Adrenal Hyperplasia Research Articles

Carrier Frequency of Autosomal Recessive Diseases in a Population Attending a Human Fertility Institute in Colombia.

To determine the carrier frequency of X-linked and autosomal recessive diseases in patients attending a human fertility institute in Colombia. This retrospective observational study included patients and gamete donors attending a Human Fertility Institute in Colombia between January 2017 and June 2023. Sociodemographic data and results of Next Generation Sequencing laboratory panels for screening of recessive disease-causing mutations were collected and analyzed. Data from 746 samples were analyzed; 599 (80.3%) were Colombian origin individuals and 147 (19.7%) were foreigners. At least one mutation was detected in 526 (70.5%) individuals. Of note, 893 pathogenic genetic variants were identified.The genetic variants most frequently observed in all the individuals studied were associated with the following diseases (carrier frequency): alpha thalassemia (10.5%), alpha-1 antitrypsin deficiency (10%), congenital adrenal hyperplasia due to 21-hydroxylase deficiency (9.4%), cystic fibrosis (7.3%), spinal muscular atrophy type 1 (5.6%) and Stargardt disease type 1 (5.0%). The most frequent genetic variant observed in the subgroup of Colombian origin individuals was associated with alpha-1 antitrypsin deficiency (11.3%). Information on the frequency of recessive diseases in Colombia is limited. This pioneering carrier genetic screening identified a high percentage of carriers for at least one recessive autosomal or X-linked in the population evaluated. Screening for recessive mutations could lead to an evolution in family planning programs and a decrease in the number of patients affected by recessive disorders. Furthermore, it could become a routine test not only in cases of assisted reproduction but also in cases of natural gestation.

Assessment of Long-Read Sequencing-Based Congenital Adrenal Hyperplasia Genotyping Assay for Newborns in Fujian, China

Assessment of Long-Read Sequencing-Based Congenital Adrenal Hyperplasia Genotyping Assay for Newborns in Fujian, China

Impaired Dietary Decision-Making in Children and Adolescents with Congenital Adrenal Hyperplasia.

Children and adolescents with congenital adrenal hyperplasia (CAH) are at increased risk for obesity and exhibit differences in brain regions associated with food reward and decision-making. We aimed to understand differences in dietary decision-making between youth with CAH compared to controls. 37 youth with CAH (12.2 ± 3.1y, 59.5% female) and 100 controls (11.7 ± 2.4y, 57% female) rated 30 low- and 30 high-calorie foods for health, taste, and liking. Participants then chose between 100 food pair trials using a mouse-tracking paradigm; 75 were discordant for health and taste ratings. Self-control success was measured as the percentage of trials in which the healthier food was chosen instead of the tastier food. Area under the curve (AUC) and maximum deviation (MD) are used as real-time indices of decision-making. Patients with CAH exhibited higher AUCs (CAH: 9.48 ± 8.08, Control: 6.40 ± 7.33; p < 0.05) and MDs (CAH: 0.20 ± 0.13, Control: 0.15 ± 0.12; p < 0.05) in self-control trials. However, patients with CAH and controls did not differ in their self-control success (CAH: 28.47 ± 24.27%, Control: 35.16 ± 25.01%; p = 0.16). In youth with CAH, testosterone was correlated with AUC (R = 0.46, p < 0.01) and MD (R = 0.38, p = 0.02) during successful self-control trials. Children and adolescents with CAH exhibit more cognitive conflict when choosing between healthy and tasty foods. Two indicators of disease severity were associated with cognitive conflict during food choice in patients with CAH. Our findings suggest impaired dietary decision-making in CAH could contribute to obesity risk.

Frequency of testicular adrenal rest tumor in male congenital adrenal hyperplasia.

Objective: To determine the frequency of testicular adrenal rest tumour (TART) in male children suffering from congenital adrenal hyperplasia (CAH). Study Design: Cross-sectional study. Setting: Department of Endocrinology, National Institute of Child Health (NICH), Karachi, Pakistan. Period: January 2024 to August 2024. Methods: Male children aged 2 to 16 years, and diagnosed cases of CAH were analyzed. Among children fulfilling the eligibility criteria, demographic and clinical characteristics were noted. TART was diagnosed on clinical evaluation, ultrasound, or biochemical analysis of hormones. Results: In a total of 121 children, the mean age was 7.34±3.69 years. The mean duration of CAH was 6.73±3.49 years, respectively. The most common presenting complaints were vomiting, dehydration, diarrhea, and abdominal pain, reported in 75 (62.0%), 41 (33.9%), 35 (28.9%), and 31 (25.6%), respectively, TART was identified in 33 (27.3%) children with CAH. The frequency of TART was significantly associated with relatively higher age (p&lt;0.001), weight (p&lt;0.001), and height (p&lt;0.001). The duration of CAH was significantly higher among children with TART (p&lt;0.001). It was noted that 17-OHP (p&lt;0.001), and ACTH (p&lt;0.001) were significantly higher among children with TART. Comparison of the frequency of TART revealed significant association with palpitation (p&lt;0.001), and pubic hairs (p=0.003). Vomiting was found to have significant association with children without TART (p=0.035). Conclusion: The prevalence of TART in male children with CAH was high, with significant associations between TART and older age, prolonged CAH duration, higher weight, height, and elevated levels of 17-OHP and ACTH.

Novel recurrent mutations and genetic diversity in Sudanese children with adrenal insufficiency.

Studies of primary adrenal insufficiency (PAI) in African children are rare, but in Sudan, congenital adrenal hyperplasia (CAH) and triple A syndrome are the most common genetic causes. Differential diagnosis is challenging, especially in resource-limited settings, where presentation can mimic common childhood diseases and facilities for biochemical and genetic testing may be restricted. Forty-eight patients from 43 families (31 male:17 female) with PAI were included (CAH/triple A excluded). Additional features seen included white matter changes on magnetic resonance imaging, auto-immune features, and/or obesity. Sanger and whole exome sequencing (WES) were employed for diagnosis, confirmation, and segregation with in vitro assays to investigate potential splice defects. In 21/43 families, a genetic aetiology consistent with non-autoimmune PAI was discovered, and in 3 families, autoimmune regulator (AIRE) mutations were found, indicating an autoimmune origin. In Sudan, adenosine triphosphate (ATP) binding cassette subfamily D member 1 (ABCD1)/nicotinamide nucleotide transhydrogenase (NNT)/AIRE mutations were commonest, including recurrent NNT splice and AIRE deletion mutations. In 2 families, we identified ARSA mutations fitting a diagnosis of metachromatic leucodystrophy (MLD), in which adrenal insufficiency has not previously been described. In the remaining 17 families, no causative gene mutations were found. Putative causal variants for comorbidities were concomitantly detected. In this population, WES revealed itself as a useful frontline tool for the differential diagnosis of individuals presenting with adrenal insufficiency, including discrimination between MLD and adrenoleucodystrophy and giving plausible gene defects for additional comorbidities such as obesity. Such genetic diagnoses are crucial to design optimal treatment plans and for genetic counselling in affected individuals and their families.

Fertility in non-classic lipoid CAH – A case report and review of the literature

Introduction: Non-classic lipoid congenital adrenal hyperplasia (LCAH) presents with adrenal insufficiency but typically lacks a gonadal phenotype or features a delayed-onset gonadal presentation. Information on fertility outcomes in affected individuals is limited. Case Presentation: We describe an adult male with severe, early-onset primary adrenal insufficiency, yet normal fertility, diagnosed in mid-adulthood with compound heterozygous STAR gene variants, including both known and novel mutations. The identified variants, c.814C&gt;T (p.Arg272Cys) and c.743A&gt;C (p.Lys248Thr), underwent structural and functional analysis, revealing partial enzymatic activity. A review of existing reports on the gonadal phenotype and fertility in non-classic LCAH identified only nine adult males. Among these, five exhibited normal gonadal function, but none had documented paternity. Conclusion: STAR variants may be present in adults with unresolved primary adrenal insufficiency and normal gonadal function. Infertility is not an inevitable outcome, as demonstrated by this case.

46, XX DSD with Atypical Genitalia: Clinical Insights and Diagnostic Approaches.

Congenital adrenal hyperplasia (CAH) is a rare disorder with autosomal recessive inheritance; it was historically known as adrenogenital syndrome. Patients with virilizing forms of CAH and a 46,XX karyotype present with varied degrees of hyperandrogenism due to different genetic defects in the adrenal steroidogenesis pathway. This comprehensive review describes a simplified diagnostic approach for patients with atypical genitalia and 46, XX DSD. It highlights the importance of a detailed history and clinical examination, with specific pointers toward the etiological diagnosis. There is a need for utilizing standardized liquid chromatography/tandem mass spectrometry (LC-MS/MS) assays to accurately diagnose these disorders of steroidogenesis. Choosing appropriate molecular testing methods has significant implications for establishing the diagnosis and providing genetic counseling.

Identification of a Homozygous Variant in the CYP21A2 Gene by Next-Generation Sequencing Analysis of Circulating Cell-Free Fetal DNA

Background/Objectives: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder caused by mutations in the CYP21A2 gene associated with 21-hydroxylase deficiency and increased levels of adrenal androgens. Affected females are at risk of ambiguous genitalia, while affected males show sexual precocity. Here, we present a case of a newborn female patient, characterized by ambiguous genitalia and previously identified as low risk for common aneuploidies by non-invasive prenatal testing (NIPT). Methods: We performed a NIPT, which showed a 46, XX genotype, confirmed by karyotype on the newborn’s DNA extracted lymphocytes. For clinical suspicion of CAH, we performed reverse dot blot and Multiple Ligation-dependent Probe Amplification (MLPA) of the CYP21A2 gene on the patients and her parents’ DNA. Then, we performed on mother’s plasma NGS analysis with an in-house developed panel of genes for monogenic diseases, including the CYP21A2 gene. Results: Reverse dot blot and MLPA detected the presence of the c.290-13A/C&gt;G (I2 splice) mutation in heterozygosity in the parents and in homozygosity in the child, respectively. NGS detected the c.290-13A/C&gt;G (I2splice) mutation in cell-free fetal DNA (cfDNA) in mother’s plasma with a variant allele frequency (VAF) of 67% with a fetal fraction (FF) of 5%. This latter suggests the presence of the variant both in the mother and in newborn cfDNA. Conclusions: The study reinforces the hypothesis that cfDNA can be used to identify point mutations, small insertions and/or deletions for the diagnosis of monogenic diseases, reducing the number of invasive tests and the risk of early miscarriages. Early detection of mutations in genes causing sexual development disorders could make it possible to start therapy in the womb.

Minimizing harm from congenital adrenal hyperplasia for babies born in Sri Lanka

No abstract available

A public health success: newborn screening for congenital adrenal hyperplasia in a middle-income Brazilian state.

A public health success: newborn screening for congenital adrenal hyperplasia in a middle-income Brazilian state.

Treatment with modified release hydrocortisone in children and adolescents with congenital adrenal hyperplasia: an expert opinion.

Recommended treatment for classic CAH in children is hydrocortisone. This therapy is intended to replace cortisol deficiency, but also to reduce the increased production of androgens and their precursors. The aim is to minimize the undesirable side effects of both cortisol deficiency and androgen excess. Short-acting conventional immediate release hydrocortisone formulations does not mimic physiological diurnal rhythm and often complicate therapy adjustment, mandating frequent administration of often supraphysiological doses- typically 3-4 times daily, including nocturnal dosing. To simulate the physiological diurnal cortisol pattern, a delayed- and sustained-release hydrocortisone preparation has been developed and its efficacy was validated through phase 2 and 3 trials in adult patients. Regulatory approval has been extended to encompass both adult and adolescent patients aged 12 years and older. This manuscript aims to provide treatment principles formulated by two expert centers specialized in pediatric CAH therapy regarding the utilization of recently registered Hydrocortisone Modified Release Capsules in the daily management and stress dosing regimen for adolescents with CAH. It elucidates proposed dosing strategies, therapeutic surveillance protocols, and the prospective accumulation of data for the assessment of treatment efficacy during childhood.

Adrenal steroid hormone responses to exercise under thermal stress: Potential role for nonclassic congenital adrenal hyperplasia in heat illness susceptibility.

We queried whether adrenal insufficiency attributable to non-classic congenital adrenal hyperplasia (21 hydroxylase deficiency, 21OHD) might contribute to heat illness susceptibility. Patients referred to a specialist heat illness clinic (n = 2 with prior hyponatremia; n = 16 lacking documentary evidence) and controls (n = 16) underwent laboratory Heat Tolerance Assessment (HTA: 60-90 min walking, 60% relative intensity, 34°C heat), synthetic adrenocorticotrophic hormone stimulation (heat illness only) and CYP21A2 genotyping (hyponatremic heat illness only). Copeptin, cortisol, 17-hydroxyprogesterone, and 21 deoxycortisol were assayed from blood at baseline and post-HTA, with precursor product [17-hydroxyprogesterone +21 deoxycortisol] expressed relative to cortisol. Saliva and urine were assayed for free cortisol (one hyponatremic case, controls). Versus controls, normonatremic heat illness exhibited greater (p < 0.05) serum cortisol across HTA, while hyponatremic heat illness showed blunted responses in aldosterone and free cortisol (salivary cortisol 1.6 and 1.6 vs. 6.0 [4.2, 19.4] and 4.2 [3.8, 19.2] nmol.L-1; urine cortisol 19 vs. 117 +/- 71 nmol.L-1). Hyponatremic heat illness demonstrated elevated precursor product consistent with 21OHD and multiple CYP21A2 mutations. One normonatremic case of heat illness also showed elevated precursor product. These data support the potential for 21OHD to precipitate heat illness under sustained physical stress and advance a case for targeted genetic screening.

Early genetic sequencing in neonates with hyperkalemia: a retrospective cross-sectional study.

The genetic etiology and clinical characteristics of neonates with hyperkalemia remain unknown. We aimed to implement early gene sequencing to identify genetic causes, optimize treatment and improve outcomes in this population. We retrospectively studied the clinical characteristics and genetic etiology of neonates with hyperkalemia who underwent exome sequencing or targeted panel sequencing from January 1, 2016, to December 31, 2023, at the Department of Neonatology, Children's Hospital of Fudan University. Among 3,757 neonates with hyperkalemia, approximately 14.08% underwent sequencing. The average gestational age was 34.82±3.94 weeks, and the average birth weight was 2,375.22±864.09 grams. Males accounted for 56.0% of the cohort. The risk factors for hereditary hyperkalemia included dry skin, pigmentation and pseudohermaphroditism. Of these factors, only pigmentation independently predicted the genetic etiology of hyperkalemia; the presence of pigmentation increased the risk of hyperkalemia by 29.586 times [odds ratio (OR) 29.586, confidence interval (CI): 4.927-177.649, P<0.001]. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, we found that 7.56% hyperkalemia neonates had a genetic diagnosis; 28 genes were identified, including 18 genes not previously reported. Among genetic diseases, congenital adrenal hyperplasia (CAH) had the highest incidence (1.7%). For neonates with mineralocorticoid deficiency, early treatment with hydrocortisone reduced adverse outcomes to some extent. Gene Ontology (GO) analysis indicated that these genes were enriched primarily in nephron development. The genetic etiology of neonatal hyperkalemia is complex. When clinical manifestations involve risk factors, it is advisable to conduct hormone testing and provide symptomatic treatment. Early genetic testing can aid in the diagnosis of hyperkalemia and improve the treatment of neonates with atypical clinical manifestations.

Maternal Hyperandrogenemia and the Long-Term Neuropsychological, Sex Developmental, and Metabolic Effects on Offspring

Maternal hormonal and metabolic disorders, such as diabetes and obesity, can adversely affect the intrauterine environment, resulting in suboptimal fetal growth and an elevated risk of cardiovascular and metabolic diseases in the later life of the offspring. In this review, we examine the long-term impact of elevated maternal androgen levels during pregnancy on offspring. Maternal hyperandrogenemia is linked to various neurodevelopmental disorders, including attention-deficit/hyperactivity disorder, autism spectrum disorder, and anxiety-like behaviors, mediated by alterations in key brain regions responsible for emotion and cognition. Furthermore, children born to mothers with hyperandrogenemia exhibit heightened risk of metabolic and cardiovascular dysfunctions, such as obesity, insulin resistance, and hypertension, which can manifest early in life. Prenatal exposure to androgens has also been linked to reduced birth weights and altered fetal growth, potentially due to impaired placental function. Additionally, maternal testosterone levels influence offspring sex ratios, often favoring male births, though exceptions occur in certain conditions, such as congenital adrenal hyperplasia. The findings of this review underscore the need for healthcare professionals to monitor maternal serum androgen profiles during pregnancy. Further research is needed to determine underlying mechanisms and potential interventions to mitigate these risks.

Bone mineral density in patients with congenital adrenal hyperplasia from prepubertal to adult age.

Patients affected by the classic form of congenital adrenal hyperplasia (CAH) need lifelong glucocorticoid therapy (GC). GC represents one of the primary causes of secondary osteoporosis, however the effect of steroid therapy on bone mineral density (BMD) in patients with CAH is still controversial. To evaluate and compare the BMD of a group of prepubertal patients and a subgroup of young adult patients with CAH receiving chronic GC therapy, with healthy controls. retrospective observational study. A referral center for pediatric endocrinology. Fifty-six prepubertal children with CAH treated with GC from diagnosis and 60 prepubertal healthy children of comparable age. A subgroup of 36 young patients was studied after the completion of puberty, and their BMD was compared to that of 51 young adult healthy volunteers. BMD was measured in the lumbar spine and in the whole body by dual-energy x-ray absorptiometry. Multivariate models were used for the comparison of BMD measurements between patients and control subjects. Whole-body BMD measurements of patients were significantly lower compared with healthy controls, both in boys and in girls. No differences were found in lumbar spine measurements. BMD expressed as Z-score decreased markedly in CAH patients from prepuberty to adulthood, particularly in young adult males. Men with CAH showed lumbar spine BMD values significantly lower than control subjects. Boys and young adult men with classic form of CAH have lower bone mineral density values compared with healthy controls. This may put them at risk of developing osteoporosis early in life.

Recent advances in treatments for congenital adrenal hyperplasia.

Recent advances in treatments for congenital adrenal hyperplasia.

Immunophenotypic Implications of Reverse-Circadian Glucocorticoid Treatment in Congenital Adrenal Hyperplasia.

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) requires lifelong glucocorticoid replacement to manage cortisol deficiency and excessive androgen production. Conventional circadian treatment (CT) tries to mimic natural cortisol rhythms, whereas reverse-circadian treatment (RC) prioritizes the suppression of adrenal androgen excess overnight through evening dosing. Limited data exist on the immunological impact of these regimens. A bi-centric study was conducted, including 41 pediatric and adolescent CAH patients. Peripheral blood samples were collected from patients on conventional treatment (n = 38) or RC (n = 16), with 11 RC patients switching to conventional treatment. Immune cell phenotypes, cytokine profiles, and natural killer (NK) cell cytotoxicity were assessed. Patients receiving RC showed lower percentages of CD4+CD25+ T cells (p = 0.0139). After the switch, patients with RC presented with a higher percentage of non-classical monocytes (p = 0.0255) and a lower percentage of Th17 cells (p = 0.0195). A lower expression of CD107 was observed with RC (p < 0.0001), as well as a higher percentage of NKp30 (p = 0.0189). Comparing patients after the switch from RC to HC, patients with RC presented with a lower NKG2D expression (p = 0.0420). Both conventional treatment and RC exhibited distinct immunological impacts, with CT showing modest advantages in normalizing immune phenotypes. These findings suggest that CT may offer immunological benefits for managing young patients with congenital adrenal hyperplasia.

Long-read sequencing resolves the clinically relevant CYP21A2 locus, supporting a new clinical test for Congenital Adrenal Hyperplasia.

Congenital Adrenal Hyperplasia (CAH), one of the most common inherited disorders, is caused by defects in adrenal steroidogenesis. It is potentially lethal if untreated and is associated with multiple comorbidities, including fertility issues, obesity, insulin resistance, and dyslipidemia. CAH can result from variants in multiple genes, but the most frequent cause is deletions and conversions in the segmentally duplicated RCCX module, which contains the CYP21A2 gene and a pseudogene. The molecular genetic test to identify pathogenic alleles is cumbersome, incomplete, and available from a limited number of laboratories. It requires testing parents for accurate interpretation, leading to healthcare inequity. Less severe forms are frequently misdiagnosed, and phenotype/genotype correlations incompletely understood. We explored whether emerging technologies could be leveraged to identify all pathogenic alleles of CAH, including phasing in proband-only cases. We targeted long-read sequencing outputs that would be practical in a clinical laboratory setting. Both HiFi-based and nanopore-based whole-genome long-read sequencing datasets could be mined to accurately identify pathogenic single-nucleotide variants, full gene deletions, fusions creating non-functional hybrids between the gene and pseudogene ("30-kb deletion"), as well as count the number of RCCX modules and phase the resulting multimodular haplotypes. On the Hi-Fi data set of 6 samples, the PacBio Paraphase tool was able to distinguish nine different mono-, bi-, and tri-modular haplotypes, as well as the 30-kb and whole gene deletions. To do the same on the ONT-Nanopore dataset, we designed a tool, Parakit, which creates an enriched local pangenome to represent known haplotype assemblies and map ClinVar pathogenic variants and fusions onto them. With few labels in the region, optical genome mapping was not able to reliably resolve module counts or fusions, although designing a tool to mine the dataset specifically for this region may allow doing so in the future. Both sequencing techniques yielded congruent results, matching clinically identified variants, and offered additional information above the clinical test, including phasing, count of RCCX modules, and status of the other module genes, all of which may be of clinical relevance. Thus long-read sequencing could be used to identify variants causing multiple forms of CAH in a single test.

Seventh ISNS Reference Preparation for Neonatal Screening for Thyroid Stimulating Hormone, Phenylalanine, and 17α-Hydroxyprogesterone in Blood Spots.

The International Society for Neonatal Screening (ISNS) has supported the standardization of the measurement of key biochemical markers for the neonatal screening of diseases: thyroid-stimulating hormone (TSH) for congenital hypothyroidism, phenylalanine (PHE) for phenylketonuria, and 17α-hydroxyprogesterone (17OHP) for congenital adrenal hyperplasia. These diseases are commonly a part of neonatal screening panels worldwide. The ISNS provides a series of secondary reference materials to the manufacturers of neonatal screening reagents to assist in the production of calibration materials for kits. This technical note describes the manufacture of the seventh combined dried blood spot reference preparation for neonatal screening (RPNS) for these analytes.

Lessons of screening two million newborns for congenital adrenal hyperplasia: 10-year experience of the Minas Gerais Public Health Program.

This is a 10-year period, descriptive and retrospective evaluation of a Brazilian State NBS-CAH public program, bringing light to the prior discussion concerning its implementation, by sharing the screening-240,000 babies annually practices. The Minas Gerais (MG) NBS program has been coordinated by NUPAD, a neonatal screening, monitoring care, and genetics center at the Federal University of Minas Gerais (UFMG), intermediating all necessary actions, under the management of the State Health Administration, and following the Brazilian universal program. The dataset was used to calculate sensitivity, specificity, positive predictive value (PPV), incidence, number of carriers, and false-positive rates. About 2,094,588 newborns were screened, and the incidence was 1:14,152; PPV was 10.8 %. Most samples were collected on the fifth day after birth (interquartile range 4-6 days); 1352 babies were referred for clinical evaluation; 1210 were false positives (0.06 %), and 142 presented the classic form; 22 % of newborns were hospitalized due to salt-loss symptoms before or at the first visit. The MG NBS-CAH success as a public program comes from the Brazilian unified public health system, with integrated care, and from the newborn screening center offering timely referred screened positive cases and its outstanding state coverage. Appropriate cutoffs and close monitoring of hospitalized newborns have been pivotal for reducing the high false-positive rates.