-
Frontiers in Endocrinology 202321-hydroxylase deficiency (21OHD) is the most common cause of congenital adrenal hyperplasia (CAH). However, patients with 21OHD manifest various phenotypes due to a...
INTRODUCTION
21-hydroxylase deficiency (21OHD) is the most common cause of congenital adrenal hyperplasia (CAH). However, patients with 21OHD manifest various phenotypes due to a wide-spectrum residual enzyme activity of different CYP21A2 mutations.
METHODS
A total of 15 individuals from three unrelated families were included in this study. Target Capture-Based Deep Sequencing and Restriction Fragment Length Polymorphism was conducted on peripheral blood DNA of the three probands to identify potential mutations/deletions in CYP21A2; Sanger sequencing was conducted with the DNA from the family members of the probands.
RESULTS
Dramatically different phenotypes were seen in the three probands of CAH with different compound heterozygous mutations in CYP21A2. Proband 1 manifested simple virilizing with mutations of 30-kb deletion/c.[188A>T;518T>A], the latter is a novel double mutants classified as SV associated mutation. Although both probands carry the same compound mutations [293-13C>G]:[518T>A], gonadal dysfunction and giant bilateral adrenal myelolipoma were diagnosed for proband 2 and proband 3, respectively.
CONCLUSION
Both gender and mutations contribute to the phenotypes, and patients with the same compound mutations and gender could present with different phenotypes. Genetic analysis could help the etiologic diagnosis, especially for atypical 21OHD patients.
Topics: Humans; Adrenal Hyperplasia, Congenital; Steroid 21-Hydroxylase; Genotype; Genetic Association Studies
PubMed: 36992809
DOI: 10.3389/fendo.2023.1095719 -
Pediatric Endocrinology, Diabetes, and... 2023In view of the modifications in the endocrine society guidelines on evaluation and management of children with congenital adrenal hyperplasia (CAH), we performed... (Review)
Review
INTRODUCTION
In view of the modifications in the endocrine society guidelines on evaluation and management of children with congenital adrenal hyperplasia (CAH), we performed a review of children and adolescents with CAH.
MATERIAL AND METHODS
An audit of 35 children with CAH presenting to the pediatric endocrinology clinic between January 2014 to November 2021 was conducted by formulating ten audit questions. The areas of focus included: genital reconstructive surgery, neonatal screening for CAH, stress dosing, need for adrenocorticotrophic hormone (ACTH) stimulation test, growth promoting therapy, bone age assessment, adrenal imaging, bone mineral density assessment, adequacy of hormone replacement and appropriate management of non-classical CAH.
RESULTS
Conservative approach to genitoplasty in female children increased from 42.9% to 88.9%. Newborn screening identified 4 babies including two asymptomatic males averting saltwasting crisis. Stress dosing of steroids were advised in all and emergency usage of injectable glucocorticoids was warranted in two children. Gonadotropin-releasing hormone (GnRH) analogue therapy improved the final median predicted height by 7 cm in 5 children. Twenty-three (65.7%) had bone age assessment with 14 (40%) having advanced bone age. ACTH stimulation test, Adrenal imaging, dual energy X-ray absorptiometry (DEXA) scan were done in accordance with the guideline. One child with nonclassical CAH was initiated on hydrocortisone replacement for advanced bone age.
CONCLUSIONS
A shift to conservative surgical management of females, utility of neonatal screening for CAH, judicious use of growth promoting therapy is highlighted. Need for bone age testing, emergency hydrocortisone provision is warranted in our series.
Topics: Male; Infant; Infant, Newborn; Child; Humans; Female; Adolescent; Adrenal Hyperplasia, Congenital; Hydrocortisone; Glucocorticoids; Bone Density; Adrenocorticotropic Hormone
PubMed: 36734395
DOI: 10.5114/pedm.2022.122547 -
Journal of Clinical Research in... Nov 2023Congenital adrenal hyperplasia (CAH) is an inherited condition in which individuals require multiple daily doses of medication and are at risk for life-threatening...
OBJECTIVE
Congenital adrenal hyperplasia (CAH) is an inherited condition in which individuals require multiple daily doses of medication and are at risk for life-threatening adrenal crisis. The chronic nature and severity of CAH place children at risk for psychiatric morbidity. The aim was to assess the degree of anxiety and depressive symptoms in children with CAH.
METHODS
A cross-sectional cohort study of children (7-17 years) with CAH and their caregivers were recruited between May and December 2021. Children with hypothyroidism (HT) and their caregivers served as unaffected controls. Validated mental health questionnaires [Children’s Depression Inventory 2 Self Report-Short (CDI-2), Screen for Child Anxiety Related Disorders (SCARED), Patient Health Questionnaire modified for Adolescents (PHQ-A); self and proxy] were completed by participants at one clinic visit. Higher scores indicated greater symptoms of anxiety and depression.
RESULTS
A total of 60 children and 56 parents participated. Among the children 34 had CAH (68% female, mean age 11.41±2.5, CAH duration 8.5±4.1) and 26 had HT (73% female, mean age 12.7±2.9 years, HT duration 6.0±4.2 years). There was no increase in anxiety and depression symptoms in children with CAH compared to controls. In sub-analyses, children with CAH and controls reported a greater number of anxiety and depression symptoms than their caregivers on the SCARED and CDI-2, respectively. There was no association between adrenal control and the degree of anxiety or depression symptoms.
CONCLUSION
Children with CAH do not have more symptoms of anxiety or depression compared to controls. Child and caregiver-proxy responses lack agreement, suggesting that children with CAH may continue to benefit from routine mental health evaluation, regardless of voiced caregiver concern.
Topics: Adolescent; Child; Humans; Female; Male; Adrenal Hyperplasia, Congenital; Depression; Cross-Sectional Studies; Anxiety
PubMed: 37470306
DOI: 10.4274/jcrpe.galenos.2023.2023-2-10 -
Journal of Endocrinological... Jan 2023P450 oxidoreductase (POR) deficiency (PORD) is characterized by congenital adrenal hyperplasia (CAH) and disorders of sex development (DSD) in both sexes. PORD can also... (Review)
Review
BACKGROUND
P450 oxidoreductase (POR) deficiency (PORD) is characterized by congenital adrenal hyperplasia (CAH) and disorders of sex development (DSD) in both sexes. PORD can also associate with skeletal defects. However, the prevalence of these phenotypes is unknown.
AIM
To evaluate the prevalence of CAH, DSD, and infertility of patients with POR gene pathogenic variants by a systematic review of the literature.
METHODS
The literature search was performed through PubMed, MEDLINE, Cochrane, Academic One Files, Google Scholar, and Scopus databases. All studies reporting information on CAH, DSD, testicular adrenal rest tumor (TARTs), and fertility in patients with POR gene pathogenic variants were included. Finally, the prevalence of abnormal phenotypes was calculated.
RESULTS
Of the 246 articles initially retrieved, only 48 were included for a total of 119 (46 males and 73 females) patients with PORD. We also included the case of a male patient who consulted us for CAH and TARTs but without DSD. This patient, found to be a carrier of combined heterozygous POR mutation, reached fatherhood spontaneously. All the patients found had CAH. The presence of DSD was found in 65.2%, 82.1%, and 82.1% of patients with compound heterozygosity, homozygosity, or monoallelic heterozygous variants, respectively. The prevalence was significantly higher in females than in males. The prevalence of TARTs in patients with PORD is 2.7%. Only 5 women with PORD became pregnant after assisted reproductive techniques and delivered a healthy baby. Except for the recently reported proband, no other studies focused on male infertility in patients with POR gene variants.
CONCLUSION
This systematic review of the literature reports the prevalence of CAH, DSD, and TARTs in patients with PORD. The unknown prevalence of POR gene pathogenetic variants and the paucity of studies investigating fertility do not allow us to establish whether PORD is associated with infertility. Further studies on both women and men are needed to clarify this relationship.
Topics: Humans; Pregnancy; Male; Female; Adrenal Hyperplasia, Congenital; Infertility, Male; Mutation; Phenotype; Heterozygote
PubMed: 35842891
DOI: 10.1007/s40618-022-01849-9 -
Hormone Research in Paediatrics 2023Congenital adrenal hyperplasia (CAH) is an autosomal recessive genetic disorder that causes defects in the adrenal cortex enzymes that impair the biosynthesis of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Congenital adrenal hyperplasia (CAH) is an autosomal recessive genetic disorder that causes defects in the adrenal cortex enzymes that impair the biosynthesis of cortisol, aldosterone, or both. The most common type is the 21-hydroxylase enzyme deficiency in approximately 95% of cases resulting from CYP21A2 gene mutations or deletions.
OBJECTIVES
This study aimed to systematically review the national differences in CAH incidence and analyze the pooled results to determine disparities and whether ethnicity can predispose people to develop CAH.
METHODS
PubMed, Scopus, and LILACS were used to achieve results until June 22, 2018. Study eligibility criteria included availability of full-text; English, Spanish, or Portuguese languages; incidence or number of new cases; and number of live births or sample population. Only the classic CAH type (salt-wasting and simple-virilizing) was considered, and no distinction was made between the enzyme deficiency types.
RESULTS
This study summarizes the findings of 58 studies and 31 countries (from 1969 to 2017), in which the overall CAH incidence was 1:9,498 (95% confidence interval: 1:9,089, 1:9,945). Countries from the Eastern Mediterranean and Southeast Asia revealed the highest CAH incidence. The lowest incidence was reported in countries of the Western Pacific of Asia. No remarkable difference was observed in the Hispanics/Latino and White groups. However, they manifested a higher incidence of CAH than people identified as Black or of African descent. Published studies on CAH incidence in the sub-Saharan African region and parts of Europe were insufficient.
CONCLUSIONS
This study highlights the at-risk population for CAH and regions that need monitoring for CAH. The highest CAH incidence could be attributed to higher consanguinity, less genetic diversity, or other genetic causes since CAH is an inherited genetic disorder. Cultural practices in some places regarding consanguineous unions or geographic isolation may directly affect the incidence. Newborn screening for CAH may be unavailable in many developing countries, thereby affecting the actual CAH incidence. Therefore, healthcare workers should be trained to recognize CAH at an early stage to reduce its complications and mortality.
Topics: Infant, Newborn; Humans; Adrenal Hyperplasia, Congenital; Neonatal Screening; Adrenal Cortex; Mutation; Steroid 21-Hydroxylase
PubMed: 35973409
DOI: 10.1159/000526401 -
Frontiers in Endocrinology 2023Dysfunction in the hypothalamic-pituitary-adrenal axis has been associated with depressive and anxiety disorders. Little is known about the risk for these disorders...
BACKGROUND
Dysfunction in the hypothalamic-pituitary-adrenal axis has been associated with depressive and anxiety disorders. Little is known about the risk for these disorders among individuals with congenital adrenal hyperplasia (CAH), a form of primary adrenal insufficiency.
OBJECTIVE
We investigated the prevalence of depressive and anxiety disorders and antidepressant prescriptions in two large healthcare databases of insured children, adolescents, and young adults with CAH in the United States.
METHODS
We conducted a retrospective cohort study using administrative data from October 2015 through December 2019 for individuals aged 4-25 years enrolled in employer-sponsored or Medicaid health plans.
RESULTS
Adjusting for age, the prevalence of depressive disorders [adjusted prevalence ratio (aPR) = 1.7, 95% confidence interval (CI): 1.4-2.0, p<0.001], anxiety disorders [aPR = 1.7, 95% CI: 1.4-1.9, p<0.001], and filled antidepressant prescriptions [aPR = 1.7, 95% CI: 1.4-2.0, p<0.001] was higher among privately insured youth with CAH as compared to their non-CAH peers. Prevalence estimates were also higher among publicly insured youth with CAH for depressive disorders [aPR = 2.3, 95% CI: 1.9-2.9, p<0.001], anxiety disorders [aPR = 2.0, 95% CI: 1.6-2.5, p<0.001], and filled antidepressant prescriptions [aPR = 2.5, 95% CI: 1.9-3.1, p<0.001] as compared to their non-CAH peers.
CONCLUSIONS
The elevated prevalence of depressive and anxiety disorders and antidepressant prescriptions among youth with CAH suggests that screening for symptoms of depression and anxiety among this population might be warranted.
Topics: United States; Adolescent; Humans; Child; Young Adult; Adrenal Hyperplasia, Congenital; Hypothalamo-Hypophyseal System; Retrospective Studies; Pituitary-Adrenal System; Anxiety Disorders; Antidepressive Agents; Prescriptions
PubMed: 37664854
DOI: 10.3389/fendo.2023.1129584 -
International Journal of Molecular... Mar 2023The adrenal glands are important endocrine organs that play a major role in the stress response. Some adrenal glands abnormalities are treated with hormone replacement... (Review)
Review
The adrenal glands are important endocrine organs that play a major role in the stress response. Some adrenal glands abnormalities are treated with hormone replacement therapy, which does not address physiological requirements. Modern technologies make it possible to develop gene therapy drugs that can completely cure diseases caused by mutations in specific genes. Congenital adrenal hyperplasia (CAH) is an example of such a potentially treatable monogenic disease. CAH is an autosomal recessive inherited disease with an overall incidence of 1:9500-1:20,000 newborns. To date, there are several promising drugs for CAH gene therapy. At the same time, it remains unclear how new approaches can be tested, as there are no models for this disease. The present review focuses on modern models for inherited adrenal gland insufficiency and their detailed characterization. In addition, the advantages and disadvantages of various pathological models are discussed, and ways of further development are suggested.
Topics: Infant, Newborn; Humans; Adrenal Hyperplasia, Congenital; Adrenal Glands; Mutation; Incidence
PubMed: 36982440
DOI: 10.3390/ijms24065365 -
Reviews in Endocrine & Metabolic... Apr 2023Adrenal insufficiency (AI) is a severe endocrine disorder characterized by insufficient glucocorticoid (GC) and/or mineralocorticoid (MC) secretion by the adrenal... (Review)
Review
Adrenal insufficiency (AI) is a severe endocrine disorder characterized by insufficient glucocorticoid (GC) and/or mineralocorticoid (MC) secretion by the adrenal glands, due to impaired adrenal function (primary adrenal insufficiency, PAI) or to insufficient adrenal stimulation by pituitary ACTH (secondary adrenal insufficiency, SAI) or tertiary adrenal insufficiency due to hypothalamic dysfunction. In this review, we describe rare genetic causes of PAI with isolated GC or combined GC and MC deficiencies and we also describe rare syndromes of isolated MC deficiency. In children, the most frequent cause of PAI is congenital adrenal hyperplasia (CAH), a group of adrenal disorders related to steroidogenic enzyme deficiencies, which will not be included in this review. Less frequently, several rare diseases can cause PAI, either affecting exclusively the adrenal glands or with systemic involvement. The diagnosis of these diseases is often challenging, due to the heterogeneity of their clinical presentation and to their rarity. Therefore, the current review aims to provide an overview on these rare genetic forms of paediatric PAI, offering a review of genetic and clinical features and a summary of diagnostic and therapeutic approaches, promoting awareness among practitioners, and favoring early diagnosis and optimal clinical management in suspect cases.
Topics: Child; Humans; Adrenal Hyperplasia, Congenital; Adrenal Insufficiency; Adrenal Glands
PubMed: 36763264
DOI: 10.1007/s11154-023-09784-7 -
The Journal of Clinical Endocrinology... Aug 2023The most common form of congenital adrenal hyperplasia is 21-hydroxylase deficiency (21OHD), which in the classic (severe) form occurs in roughly 1:16 000 newborns... (Review)
Review
The most common form of congenital adrenal hyperplasia is 21-hydroxylase deficiency (21OHD), which in the classic (severe) form occurs in roughly 1:16 000 newborns worldwide. Lifelong treatment consists of replacing cortisol and aldosterone deficiencies, and supraphysiological dosing schedules are typically employed to simultaneously attenuate production of adrenal-derived androgens. Glucocorticoid titration in 21OHD is challenging as it must balance the consequences of androgen excess vs those from chronic high glucocorticoid exposure, which are further complicated by interindividual variability in cortisol kinetics and glucocorticoid sensitivity. Clinical assessment and biochemical parameters are both used to guide therapy, but the specific purpose and goals of each biomarker vary with age and clinical context. Here we review the approach to medication titration for children and adults with classic 21OHD, with an emphasis on how to interpret adrenal biomarker values in guiding this process. In parallel, we illustrate how an understanding of the pathophysiologic and pharmacologic principles can be used to avoid and to correct complications of this disease and consequences of its management using existing treatment options.
Topics: Child; Adult; Humans; Infant, Newborn; Adrenal Hyperplasia, Congenital; Glucocorticoids; Hydrocortisone; Steroids; Biomarkers; Disease Management; Steroid 21-Hydroxylase
PubMed: 36950738
DOI: 10.1210/clinem/dgad134 -
Journal of Child Neurology Aug 2022Congenital adrenal hyperplasia (CAH) is a group of genetic disorders that affects the adrenal glands and is the most common cause of primary adrenal insufficiency in...
BACKGROUND
Congenital adrenal hyperplasia (CAH) is a group of genetic disorders that affects the adrenal glands and is the most common cause of primary adrenal insufficiency in children. In the past few decades, magnetic resonance imaging (MRI) has been implemented to investigate how the brain may be affected by CAH. A systematic review was conducted to evaluate and synthesize the reported evidence of brain findings related to CAH using structural, functional, and diffusion-weighted MRI.
METHODS
We searched bibliographical databases through July 2021 for brain MRI studies in individuals with CAH.
RESULTS
Twenty-eight studies were identified, including 13 case reports or series, 10 studies that recruited and studied CAH patients vs unaffected controls, and 5 studies without a matched control group. Eleven studies used structural MRI to identify structural abnormalities or quantify brain volumes, whereas 3 studies implemented functional MRI to investigate brain activity, and 3 reported diffusion MRI findings to assess white matter microstructure. Some commonly reported findings across studies included cortical atrophy and differences in gray matter volumes, as well as white matter hyperintensities, altered white matter microstructure, and distinct patterns of emotion and reward-related brain activity.
CONCLUSIONS
These findings suggest differences in brain structure and function in patients with CAH. Limitations of these studies highlight the need for CAH neuroimaging studies to incorporate larger sample sizes and follow best study design and MRI analytic practices, as well as clarify potential neurologic effects seen across the lifespan and in relation to clinical and behavioral CAH phenotypes.
Topics: Adrenal Hyperplasia, Congenital; Brain; Diffusion Magnetic Resonance Imaging; Emotions; Humans; Magnetic Resonance Imaging
PubMed: 35746874
DOI: 10.1177/08830738221100886