Congenital adrenal hyperplasia – current insights in pathophysiology, diagnostics and management

Abstract Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting cortisol biosynthesis. Reduced activity of an enzyme required for cortisol production leads to chronic overstimulation of the adrenal cortex and accumulation of precursors proximal to the blocked enzymatic step. The most common form of CAH is caused by steroid 21- hydroxylase deficiency due to mutations in CYP21A2. Since the last publication summarizing CAH in Endocrine Reviews in 2000 there have been numerous new developments. These include more detailed understanding of steroidogenic pathways, refinements in neonatal screening, improved diagnostic measurements utilizing chromatography and mass spectrometry coupled with steroid profiling, and improved genotyping methods. Clinical trials of alternative medications and modes of delivery have been recently completed or are under way. Genetic and cell-based treatments are being explored. A large body of data concerning long-term outcomes in patients affected by CAH, including psychosexual well-being, has been enhanced by the establishment of disease registries. This review provides the reader with current insights in congenital adrenal hyperplasia with special attention to these new developments.

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A Case of Salt-Wasting Congenital Adrenal Hyperplasia with Triple Homozygous Mutation: Review of Literature

Journal of Pediatric Genetics ◽

10.1055/s-0040-1705110 ◽

2020 ◽

Author(s):

Maria Laura Iezzi ◽

Gaia Varriale ◽

Luca Zagaroli ◽

Stefania Lasorella ◽

Marco Greco ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Autosomal Recessive ◽

Homozygous Mutation ◽

Adrenal Hyperplasia ◽

Phenotype Correlation ◽

Hydroxylase Deficiency ◽

Autosomal Recessive Disorders ◽

Salt Wasting ◽

21 Hydroxylase Deficiency ◽

Recessive Disorders

AbstractCongenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency represents a group of autosomal recessive disorders characterized by impaired cortisol production due to altered upstream steroid conversions, subclassified as classic and nonclassic forms. The genotype–phenotype correlation is possible in the most frequent case but not in all. Despite in literature many mutations are known, there is the possibility of finding a new genetic pattern in patients with CAH.

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Case Report: Infant With Congenital Adrenal Hyperplasia and 47,XXY

Frontiers in Genetics ◽

10.3389/fgene.2021.808006 ◽

2022 ◽

Vol 12 ◽

Author(s):

Sophia Q. Song ◽

Andrea Gropman ◽

Robert W. Benjamin ◽

Francie Mitchell ◽

Michaela R. Brooks ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Genetic Disorders ◽

Gene Mutations ◽

Tall Stature ◽

Clinical Report ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Autosomal Recessive Disorders ◽

21 Hydroxylase Deficiency ◽

Recessive Disorders

Congenital adrenal hyperplasia is a group of autosomal recessive disorders in which enzymes in the cortisol biosynthesis pathways are disrupted by gene mutations. The most common form of congenital adrenal hyperplasia, caused by 21-hydroxylase deficiency, is characterized by decreased cortisol and aldosterone synthesis and excessive androgen production. Adult height is often compromised in affected patients. Intellectual capability remains intact in patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency, based on previous studies. 47,XXY (KS) is a sex chromosomal aneuploidy that manifests with hypergonadotropic hypogonadism, tall stature, and variable intellectual and behavioral dysfunction. This clinical report describes an infant with 21-hydroxylase deficiency congenital adrenal hyperplasia and 47,XXY. The results of his neurodevelopmental, endocrine, neurological, and physical therapy evaluations during his first 22 months are included and were normal. This is the first published case investigating the neurodevelopmental profile of a patient with the combination of these two genetic disorders.

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Classic congenital adrenal hyperplasia and puberty

Acta Endocrinologica ◽

10.1530/eje.0.151u077 ◽

2004 ◽

pp. U77-U82 ◽

Cited By ~ 32

Author(s):

E Charmandari ◽

CG Brook ◽

PC Hindmarsh

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Serum Insulin ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Autosomal Recessive Disorders ◽

The Metabolic Syndrome ◽

Adrenal Hyperandrogenism ◽

Free Cortisol ◽

21 Hydroxylase Deficiency ◽

And Function

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders resulting from deficiency of one of the five enzymes required for synthesis of cortisol in the adrenal cortex. The most common form of the disease is classic 21-hydroxylase deficiency, which is characterized by decreased synthesis of glucocorticoids and often mineralocorticoids, adrenal hyperandrogenism and impaired development and function of the adrenal medulla. The clinical management of classic 21-hydroxylase deficiency is often suboptimal, and patients are at risk of developing in tandem iatrogenic hypercortisolism and/or hyperandogenism. Limitations of current medical therapy include the inability to control hyperandrogenism without employing supraphysiologic doses of glucocorticoid, hyperresponsiveness of the hypertrophied adrenal glands to adrenocorticotropic hormone (ACTH) and difficulty in suppressing ACTH secretion from the anterior pituitary. Puberty imposes increased difficulty in attaining adrenocortical suppression despite optimal substitution therapy and adherence to medical treatment. Alterations in the endocrine milieu at puberty may influence cortisol pharmacokinetics and, consequently, the handling of hydrocortisone used as replacement therapy. Recent studies have demonstrated a significant increase in cortisol clearance at puberty and a shorter half-life of free cortisol in pubertal females compared with males. Furthermore, children with classic CAH have elevated fasting serum insulin concentrations and insulin resistance. The latter may further enhance adrenal and/or ovarian androgen secretion, decrease the therapeutic efficacy of glucocorticoids and contribute to later development of the metabolic syndrome and its complications.

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No Evidence for a Difference in 2D:4D Ratio between Youth with Elevated Prenatal Androgen Exposure due to Congenital Adrenal Hyperplasia and Controls

10.1101/2020.05.07.082529 ◽

2020 ◽

Author(s):

Gideon Nave ◽

Christina M. Koppin ◽

Dylan Manfredi ◽

Gareth Richards ◽

Steven J. Watson ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Large Body ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Left Hand ◽

Androgen Exposure ◽

Wide Range ◽

Prenatal Androgen Exposure ◽

21 Hydroxylase Deficiency ◽

Prenatal Androgen

AbstractThe second-to-fourth digit ratio (2D:4D) has been associated with sexual dimorphism, with a lower 2D:4D in males. A large body of research has relied on the 2D:4D as a proxy for prenatal androgen exposure, and includes reports of relationships between 2D:4D and a wide range of human traits. Here, we examine the validity of the 2D:4D proxy by studying the association between 2D:4D and classical Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency, a condition characterized by excessive prenatal exposure to androgens during most of the gestational period. To this end, we retrospectively examine 513 serial radiographs of the left hand obtained clinically in 90 youth with classical CAH (45 female) and 70 control youth (31 female). Replicating previous reports, we observe associations of the 2D:4D with sex (lower 2D:4D in males) and age (increase of 2D:4D through development). However, we find no evidence for differences in 2D:4D between CAH and controls (full sample: □ = -0.001 (−0.008, 0.006)]; females: □ = -0.004 [-0.015, 0.007]; males: □ = 0.001, [-0.008, 0.011]). Although our findings do not rule out a small association between the 2D:4D and CAH, they cast doubt on the usefulness of the 2D:4D as a biomarker for prenatal androgen exposure in behavioral research.

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Sexual Well-Being in Adult Male Patients with Congenital Adrenal Hyperplasia

International Journal of Endocrinology ◽

10.1155/2014/469289 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 8

Author(s):

Bogna Dudzińska ◽

Jonas Leubner ◽

Manfred Ventz ◽

Marcus Quinkler

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Well Being ◽

Adrenal Hyperplasia ◽

Hydroxylase Deficiency ◽

Salt Wasting ◽

Sexual Drive ◽

Sf 36 ◽

Adrenal Rest ◽

21 Hydroxylase Deficiency ◽

Prospective Longitudinal

Introduction.Men with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency show impaired fecundity due to testicular adrenal rest tumors and/or suppression of the gonadal axis. Sexual well-being might be an additional factor; however, no data exists.Patients and Methods.Prospective longitudinal monocentric study included 20 male CAH patients (14 salt wasting, 6 simple virilizing; age 18–49 yr). Clinical assessment, testicular ultrasound, biochemical and hormonal parameters, three validated self-assessment questionnaires (SF-36, GBB-24, and HADS), and male Brief Sexual Function Inventory (BSFI) were analyzed at baseline and after two years.Results.Basal LH and testosterone levels suggested normal testicular function. LH and FSH responses to GnRH were more pronounced in patients with a good therapy control according to androstenedione/testosterone ratio < 0.2. This group had significant higher percentage of patients on dexamethasone medication. GBB-24, HADS, and SF-36 showed impairedz-scores and no changes at follow-up. BSFI revealed impairments in dimensions “sexual drive,” “erections,” and “ejaculations,” whereas “problem assessment” and “overall satisfaction” revealed normalz-scores. Androstenedione levels correlated (P=0.036) inversely withz-scores for “sexual drive” with higher levels associated with impaired “sexual drive.”Conclusion.Male CAH patients showed a partly impaired sexual well-being which might be an additional factor for reduced fecundity.

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