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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 -
Current Opinion in Endocrinology,... Jun 2022Clinicians recognize 21-hydroxylase deficiency as the most common form of congenital adrenal hyperplasia (CAH), and many papers have been published on this condition. In... (Review)
Review
PURPOSE OF REVIEW
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.
RECENT FINDINGS
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.
SUMMARY
This article summarizes the pathophysiology, diagnosis, and management of rare forms of CAH.
Topics: Adrenal Hyperplasia, Congenital; Humans; Hydrocortisone; Mixed Function Oxygenases; Steroids
PubMed: 35621178
DOI: 10.1097/MED.0000000000000727 -
Tidsskrift For Den Norske Laegeforening... Apr 2017Congenital adrenal hyperplasia is attributed to inherited enzyme defects in the adrenal cortex. The classical form results in reduced production of cortisol and... (Review)
Review
Congenital adrenal hyperplasia is attributed to inherited enzyme defects in the adrenal cortex. The classical form results in reduced production of cortisol and aldosterone, accompanied by an increase in production of adrenal cortical androgens. This causes virilisation in girls, adrenocortical failure and early puberty in both sexes. This article describes the genetics, clinical picture, diagnostics and treatment.
Topics: Adrenal Hyperplasia, Congenital; Female; Glucocorticoids; Humans; Male; Puberty, Precocious; Steroid 21-Hydroxylase; Virilism
PubMed: 28383228
DOI: 10.4045/tidsskr.16.0376 -
Frontiers in Endocrinology 2021Disorders of Sex Development (DSD) are anomalies occurring in the process of fetal sexual differentiation that result in a discordance between the chromosomal sex and... (Review)
Review
Disorders of Sex Development (DSD) are anomalies occurring in the process of fetal sexual differentiation that result in a discordance between the chromosomal sex and the sex of the gonads and/or the internal and/or external genitalia. Congenital disorders affecting adrenal function may be associated with DSD in both 46,XX and 46,XY individuals, but the pathogenic mechanisms differ. While in 46,XX cases, the adrenal steroidogenic disorder is responsible for the genital anomalies, in 46,XY patients DSD results from the associated testicular dysfunction. Primary adrenal insufficiency, characterized by a reduction in cortisol secretion and overproduction of ACTH, is the rule. In addition, patients may exhibit aldosterone deficiency leading to salt-wasting crises that may be life-threatening. The trophic effect of ACTH provokes congenital adrenal hyperplasia (CAH). Adrenal steroidogenic defects leading to 46,XX DSD are 21-hydroxylase deficiency, by far the most prevalent, and 11β-hydroxylase deficiency. Lipoid Congenital Adrenal Hyperplasia due to StAR defects, and cytochrome P450scc and P450c17 deficiencies cause DSD in 46,XY newborns. Mutations in SF1 may also result in combined adrenal and testicular failure leading to DSD in 46,XY individuals. Finally, impaired activities of 3βHSD2 or POR may lead to DSD in both 46,XX and 46,XY individuals. The pathophysiology, clinical presentation and management of the above-mentioned disorders are critically reviewed, with a special focus on the latest biomarkers and therapeutic development.
Topics: Adrenal Hyperplasia, Congenital; Adrenal Insufficiency; Disorders of Sex Development; Humans; Sex Differentiation
PubMed: 34987475
DOI: 10.3389/fendo.2021.770782 -
The Journal of Clinical Endocrinology... Jan 2022
Topics: 17-alpha-Hydroxyprogesterone; Adrenal Hyperplasia, Congenital; Androstenedione; Humans
PubMed: 34331764
DOI: 10.1210/clinem/dgab555 -
Frontiers in Endocrinology 2021Substantial research has been performed during the last decades on the clinical and genetic variability of congenital adrenal hyperplasia (CAH) and its most common form,... (Review)
Review
Substantial research has been performed during the last decades on the clinical and genetic variability of congenital adrenal hyperplasia (CAH) and its most common form, 21-hydroxylase deficiency (21OHD). CAH is one of the most prevalent autosomal recessive diseases in humans, and it can be divided into classic-further subdivided into salt wasting (SW) and simple virilizing (SV)-and non-classic (NC) forms. Pathogenic variants of gene, encoding the 21-hydroxylase enzyme, have been reported with variable prevalence in different populations. NM_000500.9:c.293-13C/A>G (In2G) variant represents the most common gene changes related to the classic 21OHD form. However, the phenotype of In2G carriers is variable depending on the variant homozygous/heterozygous status and combination with other pathogenic variants. In addition, identical genotypes, harboring the homozygous In2G variant, can present with variable phenotypes including the SW and SV or rarely NC form of the disease. Here, we analyze and present the clinical aspects, genotype/phenotype correlations, and other characteristics related to the In2G variant.
Topics: Adrenal Hyperplasia, Congenital; Genotype; Humans; Introns; Phenotype; Steroid 21-Hydroxylase
PubMed: 35140681
DOI: 10.3389/fendo.2021.788812 -
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 -
Journal of Clinical Research in... Mar 2017Congenital adrenal hyperplasia (CAH) is classified as classical CAH and non-classical CAH (NCCAH). In the classical type, the most severe form comprises both... (Review)
Review
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.
Topics: Adrenal Hyperplasia, Congenital; Child; Diagnosis, Differential; Female; Genetic Testing; Humans; Male; Mutation; Steroid 21-Hydroxylase; Virilism
PubMed: 27354284
DOI: 10.4274/jcrpe.3378 -
The Journal of Clinical Endocrinology... Apr 2021Virilization is the medical term for describing a female who develops characteristics associated with male hormones (androgens) at any age, or when a newborn girl shows... (Review)
Review
UNLABELLED
Virilization is the medical term for describing a female who develops characteristics associated with male hormones (androgens) at any age, or when a newborn girl shows signs of prenatal male hormone exposure at birth. In girls, androgen levels are low during pregnancy and childhood. A first physiologic rise of adrenal androgens is observed at the age of 6 to 8 years and reflects functional activation of the zona reticularis of the adrenal cortex at adrenarche, manifesting clinically with first pubic and axillary hairs. Early adrenarche is known as "premature adrenarche." It is mostly idiopathic and of uncertain pathologic relevance but requires the exclusion of other causes of androgen excess (eg, nonclassic congenital adrenal hyperplasia) that might exacerbate clinically into virilization. The second modest physiologic increase of circulating androgens occurs then during pubertal development, which reflects the activation of ovarian steroidogenesis contributing to the peripheral androgen pool. However, at puberty initiation (and beyond), ovarian steroidogenesis is normally devoted to estrogen production for the development of secondary female bodily characteristics (eg, breast development). Serum total testosterone in a young adult woman is therefore about 10- to 20-fold lower than in a young man, whereas midcycle estradiol is about 10- to 20-fold higher. But if androgen production starts too early, progresses rapidly, and in marked excess (usually more than 3 to 5 times above normal), females will manifest with signs of virilization such as masculine habitus, deepening of the voice, severe acne, excessive facial and (male typical) body hair, clitoromegaly, and increased muscle development. Several medical conditions may cause virilization in girls and women, including androgen-producing tumors of the ovaries or adrenal cortex, (non)classical congenital adrenal hyperplasia and, more rarely, other disorders (also referred to as differences) of sex development (DSD). The purpose of this article is to describe the clinical approach to the girl with virilization at puberty, focusing on diagnostic challenges. The review is written from the perspective of the case of an 11.5-year-old girl who was referred to our clinic for progressive, rapid onset clitoromegaly, and was then diagnosed with a complex genetic form of DSD that led to abnormal testosterone production from a dysgenetic gonad at onset of puberty. Her genetic workup revealed a unique translocation of an abnormal duplicated Y-chromosome to a deleted chromosome 9, including the Doublesex and Mab-3 Related Transcription factor 1 (DMRT1) gene.
LEARNING OBJECTIVES
Identify the precise pathophysiologic mechanisms leading to virilization in girls at puberty considering that virilization at puberty may be the first manifestation of an endocrine active tumor or a disorder/difference of sex development (DSD) that remained undiagnosed before and may be life-threatening. Of the DSDs, nonclassical congenital adrenal hyperplasia occurs most often.Provide a step-by-step diagnostic workup plan including repeated and expanded biochemical and genetic tests to solve complex cases.Manage clinical care of a girl virilizing at puberty using an interdisciplinary team approach.Care for complex cases of DSD manifesting at puberty, such as the presented girl with a Turner syndrome-like phenotype and virilization resulting from a complex genetic variation.
Topics: Adrenal Hyperplasia, Congenital; Adrenarche; Androgens; Child; Female; Humans; Puberty; Virilism
PubMed: 33367768
DOI: 10.1210/clinem/dgaa948 -
Frontiers in Endocrinology 2020
Topics: Adolescent; Adrenal Hyperplasia, Congenital; Adult; Child; Female; Hirsutism; Humans; Male; Patient-Centered Care; Polycystic Ovary Syndrome; Prognosis; Treatment Outcome; Young Adult
PubMed: 32296393
DOI: 10.3389/fendo.2020.00170