Congenital adrenal hyperplasia

2011 ◽  
pp. 865-878
Author(s):  
Nils Krone
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Regulatory Protein ◽  
Signs And Symptoms ◽  
Adrenal Hyperplasia ◽  
Steroidogenic Enzymes ◽  
Autosomal Recessive Disorders ◽  
Chain Cleavage ◽  
Adrenal Steroidogenesis ◽  
Steroidogenic Acute Regulatory ◽  
Recessive Disorders

Congenital adrenal hyperplasia (CAH) represents a group of autosomal recessive disorders of steroidogenesis caused by defects in steroidogenic enzymes involved in glucocorticoid synthesis or in enzymes providing cofactors to steroidogenic enzymes (1, 2). Congenital lipoid adrenal hyperplasia (CLAH) caused by steroidogenic acute regulatory protein (StAR) deficiency is distinct in origin and presentation from the conventional variants of CAH, with the unique feature of lipid accumulation subsequently leading to destruction of adrenal function. This chapter will also mention aldosterone synthase deficiency, which is the only defect in adrenal steroidogenesis causing deficient mineralocorticoid biosynthesis without affecting glucocorticoid biosynthesis. The disorder cannot strictly be considered a CAH variant as it does not result in increased ACTH drive and thus not in adrenal hyperplasia. Novel forms of CAH have emerged during recent years. These include P450 oxidoreductase deficiency (ORD), P450 side-chain cleavage (CYP11A1) deficiency, the nonclassic form of CLAH (StAR deficiency), and apparent cortisone reductase deficiency. All forms of congenital adrenal hyperplasia resemble a disease continuum spanning from mild nonclassic presentations to classic onset with severe signs and symptoms.

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

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.

scholarly journals MECHANISMS IN ENDOCRINOLOGY: Rare defects in adrenal steroidogenesis

2018 ◽  
Vol 179 (3) ◽  
pp. R125-R141 ◽  
Author(s):  
Walter L Miller
Keyword(s):  
Genetic Disorders ◽  
Regulatory Protein ◽  
Hydroxylase Deficiency ◽  
Rare Mutations ◽  
Chain Cleavage ◽  
Adrenal Steroidogenesis ◽  
Cleavage Enzyme ◽  
Different Populations ◽  
Steroidogenic Acute Regulatory ◽  
21 Hydroxylase Deficiency

Congenital adrenal hyperplasia (CAH) is a group of genetic disorders of adrenal steroidogenesis that impair cortisol synthesis, with compensatory increases in ACTH leading to hyperplastic adrenals. The term ‘CAH’ is generally used to mean ‘steroid 21-hydroxylase deficiency’ (21OHD) as 21OHD accounts for about 95% of CAH in most populations; the incidences of the rare forms of CAH vary with ethnicity and geography. These forms of CAH are easily understood on the basis of the biochemistry of steroidogenesis. Defects in the steroidogenic acute regulatory protein, StAR, disrupt all steroidogenesis and are the second-most common form of CAH in Japan and Korea; very rare defects in the cholesterol side-chain cleavage enzyme, P450scc, are clinically indistinguishable from StAR defects. Defects in 3β-hydroxysteroid dehydrogenase, which also causes disordered sexual development, were once thought to be fairly common, but genetic analyses show that steroid measurements are generally unreliable for this disorder. Defects in 17-hydroxylase/17,20-lyase ablate synthesis of sex steroids and also cause mineralocorticoid hypertension; these are common in Brazil and in China. Isolated 17,20-lyase deficiency can be caused by rare mutations in at least three different proteins. P450 oxidoreductase (POR) is a co-factor used by 21-hydroxylase, 17-hydroxylase/17,20-lyase and aromatase; various POR defects, found in different populations, affect these enzymes differently. 11-Hydroxylase deficiency is the second-most common form of CAH in European populations but the retention of aldosterone synthesis distinguishes it from 21OHD. Aldosterone synthase deficiency is a rare salt-losing disorder. Mild, ‘non-classic’ defects in all of these factors have been described. Both the severe and non-classic disorders can be treated if recognized.

scholarly journals Congenital adrenal hyperplasia in pregnancy: approach depends on who is the ‘patient’

2012 ◽  
Vol 5 (4) ◽  
pp. 154-160 ◽  
Author(s):  
Erin Keely ◽  
Janine Malcolm
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Autosomal Recessive ◽  
First Trimester ◽  
Female Child ◽  
Fetal Exposure ◽  
Adrenal Hyperplasia ◽  
Autosomal Recessive Disorders ◽  
Adrenal Steroid ◽  
Recessive Disorders ◽  
In Pregnancy

Congenital adrenal hyperplasia (CAH) is a group of autosomal-recessive disorders caused by a reduced or absent enzymatic activity at one of the stages of adrenal steroid biosynthesis. Prenatal exposure to androgens leads to external genital masculinization of the affected female child. In pregnancy, the provider may be optimizing care for the woman with CAH or targeting treatment to reduce virilization in the affected unborn child. For the affected adult woman the goals of therapy in pregnancy are to prevent adrenal insufficiency, reduce fetal exposure to androgens and glucocorticoids and to avoid damage to reconstructed genitalia. For prenatal therapy for prevention of virilization of possibly affected female children, dexamethasone is used. However, questions remain about the efficacy and safety of exposing 7/8 unaffected children in the first trimester. Prenatal treatment should only be undertaken after careful discussion with the parents of the risks and benefits in an experienced centre or as part of a research protocol.

scholarly journals Spontaneous Feminization in a 46,XX Female Patient with Congenital Lipoid Adrenal Hyperplasia Due to a Homozygous Frameshift Mutation in the Steroidogenic Acute Regulatory Protein*

1997 ◽  
Vol 82 (5) ◽  
pp. 1511-1515 ◽  
Author(s):  
Himangshu S. Bose ◽  
Ora Hirsch Pescovitz ◽  
Walter L. Miller
Keyword(s):  
Frameshift Mutation ◽  
Regulatory Protein ◽  
Severe Form ◽  
Adrenal Hyperplasia ◽  
Hormone Production ◽  
Chain Cleavage ◽  
Cleavage Enzyme ◽  
Low Levels ◽  
Steroidogenic Cells ◽  
Steroidogenic Acute Regulatory

Abstract The most severe form of congenital adrenal hyperplasia (CAH) is lipoid CAH. It was once thought that this disease was due to mutations in the cholesterol side-chain cleavage enzyme system, thus eliminating the ability to convert cholesterol to pregnenolone, causing a complete absence of steroid hormone production. We recently showed that lipoid CAH is due to mutations in the steroidogenic acute regulatory (StAR) protein, thus preventing acutely stimulated adrenal and gonadal responses to tropic stimulation. However, this lesion may permit low levels of StAR-independent steroidogenesis to persist until the accumulation of intracellular lipid deposits destroys steroidogenic capacity. This model would predict that the steroidogenic cells of the ovaries of affected 46,XX females should remain undamaged until puberty, at which time low levels of StAR-independent estrogen biosynthesis should be detectable. We describe a 15.5-yr-old 46,XX female with a classic history of lipoid CAH who underwent spontaneous feminization and cyclical vaginal bleeding beginning at age 13. Genetic analysis of the patient and her parents showed that she was homozygous for the novel StAR frameshift mutation 261delT. This is the first adolescent female with lipoid CAH who has undergone spontaneous feminization and who has been analyzed genetically. Finding an inactive StAR gene in this patient confirms our two-hit model of the pathogenesis of lipoid CAH, in which loss of StAR activity initially preserves StAR-independent steroidogenesis, which is lost only after cells undergo chronic tropic stimulation and subsequent damage from accumulation of cholesterol esters.

scholarly journals Congenital Adrenal Hyperplasia with Salt Wasting Crisis: A Case Report

2020 ◽  
Vol 58 (221) ◽  
Author(s):  
Deependra Mandal ◽  
Deepa Khanal ◽  
Rajan Phuyal ◽  
Uttara Adhikari
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Elevated Level ◽  
Autosomal Recessive ◽  
Oral Prednisolone ◽  
Severe Form ◽  
Adrenal Hyperplasia ◽  
Autosomal Recessive Disorders ◽  
Salt Wasting ◽  
17 Hydroxyprogesterone ◽  
Recessive Disorders

Congenital Adrenal Hyperplasia is a group of autosomal recessive disorders due to deficienciesof enzymes involved in steroidogenesis. The most common form is a 21-hydroxylase deficiencywhich can be classical or non-classical. The severe form also called Classical Congenital AdrenalHyperplasia is usually detected after birth to infant period. If Congenital Adrenal Hyperplasia is notdiagnosed and treated early, neonates are susceptible to sudden death in the early weeks of life. Wereport a case of thirty-five days male with a salt-wasting variant of congenital adrenal hyperplasia.The diagnosis was based on an elevated level of 17-hydroxyprogesterone. He was managed and lifelong oral Prednisolone and Fludrocortisone were prescribed.

scholarly journals A novel mutation of the StAR gene with congenital adrenal hyperplasia and its association with heterochromia iridis: a case report

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Vera Splittstösser ◽  
Felix Schreiner ◽  
Bettina Gohlke ◽  
Maik Welzel ◽  
Paul-Martin Holterhus ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Novel Mutation ◽  
Regulatory Protein ◽  
Homozygous Mutation ◽  
Elevated Concentration ◽  
Adrenal Hyperplasia ◽  
Heterochromia Iridis ◽  
Phenotypical Feature ◽  
Steroidogenic Acute Regulatory ◽  
Star Gene

Abstract Background We report a novel mutation within the StAR gene, causing congenital adrenal hyperplasia, with the so far unreported association with heterochromia iridis. Case presentation In a now 15-year-old girl (born at 41 + 6 weeks of gestation) adrenal failure was diagnosed in the neonatal period based on the clinical picture with spontaneous hypoglycaemia, hyponatremia and an extremely elevated concentration of ACTH (3381 pmol/l; ref. level 1,1–10,1 pmol/l), elevated renin (836 ng/l; ref. level 5–308 ng/l), and a decreased concentration of aldosterone (410 pmol/l; ref. level 886–3540 pmol/l). In addition to hyperpigmented skin the patient exhibited sectorial heterochromia iridis. Sequence analysis of the steroidogenic acute regulatory protein (StAR) gene showed a novel homozygous mutation (c.652G > A (p.Ala218Thr), which was predicted in-silico to be possibly damaging. Under daily steroid substitution her electrolyte levels are balanced while she became obese. Puberty occurred spontaneously. Conclusion A novel mutation in the StAR gene was identified in a patient with severe adrenal hypoplasia and sectorial heterochromia iridis. We discuss a causal relationship between these two rare phenotypes, i.e. whether very high levels of ACTH and alpha-MSH during early development might have disturbed early differentiation and distribution of uveal melanocytes. If confirmed in additional cases, discolorization of the iris might be considered as an additional phenotypical feature in the differential diagnosis of congenital adrenal insufficiency.

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

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.

scholarly journals Characterization of Two Novel Variants of the Steroidogenic Acute Regulatory Protein Identified in a Girl with Classic Lipoid Congenital Adrenal Hyperplasia

2020 ◽  
Vol 21 (17) ◽  
pp. 6185
Author(s):  
Efstathios Katharopoulos ◽  
Natascia Di Iorgi ◽  
Paula Fernandez-Alvarez ◽  
Amit V. Pandey ◽  
Michael Groessl ◽  
...  
Keyword(s):  
Protein Expression ◽  
Congenital Adrenal Hyperplasia ◽  
Regulatory Protein ◽  
Cell System ◽  
Adrenal Hyperplasia ◽  
Missense Variants ◽  
Pathogenic Variants ◽  
Novel Variants ◽  
Steroidogenic Acute Regulatory ◽  
The Impact

Congenital adrenal hyperplasia (CAH) consists of several autosomal recessive disorders that inhibit steroid biosynthesis. We describe a case report diagnosed with adrenal insufficiency due to low adrenal steroids and adrenocorticotropic hormone excess due to lack of cortisol negative feedback signaling to the pituary gland. Genetic work up revealed two missense variants, p.Thr204Arg and p.Leu260Arg in the STAR gene, inherited by both parents (non-consanguineous). The StAR protein supports CYP11A1 enzyme to cleave the side chain of cholesterol and synthesize pregnenolone which is metabolized to all steroid hormones. We used bioinformatics to predict the impact of the variants on StAR activity and then we performed functional tests to characterize the two novel variants. In a cell system we tested the ability of variants to support cholesterol conversion to pregnenolone and measured their mRNA and protein expression. For both variants, we observed loss of StAR function, reduced protein expression and categorized them as pathogenic variants according to guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. These results fit the phenotype of the girl during diagnosis. This study characterizes two novel variants and expands the list of missense variants that cause CAH.

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