS), with radiological evidence of ovarian adrenal rest tumor in one. The median IQ was 90 (43–105), >100 in only two patients and <70 in three.ConclusionsThe prevalence of 3βHSD2 deficiency in Algeria appears high, with p.Pro222Gln being the most frequent mutation. Mortality is also high, with significant morbidity from adrenal tumors and PCOS in adolescence and an increased risk of learning disability. The finding of adrenal tumors in older patients with 3βHSD2 indicates under-replacement, requiring effective hydrocortisone and fludrocortisone treatment rather than surgical removal.

The uncommon forms of congenital adrenal hyperplasia.

Clinicians recognize 21-hydroxylase deficiency as the most common form of congenital adrenal hyperplasia (CAH), and many papers have been published on this condition. In contrast, much less awareness has been addressed to the other, rare forms of CAH. The second most common form of CAH varies with country and ethnic background. In Brazil, 17-hydroxylase/17,20-lyase deficiency is the second most common, whereas 11-hydroxylase deficiency is most common in the Middle East. In Japan and Korea, both congenital lipoid adrenal hyperplasia and P450-oxidoreductase deficiency are more common than in the rest of the world. Finally, 3β-hydroxysteroid dehydrogenase/isomerase deficiency is rare worldwide, but pockets of affected populations, such as the Amish in Lancaster County, Pennsylvania are found. The treatment of each form varies by both the nature of steroids produced in excess above the enzymatic block and the deficiencies of steroids other than cortisol past these blocks. This article summarizes the pathophysiology, diagnosis, and management of rare forms of CAH.

Practical approaches to the use of markers of biochemical hyperandrogenism in women

Hyperandrogenism (HA) remains an actual problem that raises a large number of questions, in particular, in cases of discrepancy between the clinical signs of HA and biochemical parameters. This review includes an analysis of recent studies of androgen synthesis and metabolism in healthy women of reproductive age; management of pathologies accompanied by HA; as well as contemporary approaches to the principles of prescribing and evaluating the results of the main available markers of biochemical HA. There are сoncepts of clinical and biochemical HA. Biochemical HA is an increase in the levels of various circulating androgens. The concept of clinical HA includes hirsutism as assessed by the modified Ferriman–Gallwey scale. The most common causes of HA include polycystic ovary syndrome, non-classical forms of congenital adrenal hyperplasia, other endocrine disorders. It is necessary to carry out a differential diagnosis of these conditions with more rare causes as a primarily tumor pathology. The choice and evaluation of laboratory markers of biochemical HA should be made taking into account clinical data such as puberty history, anovulation, polycystic ovarian morphotype, obesity; presence and degree of hirsutism and/or other androgen-associated dermatopathies, the characteristics of the course of clinical HA (sudden onset, rapid progression), presence of other endocrinopathies, liver and kidney dysfunction; diabetes mellitus. The objectives of the laboratory assessment of HA are determination of HA severity; determination of the source of excess androgen synthesis (ovaries, adrenal glands); assessment of the free fraction of circulating active androgens; in some cases, assessment of the formation of active androgens in the skin. The following indicators are used to solve the tasks in laboratory diagnostics: total testosterone, free testosterone, free androgen index, androstenedione, dehydroepiandrosterone sulfate, 17-hydroxyprogesterone, dihydrotestosterone. A comprehensive assessment of these indicators allows not only assessing the presence of HA and its severity, but also the nature of its leading and secondary components, which determine the presence and prognosis of metabolic risks and allow individualizing therapeutic approaches.

Detection of Small CYP11B1 Deletions and One Founder Chimeric CYP11B2/CYP11B1 Gene in 11β-Hydroxylase Deficiency.

Objective11β-Hydroxylase deficiency (11β-OHD) caused by mutations in the CYP11B1 gene is the second most common form of congenital adrenal hyperplasia. Both point mutations and genomic rearrangements of CYP11B1 are important causes of 11β-OHD. However, the high degree of sequence identity between CYP11B1 and its homologous gene CYP11B2, presents unique challenges for molecular diagnosis of suspected 11β-OHD. The aim of this study was to detect the point mutation, indel, small deletion of CYP11B1 and chimeric CYP11B2/CYP11B1 gene in a one-tube test, improving the genetic diagnosis of 11β-OHD.MethodsOptimized custom-designed target sequencing strategy was performed in three patients with suspected 11β-OHD, in which both the coverage depth of paired-end reads and the breakpoint information of split reads from sequencing data were analysed in order to detect genomic rearrangements covering CYP11B1. Long-range PCR was peformed to validate the speculated CYP11B1 rearrangements with the breakpoint-specifc primers.ResultsUsing the optimized target sequencing approach, we detected two intragenic/intergenic deletions of CYP11B1 and one chimeric CYP11B2/CYP11B1 gene from three suspected patients with 11β-OHD besides three pathogenic heterozygous point mutation/indels. Furthermore, we mapped the precise breakpoint of this chimeric CYP11B2/CYP11B1 gene located on chr8:143994517 (hg19) and confirmed it as a founder rearrangement event in the Chinese population.ConclusionsOur optimized target sequencing approach improved the genetic diagnosis of 11β-OHD.

Clinical, biochemical, and biomolecular aspects ofcongenital adrenal hyperplasia in a group ofCameroonian children and adolescents.

Congenital adrenal hyperplasia (CAH) remains one of the most challenging endocrine disorders todiagnose, manage, and treat, especially in Africa where there is lack of neonatal screening program, and limited access to care. Data on biomolecular anomaly are sparse, therefore type of mutations are unknown, increasing management challenges and genetic counseling. The present study aims to describe clinical, biomolecular aspects of a group of Cameroonian patients. We did an observational retrospective study atthe pediatric endocrinology unit of the Mother and ChildCentre of the Chantal Biya Foundation in Yaounde from May 2013 to December 2019, including all patients diagnosed with CAH. We consecutively included 31 patients aged lessthan 21 years, diagnosed CAH. Median age at diagnosis was 1.71 years (IQR 0.08-2.57 years). Abnormal genitalia was the main complain in 48.4%(n=15). The most prevalent genetic anomaly found in our study population (n=24) wason CYP11, found in 16 patients (66.6%) followed byCYP21A2 mutation found in 8 patients. Homozygous mutation of p.Q356X was found in half of patients with 11hydroxylase deficiency. This mutation was mostly foundin people from semi-Bantu tribes, declared non consanguineous. 11 hydroxylase deficiency is the most prevalent form of CAH found in this group of Cameroonian children.

50 Years Ago in TheJournalofPediatrics: Isolated Cortisol Deficiency due to ACTH Resistance: An Early Description of Familial Glucocorticoid Deficiency

50 Years Ago in TheJournalofPediatrics: Isolated Cortisol Deficiency due to ACTH Resistance: An Early Description of Familial Glucocorticoid Deficiency

Adrenal Insufficiency

Adrenal insufficiency (Addison disease) can be categorized as primary or secondary; the former results from adrenal cortex destruction, whereas the latter is caused by disruption of pituitary secretion of adrenocorticotropic hormone. The clinical pictures are the same, and their signs can be differentiated only by the presence of hyperpigmentation and vitiligo in autoimmune disease. Diagnosing both chronic and acute syndromes requires laboratory confirmation; however, the only available diagnostic test for adrenal insufficiency is cosyntropin stimulation. Relative adrenal insufficiency is a hypothetical situation stemming from misinterpretation of this test, and there is no pathophysiologic evidence of its existence. The most common form of congenital adrenal hyperplasia is the 21-hydroxylase deficiency syndrome. This module contains 1 highly rendered figure, 2 tables, 4 references, and 5 MCQs.

Adrenal Insufficiency

Adrenal insufficiency (Addison disease) can be categorized as primary or secondary; the former results from adrenal cortex destruction, whereas the latter is caused by disruption of pituitary secretion of adrenocorticotropic hormone. The clinical pictures are the same, and their signs can be differentiated only by the presence of hyperpigmentation and vitiligo in autoimmune disease. Diagnosing both chronic and acute syndromes requires laboratory confirmation; however, the only available diagnostic test for adrenal insufficiency is cosyntropin stimulation. Relative adrenal insufficiency is a hypothetical situation stemming from misinterpretation of this test, and there is no pathophysiologic evidence of its existence. The most common form of congenital adrenal hyperplasia is the 21-hydroxylase deficiency syndrome. This module contains 1 highly rendered figure, 2 tables, 4 references, and 5 MCQs.

Syndromes of Pseudo-Hyperaldosteronism.

Syndromes of Pseudo-Hyperaldosteronism.

Twenty Years of Neonatal Screening for Congenital Adrenal Hyperplasia in North-Eastern Italy: Role of Liquid Chromatography-Tandem Mass Spectrometry as a Second-Tier Test

Background: Newborn screening for congenital adrenal hyperplasia (CAH) based on 17-hydroxyprogesterone (17-OHP) concentration in dried blood spots has been taking place in North-Eastern Italy since 2001. Since 2017, liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been introduced, for the first time in Italy, as a second-tier test. Aims: Our study aims to evaluate, on the one hand, the effectiveness of the newborn screening for CAH after 20 years of testing and, on the other, the impact that the introduction of the second-tier test had on the diagnostic accuracy of the screening program. Methods: Since 2001 dried blood spots taken from newborns have been screened with a time-resolved fluoroimmunoassay for 17-OHP determination. Over the years, the cut-off levels of 17-OHP were adjusted according to gestational age. Since 2017, a second-tier test in LC-MS/MS was introduced for samples displaying fluoroimmunoassay 17-OHP exceeding the cut-off. Results: In total, 862,521 newborns have been screened over a period of 20 years. The total incidence of 21-hydroxylase deficiency (21-OHD) was 1:25,368, moreover, a case of 11-β-hydroxylase deficiency was identified. All these diagnoses were genetically confirmed. The sensitivity and specificity of the screening program were 97% and 99.4%, respectively. The use of LC-MS/MS as a second-tier test significantly reduced the recall rate and increased the positive predictive value. Conclusions: Screening for CAH is useful in the neonatal diagnosis of a classic form of 21-OHD, allowing a precocious treatment of affected children. The introduction of an LC-MS/MS second-tier reduced the recall rate, avoiding unnecessary blood withdrawal and medical evaluations and preventing stress to families. Furthermore, it helped identify rarer forms of CAH.